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Emergency management of acute apical periodontitis in the permanent

dentition: a systematic review of the literature

Article in Journal (Canadian Dental Association) · April 2003

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 C L I N I C A L P R A C T I C E

Emergency Management of Acute Apical

Periodontitis in the Permanent Dentition:
A Systematic Review of the Literature
• Susan Sutherland, DDS •
• Debora C. Matthews, DDS, Dip Perio, MSc •

A b s t r a c t
Objective: To perform a systematic literature review and meta-analysis on the effectiveness of interventions used in the
emergency management of acute apical periodontitis in the permanent dentition.
Methods: Electronic databases were searched from their inception to 2001. These searches, combined with manual search-
ing, yielded 1,097 citations, of which 92 were relevant. Independent application of inclusion criteria by 2 teams of
reviewers yielded 15 eligible randomized controlled trials. Data on population, interventions, outcomes (pain relief
or change in intensity of pain as reported by patients or clinicians) and methodological quality were determined by
independent duplicate review. Disagreements were resolved by consensus.
Results: Meta-analysis showed that pre-emptive analgesics (nonsteroidal anti-inflammatory drugs [NSAIDs]) in conjunc-
tion with pulpectomy provided a significant benefit (weighted mean difference –11.70, 95% confidence interval
–22.84 to –0.56). Three interventions did not show significant benefit: systemic antibiotics, intracanal treatment with
a steroid–antibiotic combination, and trephination through attached gingiva.
Conclusions: In the management of pain associated with acute apical periodontitis, there is strong evidence to support the
use of systemic NSAIDs in conjunction with nonsurgical endodontics. The use of antibiotics is not recommended.

MeSH Key Words: endodontics; meta-analysis; periapical periodontitis; toothache

© J Can Dent Assoc 2003; 69(3):160

This article has been peer reviewed.

A
cute apical periodontitis (AAP) is an inflammatory negative or delayed positive result on vitality testing;
condition of the periapical tissues of the periodon- absence of thermal sensitivity of the tooth; and pain on
tium, usually resulting from irreversible pulpitis biting or percussion.4 Radiographic changes such as widen-
and pulpal necrosis. Although chemical and physical factors ing of the periodontal ligament may be present, but frank
can cause pulpitis, most cases have a microbial cause, radiolucency will not be observed.
usually secondary to caries or trauma.1 Although the pres- Because of the progression from inflamed pulp to
ence of some bacteria in the periapical region of an affected
AAP, the diagnosis is not always straightforward. Vitality
tooth has been demonstrated,2 AAP is predominantly an
tests are affected by a number of factors, including the
inflammatory, rather than an infectious, process.
Patients with AAP often have moderate to severe pain, amount of residual pulp in the periapical area and the size
which results in the need for emergency treatment.3 of any restoration on the tooth.5 Sensitivity of the tooth to
Because the transition from inflamed pulp to necrotic pulp thermal changes may be due to recession,6 occlusal trauma,
to acute periapical disease occurs along a continuum, not orthodontic movement or sinusitis.7 Tooth pain may also
all of the signs and symptoms, as described below, will be be referred from other orofacial structures or sites distant
present in all patients. Patients with AAP usually present from the tooth.8 A misdiagnosis may lead to inappropriate
with dull, throbbing, constant pain; absence of swelling; a treatment.

160 March 2003, Vol. 69, No. 3 Journal of the Canadian Dental Association
 Emergency Management of Acute Apical Periodontitis: A Systematic Review of the Literature

Although toothache is a subjective symptom, it can have Pharmacotherapeutics included systemic therapy (antibi-
a significant social impact.9 Emergency dental treatment otics, corticosteroids, and NSAIDs or analgesics) and local
accounts for 2% to 6% of the costs of all dental therapy, an therapy (irrigants, intracanal medicaments). Surgical
amount similar to all periodontal treatment costs.10 The measures encompassed the establishment of drainage either
prevalence of perceived toothache is difficult to determine. through the tooth (pulpectomy, open or closed) or bone
Most epidemiologic research combines pain from a tooth (trephination). Extraction, occlusal adjustment and no treat-
with pain from oral lesions and temporomandibular ment were also investigated; however, for these interventions,
dysfunction. There are no data on the prevalence of AAP either no evidence was available for analaysis, the outcomes
specifically. Toothache itself is rarely defined in the litera- did not fit the eligibility criteria, or the data were not suit-
ture, which means the pain may be from any of these able for analysis.
sources or of non-odontogenic origin. The prevalence of Titles and abstracts, where available, were examined by
toothache is reported to range from 12%11 to 50%.12 It is 2 reviewers, and all papers deemed relevant or possibly rele-
reported more frequently in men and in lower socioeco- vant by either reviewer were obtained. The reference lists of
nomic groups. all retrieved articles, review papers and relevant book chap-
Because AAP is due to pulpal death, the recommended ters were scanned, and pertinent citations identified in this
treatment is relief of the inflammatory pressure in the peri- manner were obtained. After the study selection process
apical area. This is usually accomplished via access through described below, endodontic experts and published authors
the tooth and extirpation of the necrotic pulp (i.e. pulpec- were contacted and asked to provide further references that
tomy).4 Other therapies, including systemic or local the search might have missed. To assess the proportion and
medicaments such as corticosteroids, analgesics and antibi- possible impact of non-English citations, no citations were
otics, have been used on their own or in conjunction with excluded from the list of relevant papers on the basis of
pulpectomy. The pain associated with AAP is not the result language. However, the full text was obtained only for
of an infectious process, so the use of antibiotics may be papers published in English or French. Throughout the
questionable. Nonetheless, up to 75% of patients with project, an ongoing literature search was carried out.
painful pulpitis are treated with antibiotic therapy.13–15 Unpublished studies were not sought.
In view of the prevalence of this condition in everyday
practice and the anecdotal evidence of practice variation,
Study Selection
a systematic review is warranted. The objective of this The following criteria were used to determine eligibility
review is to determine the effectiveness of the various inter- of studies for inclusion in the review.
ventions used in the management of AAP in the permanent Target Population: Patients presenting with AAP result-
dentition. ing from nonvital pulp in the permanent dentition. Given
the variation in the definition of AAP in the endodontic
Prior Reviews literature, for the purposes of this review the condition was
Before this review was initiated, the MEDLINE database considered to be characterized by dull, throbbing, constant
and the Cochrane Library were searched for the period pain; absence of swelling; a negative or delayed positive
1991 to 2001. The terms “apical periodontitis,” “pulpitis,” result on vitality testing; absence of thermal sensitivity; pain
“toothache” and “emergency care,” with limitations of on biting or percussion; and presence or absence of radi-
human studies published in English and application of ographic changes (such as widening of the periodontal liga-
“review articles” as a publication-type limit, were used in an ment space but not periapical radiolucency).
attempt to locate systematic reviews related to this topic. Interventions: Systemic and local pharmacotherapeutics,
No other reviews were identified. local surgical measures, occlusal adjustment, no treatment,
extraction.
Methods Outcome Measures: The effect on patient outcomes in
Study Identification terms of symptom relief as measured by patients or clinicians.
To identify relevant clinical trials, the MEDLINE Types of Studies: Randomized controlled trials and
and EmBase databases and the Controlled Trials Register of controlled clinical trials that met the eligibility criteria.
the Cochrane Library were searched from their time of The eligibility criteria were tested, and reviewers were
inception to August 2001. A further search of the trained on a small sample of papers, in a pilot test, before
Specialized Register of Clinical Trials of the Cochrane the start of the formal study. Two teams of 2 reviewers then
Oral Health Group was also performed. The search strategy explicitly applied the criteria to the studies retrieved, with
for nonsteroidal anti-inflammatory drugs (NSAIDs) in each team reviewing half of the selected papers. Within
the management of AAP is outlined in Appendix 1. This each team, the 2 reviewers assessed the papers indepen-
search was repeated for all reasonable interventions. dently. Agreement on eligibility was measured with the

Journal of the Canadian Dental Association March 2003, Vol. 69, No. 3 160a
Sutherland, Matthews

Table 1 Quality Assessment Scale (adapted from Jadad and others16)

Question Answera Points
1. Was the study described as randomized No 0
(this includes use of words such as “randomly,” Yes 1
“random” and “randomization”)? Yes, and the method to generate the sequence of randomization 2
was described and it was appropriate (table of random numbers,
computer generated, etc.)
Yes, and the method to generate the sequence of randomization was 0
described and it was inappropriate (patients were allocated
alternately or according to date of birth, hospital number, etc.)
2. Was the study described as double-blind? No 0
Yes 1
Yes, and the method of double blinding was described and 2
appropriate (identical placebo, active placebo, dummy, sham)
Or, if double-blinding was not appropriate to No 0
the nature of the study, was the study described Yes 1
as blinded? Yes, and the person evaluating the outcome was blinded to the 2
treatment allocation of the patient
3. Was there a description of withdrawals No 0
and dropouts? Yes 1
Total possible score 5
aFor each question, pick only the best answer and circle the points for that question.

kappa statistic, which corrects for chance agreement. The Data Analysis
reviewers then discussed reasons for disagreement to reach Potential sources of variability among the included
consensus. studies in terms of the population, exposures, outcomes
and methods were identified. Within each category of
Assessment of Methodological Quality
intervention, trials that were not too clinically different
Two reviewers used a checklist to independently (i.e., not too heterogeneous) were pooled and evaluated
assess the methodological quality of all selected studies. statistically by means of meta-analytic techniques.
The checklist addressed whether the population, interven- SPSS 11.0 for Windows (SPSS Inc., Chicago, Ill.) was
tion(s), outcomes and study design were described clearly. used to calculate the kappa statistic. RevMan 4.1 for
In addition, the validated assessment tool developed by Windows (Cochrane Collaboration, Oxford, UK) was used
Jadad and others16 (the Quality Assessment Scale) was used to perform the meta-analysis.
to assign a score to the quality of controlled trials, as
Meta-analysis
described in Table 1. The maximum possible score was 5.
The outcomes of interest were relief of pain or change in
Data Extraction intensity of pain as assessed by patients or clinicians. These
Pertinent information was abstracted from each study, data were summarized for all studies for which they were
including study design and sample size, population (includ- available. For outcomes reported as binary data, individual
ing the study setting), patient characteristics and eligibility odds ratio (OR) of response to treatment (test versus
criteria, interventions and comparisons used (including control) and associated 95% confidence intervals were
dose, schedule and route of drugs, or specifics of the tech- calculated for each trial. For outcomes reported as continu-
ous data, individual weighted mean differences (WMD)
nique; co-interventions were allowed), outcome measures
were calculated for each study. When calculating the
and results.
combined mean effect of treatment from several studies,
There was considerable variation among the studies in
this method gives greater weight to studies with larger
the schedules for patient evaluation, which made it impos- sample sizes. Where different numeric scales were used by
sible to extract data for the same time frame for each study. different researchers, data were transformed to a common
Instead, the most comparable time frames were chosen, percentage scale, by means of the method described by
taking into consideration the pharmacokinetics of the Eisenberg and others,17 according to the following formula:
particular drug and the timing of local anesthetic, if used. (reported value of scale) / (scale maximum value – scale
For papers published within the past 15 years for which minimum value) × 100 = value (%). A pooled interval
data were missing or unclear, the authors were contacted estimate of the population OR or WMD was calculated.
and asked to provide detailed information. Heterogeneity was assessed with the chi-square test.

160b March 2003, Vol. 69, No. 3 Journal of the Canadian Dental Association
 Emergency Management of Acute Apical Periodontitis: A Systematic Review of the Literature

Table 2 Reasons for exclusion of 68 studies Trial Characteristics

Reason No. of studies
A total of 15 papers,20–34 all randomized controlled trials,
met all eligibility criteria. A total of 1,115 patients were
Wrong population 43
Wrong study type (case series, review or letter) 10
included in the 15 studies. Grouped by intervention,
Wrong outcome measure 11 8 studies dealt with systemic pharmacotherapeutics, 3 with
Data not usable 4 intracanal medicaments, 3 with surgical measures and
1 with occlusal reduction. The salient features of the trials
Significance for this test was set liberally at p ≤ 0.1, since, in are shown in Table 3.
practice, the test often lacks the power to detect interstudy
differences of treatment effect.18 The DerSimonian and
Methodological Quality
Laird Random Effects Model of pooling19 was used, on the The median quality score was 3 (range 1–5). Five stud-
assumption of the presence of interstudy variability, to ies were of low quality (score 1 or 2), 2 studies had a score
provide a more conservative estimate of the true effect. of 3, 7 studies had a score of 4, and 1 study had a score of
Several sources of heterogeneity were anticipated. To 5 (Table 3). Although all studies stated that they were
explore the relationship between treatment effect and study randomized, only 3 described the method of randomiza-
features, several a priori hypotheses regarding heterogeneity tion.23,24,29 Twelve of the studies were described as double
were developed and subgroup analyses planned. A separate blind, with the method of blinding clearly appropriate in
analysis was proposed for each intervention, if there were 11.21,23–26,28–32,34 Four of the 15 provided a statement on
sufficient studies (more than one) for pooling within each withdrawals and dropouts;23,25,30,34 this information was
category. Subgroup analyses were also planned for studies obtained for 2 more studies by means of author contacts.21,32
that examined analgesics given to relieve pain in the preop- Agreement for the quality of studies was modest
erative period, analgesics given to relieve pain in the post- (kappa = 0.43). Disagreements were related both to over-
operative period and analgesics given pre-emptively in the sights and to subjective interpretation of unclear reports. The
preoperative period to relieve post-operative pain. A sensi- final scores represent consensus between the 2 reviewers.
tivity analysis was planned to evaluate the influence of Meta-analysis
methodological quality (score ≥ 3 versus score < 3). Of the 15 included trials, 5 provided continuous data
Results that could be analyzed for the outcome “mean pain
relief ”20,21,23,30,32 and 425–27,34 provided insufficient infor-
Study Identification and Selection mation (means but no standard deviations) for statistical
In total, 1,097 English- and French-language studies analysis. One trial32 studied the effect of an NSAID or
were identified by the search. (Twenty-one reports in local anesthetic injected intraorally or intramuscularly,
languages other than English or French were retrieved but 30 minutes preoperatively, on both preoperative and post-
were not reviewed because of lack of resources for transla- operative pain. The 2 sets of data in this study were sepa-
tion.) Ninety-two of the 1,097 papers met the broad screen- rated for the purpose of this analysis.
ing criteria and were retrieved and reviewed. Upon closer Eight trials22–25,28–31 reported relevant binary data on the
scrutiny by the 2 teams of reviewers, a further 68 studies outcome of intensity of pain (proportions of patients in the
(including 12 papers in French) were eliminated because treatment and control groups experiencing clinically accept-
they did not meet the inclusion criteria. The reasons for able pain; i.e., no or mild pain) after administration of the
exclusion are shown in Table 2. References for these intervention or comparison. Four trials26,27,33,34 did not
excluded studies are listed in Appendix 2. report any usable continuous or binary data for the outcome
Agreement on eligible studies between the 2 reviewers in of interest and could not be included in either analysis.
each of the 2 groups was high (0.60 and 0.86), and the Subgroup analysis was not possible for antibiotics or postop-
kappa value was fair (kappa = 0.41 and 0.21). Discrepancies erative use of analgesics or anti-inflammatory drugs, as there
were due to oversights on the part of one of the reviewers or was only one study in each of those categories.
unclear reports. These were resolved by consensus. The low
kappa scores may have been influenced by the large number Outcome: Mean Pain Relief
of rejected papers compared with the small number of The results for the 5 studies that provided continuous data
accepted papers. are shown in Fig. 1. When all interventions were included in
For the remaining 24 papers, 15 authors were contacted the analysis, there was a significant treatment effect
for clarification or verification of the population, intervention (WMD –22.70; 95% confidence interval [CI] –36.20 to
or outcome. Thirteen responded, and on the basis of the –9.21). There was significant heterogeneity of the results of
information provided, 10 additional papers were excluded the individual studies (chi-square = 219.15, p < 0.00001),
and one study not found in the original search was included. which was expected, given the diversity of the interventions.

Journal of the Canadian Dental Association March 2003, Vol. 69, No. 3 160c
Sutherland, Matthews

Table 3 Features of 15 included trials

Study (and No. of Pain scale Baseline pain Intervention Comparison Endodontic Follow-up
quality score) patients used intensitya therapy period
analyzed

Systemic pharmacotherapeutics

Curtis and 40 100 mm VAS Severe Ketorolac 60 mg IM Placebo None 90 minutes

others20 (1)

Penniston and 52 100 mm VASc Moderate Ketorolac 30 mg IM Placebo IM or Pulpotomy 6 hours

Hargreaves32 or infiltration infiltration;
(4b) 60 minutes pre-op mepivicaine 2% +
vasoconstrictor
infiltration
dSadeghein 63 10 cm VAS Severe Ketorolac 10 mg po Acetaminophen “Appropriate 90 minutes
and others34 90 minutes pre-op 325 mg/codeine dental treatment
(4) 15 mg to eliminate pain”

Flath and 120e 100 mm VASc Moderate Flurbiprofen 100 mg Placebo Pulpectomy/ 24 hours
others23 (5) po 30 minutes pre-op debridement

Doroschak 49 100 mm VASc Moderate Post-op flurbiprofen Placebo Pulpectomy/ 2 days

and others21 to severe 100 mg loading dose debridement
(4b) then 50 mg q6h
× 2 days po or
tramadol 100 mg/
50 mg po as above or
flurbiprofen 100 mg/
50 mg + tramadol
100 mg/50 mg po
as above
dLiesinger 106 9-point Moderate Post-op Placebo Pulpectomy/ 5 days
and others26 categorical dexamethasone debridement ±
(3) scale IM at 2, 4, 6 obturation
or 8 mg/mL

Krasner and 48 100-point Low to Post-op Placebo Pulpectomy/ 24 hours

Jackson25 scale moderate dexamethasone debridement
(4) 2.25 mg po loading
dose and 0.75 mg
q3h × 4 doses

Nagle29 40 4-point Moderate Penicillin VK Placebo None until 7 days

(4) categorical to severe 500 mg po q6h day 7, then
scale × 7 days pulpectomy

Local pharmacotherapeutics

Moskow 50 100-point 36/50 Dexamethasone Placebo Pulpectomy/ 72 hours

and others28 scale, reported patients had 4 mg/mL debridement
(2) as 4 categories moderate solution
to severe

Negm30 393 4-point Moderate NSAID Placebo Pulpectomy/ 3 days

(4) categorical (ketoprofen or debridement
scale diclofenac)

Fava22 48 patients, Unclear Not stated Corticosteroid– Calcium-hydroxide Pulpectomy/ 7 days

(1) 60 teeth antibiotic solution paste (Calen) debridement
(Otosporin)

Occlusal adjustment
dRosenberg 53 teeth Unclear Not stated Occlusal reduction Simulated or Endodontic 48 hours
and others33 no reduction therapy
(1)

160d March 2003, Vol. 69, No. 3 Journal of the Canadian Dental Association
 Emergency Management of Acute Apical Periodontitis: A Systematic Review of the Literature

Table 3 continued
Study (and No. of Pain scale Baseline pain Intervention Comparison Endodontic Follow-up
quality score) patients used intensitya therapy period
analyzed

Trephination
dMoos and 17 100 mm VAS Severe Pulpectomy + Pulpectomy Pulpectomy + 6 days
others27 gingival incision and alone calcium-hydroxide
(1) trephination with paste
#4 round bur, slow-
speed handpiece
Houck and 50 4-point Mild to Pulpectomy + Pulpectomy + Pulpectomy/ 7 days
others24 categorical scale moderate trephination with mock trephination debridement
(4) Stabident perforator
through bone at level
of attached gingiva
Nist and 50 4-point Not stated Pulpectomy + Pulpectomy + Pulpectomy/ 7 days
others31 categorical scale trephination with mock trephination debridement
(3) Stabident perforator
through bone at level
of attached gingiva
VAS = Visual Analog Scale, IM = intramuscular, po = by mouth, NSAID = nonsteroidal anti-inflammatory drug.
a Pain intensity: mild < 30/100; moderate 30–69/100; severe < 70/100
b Quality score upgraded from 3, based on information from author.
c More than one scale was used in study; 100-mm VAS results were used in the present analysis.
d Unable to abstract useable data.
e There were a total of 120 patients in the study, of whom 56 were symptomatic on entry. Data for these patients were analyzed separately in the study

and therefore could be included in the meta-analysis reported here.

Thus, there is no overlap in confidence intervals for 2 of the Although a trend toward effectiveness was demonstrated in
studies, Curtis and others20 and Negm30 (Fig. 1). all subgroups, no intervention was statistically significant.
When the low-quality trial (Quality Assessment Score of The test for heterogeneity showed considerable variation
2 or less) was excluded in a sensitivity analysis, the significant in the results for the anti-inflammatory subgroups (one trial
benefit of the treatments did not persist, although a trend studied an NSAID, the other a corticosteroid). The test for
toward treatment effectiveness (Fig. 2) was still observed. heterogeneity was nonsignificant for the intracanal medica-
Results of the subgroup analyses for “mean pain relief ” ment and trephination subgroups, indicating that there was
are shown in Table 4. There was a statistically significant no substantial variation in the results of these trials.
difference when pre-emptive or immediate preoperative Discussion
analgesia was used (WMD –11.70, 95% CI –22.84 to In this overview, a systematic review35 was used to assem-
–0.56). There was a nonsignificant trend toward a differ- ble and synthesize evidence from the international literature
ence between treatment and control when analgesics were on interventions used in the management of AAP and to
used for adequate pain relief before (or in lieu of ) definitive evaluate the effectiveness of those interventions. The results
endodontic therapy. of the meta-analysis suggest that, overall, current interven-
tions used in endodontic therapy are effective in relieving
Outcome: Intensity of Pain
pain associated with AAP and that pre-emptive analgesia, in
The combined results of the ORs of the 8 studies that
conjunction with nonsurgical endodontic therapy, provides
reported data for the outcome “intensity of pain” are shown
significant benefit. Other subgroups of pooled interven-
in Fig. 3. The combined results suggest a trend for a tions, given in addition to definitive pulpal therapy, showed
difference in the treatment of pain between treatment and nonsignificant trends in favour of treatment. For the
control groups (OR 0.48, 95% CI 0.18 to 1.27), but outcome “mean pain relief,” all individual studies showed
statistical significance was not achieved. Significant either a significant benefit or a positive trend favouring the
heterogeneity of the results of the studies was evident particular intervention. When primary studies that
(chi-square = 34.47, p < 0.00001). A separate analysis reported the proportion of patients achieving no or mild
excluding low-quality trials did not substantially affect the pain were examined, 3 interventions (intracanal treatment
results. Results of the subgroup analyses for “proportion of with a steroid–antibiotic combination, trephination
patients with no or mild pain” are shown in Table 5. through attached gingiva and systemic antibiotics) showed

Journal of the Canadian Dental Association March 2003, Vol. 69, No. 3 160e
Sutherland, Matthews

Treatment Control WMD WMD

Study n Mean (SD) n Mean (SD) 95% CI random) 95% CI random)
Curtis and others20 20 14.40 (16.40) 20 86.50 (7.10) -72.10 [-79.93 to -64.27]
Doroschak and others21 12 35.80 (21.20) 12 39.10 (22.10) -3.30 [-20.63 to 14.03]
Flath and others23 57 15.00 (10.00) 59 32.00 (10.00) -17.00 [-20.64 to -13.36]
Negm30 267 53.33 (6.30) 124 82.00 (6.67) -28.67 [-30.07 to -27.27]
Penniston and Hargreaves32 (post-op) 10 5.50 (10.00) 14 11.10 (6.00) -5.60 [-12.55 to 1.35]
Penniston and Hargreaves32 (pre-op) 10 17.00 (12.00) 14 22.00 (17.00) -5.00 [-16.60 to 6.60]

Total (95% CI) 376 243 -22.70 [-36.20 to -9.21]

Test for heterogeneity chi-square = 219.15 df = 5 p < 0.00001
Test for overall effect z = 3.30 p = 0.0010

-100 -50 0 50 100

Favours treatment Favours control

Figure 1: Results of the meta-analysis (all interventions) for the outcome mean pain relief, at comparable follow-up times. SD = standard
deviation, WMD = weighted mean difference, CI = confidence interval, df = degrees of freedom.

Treatment Control WMD WMD

Study n Mean (SD) n Mean (SD) (95% CI random) (95% CI random)
Doroschak and others21 12 35.80 (21.20) 12 39.10 (22.10) -3.30 [-20.63 to 14.03]
Flath and others23 57 15.00 (10.00) 59 32.00 (10.00) -17.00 [-20.64 to -13.36]
Negm30 267 53.33 (6.30) 124 82.00 (6.67) -28.67 [-30.07 to -27.27]
Penniston and Hargreaves32 (post-op) 10 5.50 (10.00) 14 11.10 (6.00) -5.60 [-12.55 to 1.35]
Penniston and Hargreaves32 (pre-op) 10 17.00 (12.00) 14 22.00 (17.00) -5.00 [-16.60 to 6.60]

Total (95% CI) 356 223 -13.17 [-23.260 to -2.74]

Test for heterogeneity chi-square = 89.81 df = 4 p < 0.00001
Test for overall effect z = 3.30 p = 0.01

-100 -50 0 50 100

Favours treatment Favours control

Figure 2: Results for the sensitivity analysis for the outcome mean pain relief. SD = standard deviation, WMD = weighted mean difference,
CI = confidence interval, df = degrees of freedom.

Control Treatment OR OR
Study n/N n/N (95% CI random) (95% CI random)

Fava22 29 / 30 28 / 30 2.07 [0.18 to 24.15]

Flath and others23 25 / 59 28 / 57 0.76 [0.37 to 1.58]
Houck and others24 21 / 25 19 / 25 1.66 [0.41 to 6.79]
Krasner and Jadison25 14 / 23 23 / 25 0.14 [0.03 to 0.72]
Moskow and others28 21 / 24 25 / 26 0.28 [0.03 to 2.90]
Nagle and others29 11 / 20 9 / 20 1.49 [0.43 to 5.19]
Negm30 16 / 124 157 / 267 0.10 [0.06 to 0.19]
Nist and others31 19 / 25 23 / 25 0.28 [0.05 to 1.53]

Total (95% CI) 156 /330 312 / 475 0.48 [0.18 to 1.27}
Test for heterogeneity chi-square = 34.47 df = 7 p < 0.00001
Test for overall effect z = -1.48 p = 0.14

.001 .02 1 50 1000

Favours treatment Favours control

Figure 3: Results of the meta-analysis (all interventions) for the outcome intensity of pain (proportion of patients achieving no or mild pain status)
after the intervention at comparable follow-up times. OR = odds ratio, CI = confidence interval, df = degrees of freedom.

Understanding meta-analysis graphs (Figs. 1–3)

For each individual study, the box represents the study result or point estimate (weighted mean difference for continuous data, odds ratio for
dichotomous data), which is the best estimate of the true value for the population from which the sample of patients was taken. The horizontal
bars on either side of the point estimate represent the 95% confidence interval, which is the uncertainty due to chance associated with the
estimate; the true result may lie anywhere within that interval. Wide confidence intervals indicate a large amount of uncertainty about the
estimate. Narrow confidence intervals lead to greater confidence that the estimate is close to the true result — there is greater precision
associated with the result. The vertical line is the line of equivalence, where there is no difference between the effect of the treatment and the
effect of the control. A point estimate that lies on the “favours treatment” side of the vertical line indicates that the intervention may be beneficial;
one that lies on the “favours control” side indicates that the control or placebo may actually be more beneficial than the treatment being studied.
However, if the confidence interval for the estimate crosses the vertical line of the graph, one of the possible values for the true estimate is zero.
In this situation, the result is deemed to be not statistically significant. The diamond at the lower end of the graph represents the combined results
of all studies and its associated 95% confidence interval.

160f March 2003, Vol. 69, No. 3 Journal of the Canadian Dental Association
 Emergency Management of Acute Apical Periodontitis: A Systematic Review of the Literature

Table 4 Results of subgroup analysis for outcome “mean pain relief ”

Intervention No. of studies No. of WMD (and 95% CI)
(reference) patients
Preoperative analgesia 2 (Curtis and others,20 64 –38.69 (–104.5 to 27.07)
Penniston and Hargreaves32)
Pre-emptive analgesiab 2 (Flath and others,23 140 –11.70 (–22.84 to –0.56) a
Penniston and Hargreaves32)
WMD = weighted mean difference, CI = confidence interval.
a Statistically significant.
bThirty to 60 minutes before local anesthesia and pulpectomy.

Table 5 Results of subgroup analysis for outcome “proportion of patients with no or mild pain”
Intervention No. of studies No. of Time Odds ratio (and 95% CI)
(references) patients after surgery
Anti-inflammatory 2 (Flath and others,23 164 7–8 hours 0.22 (0.01–4.00)
drugs Krasner and Jackson25) 24 hours 0.38 (0.07–2.01)
Intracanal 3 (Fava,22 Moskow and others,28 501 48 hours 0.29 (0.05–1.66)
medicaments Negm30)
Trephination 2 (Houck and others,24 100 24 hours 0.51 (0.09–2.74)
Nist and others31) Day 3 0.72 (0.12–4.19)
Day 5 6.83 (0.78–59.81)
CI = confidence interval.

a nonsignificant trend favouring the control group. This outcome measures, mostly with unadjusted p values. Many
result suggests that these are not effective choices in the of the outcomes used in some trials were not reported in
management of pain associated with AAP. For systemic others, which rendered pooling of studies difficult. None of
antibiotics, this makes biologic sense, given the absence of the trials stated a priori the primary outcome or efficacy
blood circulation within necrotic pulp. Because antibiotics measure upon which the overall conclusion of the study
cannot reach and eliminate microorganisms present in the would be based. Using endpoints in this manner is suitable
root canal system, the source of the problem is unaffected for exploratory rather than definitive research.37
by systemic antibiotic therapy.1 While the overall quality scores (according to the Jadad
The results of these analyses must be interpreted with scoring system) were good, examination of some key
caution. By pooling the results of a number of studies, methodological features of these studies is informative. Of
meta-analysis can increase the statistical power of the the 15 trials, 13 stated that they were randomized, but only
combination of studies to detect a treatment effect if one 3 described the method of randomization. It has been
truly exists, even though individual studies may not detect demonstrated empirically that inadequate allocation
the effect. However, a pool of a scant number of small trials concealment can exaggerate the estimate of treatment effect
(especially in a subgroup analysis) may still be underpow- by 41% and that when the concealment methods are
ered to detect an effect. Most of the studies in this review unclear the estimate of effect is exaggerated, on average, by
had 60 or fewer patients, and only one study reported a 30%.38 Eleven of the 15 papers did not mention or describe
power-based sample size calculation. Furthermore, the withdrawals or dropouts (although this information was
quality of reporting and the inability to obtain vital infor- provided subsequently by the authors of 2 papers), and
mation (particularly related to outcome data) from some none stated a planned intention-to-treat analysis. This tech-
authors, led to the omission of some studies that otherwise nique analyzes patients within the group to which they were
might have been included. This problem was compounded originally randomly allocated and serves to preserve the
by inconsistencies in research designs, unclear definitions of powerful function of randomization. Overall, given some of
disease entities and reporting of multiple outcome the design and statistical issues, all trials in this review had
measures. In some studies, the rationale for including some risk of bias.
patients was unclear. For example, where the outcome These combined findings related to design, quality and
measure was related to pain relief, patients were included reporting of trials studying interventions for the management
who had no or mild pain at baseline. A few studies used of AAP suggest the need for an organized, methodical
teeth, rather than patients, as the unit of analysis. For research agenda in endodontics. Future research should be
measurement of a patient outcome such as pain, this is designed to provide consistent definitions of disease entities
clearly inappropriate.36 All studies reported multiple and should clearly state appropriate eligibility criteria for

Journal of the Canadian Dental Association March 2003, Vol. 69, No. 3 160g
Sutherland, Matthews

various types of trials. More consistent and clinically relevant • There is good evidence to support the use of NSAIDs
outcome measures, with patients as the unit of analysis, are for pain relief and pain control (grade A), especially
important if efficacy is to be compared among therapies. when given immediately preoperatively (grade A).
Rigorous design and reporting of randomized controlled • The use of antibiotics in the management of AAP is not
trials, consistent with the CONSORT statement,39 would recommended (grade B).
provide consistency in the reporting of research results. • There is some evidence to support the use of an NSAID
Much of the pain research that has been published used solution as an intracanal medicament (grade B).
continuous scales such as the 100-mm Visual Analog Scale
(VAS) to measure pain. Use of binary or dichotomous • Trephination through bone may be useful when done in
the periapical region (grade B), but entry through the
outcomes (for example, proportion of patients who achieve
attached gingiva is not recommended (grade B).
50% pain relief or total pain relief by a certain time point)
would enable the output from meta-analyses to be more • There is weak evidence to support the use of steroidal anti-
intuitively understandable. Such methods would also be inflammatory drugs (grade C) for pain management. C
more useful to clinicians, because they would allow calcula-
tion of the numbers needed to treat.40 The number needed Acknowledgments: We would like to thank Drs. Jeff Coil and
William Christie for their assistance with determining the validity and
to treat can be applied to treatment efficacy, adverse events methodological quality of the studies, members of the Clinical
and other clinical endpoints, is easily understood by clini- Advisory Group of the Canadian Collaboration on Clinical Practice
Guidelines in Dentistry for focusing the clinical question and devel-
cians and has immediate relevance for clinical decision oping the recommendations for clinical practice (Drs. Jeff Coil,
making.41,42 For example, 30 patients would have to be William Christie, Charmaine Trent, Don Young and Mike
treated with a steroid–antibiotic intracanal medicament to Hornyak), all authors who answered our queries, and Drs. Cal
Torneck (University of Toronto), Kenneth Hargreaves (University of
ensure that 1 patient had mild or no pain postoperatively. Minnesota) and Roy Walton (University of Georgia) for their helpful
On the other hand, only 4 patients would have to be treated comments and suggestions.
with a preoperative systemic NSAID in conjunction with a This project was funded by the Canadian Collaboration on Clinical
Practice Guidelines in Dentistry (http//:www.cccd.ca/), Dalhousie
pulpectomy for the same result. Clearly, the latter is a more University and Sunnybrook and Women’s College Health Sciences
effective therapy. Centre. The authors retain full intellectual property rights for this
manuscript.
In this review, comprehensive search methods were used
Dr. Sutherland is active staff, department of dentistry, Sunnybrook
to minimize bias. Potential sources of bias include publica- and Women’s College Health Sciences Centre, Toronto, Ontario.
tion bias (unpublished studies were not sought) and Dr. Matthews is head, division of periodontics, Dalhousie University,
language bias. Resources did not permit the costly transla- Halifax, Nova Scotia.
tion of studies published in languages other than English or Correspondence to: Dr. Susan Sutherland, Department of Dentistry,
Sunnybrook and Women’s College Health Sciences Centre,
French. However, a recent study of a number of disease H-126–2075 Bayview Avenue, Toronto, ON M4N 3M5. E-mail:
areas has shown that language-restricted and language- [email protected]
inclusive meta-analyses do not differ with respect to the
estimate of benefit of an intervention.43
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Sutherland, Matthews

Appendix 1 Search strategy based on Medical Subject Headings (MeSH) for nonsteroidal
anti-inflammatory drugsa
Steps Medical Subject Headings No. of citations
1 toothache/ 1,306
2 pulpitis/ 1,501
3 pulpitis. mp. (mp = title, abstract, registry number word, MeSH heading) 1,582
4 toothache.mp. (mp = title, abstract, registry number word, MeSH heading) 1,396
5 1 or 2 or 3 or 4 2,855
6 Periapical periodontitis/ 629
7 5 or 6 3,405
8 exp Anti-inflammatory agents, non-steroidal/ 90,129
9 7 and 8 108
10 Limit 9 to human 90
11 Limit 10 to (clinical trial or clinical trial, phase i or clinical trial, phase ii
or clinical trial, phase iii or clinical trial, phase iv or consensus development
conference or consensus development conference, nih or controlled clinical
trial or meta analysis or multicenter study or practice guideline or randomized
controlled trial) 27
12 Limit 11 to English language 16
13 exp treatment outcome/ 114,518
14 exp “signs and symptoms”/ 622,459
15 13 or 14 726,437
16 12 and 15 16
17 From 12 keep 1–16 16
exp = explode (MEDLINE abbreviation; designates a method whereby a subject heading is used as an umbrella term to capture more specific headings on the
same subject).
aThe same strategy was used for all interventions, with appropriate key words used in step 8.

Appendix 2 Studies excluded from analysis

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Sutherland, Matthews

Appendix 3 Grading of evidence44,45

Level or gradea Definition
Evidence
Ia Evidence obtained from meta-analysis of randomized controlled trials
Ib Evidence obtained from at least one randomized controlled trial
IIa Evidence obtained from at least one well-designed controlled study without randomizationb
IIb Evidence obtained from at least one other type of well-designed quasi-experimental study
III Evidence obtained from well-designed nonexperimental descriptive studies, such as comparative studies,
correlation studies and case studies
IV Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected
authorities
Recommendations
A Based on at least one randomized controlled trial as part of a body of literature of overall good quality and
consistency addressing the specific recommendation (evidence levels Ia, Ib)
B Based on well-conducted clinical studies but no randomized clinical trials on the topic of the recommendation
(evidence levels IIa, IIb, III); alternatively, small randomized trials with uncertain results (and moderate to high
risk of error)
C Based on evidence obtained from expert committee reports or opinions and/or clinical experiences of
respected authorities; absence of directly applicable clinical studies of good quality (evidence level IV)
a“Level” applies to categories of evidence; “grade” applies to categories of recommendations.
bRandomized controlled trials are considered to represent level IIa evidence if method of randomization is not clear.

160l March 2003, Vol. 69, No. 3 Journal of the Canadian Dental Association

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