Clinical Oral Investigations

https://doi.org/10.1007/s00784-020-03401-6

REVIEW

Pharmacological management of pain after periodontal surgery:

a systematic review with meta-analysis
Leonardo Stephan Caporossi 1 & Cinthia Studzinski dos Santos 1 & Thayanne Brasil Barbosa Calcia 2 &
Maximiliano Sergio Cenci 3 & Francisco Wilker Mustafa Gomes Muniz 4 & Giana da Silveira Lima 3

Received: 21 April 2020 / Accepted: 9 June 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Objectives To assess and compare the pharmacological effect of different drugs on pain relief after periodontal surgery.
Materials and methods Five databases were searched up to September 2019. The eligible studies comprised randomized clinical
trials, involving only adult individuals that received any periodontal surgery and presenting two distinct groups of therapeutic
regimens to control postoperative pain. Placebo groups could be included. The risk of bias was assessed with the RoB 2 Cochrane
tool and the GRADE system. Meta-analyses were performed using different follow-up and drug comparisons.
Results Overall, 2398 studies were identified, of which 35 were included. Low risk of bias was determined for the majority of the
studies. The meta-analyses showed that the comparison of dexamethasone or non-steroidal anti-inflammatory drugs (NSAID)
versus placebo favored the use of both interventions in a follow-up of 1 to 8 h for open flap procedures (OFP). However, no
statistical difference was found for the comparison between NSAID and dexamethasone for OFP.
Conclusions Patients may benefit from several pharmacological schemes for pain relief after periodontal surgeries. However, due
to the high heterogeneity among studies, no fixed pharmacological protocol could be proposed.
Clinical relevance There is not enough evidence to recommend one therapeutic scheme. However, untreated pain is harmful to
the patients and it is not advisable.

Keywords Oral surgical procedures . Periodontics . Analgesics . Periodontal diseases . Anti-inflammatory agents non-steroidal

Introduction inflammation leads to progressive loss of supporting tissues,

and in the most severe outcome, may cause tooth loss [2].
Periodontal disease is a chronic inflammatory infection that Thus, many periodontal surgeries are performed to reach sat-
presents a high prevalence worldwide [1]. Chronic isfactory results regarding health and aesthetic characteristics.
Postoperative pain following periodontal surgeries is a
common clinical complaint, which may vary considerably
Leonardo Stephan Caporossi and Cinthia Studzinski dos Santos among patients according to sex, age, and type of surgery
contributed equally to this work. [3]. Pain can be defined as a complex sensorial and emotional
experience associated with actual or potential tissue damage,
* Giana da Silveira Lima which is subjective and unique. Pain perception could be in-
[email protected] fluenced by several factors, such as duration, extent and com-
1
plications of the surgery [4], anxiety, previous experiences,
Graduate Program in Dentistry, Federal University of Pelotas, 457,
Gonçalves Chaves St., Pelotas, Rio Grande do Sul, Brazil
stress, and smoking [5].
2
Nonsteroidal anti-inflammatory drugs (NSAIDs) and non-
Faculty of Medicine, Arthur Sá Earp Neto School, 1003, Barão do
Rio Branco Ave., Petrópolis, Rio de Janeiro, Brazil
opioids analgesics are commonly the first options in pain man-
3
agement after surgical procedures, especially due to the less
Department of Operative Dentistry, Graduate Program in Dentistry,
School of Dentistry, Federal University of Pelotas, 457, Gonçalves
severe side effects compared to others [6]. Conversely, opi-
Chaves, St., Pelotas, Rio Grande do Sul, Brazil oids related-side effects are highly prevalent [7]. Furthermore,
4
Department of Periodontology, Graduate Program in Dentistry,
different drugs can be associated towards different situations.
School of Dentistry, Federal University of Pelotas, 457, Gonçalves A systematic review has evaluated pain relief after oral sur-
Chaves St., Pelotas, Rio Grande do Sul, Brazil gery, such as wisdom teeth removal, and found that there is
 Clin Oral Invest

high-quality evidence to prove that ibuprofen is superior to and any form of postoperative pain assessment, such as the
acetaminophen and that the combined drugs containing both use of visual analogue scale (VAS) or postoperative pain re-
agents showed promising results [8]. However, different pat- port. Studies that evaluated other morbidities, such as discom-
terns of postoperative pain may be expected for wisdom teeth fort or prostration, were also included. Reviews (systematic or
removal and periodontal surgeries [9]. not), case reports, observational studies, in vitro or animal
In this sense, no systematized information is available model studies, and letters to the editor were excluded.
about the efficacy of the pharmacological management of pain Studies that did not present separate information for different
after periodontal surgeries. Therefore, this study aimed to sys- therapeutic regimens were excluded.
tematically review the literature about the pharmacological
effect of different drugs, on pain relief, after periodontal Search strategy
surgeries.
Literature search was conducted up to September 2019 in the
following electronic databases: PubMed, Embase, Web of
Material and methods Science, Cochrane, and Scopus. No language or publication
date restriction was applied. The following search strategy
This systematic review followed the recommendation of the was performed in PubMed:
Preferred Reporting Items for Systematic Reviews and Meta- # 1: Crown Lengthening[Mesh Term] OR Crown
Analysis [10]. Literature search was performed to answer the Lengthening[Title/abstract] OR Gingivectomy[Mesh Term]
following focused questions: “In adult individuals receiving OR Gingivoplasty[Mesh Term] OR Dental Scaling[Mesh
periodontal surgeries, is there any differences regarding the Term] OR Root Planing[Title/abstract] OR open flap
pharmacological effects of different drugs, on pain relief, after debridement[Title/abstract] OR Widman flap[Title/abstract]
periodontal surgeries?” and “Is there a necessity for pharma- OR periodontal surgery[Title/abstract] OR rhizectomy[Title/ab-
cological pain control after periodontal surgeries?” Therefore, stract] OR Apicoectomy[Mesh Term] OR Apicoectomy[Title/
PICO framework was centered on the following aspects: abstract] OR root amputation[Title/abstract] OR tunnel
procedure[Title/abstract] OR Guided Tissue Regeneration
& Patients: Adult individuals that received any type of peri- [Mesh Term] OR coronally advanced flap[Title/abstract] OR
odontal surgery, such as crown lengthening for esthetic laterally positioned flap[Title/abstract] OR periodontal flap
reasons, crown lengthening for reestablishment of surgery[Title/abstract] OR double-flap incision[title/abstract]
supracrestal structures, root coverage surgeries, open flap OR periodontal incision[title/abstract] OR root coverage[Title/
procedures for scaling and root planing (SRP), gingivec- abstract] OR Gingival recession[Mesh Terms] OR Gingival
tomy, gingivoplasty, apicoectomy, periodontal guided tis- recession[Title/abstract] OR soft tissue augmentation[Title/ab-
sue regeneration, tunneling, or rhizectomy. stract] OR periodontal connective tissue graft[Title/abstract]
& Intervention: Use of any pharmacological scheme, by oral OR gingival graft[Title/abstract] OR periodontal osseous
or other administration routes. surgery[Title/abstract] OR periodontal osseous surgeries[Title/
& Comparison: Use of another pharmacological scheme, by abstract]
oral or other administration routes, including a placebo # 2: Analgesia[Mesh Term] OR Analgesia[Title/abstract]
substance. OR Patient-Controlled Analgesia[Title/abstract] OR Pain
& Outcome: Any postoperative pain assessment at any time. Measurement[Mesh Term] OR Pain Measurement[Title/ab-
stract] OR Analgesics[Mesh Term] OR Analgesics[Title/ab-
Studies were selected when the title or abstract fulfilled the stract] OR Analgesic[Title/abstract] OR Anti-Inflammatory
following inclusion criteria: randomized clinical trials (both Agents, Non-Steroidal[Title/abstract] OR NSAID[Title/ab-
parallel or split-mouth designs); blind, double-blind or non- stract] OR Aspirin[Title/abstract] OR Cyclooxygenase
blind studies; studies involving only adult individuals at least Inhibitors[Mesh Term] OR Cyclo-Oxygenase Inhibitors[Title/
18 years old; patients receiving any of the following periodon- abstract] OR Non Opioid Analgesics[Title/abstract] OR Non-
tal surgeries: crown lengthening for aesthetic reasons, crown Opioid Analgesics[Title/abstract] OR Nonnarcotic Analgesics
lengthening for reestablishment of the supracrestal structures, [Title/abstract] OR Short-Acting Analgesics[Title/abstract] OR
root coverage surgeries, open flap procedures for SRP, gingi- Analgesics, Opioid[Mesh Term] OR Phenacetin[Mesh Term]
vectomy, gingivoplasty, apicoectomy, periodontal guided tis- OR Phenacetin[Title/abstract] OR Acetanilides[Mesh Term]
sue regeneration, tunneling, or rhizectomy; studies that pres- OR Acetanilides[Title/abstract] OR Dipyrone[Mesh Term]
ent two different groups of pharmacological scheme, by oral OR Ibuprofen[Mesh Term] OR Aspirin[Mesh Term] OR
or other administration routes, involving the use of drugs to Ibuprofen[Title/abstract] OR Aspirin[Title/abstract] OR
control postoperative pain, and including different doses of Salicylates[Title/abstract] OR Acetaminophen[Mesh Term]
the same drug, use of different drugs or placebo substance; OR Tylenol[Title/abstract] OR Diclofenac[Mesh Term] OR
Clin Oral Invest

Diclofenac[Title/abstract] OR Analgesics [Pharmacological discrepancies were solved by a discussion with a third re-
Action] OR Flurbiprofen[Mesh Term] OR Flurbiprofen[Title/ viewer (FWMGM).
abstract] OR celecoxib[Mesh Term] OR Etoricoxib[Mesh Regarding the RoB 2 tool, studies were classified as low
Term] OR etoricoxib[Title/abstract] risk of bias if sufficient information was available, resulting
# 3: No. 1 AND No. 2 in a positive marker. The criteria were classified as high risk
The abovementioned search strategy was adapted in the of bias when no information was available, and a negative
other databases. A hand search was performed in the follow- marker was attributed. When there was insufficient informa-
ing journals: Journal of Periodontology, Journal of Clinical tion and the risk of bias was not possible to be determined,
Periodontology, Journal of Periodontal Research, and The the item was classified as presenting “some concerns.” The
International Journal of Periodontics and Restorative included studies present a patient-reported outcome, thus, in
Dentistry. In each journal, all articles published until the year the fourth domain (outcome measurement), the question
2010 were reviewed. Additionally, a hand search was per- “Were the outcome evaluators aware of the intervention re-
formed on the reference list of every study selected. The gray ceived by the study participants?” was evaluated considering
literature was searched for additional eligible references, using patients’ perceptions.
the Google Scholar database.

Studies selection Statistical analysis

Studies resulting from the search strategy were screened inde- The meta-analyses, using random-effects model, were applied
pendently by three researchers (LSC, GSL, and CSS). Any with RevMan 5.3 (RevMan 5.3, The Nordic Cochrane Centre,
discrepancy regarding the inclusion or exclusion of a study Copenhagen). Heterogeneity was assessed by Q test and quan-
was discussed with a third researcher (FWMGM) when a con- tified with I2 statistics. Data on mean difference (MD) and
sensus could not be reached. Studies which abstract was not standard deviation were obtained from selected studies. Pain
available, but the title suggested any relation to inclusion score after periodontal surgery was considered the main out-
criteria of the present study, were also screened for eligibility. come, and analyses were presented for different therapeutic
regimens, considering different drugs or different dosages.
Data extraction Comparisons between NSAID vs. corticosteroids and between
dexamethasone vs. placebo were performed, using standardized
Two independent reviewers (LSC and CSS) performed da- mean difference (SMD), as different pain assessment tools were
ta extraction from the included studies, using a spreadsheet used among the studies. Conversely, MD was estimated for
in Excel format (Microsoft Corporation, Redmond, WA, NSAID vs. placebo comparison. In NSAID vs. placebo analy-
USA). The following data were recorded: author, publica- ses, the following subgroups were considered: Ibuprofen,
tion year, country, design of the study, type of surgery, Celecoxib, Etoricoxib, and Ketorolac. Additionally, different
characteristics of each experimental group (number of pa- meta-analyses were performed for the VAS and 4-points scale
tients, age, number of males/females, number of smokers, of pain outcomes. To all meta-analyses performed, when suffi-
drug administered, route of administration, dosage, and use cient information was available, different follow-up periods
of placebo substance), anesthetic used, quantity and use of were considered, such as 1–4 h and 8 h.
vasoconstrictor, surgery duration, presence of adverse ef-
fects, use of backup medication, pain assessment method,
and frequency. The corresponding authors were contacted
by email in case of the need for additional data. Studies Results
with missing data were maintained in the systematic re-
view, but not included in the quantitative analysis. Studies selection

Risk of bias assessment Overall, 2,391 studies were identified by electronic database
search. Seven additional studies were identified in the hand
The individual risk of bias assessment of studies was per- search. A flowchart, with the main reasons for exclusion after
formed using RoB 2, the tool recommended by Cochrane to full-text reading, is demonstrated in Fig. 1. It was not possible
assess the risk of bias in randomized trials [11]. Additionally, to translate one study written in Persian [13]. In addition, four
the overall quality of evidence for each of the main outcomes studies were not found, although the corresponding author
included in the meta-analyses was rated using GRADE sys- was contacted by e-mail and on Research Gate website.
tem [12]. To both tools, each selected study was evaluated Therefore, 35 studies fulfilled the inclusion criteria and were
independently by two reviewers (GSL and CSS). Any included in the present study.
 Clin Oral Invest

Fig. 1 Flowchart of studies

selection process

Studies characteristics received [23–26]. Only 4 studies reported the exclusion of

smokers [16, 18, 19, 27].
The final sample of selected studies comprised a total of 1,979 The most prevalent local anesthetic used was 2% lidocaine
patients between 18 and 79 years old with more female par- with adrenaline 1:100,000, ranging from 99 to 144 mg per
ticipants (54.8%), although 9 studies have not reported the procedure. Two percent mepivacaine with epinephrine
proportion. Tables 1 and 2 show the main characteristics and 1:100,000 was the second most used local anesthetic with
results of included studies. Ten studies had a split-mouth de- the final amount varying from 3.4 to 4.8 ml. Articaine was
sign, in which patients received two to three periodontal sur- used only in two studies [19, 20]. Norepinephrine was also
geries in different quadrants with a washout period, ranging used in some studies in association with lidocaine or
from 1 to 6 weeks. The sequences of the pharmacological mepivacaine. However, sixteen studies did not provide infor-
scheme were randomly determined in all studies. mation regarding the type and amount of local anesthesia ap-
The periodontal surgeries addressed were open flap for plied on surgery. Operative time varied from 22.8 min to a
SRP, gingivectomies [14, 15], root coverage associated with maximum of 2 h. Regarding the occurrence of side effects,
a subepithelial connective tissue graft [16, 17], free gingival patients had no adverse effect after the use of different anal-
graft [18–20], and crown lengthening [21, 22]. Four studies gesics in 16 studies. When they did occur, were generally mild
did not specify the type of periodontal surgery that patients and equally distributed among treatment groups. Effects as
Table 1 Main methodological characteristics results from the selected studies considering the orally administered drugs

Author, year, country Design Drugs used (dosage) and prescription N per group; male/female; Was a backup Pain assessment Main findings
age (mean ± SD or range) medication used? (method and
Clin Oral Invest

Which one? follow-up period)

Open flap surgery

Aghasizadeh 2011, Iran Split-mouth RCT In group 1, ibuprofen (400 mg) was administered 3 30; 12/18; 32.1 ± 5.83 Not administered VAS: 1, 2, 6, Naproxen is more efficient
times a day and the first dose was taken and 24 h PO. in long-term swelling and
immediately after first periodontal surgery, pain control.
whereas naproxen (250 mg) was given after the
second. In group 2, the reverse regimen was
applied.
Betancourt, 2004, USA Split-mouth RCT Ibuprofen (400 mg) + hydrocodone (5 mg) or 12; 4/8; 25–65 Available, but was not used VAS: Immediately Association between ibuprofen
ibuprofen (400 mg); first dose of medication by the participants (not after surgery and 2, 4, 6, and hydrocodone results in
was taken after surgery and every 4 h within a specified which one) 8, 10, 12 h PO. better pain control compared
12-h period. to ibuprofen itself.
Diwan 2019, India Split-mouth RCT Transdermal diclofenac patch (200 mg) or oral 20; 12/8; 20–50 Two patients with VAS and pain intensity Diclofenac administered
diclofenac sodium (100 mg); twice a day for transdermal patch took scale: 24 h PO. transdermally has equal
24 h. Patients were instructed to continue the supportive medication potency in relieving PO pain
same medication for the next 2 days if pain (not specified which one) as compared to orally
persists. administered diclofenac.
Gallardo 1990, Chile Parallel RCT Flurbiprofen (100 mg), acetaminophen (500 mg) Flurbiprofen: 20; 9/11; 21–49 Take another dose after 1 h Numerical scale (0 to 3): Flurbiprofen is an alternative for
or placebo; patients were instructed to take one Acetaminophen: 21; 10/11; if the pain was not 1–3 h PO. the proper treatment of pain
tablet every 6 h when PO pain reached 19–48 reduced following periodontal
moderate to severe intensity. Placebo: 22; 9/13; 18–52 surgery.
Gallardo 1992, Chile Parallel RCT Meclofenamate (100 mg), aspirin (500 mg) or Meclofenamate: 34; 14/20; Acetominophen Numerical scale (0 to 3): Meclofenamate is a NSAID
placebo; patients should take one tablet every 33.6 ± 3.05 or aspirin 1–3 h PO. drug with interesting
6 h when PO pain reached moderate to severe Aspirin: 35; 10/25; 32.4 ± 3.26 analgesic properties, which
intensity. Placebo: 30; 9/21; 34.4 ± 3.32 can be used as an alternative
to aspirin or acetaminophen
for the control of PO.
Hungund 2011, India Split-mouth RCT KT (10 mg) or placebo; drugs were 40; NR/NR; NR Not administered VAS: Immediately Ketorolac administered
administered 30 min before anesthesia. after surgery. preemptively was able to
dampen postoperative
painful sequelae.
Konuganti 2015, India Parallel RCT Dexamethasone (8 mg), etoricoxib 20; NR/NR; 18–65 Acetaminophen (650 mg) NRS-101 and VRS 4: 1–8 h The use of preemptive
(120 mg) or placebo; drugs were administered (to all groups) PO and 3 times a day on medication, either etoricoxib
1 h prior to surgery. the following 3 days or dexamethasone, can be an
effective medication for PO
pain prevention.
O’brien, 1996, USA Split-mouth RCT Ibuprofen (800 mg) or placebo; initial dose was 9; 2/7; 35–63 Not administered VAS and category rating Ibuprofen can successfully
administered 1 h before surgery and scale: 0–240 min PO reduce PO pain and
immediately PO, patients received a second inflammation.
dose of either ibuprofen
400 mg or a placebo.
Pearlman 1997, Australia Parallel RCT Ibuprofen (400 mg) or placebo at least 30 min Ibuprofen: 66; Not administered VAS: First onset of pain; The “as directed group” showed
before administration of local anesthesia. NR/NR; 48 ± 11 time when the medication no significant difference in
Postoperatively, all patients were randomly Placebo: 61; NR/NR; 48 ± 13 was taken; At 1, 2, 5, and pain experience between
divided into 2 groups: “As directed” who were 68 (male) and 62 9 h PO; at bedtime. preoperative and PO only
instructed to take the drug regularly for 2 days (female)–whole sample medication, but the “as
PO and “As required”, who were to take the required group” experienced
drug only if needed for pain relief. significantly less pain and
required for medication if the
Table 1 (continued)

Author, year, country Design Drugs used (dosage) and prescription N per group; male/female; Was a backup Pain assessment Main findings
age (mean ± SD or range) medication used? (method and
Which one? follow-up period)

ibuprofen was administered

preoperatively.
Pilatti 2006, Brazil Split-mouth RCT Dexamethasone (4 mg), celecoxib (200 mg) or 20; 9/11; 27–52 Acetaminophen (750 mg) VRS-4: 1–8 h PO and 3 Preemptive and PO use of
placebo; 1 h before the surgery and 8 h after the times a day on the celecoxib or dexamethasone
first dose. following 3 days were effective in the
management of PO pain.
Rashwan 2009, Egypt Split-mouth RCT Acetaminophen (500 mg) and caffeine (30 mg) or 15; 4/11; 37;9 ± 7.5 Aspirin (300 mg) NRS-101 and VRS-4: 1–8 h Acetaminophen can efficiently
ibuprofen (400 mg); drugs were administered PO and 3 times a day on control PO pain.
immediately after surgery and 8 h later the following 3 days
Singh 2014, India Split-mouth RCT Ibuprofen (400 mg) or placebo; patients received 10; NR/NR; NR Not administered VAS: Immediately after Preoperative treatment with
medication 30 min before administration of and 2 h PO. ibuprofen significantly
anesthesia. reduced initial intensity of
operative and PO pain as
compared with the placebo.
Steffens 2010, Brazil Split-mouth RCT Dexamethasone (8 mg), etoricoxib (120 mg) or 20; 10/10; 18–56 Acetaminophen (750 mg) NRS-101: Hourly for the The adoption of a preemptive
placebo; drugs were delivered 1 h before first 8 h after surgery and medication protocol, using
surgery. 3 times a day on the etoricoxib or dexamethasone,
following 3 days. may be considered effective
for pain and discomfort
prevention.
Steffens 2011b, Brazil Parallel RCT Celecoxib (200 mg); 1 h before surgery and 12 h Whole sample Acetaminophen (750 mg) VAS: Every hour for the first A single dose of etoricoxib is not
after; etoricoxib (120 mg) and placebo 1 h (before exclusion): 8 h after surgery, and 3 superior towards two split
before surgery; or dexamethasone (8 mg) and 56; 26;30; 38 ± 8 times a day on the doses of celecoxib for PO
placebo 1 h before surgery. following day. pain.
Steffens 2011a, Brazil Parallel RCT Dexamethasone (4 mg); 1 h before surgery Dexamethasone (4 mg): Acetaminophen (750 mg) VAS: Every hour for the first Eight mg of dexamethasone
and 8 h after the first dose; dexamethasone 19; NR/NR; 36.0 ± 6.5 8 h PO. when administered 1 h
(8 mg); 1 h before surgery; or placebo; Dexamethasone (8 mg); before surgery is more
1 h before surgery 18; NR/NR; 39.7 ± 9.3 effective than two split doses
Placebo: 20; NR/NR; 39.0 ± 8.2 of 4 mg for
30 (male) and 27 PO pain.
(female) – whole sample
Trombelli 1996, Italy Parallel RCT Ketorolac (20 mg) or placebo were given Ketorolac: 22; 5/17; Naproxen sodium (550 mg) VAS: Hourly for the first Preoperative treatment with
immediately before surgery; 43.5 ± 10.58 10 h on the day of ketorolac significantly
Placebo: 21; 8/13; 44.52 ± 6.87 surgery and 4 times daily reduced initial pain intensity
on the 1st and 2nd PO and delayed the onset of PO
days. pain when compared to
placebo.
Tucker 1996, USA Parallel RCT Etodolac (300 mg); patients in etodolac group Etodolac: 13; 7/6; NR Not administered VAS: Hourly for the first 8 h Both regimens were effective in
received a 600-mg oral dose 30 min before the Acetaminophen + hydrocodone: (starting 30 min before the treatment of PO pain.
surgery and 1 capsule every 6 to 8 h. 11; 4/7; NR surgery).
Acetaminophen with hydrocodone,
patients were not premedicated and take
1 or 2 tablets every 4 to 6 h.
Vogel 1992, USA Parallel RCT Pre-treatment group: ibuprofen (600 mg) 5 to Pre-treatment: 19; 9/10; Acetaminophen with Numerical scale: 1 h PO and Ibuprofen either immediately
10 min before delivery of local anesthesia and 49.2 ± 9.7 codeine hourly for 8 h. before or immediately after
placebo immediately after suturing. Post-treatment: 17; 9/8; periodontal surgery
Post-treatment group: placebo 5 to 10 min 46.8 ± 12.2 significantly delays the onset
before local anesthesia and ibuprofen (600 mg) Placebo: 17; 7/10; 43.0 ± 12.7 of pain as compared to
placebo, with dosing after
Clin Oral Invest
Table 1 (continued)

Author, year, country Design Drugs used (dosage) and prescription N per group; male/female; Was a backup Pain assessment Main findings
age (mean ± SD or range) medication used? (method and
Clin Oral Invest

Which one? follow-up period)

after suturing. Placebo group: placebo surgery demonstrating a

tablets at both times. significantly greater delay of
onset of pain as compared to
preemptive administration.
Yaghini 2011, Iran Crossover RCT Diclofenac mouthwash + ibuprofen (400 mg); four 20; 5/15; 22–54 (whole-sample) Not administered VAS: On the first, second, Diclofenac mouthwash was
times a day (30 s each time) for a week and and third days and a week effective in reducing
ibuprofen every 6 h; or placebo + ibuprofen after the operation. periodontal PO pain when
(400 mg); Patients associated with ibuprofen.
were advised to use ibuprofen only in
case of pain and to record the number of
ibuprofen pills taken.
Crown lengthening
Kashefimehr 2017, Iran Parallel RCT Novafen: Acetaminophen (325 mg), ibuprofen 70; 33/37; 25–40 Not administered VAS: 30 min, 1, and 3 h PO Patients that received Novafen
(200 mg), and caffeine (40 mg) or placebo; (whole-sample) intervals. before surgery and half an
drugs were administered immediately after hour after surgery, showed
surgery. less pain compared to
placebo group.
Peres 2012, Brazil Parallel RCT Lumiracoxib (400 mg) or dexamethasone (4 mg); Lumiracoxib: 14; 4/10; Dipyrone (500 mg) VAS: Immediately and after Both drugs presented a similar
patients received medication 1 h before the 34.43 ± 8.37 4, 8, 12, and 24 h PO. potential for pain and edema
surgery. Dexamethasone: 14; 2/12; relief.
33.0 ± 10.91
Root coverage procedures
Giorgetti 2018, Brazil Parallel RCT Ibuprofen (400 mg) or dexamethasone (4 mg); Ibuprofen: 10; 3/10; Not administered NRS-101 and VRS-4: Dexamethasone seemed to
preemptive medications were administered 1 h 43.4 ± 15.09 Hourly for 8 h after provide pain relief when
prior surgery, and PO medication was Dexamethasone: 10; 4/6; surgery and once a day compared to ibuprofen, with
administered 8 and 16 h after, but only if 44.3 ± 12.6 for 3 days. a significant difference
patients experienced pain. observed at 3 h after the
procedure.
Popova 2008, Bulgaria Parallel RCT Nimesulide (100 mg) or ibuprofen (200 mg); Nimesulide: 7; NR/NR; NR Not administered VRS-4: Every hour for the Aulin® and ibuprofen® were
drugs were administered 1-h PO and twice daily Ibuprofen: 8; NR/NR; NR first 8 h after the surgical effective in the management
for the next 3 days. 18–62 (age, whole-sample) procedure and 3 times a of PO pain.
day on the following
3 days.
Tejaswi 2014, India Split-mouth RCT Transdermal diclofenac patch; 3 patches 20; 10/10; 18–35 Not administered VAS: Baseline (immediately The transdermal diclofenac
were used for the first 3 PO days, and each before the patch was patch was effective in PO
patch was applied on skin devoid of hair for applied), then 2, 4, 8, 12, pain control. Pain tolerance
24 h. Diclofenac sodium (100 mg); Once a day 24, 48, and 72 h PO. was higher with the patch
for 3 days. group as compared to oral
administration group, as it
did not cause any
gastrointestinal
complications.
Gingivectomy
Cantor 1968, USA Parallel RCT Percogesic: acetaminophen (325 mg), Percogesic: 50; 37/13; 19–56 Not administered Numerical scale: 24–48 h Percogesic had substantially
phenyltoxamine (30 mg); homatropine Darvon: 50; 37/13; 19–53 higher scores than Darvon on
methylbromide (2.5 mg); caffeine (30 mg); or the rapidity of onset of action
and degree of pain relief.
Table 1 (continued)

Author, year, country Design Drugs used (dosage) and prescription N per group; male/female; Was a backup Pain assessment Main findings
age (mean ± SD or range) medication used? (method and
Which one? follow-up period)

Darvon: dextropropoxifeno (32 mg); 2 capsules

were administered every 4 h.
Gallardo 1980, Chile Parallel Clinical Trial Naproxen 250 mg; ibuprofen 200 mg; Naproxen: 28; NR/NR; NR Acetylsalicylic acid Numerical scale (0 to 3): A statistically significant
acetaminophen 500 mg; placebo. The patients Ibuprofen: 25; NR/NR; NR Immediately after taking difference was found when
were requested to take medication following Acetaminophen: 20; NR/NR; medication and over a 3-h the effect of these
surgery only if they experienced pain. NR period. medications was compared
Placebo: 25; NR/NR; NR with that of a placebo, but no
statistically significant
difference was found among
them.
Not specified the type of periodontal surgery
Cooper 1983, USA Parallel RCT Suprofen (400 mg), suprofen (200 mg), aspirin Suprofen (400 mg): 45; 19/26; Acetaminophen with Numerical scale (0 to 3): Both doses of suprofen were
(650 mg) or placebo; Immediately following 46.6 ± NR codeine (15 mg) 30 min and 1–6 h after able to provide pain relief
surgery, patients were given a single dose of Suprofen (200 mg): 44; 15/29; ingesting the medication. when compared to aspirin
medication. Patients were instructed to take the 45.7 ± NR 650 mg or placebo.
medication during the first 24 h following Aspirin: 43; 21/22; 46.2 ± NR
surgery when they began to experience at least Placebo: 44; 19/25; 42.3 ± NR
moderate pain.
Cooper 1986, USA Parallel RCT Suprofen (200 mg), codeine (60 mg), Suprofen: 51; 15/36; 22–68 Acetominophen (600 mg) Numerical scale (0 to 3): Suprofen was consistently better
propoxyphene HCl (65 mg) or placebo; drugs Codeine: 50; 24/26; 22–72 plus 30 min and 1–6-h than all other treatments in
were administered 2 h after surgery. Propoxyphene HCl: 55; 26/29; codeine (30 mg) evaluation period. peak effect and total effect for
18–67 both values.
Placebo: 56; 26/30; 23–64
Minutello 1988, USA Parallel RCT Diflunisal (500 mg); the pre-operative diflunisal 44; NR/NR; 18–60 Acetaminophen (650 mg) MPQ: 6 h PO and 30 min Therapeutic doses of diflunisal,
group was given a loading dose of 1000 mg of (whole-sample) plus codeine phosphate after taking the PO given preoperatively, are
diflunisal 8 h preoperatively; 500 mg of (30 mg) placebo dose. significantly more effective
diflunisal 1 h preoperatively, and a placebo 6 h than placebo in limiting PO
PO; pain.
or placebo; The preoperative placebo group was
given placebo 8 h preoperatively, a placebo 1 h
preoperatively and a placebo 6 h PO.
Minutello 1991, USA Parallel RCT Diflunisal (500 mg); The PO diflunisal group was 20; NR/NR; 20–60 Acetaminophen (650 mg) MPQ: Immediately before Therapeutic doses of diflunisal,
given a loading dose of 1000 mg of diflunisal (whole-sample) plus codeine phosphate and 30 min after the 6 h given postsurgically, are
immediately after surgery and 500 mg of (30 mg) PO dose. significantly more effective
diflunisal 6 h PO. Placebo; the PO placebo than placebo in reducing PO
group was given placebo immediately after pain.
surgery and 6 h PO.

KT, ketorolac tromethamine; MPQ, McGill Pain Questionnaire; NR, not reported; NSAID, non-steroidal anti-inflammatory; PO, postoperative; RCT, randomized clinical trial; VAS, visual analogue scale
Clin Oral Invest
Table 2 Main methodological characteristics and results of selected studies considering different routes of administrations (not orally)
Clin Oral Invest

Author, year, country Design Drugs used (dosage) and N per group; Was a backup Pain assessment (method and Main findings
prescription male/female medication used? follow-up period)
mean ± SD (age) Which one?

Open flap surgery

Agarwal et al., 2010, India Parallel RCT 0.074% diclofenac mouthwash or 20; 11/9; 35–45 Not administered VAS: Baseline on the day Spontaneous pain was
placebo; patients were (whole-sample) of the surgery; Spontaneous significantly reduced by
instructed to rinse 15 ml pain was evaluated daily at diclofenac mouthwash. 0.074%
solution twice a day for 7 days 8 AM for 7 days. diclofenac mouthwash is an
after surgery. effective and tolerable drug for
PO pain relief.
Mishra 2017, India Parallel RCT 0.074% diclofenac mouthwash 30; NR/NR; 25–45 Not administered VAS and Wong-Baker Facial Intergroup comparisons showed
(Disoral); Patients were (whole-sample) Rating Scale (FRS): On the day no significant reduction in pain
instructed to rinse 15 ml of surgery (baseline) and twice scores between groups.
solution for 30 s, twice daily for daily on the following 7 days. Diclofenac mouthwash is as
3 days. Diclofenac (50 mg); effective as oral administration.
Twice daily for 3 days.
Rajeswari 2015, India Parallel RCT Meloxicam (45 mg), (30 mg), 45 mg: 15; 6/9; 30–65 Diclofenac (50 mg) VAS: 1, 2, 3, 4, 5, 24 and 48 h PO. Transmucosal delivery of
(20 mg) or (10 mg) containing 30 mg: 15; 7/8; 30–65 meloxicam was found to be
film; after suturing, the 20 mg: 15; 8/7; 30–65 effective and safe in PO pain
preformed 10 mg: 15; 7/8; 30–65 control. 30 mg was the
meloxicam-containing films minimum effective dosage.
were placed on the attached
gingiva, over which periodontal
pack was placed.
Root coverage procedures
Al-Hezaimi 2011, Parallel RCT KT film or placebo; preparations 60; 31/37; 18–64 Acetaminophen (300 mg) VAS: Immediately before the The treatment group reported a
Saudi Arabia were placed onto the graft. (whole-sample) plus codeine (30 mg) adhesive film was applied, 1, 2, significant reduction of pain
3, 4, 5, 24 and 48 h thereafter, intensity during the first 2 h
or immediately before taking after surgery. The adhesive film
other pain medication. containing 30 mg of KT was
effective in controlling PO pain.
Isler 2018, Turkey Parallel RCT Oral spray of flurbiprofen or Flurbiprofen: 12; 6/6; Flurbiprofen (100 mg) Numerical scale (0 to 10): 1, 3, 7, Oral flurbiprofen spray reduces
FGG procedures placebo; drugs were 38.9 ± 10.8 14, 21 days after the surgery. morbidity; however, it might
administered 3 times Placebo: 12; 6/6; 40.9 ± 6.69 have negative effects on
2a day for a week. epithelialization of secondary
wound healing after FGG
procedures.
(Isler et al. 2018), Turkey Parallel RCTSCTG Oral spray of flurbiprofen or Flurbiprofen: 12; 4/8; Flurbiprofen (100 mg) Numerical scale (0 to 10): 1, 3, 7, In SCTG procedures, it does not
procedures placebo; drugs were 43.28 ± 9.34 14, 21 days after the surgery. seem to provide any additional
administered 3 times Placebo: 12; 5/7; 42.4 ± 14.6 benefit on morbidity and
a day for a week. primary wound healing at their
palatal sites.

FGG, free gingival graft; KT, ketorolac tromethamine; NR, not reported; PO, postoperative; RCT, randomized clinical trial; SCTG, subepithelial connective tissue graft; VAS, visual analogue scale
 Clin Oral Invest

drowsiness, nausea, headache, and dizziness were more fre-

quently reported.
Drugs and protocol regimen used in the studies are de-
scribed in Tables 1 and 2. Most of included studies adminis-
trated the drugs orally. Among them, the most prevalent used
were ibuprofen, followed by dexamethasone and acetamino-
phen. Some studies provided a comparison between two or
more different drugs. Placebo substances were used in 26
studies. Five studies assessed pain relief promoted by drugs
administered on different routes [18, 19, 28–30].
Backup medication was provided in 20 studies, in case of
persisting pain despite the use of drugs under investigation. In
those studies, acetaminophen and acetaminophen plus co-
deine were the most commonly selected medication. In two
studies, patients who needed to take backup medication were
excluded from the analysis [18, 30]. In most cases, patients
who needed backup medication were part of placebo group
[15, 19, 23, 25, 26, 31–33].
Different tools were used to assess pain: VAS [34] was
applied in 20 studies, VRS-4 [35] and NRS-101 [36] in 5
studies, McGill Pain Questionnaire [37] in 2 studies, and an-
other numerical rating scales were used in 12 studies.
Similarly, the frequency of pain assessment ranged from im-
mediately after surgery to 21 days after surgery, but the most
frequently assessed periods were 1 to 8 h and 24 to 72 h.

Risk of bias

The methodological quality of included studies was assessed

to estimate the potential risk of bias (Fig. 2). The methodolog-
ical quality of each study was classified as low, high, or some
concerns. A substantial risk of bias was determined for 9 stud-
ies [14, 15, 17, 20, 29, 31, 38–40], some concerns for one
study [28], and a low risk of bias for the others.
This systematic review examined the quality of evidence
for each meta-analyses outcome, and the strength of recom-
mendation was rated as moderate in most of the cases.
However, in five analyses, the GRADE rating was considered
as low or very low (Table 3).

Qualitative results—open flap surgeries (oral

administration)

Fourteen studies compared different pharmacological proto-

cols with placebo pill or with the absence of therapy after open
flap procedures to treat periodontitis. To all studies, in at least
one follow-up period, the test groups demonstrated superior
pain relief when compared to placebo, except for Fig. 2 Risk of bias analysis: review authors’ judgments about each risk of bias
item for each included study using the COCHRANE criteria (RoB 2 tool)
acetylsalicylic acid [41] and 4 mg of dexamethasone [42].
Only two studies compared acetaminophen with an
NSAID after open flap procedures [43, 44]. Contradictory of follow-up [43], but acetaminophen and caffeine demon-
results were detected in these studies, as one study demon- strated significantly lower pain scores, after 1 to 2 h of fol-
strated that flurbiprofen promoted superior pain relief up to 3 h low-up, when compared to ibuprofen [44].
Table 3 Summary of the quality assessment of all outcomes included in the meta-analyses

Certainty assessment No. of patients Effect Certainty

Clin Oral Invest

No. of Study design Risk of bias Inconsistency Indirectness Imprecision Other Analgesic Other Relative Absolute (95% CI)
studies considerations drug analgesic (95% CI)
drug or
placebo

Postoperative pain-NSAID vs. dexamethasone (open flap surgeries only) (follow up: mean 1 h; assessed with: VAS; scale from: 0 to 100)
2 Randomized trials Not serious Not serious Not serious Seriousa None 35 35 – SMD 0.13 lower (0.6 lower ⨁⨁⨁◯Moderate
to 0.34 higher)
Postoperative pain-NSAID vs. dexamethasone (open flap surgeries only) (follow up: mean 2 h; assessed with: VAS; scale from: 0 to 100)
2 Randomized trials Not serious Not serious Not serious Seriousa None 35 35 – SMD 0.03 lower (0.5 lower ⨁⨁⨁◯Moderate
to 0.44 higher)
Postoperative pain-NSAID vs. dexamethasone (open flap surgeries only) (follow up: mean 3 h; assessed with: VAS; scale from: 0 to 100)
2 Randomized trials Not serious Not serious Not serious Seriousa None 35 35 – SMD 0.2 lower (0.67 lower ⨁⨁⨁◯Moderate
to 0.27 higher)
Postoperative pain-NSAID vs. dexamethasone (open flap surgeries only) (follow up: mean 4 h; assessed with: VAS; scale from: 0 to 100)
2 Randomized trials Not serious Not serious Not serious Seriousa None 35 35 – SMD 0.39 lower (0.87 lower ⨁⨁⨁◯Moderate
to 0.08 higher)
Postoperative pain-NSAID vs. dexamethasone (open flap surgeries only) (follow up: mean 8 h; assessed with: VAS; scale from: 0 to 100)
2 Randomized trials Not serious Seriousb Not serious Seriousa None 35 35 – SMD 0.01 higher(0.67 lower ⨁⨁◯◯Low
to 0.69 higher)
Postoperative pain-NSAID vs. placebo (open flap surgeries only) (follow up: mean 1 h; assessed with: VAS; scale from: 0 to 100)
5 Randomized trials Not serious Not serious Not serious Seriousa None 155 129 – MD 7.34 lower (11.28 lower ⨁⨁⨁◯Moderate
to 3.4 lower)
Postoperative pain-NSAID vs. placebo (open flap surgeries only) (follow up: mean 2 h; assessed with: VAS; scale from: 0 to 100)
5 Randomized trials Not serious Very seriousb Not serious Seriousa None 109 88 – MD 9.11 lower (18.3 lower ⨁◯◯◯Very low
to 0.08 higher)
Postoperative pain-NSAID vs. placebo (open flap surgeries only) (follow up: mean 3 h; assessed with: VAS; scale from: 0 to 100)
4 Randomized trials Not serious Not serious Not serious Seriousa None 89 68 – MD 20.18 lower (25.1 lower ⨁⨁⨁◯Moderate
to 15.27 lower)
Postoperative pain-NSAID vs. placebo (open flap surgeries only) (follow up: mean 4 h; assessed with: VAS; scale from: 0 to 100)
4 Randomized trials Not serious Very serious b Not serious Seriousa None 89 68 – MD 17.38 lower(27.8 lower ⨁◯◯◯Very low
to 6.96 lower)
Postoperative pain-NSAID vs. placebo (open flap surgeries only) (follow up: mean 8 h; assessed with: VAS; scale from: 0 to 100)
3 Randomized trials Not serious Not serious Not serious Seriousa None 80 59 – MD 6.69 lower(10.92 lower ⨁⨁⨁◯Moderate
to 2.45 lower)
Postoperative pain-NSAID vs. placebo (open flap surgeries only) (follow up: mean 1 days; assessed with: VAS; scale from: 0 to 100)
2 Randomized trials Not serious Not serious Not serious Seriousa None 58 38 – MD 2.72 lower (7.15 lower ⨁⨁⨁◯Moderate
to 1.7 higher)
Postoperative pain-NSAID vs. placebo (open flap surgeries only) (follow up: mean 1 h; assessed with: 4-point scale; scale from: 0 to 3)
2 Randomized trials Not serious Seriousb Not serious Seriousa None 28 26 – MD 0.48 lower (0.82 lower ⨁⨁◯◯Low
to 0.13 lower)
Postoperative pain-NSAID vs. placebo (open flap surgeries only) (follow up: mean 2 h; assessed with: 4-point scale; scale from: 0 to 3)
2 Randomized trials Not serious Seriousb Not serious Seriousa None 28 26 – MD 0.93 lower (1.44 lower ⨁⨁◯◯Low
to 0.43 lower)
Postoperative pain-NSAID vs. placebo (open flap surgeries only) (follow up: mean 3 h; assessed with: 4-point scale; scale from: 0 to 3)
2 Randomized trials Not serious Not serious Not serious Seriousa None 28 26 – ⨁⨁⨁◯Moderate
Table 3 (continued)

Certainty assessment No. of patients Effect Certainty

No. of Study design Risk of bias Inconsistency Indirectness Imprecision Other Analgesic Other Relative Absolute (95% CI)
studies considerations drug analgesic (95% CI)
drug or
placebo

MD 1.07 lower(1.33 lower to

0.8 lower)
Postoperative pain-NSAID vs. placebo (open flap surgeries only) (follow up: mean 4 h; assessed with: 4-point scale; scale from: 0 to 3)
2 Randomized trials Not serious Not serious Not serious Seriousa None 28 26 – MD 1.08 lower(1.33 lower to ⨁⨁⨁◯Moderate
0.83 lower)
Postoperative pain-dexamethasone vs. placebo (open flap surgeries only) (follow up: mean 1 h; assessed with: VAS; scale from: 0 to 100)
3 Randomized trials Not serious Not serious Not serious Seriousa None 72 55 – SMD 0.23 lower (0.59 lower ⨁⨁⨁◯Moderate
to 0.13 higher)
Postoperative pain-dexamethasone vs. placebo (open flap surgeries only) (follow up: mean 2 h; assessed with: VAS; scale from: 0 to 100)
3 Randomized trials Not serious Not serious Not serious Seriousa None 72 55 – SMD 0.37 lower(0.73 lower ⨁⨁⨁◯Moderate
to 0.01 lower)
Postoperative pain-dexamethasone vs. placebo (open flap surgeries only) (follow up: mean 3 h; assessed with: VAS; scale from: 0 to 100)
3 Randomized trials Not serious Not serious Not serious Seriousa None 72 55 – SMD 0.72 lower (1.09 lower ⨁⨁⨁◯Moderate
to 0.35 lower)
Postoperative pain-dexamethasone vs. placebo (open flap surgeries only) (follow up: mean 4 h; assessed with: VAS; scale from: 0 to 100)
3 Randomized trials Not serious Not serious Not serious Seriousa None 72 55 – SMD 0.56 lower (0.97 lower ⨁⨁⨁◯Moderate
to 0.16 lower)
Postoperative pain-dexamethasone vs. placebo (open flap surgeries only) (follow up: mean 8 h; assessed with: VAS; Scale from: 0 to 100)
3 Randomized trials Not serious Not serious Not serious Seriousa None 72 55 – SMD 0.51 lower(0.88 lower ⨁⨁⨁◯Moderate
to 0.14 lower)

CI, confidence interval; MD, mean difference; SMD: Standardized mean difference; a Whenever there are sample sizes that are less than 400, review authors and guideline developers should certainly
consider rating down for imprecision. b While determining what constitutes a large I2 value is subjective, the following rule-of-thumb can be used: < 40% may be low; 30–60% may be moderate; 50–90%
may be substantial; 75–100% may be considerable
Clin Oral Invest
Clin Oral Invest

Fig. 3 Forest plots for the pain

relief comparison between
NSAID and corticoid after open
flap. The SMD was applied
considering that different pain
assessment scales were used

Qualitative results—open flap surgeries (topical acetaminophen, 200 mg of ibuprofen, and 40 mg of caffeine
administration) with a placebo administered after surgery [21]. It was demon-
strated that, after 1 h and 3 h of follow-up, the placebo group
Three studies performed open flap procedures to treat peri- presented significantly higher pain levels.
odontitis and used topical drugs to manage postoperative pain. Conversely, another study administered, 1 h before
Two studies used a 0.074% diclofenac-containing mouth- surgery, a single dose of lumiracoxib (400 mg) or a
wash, which was compared with a placebo rinse [28] and oral single dose of dexamethasone (4 mg) [22]. No statisti-
diclofenac sodium (50mg) [29]. When a placebo rinse was cally significant difference between groups was ob-
used, significantly lower pain levels were observed for 7 days served regarding any follow-up.
in the group that used diclofenac-containing mouthwash [28].
However, no significant difference was demonstrated between Qualitative results—root coverage procedures
both topical and oral administrations of diclofenac [29]. One
study used mucoadhesive films with meloxicam in different Five studies evaluated different protocols for pain man-
doses (45 mg, 30 mg, 20 mg, and 10 mg). Authors concluded agement after root coverage procedures. Oral adminis-
that the minimum effective dosage for meloxicam was found tration of drugs was performed in three studies [16, 17,
to be 30 mg [30]. 20]. One study demonstrated no statistically significant
difference when comparing the combination of preemp-
Qualitative results—crown lengthening surgeries tive and postoperative administration of ibuprofen
(400 mg–60 min preemptively; 400 mg–postoperatively)
Only two studies evaluated the pharmacological management and dexamethasone (4mg–60 min preemptively; 4mg–
of postoperative pain after crown lengthening [21, 22]. postoperatively) [16].
Different pharmacological protocols were used in these stud- One to 8 h postoperatively, the comparison between
ies. One study compared the combination of 325 mg of nimesulid (100 mg) and ibuprofen (200 mg) also showed no
 Clin Oral Invest

Fig. 4 a Forest plot for the comparison between NSAID and placebo, after open flap periodontal surgeries, using VAS. b Forest plot for the comparison
between NSAID and placebo, after open flap periodontal surgeries, at 4 and 8 h follow-up, using VAS
Clin Oral Invest

Fig. 4 (continued)

statistically significant difference in pain relief [20]. No dif- Topical administration of drugs was performed in two stud-
ference in pain relief was also observed between oral ies [18, 19]. Adhesive films with ketorolac (30 mg) [18] and a
diclofenac sodium (100 mg) and a transdermal diclofenac spray with flurbiprofen (0.075 g) [19] were compared to pla-
patch [17]. cebo adhesive films and spray, respectively. Adhesive film
 Clin Oral Invest

Fig. 5 Forest plots for the

comparison between NSAID and
placebo, after open flap
periodontal surgeries, considering
1 to 4 h of follow-up period and
the 4-point scale of pain

with ketorolac provided significantly lower pain relief up to Similarly, in Fig. 5, the analgesic effect analysis between
2 h [18]. When spray with flurbiprofen was used, significantly NSAID and placebo for open flap surgeries, using a 4-point
lower pain was demonstrated only after 3 days [19]. scale [46, 48], revealed a similar trend of results. NSAID
produced significantly higher postoperative pain relief than
placebo in 1- up to 4-h follow-up.
Quantitative results The comparisons for pain relief between dexamethasone
and placebo, from 1h to 8h, are demonstrated in Fig. 6 [33,
Due to the high heterogeneity among the studies and the im- 42, 45]. Significantly higher pain relief was achieved when
possibility of standardization of available data, only nine stud- dexamethasone was used only at the follow-ups 3h, 4h, and
ies were included in quantitative analysis of the present study. 8h. Among the three included studies, no side effects were
Additionally, meta-analyses were grouped according to the reported to all experimental groups.
type of periodontal surgery, drugs used, pain scale applied,
and follow-up period assessment. In order to increase homo-
geneity, only studies that performed open flap procedures Discussion
were meta-analyzed, since no other procedure had more than
two studies with sufficient information. This is the first systematic review to evaluate postoperative
Fig. 3 shows the comparison between NSAIDs, celecoxib pharmacological pain relief in adults submitted to periodontal
[45] and etoricoxib [33], and dexamethasone for open flap surgeries. In this study, dexamethasone or NSAID, when
surgeries. In this analysis, no statistically significant differ- compared to placebo, were able to decrease pain in almost
ence could be found for pain relief to all follow-up periods. all follow-up periods. Low risk of bias was determined for
Regarding the comparison between NSAID versus pla- majority of the studies, and quality of evidence of the review
cebo, using VAS, subgroup meta-analyses were performed was rated as moderate.
(Fig. 4a, b) considering different NSAIDs, such as ibupro- Different types of periodontal surgeries were performed
fen [39, 46], celecoxib [32, 45], etoricoxib [32], and among the included studies. It is important to point out that
ketorolac [47]. After 1 to 8 h, significant pain relief was pain perception could be influenced by time and extent of the
observed favoring the use of NSAID. However, on the day surgery [4]. Additionally, it may be expected that postopera-
after surgery procedure, there was no significant difference tive pain after periodontal procedures tends to be milder and
in pain relief between both groups. shorter than in more complex oral surgeries [3]. Literature
Clin Oral Invest

Fig. 6 Forest plot for the

comparison between
dexamethasone and placebo,
open flap periodontal surgeries,
considering from 1 to 8 h of
follow-up and the VAS

shows that postoperative pain is a common feature between as interaction with the endocannabinoid system [53] or ionic
patients submitted to periodontal surgeries [3] and also non- channels [54].
surgical periodontal therapy under local anesthesia [49]. Literature suggests that NSAIDs may be a sufficient anal-
Moreover, the effect of dentin/root hypersensitivity must not gesic to treat most postoperative dental pain [55], and there is
be ruled out after periodontal treatment [50]. a growing consensus that opioids are not needed for routine
Postoperative pain has been reported to a greater intensity oral health care [56]. A systematic review investigated the
among the first 24 h after periodontal surgery, decreasing optimal dose of ibuprofen versus acetaminophen, for wisdom
subsequently [9]. In the present study, no statistically signif- teeth removal surgery, and concluded that the combination of
icant difference was found on the day after surgery proce- both agents showed superior pain relief when compared to
dure, considering the comparison between NSAID and pla- separated drugs [8]. More importantly, this combination re-
cebo, corroborating these findings. Instead, a significant dif- sulted in similar side effects, which is in contrast to the higher
ference was observed on 1- to 8-h follow-up period, favor- side effects of opioid-containing drugs [6], especially drug
ing NSAIDs. These results are consistent, as similar results abuse [57].
were detected to both VAS and the 4-points scale of pain. In the present study, pain relief of NSAIDs compared to
The mechanism of action of NSAIDs related to pain reduc- dexamethasone showed no statistically significant differences
tion is classically attributed to impaired production of pros- at any postoperative time. However, when dexamethasone
taglandins due to cyclooxygenase inhibition, avoiding pe- was compared to placebo, a superior efficacy of this drug
ripheral and central sensitization [51, 52]. However, other was observed. After periodontal surgeries, it is expected pain
mechanisms could be related to their analgesic effects, such of mild intensity, which does not configure a precise
 Clin Oral Invest

indication for the use of corticosteroids in these procedures. In Conclusions

fact, due to its mechanism of action, corticosteroids are more
suitable to prevention of edema related to surgical manipula- Patients can experience benefits from several pharmacological
tion and frequently show no superior effect on acute pain schemes for pain relief after periodontal surgeries.
inhibition when compared with NSAIDs [58, 59]. The use Pharmacological therapy for pain relief, after periodontal sur-
of dexamethasone in Dentistry is largely demonstrated for geries, must consider patients and professional preferences, as
the control of pain, swelling, and trismus after extractions of there is not enough evidence to suggest a standard treatment.
third molars [60]. In this sense, the use of NSAID and/or
analgesics is recommended for relieving pain after periodontal Funding information This study was financed in part by the
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil
surgical procedures.
(CAPES)-Finance Code 001.
Diclofenac sodium is an NSAID available for oral and
topical administration. However, systemic administration
Compliance with ethical standards
can lead to adverse effects [61]. Considering this, one study
[29] compared the local (mouthwash) and systemic use of Conflict of interest The authors declare that they have no conflict of
diclofenac, showing no significant differences between interest.
groups. This demonstrates that mouthwash could be a good
therapeutic alternative, in terms of patients’ acceptance and Ethical approval Ethical approval does not apply to systematic reviews.
occurrence of less adverse effects. Another study [62] also
evaluated the diclofenac mouthwash effect on analgesic effi- Informed consent Informed consent does not apply to systematic
reviews.
cacy after periodontal surgery. Similarly, it was detected that
this mouthwash was effective in reducing postoperative pain.
However, it must be emphasized that there is no sufficient
information to recommend the use of a locally delivered drug
References
for pain control after periodontal surgical procedures.
A limitation of this systematic review is the high var- 1. Kassebaum NJ, Bernabé E, Dahiya M, Bhandari B, Murray CJL,
iability of included studies, suggesting differences among Marcenes W (2014) Global burden of severe periodontitis in 1990-
them, such as follow-up time, risk of bias, different anal- 2010: a systematic review and meta-regression. J Dent Res 93:
gesics, and parameters to assess pain. Moreover, the ex- 1045–1053. https://doi.org/10.1177/0022034514552491
2. Papapanou PN, Sanz M, Buduneli N, Dietrich T, Feres M, Fine
clusion of a study written in Persian and exclusion of four DH, Flemmig TF, Garcia R, Giannobile WV, Graziani F,
not found studies must be addressed. Additionally, the Greenwell H, Herrera D, Kao RT, Kebschull M, Kinane DF,
findings of this study should be interpreted with caution, Kirkwood KL, Kocher T, Kornman KS, Kumar PS, Loos BG,
as most studies had included few individuals and did not Machtei E, Meng H, Mombelli A, Needleman I, Offenbacher S,
Seymour GJ, Teles R, Tonetti MS (2018) Periodontitis: consensus
perform adjusted analysis for potential confounders. report of workgroup 2 of the 2017 world workshop on the classifi-
Additionally, pain threshold levels are highly subjective cation of periodontal and peri-implant diseases and conditions. J
and must be considered in the present study. Clin Periodontol 89:S173–S182. https://doi.org/10.1111/jcpe.
Due to the heterogeneity of drugs evaluated by the studies, 12946
it was not possible to perform meta-analyses with more stud- 3. Mei CC, Lee FY, Yeh HC (2016) Assessment of pain perception
following periodontal and implant surgeries. J Clin Periodontol 43:
ies. However, most of them presented a low risk of bias, and 1151–1159. https://doi.org/10.1111/jcpe.12618
meta-analyses also showed low to moderate heterogeneity, 4. Canakçi CF, Canakçi V (2007) Pain experienced by patients under-
demonstrating the high clinical applicability of current going different periodontal therapies. J Am Dent Assoc 138:1563–
findings. 1573. https://doi.org/10.14219/jada.archive.2007.0105
5. Riley JL, Tomar SL, Gilbert GH (2004) Smoking and smokeless
Few studies were available for crown lengthening and
tobacco: increased risk for oral pain. J Pain 5:218–225. https://doi.
root coverage procedures. Further randomized clinical org/10.1016/j.jpain.2004.03.003
trials are warranted in this field in order to find the best 6. Moore PA, Hersh EV (2013) Combining ibuprofen and acetamin-
pharmacological scheme for these periodontal surgeries. ophen for acute pain management after third-molar extractions:
In this context, split-mouth design studies may be ideal translating clinical research to dental practice. J Am Dent Assoc
144:898–908. https://doi.org/10.14219/jada.archive.2013.0207
for postoperative pain evaluation due to some advan-
7. Khademi H, Kamangar F, Brennan P, Malekzadeh R (2016) Opioid
tages, such as each participant is his or her own control, therapy and its side effects: a review. Arch Iran Med 19:870–876
eliminating among-participant variation. Furthermore, we 0161912/AIM.0010
recommended that those studies do not include dexa- 8. Bailey E, Worthington H, Coulthard P (2014) Ibuprofen and/or
methasone as postoperative pain relief drug, as NSAID paracetamol (acetaminophen) for pain relief after surgical removal
of lower wisdom teeth, a Cochrane systematic review. Br Dent J
demonstrated similar to superior pain relief without the 216:451–455. https://doi.org/10.1038/sj.bdj.2014.330
risk of higher side effects.
Clin Oral Invest

9. Seymour RA, Blair GS, Wyatt FAR (1983) Post-operative dental 26. Minutello JS, Newell DH, Thrash WJ, Terezhalmy GT (1991)
pain and analgesic efficacy. Part I. Br J Oral Surg 21:290–297. Evaluation of postoperative diflunisal for periodontal surgery pain.
https://doi.org/10.1016/0007-117X(83)90017-3 Am J Dent 4:33–36
10. Moher D, Liberati A, Tetzlaff J, Altman D (2009) Preferred 27. Betancourt JW, Kupp LI, Jasper SJ, Farooqi OA (2004) Efficacy of
Reporting Items for Systematic Reviews and MetaAnalyses: the ibuprofen-hydrocodone for the treatment of postoperative pain after
PRISMA statement. PLoS Med 6:e1000097. https://doi.org/10. periodontal surgery. J Periodontol 75:872–876. https://doi.org/10.
7326/0003-4819-151-4-200908180-00135 1902/jop.2004.75.6.872
11. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, 28. Agarwal S, Mathu S, Kothiwale S, Benjamin A (2010) Efficacy and
Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM, acceptability of 0.074% diclofenac-containing mouthwash after
Emberson JR, Hernán MA, Hopewell S, Hróbjartsson A, periodontal surgery: a clinical study. Indian J Dent Res 21:408–
Junqueira DR, Jüni P, Kirkham JJ, Lasserson T, Li T, McAleenan 412. https://doi.org/10.4103/0970-9290.70814
A, Reeves BC, Shepperd S, Shrier I, Stewart LA, Tilling K, White 29. Mishra A, Amalakara J, Avula H, Reddy K (2017) Effect of
IR, Whiting PF, Higgins JPT (2019) RoB 2: a revised tool for diclofenac mouthwash on postoperative pain after periodontal sur-
assessing risk of bias in randomised trials. BMJ 366:l4898. gery. J Clin Diagn Res 11:ZC24–ZC26. https://doi.org/10.7860/
https://doi.org/10.1136/bmj.l4898 JCDR/2017/22165.965
12. Guyatt GH, Oxman AD, Schünemann HJ, Tugwell P, Knottnerus A 30. Rajeswari S, Gowda T, Kumar T et al (2015) An appraisal of inno-
(2011) GRADE guidelines: a new series of articles in the journal of vative meloxicam mucoadhesive films for periodontal postsurgical
clinical epidemiology. J Clin Epidemiol 64:380–382. https://doi. pain control: a double-blinded, randomized clinical trial of effec-
org/10.1016/j.jclinepi.2010.09.011 tiveness. Contemp Clin Dent 6:299–304. https://doi.org/10.4103/
13. Naseh M, Rezaiekalat S (2012) Comparison of the effects of 0976-237X.161857
celecoxib, naproxen and ibuprofen on pain control after periodontal 31. Konuganti K, Rangaraj M, Elizabeth A (2015) Pre-emptive 8 mg
surgeries. J Mash Dent Sch 35:307–314 dexamethasone and 120 mg etoricoxib for pain prevention after
14. Cantor M (1968) A comparison of propoxyphene HCl (Darvon) periodontal surgery: a randomised controlled clinical trial. J
and an analgesic mixture (Percogesic) in pain relief after gingivec- Indian Soc Periodontol 19:474–476. https://doi.org/10.4103/0972-
tomy. J Oral Ther Pharmacol 4:224–228 124X.153475
15. Gallardo F, Rossi E (1980) Double-blind evaluation of naproxen 32. Steffens JP, Santos FA, Pilatti GL (2011) The use of etoricoxib and
and ibuprofen in periodontal surgery. Pharmacol Ther Dent 5:69– celecoxib for pain prevention after periodontal surgery: a double-
72 masked, parallel-group, placebo-controlled, randomized clinical tri-
16. Giorgetti APO, De Matos R, Casarin RCV et al (2018) Preemptive al. J Periodontol 82:1238–1244. https://doi.org/10.1902/jop.2011.
and postoperative medication protocols for root coverage combined 100682
with connective tissue graft. Braz Dent J 29:23–29. https://doi.org/ 33. Steffens JP, Santos FA, Sartori R, Pilatti GL (2010) Preemptive
10.1590/0103-6440201801452 dexamethasone and etoricoxib for pain and discomfort prevention
17. Tejaswi DV, Prabhuji MLV, Shaeesta Khaleelahmed B (2014) after periodontal surgery: a double-masked, crossover, controlled
Comparative evaluation of transdermal diclofenac patch and oral clinical trial. J Periodontol 81:1153–1160. https://doi.org/10.1902/
diclofenac as an analgesic modality following root coverage proce- jop.2010.100059
dures. Gen Dent 62:68–71 34. Huskisson EC (1974) Measurement fo pain. Lancet 2:1127–1131.
18. Al-Hezaimi K, Al-Askar M, Selamhe Z et al (2011) Evaluation of https://doi.org/10.1016/s0140-6736(74)90884-8
novel adhesive film containing ketorolac for post-surgery pain con- 35. Ohnhaus EE, Adler R (1975) Methodological problems in the mea-
trol: a safety and efficacy study. J Periodontol 82:963–968. https:// surement of pain: a comparison between the verbal rating scale and
doi.org/10.1902/jop.2010.100553 the visual analogue scale. Pain 1:379–384. https://doi.org/10.1016/
19. Isler SC, Eraydin N, Akkale H, Ozdemir B (2018) Oral flurbiprofen 0304-3959(75)90075-5
spray for mucosal graft harvesting at the palatal area: a randomized 36. Jensen MP, Karoly P, Braver S (1986) The measurement of clinical
placebo-controlled study. J Periodontol 89:1174–1183. https://doi. pain intensity: a comparison of six methods. Pain 27:117–126.
org/10.1002/JPER.17-0381 https://doi.org/10.1016/0304-3959(86)90228-9
20. Popova C, Mlachkova A, Emilov D (2008) Effectiveness of 37. Melzack R, Katz J (2001) The McGill pain questionnaire: appraisal
NSAIDs Aulin and ibuprofen on the postoperative pain at gingival and current status
graft procedures - a preliminary study. J IMAB 2:12–15 38. Diwan V, Srinivasa T, Ramreddy K, Agrawal V, Nagdeve S,
21. Kashefimehr A, Babaloo A, Ghanizadeh M, Ghasemi SH, Parvez H (2019) A comparative evaluation of transdermal
Mollazadeh H (2017) Effect of prophylactic administration of diclofenac patch with oral diclofenac sodium as an analgesic drug
Novafen for periodontal surgery on postoperative pain relief. J following periodontal flap surgery: a randomized controlled clinical
Med Life 10:127–130 study. Indian J Dent Res 30:57–60. https://doi.org/10.4103/ijdr.
22. Peres MFS, Ribeiro FV, Ruiz KGS, Nociti-Jr FH, Sallum EA, IJDR-84-17
Casati MZ (2012) Steroidal and non-steroidal cyclooxygenase-2 39. Pearlman B, Boyatzis S, Daly C, Evans R, Gouvoussis J, Highfield
inhibitor anti-inflammatory drugs as pre-emptive medication in pa- J, Kitchings S, Liew V, Parsons S, Serb P, Tseng P, Wallis C (1997)
tients undergoing periodontal surgery. Braz Dent J 23:621–628. The analgesic efficacy of ibuprofen in periodontal surgery: a
https://doi.org/10.1590/S0103-64402012000600001 multicentre study. Aust Dent J 42:328–334. https://doi.org/10.
23. Cooper SA, Wagenberg B, Eskow R, Zissu J (1983) Double-blind 1111/j.1834-7819.1997.tb00139.x
evaluation of Suprofen and aspirin in the treatment of periodontal 40. Tucker PW, Smith JR, Adams DF (1996) A comparison of 2 anal-
pain. Pharmacology 27:23–30. https://doi.org/10.1159/000137896 gesic regimens for the control of postoperative periodontal discom-
24. Cooper SA, Wagenberg B, Zissu J, Kruger GO, Reynolds DC, fort. J Periodontol 67:125–129. https://doi.org/10.1902/jop.1996.
Gallegos LT, Allwein JB, Desjardins PJ, Friedmann N, Danna RP 67.2.125
(1986) The analgesic efficacy of suprofen in periodontal and oral 41. Gallardo F, Rossi E (1992) Effects of sodium meclofenamate on
surgical pain. Pharmacotherapy 6:267–276 postoperative pain following periodontal surgery. J Periodontol 63:
25. Minutello JS, Newell DH, Thrash WJ, Terezhalmy GT (1988) 166–168. https://doi.org/10.1902/jop.1992.63.3.166
Evaluation of preoperative diflunisal for postoperative pain follow- 42. Steffens JP, Santos FA, Pilatti GL (2011) Postoperative periodontal
ing periodontal surgery. J Periodontol 59:390–393 pain prevention using two dexamethasone medication protocols: a
 Clin Oral Invest

double-blind, parallel-group, placebo-controlled randomized clini- 53. Guindon J, LoVerme J, De Léan A et al (2006) Synergistic
cal trial. Am J Dent 24:354–356 antinociceptive effects of anandamide, an endocannabinoid, and
43. Gallardo F, Rossi E (1990) Analgesic efficacy of flurbiprofen as nonsteroidal anti-inflammatory drugs in peripheral tissue: a role
compared to acetaminophen and placebo after periodontal surgery. for endogenous fatty-acid ethanolamides? Eur J Pharmacol 550:
J Periodontol 61:224–227. https://doi.org/10.1902/jop.1990.61.4. 68–77. https://doi.org/10.1016/j.ejphar.2006.08.045
224 54. Arslan R, Bektas N (2018) The role of TRP and K+ ion channels in
44. Rashwan WAM (2009) The efficacy of acetaminophen–caffeine analgesic effect of NSAIDs. Clin Exp Heal Sci 8:301–307. https://
compared to ibuprofen in the control of postoperative pain after doi.org/10.5152/clinexphealthsci.2018.832
periodontal surgery: a crossover pilot study. J Periodontol 80: 55. Wong YJ, Keenan J, Hudson K et al (2016) Opioid, NSAID, and
945–952. https://doi.org/10.1902/jop.2009.080637 OTC analgesic medications for dental procedures: PEARL network
45. Pilatti GL, André dos Santos F, Bianchi A, Cavassim R, Tozetto findings. Compend Contin Educ Dent 37:710–718
CW (2006) The use of celecoxib and dexamethasone for the pre- 56. Thornhill MH, Suda KJ, Durkin MJ, Lockhart PB (2019) Is it time
vention and control of postoperative pain after periodontal surgery. US dentistry ended its opioid dependence? J Am Dent Assoc 150:
J Periodontol 77:1809–1814. https://doi.org/10.1902/jop.2006. 883–889. https://doi.org/10.1016/j.adaj.2019.07.003
060128 57. Schroeder AR, Dehghan M, Newman TB, Bentley JP, Park KT
46. O’brien TP, Roszkowski MT, Wolff L et al (1996) Effect of a non- (2019) Association of opioid prescriptions from dental clinicians
steroidal anti-inflammatory drug on tissue levels of immunoreactive for US adolescents and young adults with subsequent opioid use
prostaglandin E2, immunoreactive leukotriene, and pain after peri- and abuse. JAMA Intern Med 179:145–152. https://doi.org/10.
odontal surgery. J Periodontol 67:1307–1316 1001/jamainternmed.2018.5419
47. Trombelli L, Schincaglia GP, Zangari F, Scapoli C, Calura G 58. Sotto-Maior BS, Senna PM, Assis NMDSP (2011) Corticosteroids
(1996) Effect of pretreatment with ketorolac tromethamine on or cyclooxygenase 2-selective inhibitor medication for the manage-
post-operative pain following periodontal surgery. J Clin ment of pain and swelling after third-molar surgery. J Craniofac
Periodontol 23:128–132. https://doi.org/10.1111/j.1600-051X. Surg 22:758–762. https://doi.org/10.1097/SCS.0b013e318207f3fe
1996.tb00545.x 59. Troullos ES, Hargreaves KM, Butler DP, Dionne RA (1990)
48. Vogel RI, Desjardins PJ, Major KVO (1992) Comparison of Comparison of nonsteroidal anti-inflammatory drugs, ibuprofen
presurgical and immediate postsurgical ibuprofen on postoperative and flurbiprofen, with methylprednisolone and placebo for acute
periodontal pain. J Periodontol 63:914–918. https://doi.org/10. pain, swelling, and trismus. J Oral Maxillofac Surg 48:945–952.
1902/jop.1992.63.11.914 https://doi.org/10.1016/0278-2391(90)90007-O
49. Schirmer C, dos Santos GO, Rost JF, Ferreira MBC, Weidlich P 60. Fernandes IA, de Souza GM, Pinheiro MLP, Falci SGM (2019)
(2018) Factors associated with pain and analgesic consumption Intramuscular injection of dexamethasone for the control of pain,
following non-surgical periodontal therapy under local anaesthesia swelling, and trismus after third molar surgery: a systematic review
and carried out by dental students. J Clin Periodontol 45:68–77. and meta-analysis. Int J Oral Maxillofac Surg 48:659–668. https://
https://doi.org/10.1111/jcpe.12833 doi.org/10.1016/j.ijom.2018.09.014
50. West NX, Lussi A, Seong J, Hellwig E (2013) Dentin hypersensi- 61. Tieppo Francio V, Davani S, Towery C, Brown TL (2017) Oral
tivity: pain mechanisms and aetiology of exposed cervical dentin. versus topical diclofenac sodium in the treatment of osteoarthritis. J
Clin Oral Investig 17:S9–S19. https://doi.org/10.1007/s00784-012- Pain Palliat Care Pharmacother 31:113–120. https://doi.org/10.
0887-x 1080/15360288.2017.1301616
51. Burian M, Geisslinger G (2005) COX-dependent mechanisms in- 62. Yaghini J, Abed AM, Mostafavi SA, Roshanzamir N (2011) The
volved in the antinociceptive action of NSAIDs at central and pe- effect of diclofenac mouthwash on periodontal postoperative pain.
ripheral sites. Pharmacol Ther 107:139–154. https://doi.org/10. Dent Res J (Isfahan) 8:146–149. https://doi.org/10.7860/JCDR/
1016/j.pharmthera.2005.02.004 2017/22165.965
52. Cashman JN (1996) The mechanisms of action of NSAIDs in an-
algesia. Drugs 52(Suppl):5–23. https://doi.org/10.2165/00003495- Publisher’s note Springer Nature remains neutral with regard to jurisdic-
199600525-00004 tional claims in published maps and institutional affiliations.