| |

Received: 13 January 2019    Revised: 26 May 2019    Accepted: 28 May 2019

DOI: 10.1111/joor.12827

REVIEW

Placebo and nocebo response magnitude on

temporomandibular disorder‐related pain: A systematic review
and meta‐analysis

André Luís Porporatti1  | Yuri Martins Costa2  | Jéssica Conti Réus3 |

Juliana Stuginski‐Barbosa4  | Paulo César Rodrigues Conti4 | Ana Míriam Velly5  |
1
Graziela De Luca Canto

1
Brazilian Centre for Evidence Based
Research, Dentistry Department, Federal Abstract
University of Santa Catarina, Florianópolis, Objectives: The aim of this systematic review (SR) was to answer the following ques-
Brazil
2 tion: “In adult patients with temporomandibular disorder (TMD)‐related pain, what is
Section of Head and Face Physiology,
Department of Biological Sciences, Bauru the placebo or nocebo effect of different therapies?”
School of Dentistry, University of São Paulo,
Methods: A SR was performed with randomised clinical placebo‐controlled trials on
Bauru, Brazil
3
Dentistry Department, Federal University
diagnosed painful TMD studies from five main databases and from three grey lit-
of Santa Catarina, Florianópolis, Brazil erature. Studies included must have sample older than 18 years, with painful TMD,
4
Department of Prosthodontics, Bauru which diagnosis was done by Research Diagnostic Criteria (RDC/TMD) or Diagnostic
School of Dentistry, University of São Paulo,
Bauru, Brazil Criteria (DC/TMD).
5
Faculty of Dentistry, McGill University, Results: Out of 770 articles obtained, 42 met the inclusion criteria for qualitative and
Montreal, Quebec, Canada
26 for quantitative analysis. Meta‐analysis indicated mean variation on pain intensity
Correspondence for placebo therapy was higher on laser acupuncture with 45.5 mm point reduction,
André Luís Porporatti, Brazilian Centre for
followed by avocado soya bean extract with 36  mm and amitriptyline 25  mg with
Evidence Based Research, Health Sciences
Center, Department of Dentistry, Federal 25.2  mm. Laser showed a 29% of placebo effect, as well medicine with 19% and
University of Santa Catarina, Campus
other therapies with 26%. Possible nocebo effect of 8% pain increase was found for
Universitário Caixa Postal 476—Trindade,
Florianópolis, Santa Catarina 88040900, intra‐articular injection of Ultracain.
Brazil.
Conclusions: Based on the available data, the placebo response could play a major
Emails: andreporporatti@yahoo.com.br;
andre.porporatti@ufsc.br effect on TMD pain management and may be responsible from 10% to 75% of pain
relief. Laser acupuncture, avocado soya bean and amitriptyline promoted the higher
placebo effect. Possible nocebo effect was found only for Ultracain injection with
8%.
Clinical Relevance: Clinicians could apply such evidence to optimise pain manage-
ment and judgement about treatment efficacy, and researches may find it useful
when designing their investigations.

KEYWORDS
adults, nocebo effect, pain, placebo effect, systematic review, temporomandibular disorders

862  | © wileyonlinelibrary.com/journal/joor

2019 John Wiley & Sons Ltd J Oral Rehabil. 2019;46:862–882.
PORPORATTI et al.
1 | I NTRO D U C TI O N
Temporomandibular disorder (TMD) is an umbrella term, embracing
conditions that involve the temporomandibular joint (TMJ) and/or
the masticatory muscles and the associated structures. Minimally 1 quantitative methods such as visual analogue scale (VAS), Numerical
invasive strategies are well‐established therapeutic proposals, and
they show solid scientific evidence of reduction in the intensity of
masticatory muscle and/or TMJ pain. 2 tions were applied on search strategy nor on the inclusion criteria.
Currently, numerous therapies for TMD are indicated and may
include medications, physiotherapies, speech therapy, cognitive‐be-
havioural therapy, occlusal splints, acupuncture, dry needling and/
or infiltrations. 3-9
Obviously, health professionals seek success with
these therapies and effective patient improvement. However, the
success of any therapy is not solely based on the technical and bio-
logical aspects, but also the social, environmental and psychosocial
factors should be taken into account. These factors are known as
non‐specific effects of treatment. 10,11
Among them, the placebo ef-
fect has been increasingly studied. 11
Placebo effect is the response from a sham therapy or a phe-
nomenon in which the patient improves his health after receiving a
“medical treatment” that in fact does not have any active substance
recognised by the physician.11,12 Placebos and sham therapies are
indicated in randomised clinical trials (RCTs), in comparison with an
“authentic” drug, device, procedure or behavioural technique, and
are commonly required to ascertain therapy efficacy. 11,13
On the
other hand, the nocebo effect is the worsening of a disease that can
occur after the administration of a placebo.14
Based on brain imaging studies, the placebo effect on pain reduc-
tion is a real and biologically measurable phenomenon. The placebo
effect can be pharmacologically blocked and behaviourally amplified,
with responses resemble opioid analgesia, as the antagonising effect of
naloxone. 15
In addition, the psychological mechanisms involved in pla-
cebo analgesia may include Pavlov's expectation and conditioning. 11,15
To the best of our knowledge, there is no systematic review and
meta‐analysis aimed to measure the magnitude of placebo effect on
TMD management. Therefore, based on these premises, the aim of
this meta‐analysis was to answer the following question: “In adult
patients with TMD‐related pain, what is the placebo or nocebo ef-
fect of pain therapies?.”
2 | M E TH O DS
2.1 | Protocol and registration
This systematic review conformed to Preferred Reporting Items for
Systematic Reviews and Meta‐Analysis PRISMA Checklist. 16
The
protocol was registered in the International Prospective Register of
Systematic Reviews (PROSPERO) under number CRD42017057770. 17
2.2 | Eligibility criteria
We included placebo‐controlled RCTs published with available
results, including only adults (18‐65  years old) with diagnosed
|
      863
TMD‐related pain. TMD should be assessed through Research
Diagnostic Criteria (RDC/TMD)18 or Diagnostic Criteria (DC/TMD).1
Studies may comprise patients with painful TMD from TMJ and/or
masticatory muscles. Assessment of pain could be with the aid of
Rating Scale (NRS) or Numerical Analogue Scale (NAS), or other
validated reported pain intensity scale. No sex or language restric-
Database searches started in 1992, based on the year of RDC/TMD
publication.18
The exclusion criteria encompassed the following: (a) no target
condition; (b) studies that included subjects under 18 years old and
elderly over 65 years old; (c) subjects with no painful TMD; (d) studies
using diagnostic tool other than the RDC/TMD or DC/TMD; (e) no
randomised placebo‐controlled; (f) reviews, letter, case reports, case
series; (g) studies assessing comorbidities as bruxism, fibromyalgia,
migraine and other headaches, otalgia, apnoea, arthritis rheumatoid;
(h) studies evaluating pain management modalities on surgical pro-
cedures (infiltrations after arthroscopy or arthrocentesis); (i) studies
with same sample used in other paper; and (j) full paper not available.
2.3 | Information sources and search
Detailed individual search strategies were developed for each
bibliographic electronic database: Cochrane, Latin American and
Caribbean Health Sciences (LILACS), PubMed (including Medline),
Scopus and Web of Science. A grey literature search was performed
on Google Scholar, Open Grey and ProQuest. The search strategy
was coordinated by an experienced librarian; the search was per-
formed by the first author and cross‐checked by the second one.
All database searches were conducted from the starting coverage
date through 11 December 2018. More information on the search
strategies was provided in Table S1 (which can be found online).
Furthermore, the authors hand‐searched the reference lists of the
selected articles for any additional references that might have been
missed in the database searches. All references were managed, and
the duplicated hits were removed by a reference manager software
(EndNote X7® Basic‐Thomson Reuters, New York, EUA).
2.4 | Study selection and data collection process
This part followed a two‐phase process. In phase 1, two authors
(ALP and YMC) independently evaluated the titles and abstracts of
all identified electronic database citations. In phase 2, the same au-
thors evaluated full‐text data from articles included from phase 1.
They independently screened paper on phases 1 and 2, applied the
same eligibility criteria, collected key information from the selected
studies and cross‐checked the information. The final selection was
based solely on full‐text assessment of the studies. When disagree-
ment appears, a third author (JSB) was involved to make a final deci-
sion about the inclusion or exclusion of studies.
For each of the included studies, these features were recorded
as follows: author(s), year of publication, country, sample size,
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864       PORPORATTI et al.

F I G U R E 1   Flow diagram of literature search and selection criteria

demographic features of the sample (n, mean age and standard devi- complete, the reviewers (ALP and JCR) attempted to contact the
ation, percentage of women), TMD diagnostic method and subtypes, study authors to retrieve any unpublished information. Three at-
information about active and placebo therapy, pain measurement, tempts were made in a 30 days’ period, by email for the first, second
results and main conclusions. When the required data were not and last author.
PORPORATTI et al.
2.5 | Risk of bias in individual studies
The methodological quality of the included RCT was evaluated
through the Cochrane Collaboration's tool for assessing risk of
bias.19 Briefly, the quality criteria were based on the randomisa-
tion and allocation methods, the completeness of the follow‐up
period, examiners blinding, selective reporting and other forms of
bias. Two reviewers (ALP and JCR) scored each item as “yes,” “no”
or “unclear,” and classified independently the quality of each in-
cluded study as “high,” “low” or “unclear” risk of bias. The same two
reviewers worked out on any differences regarding data analysis. A
third author (JSB) was involved to steer decision in case of uncer-
tainty. Following these answers, the risk of bias was categorised
according to: (a) low risk of bias, if all criteria were met, (b) unclear
risk of bias, if one or more criteria were not described exactly how
was met, and (c) high risk of bias, if one or more criteria were not
met. Figures of the quality assessment of all included studies were
generated with Review Manager 5.3 (RevMan 5.3; The Nordic
Cochrane Centre).
2.6 | Study outcomes and summary measures
We considered the results from absolute and relative differences in
pain intensity after different therapies. Any type of outcome meas-
urement was considered. Authors tried to standardise the measure-
ments in mean and standard deviation (SD) at baseline and after
therapy, for active or placebo one.
2.7 | Synthesis of results
Statistical pooling of data using meta‐analysis was planned when-
ever trials were considered combinable and relatively homogeneous
in relation to design, interventions and outcomes. Heterogeneity
within studies was evaluated either by using considering clinical
(differences about participants, type of interventions and results),
methodological (design and risk of bias) and statistical characteris-
2
tics (effect of studies) or by using inconsistency index (I ) statistical
test.
To measure the placebo or nocebo effect on altering pain from
different therapies in diagnosed painful TMD, a meta‐analysis
was performed with the aid of 5.3.5 version of Review Manager
software (Nordic Cochrane Center, Copenhagen, Denmark) for
continuous data following the appropriate Cochrane Guidelines.19
Inverse variance was the statistical method, and the main differ-
ence was the effect measure. Numerical Scales or VAS from 0 to
10 cm was transformed to a VAS from 0 to 100 mm. On analysis
model, fixed or random effect was based on heterogeneity values.
Heterogeneity was calculated by I2 , and a value greater than 50%
was considered an indicator of substantial heterogeneity between
studies, and the choice for random effect was preferred. The
significance level was set at 5%.19 As secondary outcome, num-
ber needed to treat (NNT) for 50% pain intensity reduction was
computed.
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2.8 | Risk of bias across studies
The risk of bias across studies was regarded to an overall risk; the
study results may present, which could influence meta‐analysis data.
Methodological and statistical heterogeneity were evaluated by
comparing the variability in study design and the risk of bias.
3 | R E S U LT S
3.1 | Study selection
The initial database search identified 1377 studies. After elimi-
nating duplicating hits, 770 studies remained; 663 of them were
excluded after title and abstract revision, resulting in 110 articles.
Furthermore, 617 studies were found on Google Scholar, 16 on
Open Grey and 640 on ProQuest. Two of them, one from Google
Scholar and one from ProQuest were selected for full‐text read-
ing. No additional studies were selected from hand search of
reference list of the included studies. Thus, 112 studies became
part of phase 2. During phase 2, a total of 70 studies were ex-
cluded (reasons for exclusion may be seen in Table S2). Forty‐two
studies were included for qualitative synthesis and 26 for quan-
titative synthesis. Sixteen studies were not included for quanti-
tative synthesis mainly because standard deviation values were
not completed on the paper, and after three attempts to contact
the authors, data were not presented. A flow chart of the process
of identification, inclusion and exclusion of studies is shown in
Figure 1.
3.2 | Study characteristics and results of
individual studies
Out of the 42 RCTs, sample size ranged from 1320 to 9921 with a total of
1657 patients, mostly women, that is from 4722 up to 100%23-31 of the
sample. Studies were conducted in Brazil,23,26,28,30,32-39 Canada,24,40
China,41 Croatia,20 Denmark,42-44 India,45 Iran,29,46 Italy,21 Korea,22
Poland,47 Spain,48 Sweden,49-51 Thailand,52 the Netherlands,53
Turkey,54-56 United Kingdom57 and United States of America
(USA).25,27,31,58-61 All studies were published in the English language.
Temporomandibular disorder diagnostic method for almost all
studies was RDC/TMD; only three used DC/TMD. 22,27,37 TMD di-
agnostic englobed myofascial pain (groups I.a and I.b) mentioned in
sixteen studies, arthralgia (III.a) in ten studies, osteoarthritis (III.b)
in six studies, osteoarthrosis (III.c) in four studies and disc displace-
ment (II.a, II.b and II.c) in four studies. Furthermore, some studies
classified TMD on muscular TMD in 15 studies and articular TMD
in two studies. Table 1 summarises the descriptive characteristics of
the included studies.
3.3 | Risk of bias in individual studies
Risk of bias was very heterogeneous among studies. Using Cochrane
Collaboration's tool, nine studies were classified as low risk of bias, 22
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866       PORPORATTI et al.

TA B L E 1   Summary of descriptive characteristics of included articles (n = 42)

Author Sample (n) TMD Diagnostic

Year Mean age (SD) Active therapy sample Placebo therapy method and
Group Country %fem (n/%fem) sample (n/%fem) subtypes Information about active therapy

Hypnosis Abrahamsen 39 19 20 RDC/TMD 4 one‐hour sessions, hypnotic induction

et al, 2011 38.6(10.9) yo NR NR Myofascial pain followed by progressive relaxation;
Denmark NR (Iab) 7d

Laser Ahrari et al, 20 10 10 RDC/TMD 12 sessions pulsed 810‐nm laser 80 W, average
2014 35.5 yo 100% 100% Myogenic TMD power of 50 mW, effective energy og 6 J and
Iran 100% dose of 3.4 J/cm2

Radio frequency Al‐Badawi et 40 20 20 RDC/TMD Pulsed Radio Frequency Energy, once every
al, 2004 22‐55 yo Arthralgia other day for 2 wk (six sessions)
USA 77.5%

Medicine Alajbeg et al, 13 AMP 25 mg: 4 4 RDC/TMD 25 mg of amitriptyline and stabilisation splint.
(Amitriptyline) 2018 NR 57.25 ± 8.13 46.5 ± 18.15 Muscle‐related Baseline (T0), 1st week (T1), 6th week (T2)
Croatia NR NR and/or joint‐ and 12th week (T3).
Splint: 5 related TMD
42.8 ± 12.45
NR

Intra‐articular Ayesh et al, 18 Cross section (same   RDC/TMD Ketamine 0.2 mL, 10 mmol/L = 0.55 mg
ketamine 2008 26.5 +‐ 1.4 yo subject received both Arthralgia
Denmark (20‐39) therapies)
83.3%

Medicine Cahlin et al, 59 30 29 RDC/TMD 400 mg Glucosamine sulphate, three capsules

(glucosamine) 2011 51 fem (60 +‐ 25 fem (61 +‐ 16 yo) 26 fem (58 +‐ 9 yo) Osteoarthritis on a daily basis for 6 wk (126 capsules)
Sweden 13 yo) 5 men (61 +‐ 9 yo) 3 men (49 +‐ 11
8 men (57+‐11 yo)
yo)

Medicine (amitrip- Calderon et al, AMP 25 mg: 11 AMP 25 mg: 32.4 (9.5) Placebo and CBT: RDC/TMD One tablet at bedtime for seven consecutive
tyline) and cogni- 2011 AMP 25 mg AMP 25 mg and CBT: 38.2 (11.1); and Muscle‐related weeks. For the groups that also received CBT,
tive‐behavioural Brazil and CBT: 12; 36.7 (13.6) placebo only: and/or joint‐ the same protocol was used in combination
therapy placebo and 34.5 (11.0) related TMD with weekly 90 min CBT sessions for 7 wk,
CBT: 11; and conducted by PhD‐level psychologists.
placebo only: Evaluations at 1 wk; 7 wk at the end of the
13 treatment; and 11 wk

Muscular ketamine Castrillon et 10 female Cross section (same Cross section RDC/TMD 2 sessions (separated by an interval of
al, 2008 (28.7 ± 2.0 yo) subject received both (same subject Myofascial TMD 12.2 ± 1.9 d), in which they received either
Denmark 4 male therapies) received both (1a or 1b) a single injection of 0.2 mL of ketamine
(26.3 ± 2.5 yo) therapies) (Ketalar 10 mmol/L; ~pH 7.0; Park Davis)
into the deep masseter muscle

Avocado soya bean Catunda et al, 14 7 7 RDC/TMD unsaponifiable oil extract consisting of 200 mg
unsaponifiable 2016 NR 43.14 (15.34) yo 42.85 (14.55) yo Arthralgia (IIIa), of soya bean oil and 100 mg of avocado oil in
extract Brazil 100% 100% 100% Osteoarthritis capsule form (Flexi‐Smart 300 mg)
(IIIb), and one capsule daily for four consecutive months
Osteoarthrosis
(IIIc)

Ozone therapy Celakil et al, 40 20 20 RDC/TMD Ozone generator was emitted electromagnetic
2017 317 84 yo 33 (9.66) 30.5 (7.02) Myofascial pain field and transform oxygen into ozone.
Turkey 100% 100% 100% This noble gasses were transmitted to the
treated area with glass omega probe (7.5 cm
deep tissue probe)
3 treatment sessions per week for 10 min for
2 wk (total, six sessions).
baseline, 1 and 3 mo

Tender point Christidis et 40 20 20 RDC/TMD 0.5 mL Granisetron (KYTRIL®; 1 mg/mL,

injections of al, 2015 NR 38.3 (15.1) yo 39.1 (16.1) yo Myofascial TMD Roche, Stockholm, Sweden)
granisetron Sweden 92.5% 90% 95% (1a or 1b) The injections were repeated after 1‐ and 2‐wk
in the most painful tender‐points at that time
6 mo follow‐up

Medicine DeNucci et al, 18 women Cross section (same Cross section RDC/TMD 2‐wk period
(Triazolam) 1998 and 1 man subject received both (same subject Muscle pain Using drug for four nights (0.125 mg)
USA (39.2 ± 9.7 yo) therapies) received both without limited
94.7% therapies) opening (Ia) and
Muscle pain with
limited opening
(Ib)
PORPORATTI et al. |
      867

Information about
placebo therapy Pain measurement Results Main conclusion

4 one‐hour sessions, CPI (average of 3 NRS CPI was reduced by 47.4% on active therapy and Reduction in daily TMD pain intensity after Hypnosis was
relaxation and visuali- scores from 7 d before 3.8% on placebo. presented.
sation of comfortable and after therapy)
safe place;
7d

NR VAS There was a 50% pain reduction in masseter body No significant difference between laser and placebo regarding
and 73% in masseter insertion on active therapy. pain.
There was a 24% reduction in masseter body and
9% in masseter insertion on placebo therapy.

Placebo Pulsed Radio NRS Mean difference from baseline was 3.07 in active A significant pain reduction in pain occurred in both active and
Frequency Energy, group and 1.15 in control. placebo.
once every other day
for 2 wk (six sessions)

Placebo pill of the same VAS 0‐100 Pain decreased continuously over time in amitrip- Amitriptyline and stabilisation splint may be effective in decreas-
size and appearance tyline group and in stabilisation splint group. In ing the intensity of pain in patients with chronic TMD.
placebo group, VAS did not change significantly
over the treatment period.

Saline 0.2 mL sodium VAS The pain upon jaw opening did not change over time There appears to be no rationale to use intra‐articular ketamine
chloride 9 mg/mL or between therapy. injection.

NR VAS There was a pain reduction over time; however, this It is not possible to determine whether glucosamine modifies the
VRS was not different between therapies. long‐term progress of Osteoarthritis. Even if some improve-
ments over time were observed, the differences in the magni-
tude of responses between the active and placebo therapies
were not large enough.

NR VAS There were no significant differences in the VAS The association between amitriptyline and CBT may be effective
scores of the four groups at baseline and 11 in reducing pain and depression levels, as well as in improving
wk after the beginning of treatment. One week the quality of life and sleep in chronic patients with TMD.
after the beginning of treatment, those receiving
amitriptyline and CBT and those receiving only pla-
cebo and CBT had VAS scores significantly higher
than the other groups.

Buffered isotonic saline NRS, VAS AUC, VAS mean, There were no significant differences in these There were no major effects of the local injection of ketamine on
NaCl 155 mmol/L, and VAS peak values parameters between the ketamine and placebo masseter muscle pain. The current findings do not support the
Alcon Lab) into the sessions. treatment of chronic myofascial TMD pain patients with local
deep masseter muscle injections of ketamine. The current findings do not support the
treatment of chronic myofascial TMD pain patients with local
injections of ketamine.

capsules containing VAS 0‐10 Significant reduction in the VAS pain score was Effectiveness of an avocado soya bean unsaponifiable extract in
10 mg of starch. The found in both groups beginning at 30 d. A signifi- patients with degenerative joint diseases and arthralgia in the
placebo capsules cant difference between the two groups was found TMJ.
were identical to the only at 120 d, favouring the ASU group.
active capsules in
shape, size, and colour

Ozone device was VAS 0‐10 VAS scores were significantly lower than Ozone therapy showed positive effects in managing pain caused
switched on, but not Placebo during sessions. by TMD.
programmed.

Isotonic saline (NaCl; VAS 0‐100 At the 1‐mo follow‐up 80% of the patients in active Granisetron has a clinically relevant pain reducing effect, both in a
0.9 mg/mL, Fresenius and 55% in placebo group reported a reduction of short‐ and long‐term aspect, in patients with chronic Myofascial
Kabi, Uppsala, 30% in weekly pain intensity. At the 2‐mo follow‐ TMD.
Sweden) up these frequencies were 60% and 30%.
At 6‐mo follow‐up 35% and 10%, respectively.

  Pain Scale (0‐20) Pain as measured by pressure algometry over the
two painful sites also was similar under both drug
and placebo treatment.
The mean daily pain diary scores did not differ
across treatments for either pain intensity or its
affective component.
Relatively short duration of drug administration in the present
study (four nights)
would not have detected a possible beneficial effect occurring
with a longer duration trial of triazolam.

(Continues)
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868       PORPORATTI et al.

TA B L E 1   (Continued)

Author Sample (n) TMD Diagnostic

Year Mean age (SD) Active therapy sample Placebo therapy method and
Group Country %fem (n/%fem) sample (n/%fem) subtypes Information about active therapy

Brain modulation Donnell et al, 24 12 12 RDC/TMD 5 daily sessions of either active HD‐tDCS. A
2015 35.2 (15.0) yo 34.8 (13.7) yo 35.6 (16.7) yo Myofascial TMD modified 2 × 2 HD‐tDCS montage was
USA 100% (1a or 1b) developed and used, with four electrodes
arranged at the corners of a 4 cm 4 cm square
centred over the caudal portion of the
putative M1, where the homuncular head and
facial region is represented

Botulinum toxin Ernberg et al, 21 Cross section (same Cross section RDC/TMD BTX‐A was prepared by dissolving 100 U of
type A 2011 38 (12) yo subject received both (same subject Myofascial pain, freeze‐dried BTX‐A (Botox; supplied by
Sweden 90.5% therapies) received both Arthralgia, Allergan Norden AB, Upplands Väsby,
therapies) Osteoarthrosis, Sweden) into 1.0 mL of room temperature
DD, and sterile isotonic saline. This was performed
Osteoarthritis immediately before injection

Laser acupuncture Ferreira et al, 40 20 20 RDC/TMD The dental laser therapy equipment used was
2013 34.17 (8.83) yo 32.2 (8.2) yo 36.2 (9.3) yo Myofascial pain the TWIN FLEX II (MM Optics, São Carlos,
Brazil 100% 100% 100% and Arthralgia SP, Brazil), in the infrared spectrum (780 nm),
with a power of 50 mW and an irradiation
time of 90 s per acupoint, in an area of 0.04
cm2, defining the energy of 4.5 J, total
irradiance of 1250 W/cm2, and total energy
density of 112.5 J/cm2. Acupoint stimulation
was repeated weekly over 12 sessions

TENS Ferreira et al, 40 20 20 RDC/TMD TENS device used was model Neurodyn
2017 75% 24.15 (3.01) 25.10 (3.87) Myofascial TMD Sapphire Compact Line, by Ibramed®,)
Brazil 75% 75% (1a or 1b) The total time of treatment was 50 min using
variations of low and high frequency (VHF),
VHF), with a sweep of 4 Hz and 100 Hz.

Medicine Herman et al, 41 Clo: 13 15 RDC/TMD Clo: 0.5 mg daily

(Clonazepam & 2002 80.48% 26.9 (10.1) yo 24.0 (4.8) yo TMJ Arthralgia Cicl: 10 mg daily. The capsules were
Cyclobenzaprine) USA 84.6% 93.3% formulated to have the same appearance,
Cicl: 13 and all subjects took one capsule 1 h before
30.3 (8.6) yo bedtime during the 3‐wk intervention
61.5% All subjects, including the placebo group,
received patient education consisting of
explanations of TMD and MFP, and a self‐care
programme

Phototherapy Herpich et al, 60 Group 1—2.62 J; 15 15 RDC/TMD Phototherapy was administered to the anterior,
2018 18‐40 yo NR NR Myofascial TMD middle, and posterior temporal muscle, as
Brazil 100% 100% 100% (1a or 1b) well as the upper and lower masseter muscles
Group 2 —5.24 J; 15 bilaterally in all groups, totalling 10 points on
NR each volunteer with a radiance area of 4 cm2
100% per point.
Group 3—7.86 J 15 Radiance time in each time point of application
NR was 20 s (Group 1), 40 s (Group 2), or 60 s
100% (Groups 3 and 4), with energy per quadrant
of 2.62 J (Group 1), 5.24 J (Group 2), 7.86 J
(Group 3))
Pre‐intervention, immediately after, 24 and
48 hours after phototherapy.

Ultrasound Hussain et al, 16 8 8 DC/TMD Ultrasound 0.4 W/cm2 100%

2018 21‐63 yo 35.9 (10.3) 39.4 (12.9) Bilateral myalgia
USA 100% 100% 100% of the masseter
muscles

Intramuscular Kang et al, 51 Morphine 1.5 mg mas- Saline masseter DC/TMD Morphine sulphate (BCworld, Korea) at 1.5 mg
morphine 2018 29 (6.3) yo for seter 13 11 Myalgia pain or 5 mg, or lidocaine HCl (2%/20 ml, Huons,
Korea women 38.4% 45.4% Korea).
28 (8.5) yo for morphine 5 mg masseter
men 11
47% 54.5%, lidocaine mas-
seter 11
45.4%
morphine 5 mg trapezius
5
60%
PORPORATTI et al. |
      869

Information about
placebo therapy Pain measurement Results Main conclusion

Sham HD‐tDCS VAS More participants in the active HD‐tDCS group Stimulation was effective for improving short‐term, highly selec-
compared to controls experienced pain relief, as tive sensory discriminative and motor clinical TMD measures
defined by VAS decrease of 50% or greater from compared to sham group.
week one (baseline) to week 6, with nine high
responders in the active group compared to four in
the sham group.

A total of 1.0 mL of VAS 0‐100 At 1‐mo follow‐up, average per cent pain reduction BTX‐A is not efficacious as an adjunct to conservative treatment
isotonic saline after BTX‐A (mean and SD) was 30 (33%) and in patients with persistent myofascial TMD pain.
after saline 11 (40%). At the 3‐mo follow‐up, pain
reduction was 23 (30%) after BTX‐A and 4 (33%)
after saline.

For the placebo VAS Most of the patients in active therapy (n ≥ 16) Laser acupuncture was efficient in obtaining complete remission
laser acupuncture, achieved total remission of symptoms. In the pla- of the symptoms of temporomandibular and myofascial pain
researchers used the cebo therapy (n ≥ 12), most only achieved a partial after 3 mo of treatment and promoted greater and faster reduc-
same specific pointer reduction of symptoms. tion of the symptoms in comparison with the placebo.
for laser acupuncture,
which remained on
the acupoint for the
same period of 90 s,
without the use of
radiation

Placebo equipment VAS 0‐100 No between‐group difference was found in the VAS Short‐term therapeutic effects of TENS are superior to those
allowed the passage values at any assessment time. However, there was of the placebo, because of the reported facial pain, deep pain
of current to the a significant decrease in VAS values at T1 and T2, sensitivity and masticatory muscle EMG activity improvement.
participant for only a when compared to T0 only in active group.
short period of time
(40 seconds). The
current was gradually
reduced in such a
way that the receiver
would not be able to
perceive the interrup-
tion in the stimulus.

Lactose filler VAS 0‐1 Patients who received cyclobenzaprine in addition Cyclobenzaprine is more effective than clonazepam or a placebo
to patient education and the self‐care programme when given in addition to patient education and a home self‐care
experienced a decrease in jaw pain from a baseline programme for the management of jaw pain upon awakening.
mean score of 0.62 to 0.17, or a 72.7% decrease.
Patients who received clonazepam in addition to
the non‐pharmacologic intervention decreased
from a mean jaw pain of 0.48 to 0.28, or a 40.1%
decrease. Patients in group 2 who received the pla-
cebo performed similarly, decreasing from a mean
jaw pain of 0.50 to 0.30, a 40.2% improvement.

0 J (placebo group) VAS 0‐10 A significant reduction in pain intensity during the A single session of combined phototherapy was capable of reduc-
post‐treatment evaluations in comparison to the ing pain intensity in individuals patients with TMD.
pre‐treatment evaluation was observed in group 1
and group 2 especially after 48 hours and group 3
especially after 24 hours,
In Group placebo, the reduction in pain in com-
parison to the pre‐treatment VAS score was only
statistically significant at the 24‐h evaluation.

Sham ultrasound VRS Changes in pain intensity did not show a significant Ultrasound may be more beneficial to sham ultrasound for the
difference between groups. There was a significant treatment of bilateral masseter myalgia.
increase in pressure pain threshold of the masseter
in the ultrasound group.

Saline (NaCl VAS 0‐100 There was a significant difference in VAS scores A single dose of intramuscular morphine produced analgesic ef-
9 g/1000 mL, JW between the morphine 5 mg group and the saline fects up to 48 hrs in patients with myofascial pain
Pharmaceutical, group favouring morphine, but not between the
Korea), morphine 5 mg and lidocaine.

(Continues)
 |
870       PORPORATTI et al.

TA B L E 1   (Continued)

Author Sample (n) TMD Diagnostic

Year Mean age (SD) Active therapy sample Placebo therapy method and
Group Country %fem (n/%fem) sample (n/%fem) subtypes Information about active therapy

Medicine Kimos et al, 36 19 17 RDC/TMD Started on 300 mg per day and the dose was
(Gabapentin) 2007 33.58 yo 100% 100% Chronic mastica- increased by 300 mg every 3 d until pain was
Canada 100% tory myalgia controlled with no adverse effects. The
maximum dose was 4200 mg.
12 wks of therapy.
The mean dose was 3315.78 mg/d at week 12

Percutaneous nee- Lopez‐Martos 60 PNE Sham needling RDC/TMD PNE

dle electrolysis et al, 2018 20 procedure (SNP) Myofascial TMD length 40 mm/ calibre 0.25 mm, with a
(PNE) and deep Spain 38.5 (18‐57) 20 (1a or 1b) cylindrical plastic guide
dry needling 75% 42 (25‐62) Procedures were performed once per week for
(DDN) DDN 95% three consecutive weeks. Clinical evaluation
20 was performed before treatment, and on days
36 (19‐58) 28, 42 and 70 after treatment.
90%

Laser Madani et al, 20 10 10 RDC/TMD low‐level laser emitting a pulsed infrared beam
2014 35‐60 yo NR NR TMJ osteoarthritis of 810 nm wavelength (Mustang 2000z,
Iran 95% Moscow, Russia). The laser was applied in
contact mode with a peak power of
approximately 80 W, 50 mW average power
at a pulse repetition rate of 1500 Hz, pulse
length of 1 ms, 6 J per point, 3.4 J/cm2, and
spot size 1.76 cm2, for 2 min per point.
Therapy three times a week for 4 wk, totalling
12 sessions.

Laser Magri et al, 91 31 30 RDC/TMD A GaAlAs laser

2017 NR 38.45 (12.56) yo 38.87 (10.88) yo) Myofascial TMD Points: the masseter (three points: upper,
Brazil 100% 100% 100% (1a or 1b) middle, and lower), the anterior temporal
(three points: upper, middle, and lower), and
the TMJ region
wavelength = 780 nm (near infrared); distance
between the points of application = 1 cm;
spot area = 0.034 cm2; for masseter and
anterior temporal: energy density = 5 J/cm2,
laser optical power = 20 mW, and time per
point = 10 s; and for the TMJ area: energy
density = 7.5 J/ cm2, laser optical power = 30
mW, and time per point = 10 s

Laser & NSAIDs Marini et al, 99 Laser: 39 30 RDC/TMD Laser: gallium‐arsenide diode superpulsed
2010 15 to 50 yo 41.93 (11.51) 35.90 (6.84) DD without laser, (LUMIX 2 HFPL Fisioline, Verduno, Italy)
Italy 74.74% 71.79% 73.33% reduction, with time pulsation < 200 ns; frequency
NSAIDs: 30 Osteoarthritis, range 1 to 50 kHz, wavelength 910 nm, mean
36.23 (11.30) Intra‐articular power 400 mW, and peak power 45 W. The
80% effusion affected TMJ areas of these patients were
treated daily in three steps (1. 20 kHz for
10 minutes; 18 kHz for 5; minutes; 16 kHz for
5 min). All patients were treated for 10
consecutive days (5 days/wk) in right and left
TMJ.
NSAIDs: 800 mg twice a day of ibuprofen
for 10 d

Bee venom Nitecka‐ 68 34 34 RDC/TMD 0.0005% bee venom ointment for topical skin
Buchta et al, 23 (22‐34 yo) NR NR Myofascial TMD application in region of masseter muscle at
2014 82.35% 88.23% (1a or 1b) the right and left side.
Poland Patients were supposed to massage their
masseter muscles three times a day for 2 wk

Botulinum toxin Nixdorf et al, 15 Cross section (same Cross section RDC/TMD A total volume of 0.2 cm3 was injected three
it A 2002 33 (18‐45) yo subject received both (same subject Myofascial TMD times into each temporalis and masseter
Canada 100% therapies) received both (1a or 1b) muscle. 25 units of 0.6 cm3 was divided
Only 10 therapies) evenly over the three injection sites of each
patients temporalis muscle and 50 U of 0.6 cm3 was
completed the divided evenly over the three injection sites of
entire study, each masseter muscle
while five
dropped out

Upper thoracic Packer et al, 32 16 16 RDC/TMD Upper thoracic manipulation technique was
manipulation 2014 18‐40 yo 23.5 (21.3‐25.6) yo 26.0 (22.6‐29.4) yo Myofascial TMD applied to the T1 vertebral segment
Brazil 100% 100% 100% (1a or 1b) The therapist placed a stabilising hand in pistol
grip at the level caudal to the segment to be
manipulated (T2), pushing the volunteer’s
arms down to flex the upper thoracic spine
PORPORATTI et al. |
      871

Information about
placebo therapy Pain measurement Results Main conclusion

NR VAS 0‐10 Subjects in the gabapentin group demonstrated Gabapentin appears to have a statistically significant difference
a clinically and statistically significant reduction with the control group at week 12 for the VAS pain.
reported on the VAS pain of 51.04% in comparison
to 24.30% in the placebo group.

Needle was pressed VAS 0‐10 Statistically significant differences (P < 0.01) were PNE and DDN showed greater pain reduction efficacy compared
against the skin with measured for the PNE and DDN groups with re- to SNP. Improvement was noted earlier in the PNE group than in
its plastic protective spect to pain reduction at rest, during chewing, and the DDN group.
tube, simulating a for maximum interincisal opening (MIO). Values
puncture. for the PNE group showed significantly earlier
improvement. Differences for PNE and DDN
groups with respect to SNP group were significant
(P < 0.05) up to day 70

The same treatment VAS 0‐10 Both laser and placebo groups experienced a general There was no significant difference in pain intensity of the TMJ
protocol with the improvement in VAS scores. No significant dif- and masticatory muscles between the laser and placebo groups
apparatus turned ference in VAS scores of the masticatory muscles at any of the treatment evaluations.
on, but without laser between the two groups.
irradiation.

Applications with a tip, VAS 0‐10 There was a decrease in pain intensity for both Laser active or placebo is effective in reducing the overall subjec-
similar to active laser groups (laser and placebo) when comparing the tive perception of myofascial pain.
tip but emitting only last session of treatment with the baseline. In the
a guide light and an evaluation of 30 d after the treatment completion,
audible signal the results regarding the perception of pain inten-
sity were still decreased for both groups.

A daily regimen of laser VAS 0‐10 Major efficacy of laser in comparison with the Our therapeutic protocol and the characteristics of laser (highest
treatment simulation, other two treatments from 5 d until the end of the peak power for a few seconds) are suggested in the treatment
using only red light observation period. of painful TMD. An important adjunctive factor is the low cost
of the laser without of the therapy.
energy for 20 min-
utes. They also were
treated for 10 days
(5 days/wk)

Ointment vehicle VAS 0‐10 In both groups, a decrease in muscle pain intensity Topical application of Bee venom ointment provides excellent
(Vaseline) in the same was observed. it was statistically relevant for bee therapeutic effects. It reduces muscular tonus and muscle pain
containers venom. For placebo group reduction in muscle intensity and gives better relief to a patient than placebo.
pain intensity was also observed, but it was not so
significant.

0.9% normal saline VAS 0‐100 The mean change was a 19 mm reduction in pain No statistically significant difference was observed in any
Outcome measurements intensity (SD: 31) for the BTX‐A group and a 1 mm outcome measures except maximum opening, which showed
were obtained at baseline reduction for the placebo group (SD: 16). BTX‐A patient opening less wide than placebo. The results do
and at 8 wk not support the use of BTX‐A in the treatment of moderate to
severe jaw muscle pain in this patient population.

Subjects were placed VAS 0‐10 No significant group‐by‐time interaction was found Upper thoracic spinal manipulation did not lead to a reduction in
in the same position, All evaluations were per- for facial pain intensity. pain in women with TMD.
except that the thera- formed after 3 d
pist's hand was open
and not in pistol grip

(Continues)
 |
872       PORPORATTI et al.

TA B L E 1   (Continued)

Author Sample (n) TMD Diagnostic

Year Mean age (SD) Active therapy sample Placebo therapy method and
Group Country %fem (n/%fem) sample (n/%fem) subtypes Information about active therapy

Splints Rodrigues‐ 57 I—Balanced splint III—Non‐occluding RDC/TMD I—acrylic stabilisation (balanced) splint on the
Conti et al 29.9 yo 19 splint DD and Arthralgia maxillary arch
2006 91.66% 28.9 yo; 18 II—acrylic full‐covered stabilisation splint with
Brazil II—Canine guidance 29.5 yo canine guidance on the maxillary arch
splint
20
31.3 yo

Laser Rodrigues et 78 Active laser placebo laser DC/TMD Laser dose: 780 nm), during, and after 30 d.
al, 2018 31.94 (9.57) 30 29 Muscle‐related In the TMJ, the applications were 75 J/cm2
Brazil 100% NR NR and/or joint‐ (60 mW/50 s),
100% 100% related TMD In the facial muscles, the application was
control group 30 J/cm2 (60 mW/20 s)
NR
19
100%

Laser Rohlig et al 40 20 20 RDC/TMD Energy of 8 J/cm2 by applying 300 mW output

2010 43.7 ± 1.8 yo 42.2 ± 3.4 yo 42.8 ± 2.1 yo TMD of myogenic power for 10 seconds. LLL treatment was
Turkey 60% 60% 60% origin applied precisely and continuously into five
points: three points of the masseter muscle
(superior point, middle point, inferior point),
one point of the temporalis (anterior point)
and one point of the sternocleidomastoid
muscle (superior SCM)

Laser Sancakli et al, 30 10 10 RDC/TMD Radiation of 820 nm wavelength. The beam

2015 39.2 ± 2.8 yo laser group I (LGI), placebo group TMD of muscular diameter of the device is 6 mm and the probe
Turkey 70% 30.80 ± 9.81 yo (PG). origin has an angle of 45°. The energy intensity
70% 31.94 ± 12.20 given to each muscle point was adjusted to
10 laser group II (LGII) 70% 3 J/cm2 by applying 300 mW output power
29.33 ± 8.59 yo for 10 s.
70% LGI—was applied precisely and continuously to
the greatest points of pain in the related
muscle (masseter and/ or temporalis)
LGII, was applied in the same manner to three
predetermined points on the masseter muscle
(superior [MS], middle [MM], and inferior [MI]
points) and three points on the temporalis
muscle.

Laser Sattayut 30 10 CLILT 10 RDC/TMD I—A conventional low energy LILT (CLILT):
& Bradley 35 +‐ 9 yo 10 MLILT Masticatory 21.4 J/cm2, 4 J per point, 60 mW irradiance
2012 100% muscle disorder
Thailand and Arthralgia II—modified high energy LILT (MLILT):
107 J/cm2, 20 J per point, 300 mW irradiance

Laser Shobha et al, 40 20 20 RDC/TMD Diode laser (Gallium, Aluminium, Arsenide;

2017 30.85 (6.31) 27.55 (4.58) Muscle‐related PICASSO, USA), non‐contact mode,
India 85% 70% and/or joint‐ continuous wave, 0.1 W (100 mW), 810 nm,
related TMD 6 J/cm2, 2‐3 times a week, for a total of eight
sessions, 60 s/session

Acupuncture Smith et al, 27 15 12 RDC/TMD Each patient received six acupuncture

2007 40.5 (13.63) yo 38.3 (13.39) yo 43.2 (4.04) yo Myofascial Pain treatments bilaterally at ST 7
United 88.88% 86.66% 91.66% Needle was inserted 6‐12 mm into the skin
Kingdom

Medicine Ta and 68 Celecoxib: 22 RDC/TMD 6‐wk treatment of either celecoxib 100 mg BID
(Celecoxib & Dionne, 67.65% 24 34.7 +‐ 10.7 TMJ DD with or naproxen 500 mg BID
Naproxen) 2004 34.5 +‐10.2 yo 60% reduction and Subjects were also given acetaminophen
USA 70% Arthralgia or 325 mg as rescue medication, with a
Naproxen Painful DD of maximum dose of 3900 mg/d
22 the TMJ
33.6 +‐ 9.3 yo
73%

Medicine Tchivileva et 40 20 20 RDC/TMD The first arm started with 1 wk of active

(propranolol) al, 2010 35.4 (1.7) 100% 100% Chronic musculo- treatment, followed by a 1‐wk washout period,
USA 100% skeletal pain and then a 1‐wk placebo period. The second
arm started with 1 wk of placebo, followed by
a 1‐wk washout period, and then a week of
active treatment. During the active treatment
period participants received 20 mg of
propranolol twice a day
PORPORATTI et al.       873|

Information about
placebo therapy Pain measurement Results Main conclusion

Non‐occluding splint VAS 0‐100
on the mandibular We monitored and evalu-
arch ated all subjects at 15
d, 1 mo, 3 mo and 6 mo
after the insertion of the
splints
The mean improvement was 52.7 mm (83.4 per cent) TMJ pain and clicking seems to subside over time, regardless of
for group I, 58.5 mm (86 per cent) for group II and the type of oral splint used. We found that the occlusal splints
35.5 mm (56.6 per cent) for group III. provided earlier improvement compared with the non‐occluding
splint.

Zero energy density VAS 0‐10 Active and placebo laser showed reduction of pain The placebo laser was also therapeutic and was not altered by the
during chewing and better recovery levels during myofunctional degree, similar to active laser.
the rest period, without differences between
groups.

Laser device was only VAS 0‐100 It was observed that there was a significant drop in Active laser treatment is superior to sham application. However,
switched on, not Every other day for 3 wk VAS after active laser treatment. the present study investigated the short‐term effects.
programmed

the laser device was VAS 0‐100
switched on, but not three treatment sessions
programmed per week for 1 mo (total,
12 sessions)
The intensity of pain was reduced more in LGI than
in LGII
Although the difference between LGI and LGII was
not statistically significant, LGI demonstrated
slightly better results. Pre‐ and post‐treatment VAS
scores differed significantly in the laser groups, but
not in the PG.
Laser showed positive effects in managing pain caused by TMD
and improving mandibular function due to its analgesic and
myorelaxant effects. The localisation of laser application (at
predetermined points vs. points of greatest pain), however, did
not affect the results of Laser.

Inactive laser Vas 0‐10
Monday, Wednesday and
Friday with each regimen
totalling three treatments
The largest number of the patients who had no Laser had a significant improvement of pressure pain threshold
myofascial pain diagnosis after the final treatment and voluntary clenching EMG in the myofascial pain and TMJ
was in the MLILT group. In the CLILT group, there arthralgia patients over the group of sham laser.
were four patients who had recovery while there
was only one patient in the placebo group who had
recovery.

NR VAS 0‐10 Pain reduction was observed in both active Laser Laser is not better than placebo at reducing TMJ pain during
and placebo groups at day 0, 8th session, and 1 mo function.
between the groups.

The sham acupuncture Vas 0‐10 Similarly, both real and sham groups showed Acupuncture had a positive influence on the signs and symptoms
needle looks exactly 3 wk improvement in the mean VAS for pain intensity. of TMD.
like a real needle, However, only the real acupuncture was shown to
but is blunt and free be statistically significant.
to slide within its
handle so that, when
pressed, it telescopes
into the handle rather
than penetrating the
skin.

6‐wk treatment of VAS 0‐100 When 50% pain reduction was used as the dif- In this 6‐wk study, celecoxib and naproxen were safe and well
placebo BID ference in pain intensity from baseline to week tolerated at the maximal recommended doses for painful TMD
6, a significantly greater number of subjects in with joint disorders.
the naproxen group responded to treatment
than either celecoxib or placebo group. Similarly,
higher number of responders was observed in the
naproxen group compared to celecoxib or placebo
group when 33% of pain reduction was used as the
responder criteria.

Placebo pills were NRS 0‐100 A significantly greater percentage of patients (67.5%
identical to the pro- vs. 32.5%) experienced reduction in PSR pain in-
pranolol pills tensity rating during the propranolol treatment pe-
riod than the placebo treatment period. However,
reduction in PSR pain intensity rating comparing
propranolol treatment to placebo treatment did
not reach the statistical significance.
The number of patients reporting a reduction
in pain intensity rating was greater during propranolol treatment
compared with placebo. Propranolol significantly reduced a
composite pain index but did not decrease other clinical and
experimental pain ratings.

(Continues)
 |
874       PORPORATTI et al.

TA B L E 1   (Continued)

Author Sample (n) TMD Diagnostic

Year Mean age (SD) Active therapy sample Placebo therapy method and
Group Country %fem (n/%fem) sample (n/%fem) subtypes Information about active therapy

Intra‐articular Tjakkes et al, 20 Cross section (same Cross section RDC/TMD Articaine hydrochloride with 1:200 000
ultracain 2007 32.5 (12.0) yo subject received both (same subject Arthralgia, epinephrine (Ultracain D‐S; Aventis, The
The 95% therapies) received both Osteoarthritis, Netherlands)
Netherlands After 2 wk therapies) and All patients were supplied with topical
Osteoarthrosis anaesthesia of the skin in the pre‐auricular
of the TMJ area (lidocaine 25 mg/prilocaine 25 mg,
EMLA, AstraZeneca, USA) for at least
45 minutes
The (most) painful TMJ of each patient was
injected

Laser Venezian et al, 48 Group I (25 J/cm2): Group II (placebo RDC/TMD GaA1As low‐level laser (780 nm—infrared
2010 41.58 (18‐60) 12 25 J/cm2): Myofascial pain Group I active: dose of 25 J/cm2 (50 mW for
Brazil 89.58% Group IV (60 J/cm2): 12 (group I.a and 20 seconds)
12 Group IV (placebo I.b) Group II placebo: dose of 25 J/cm2 (50 mW for
25 J/cm2): 20 seconds)
12 Group III active: dose of 60 J/cm2 (60 mW for
40 seconds)
Group IV placebo: dose of 60 J/cm2 (60 mW
for 40 s).
Two weekly sessions for the applications, with
a total of eight session.
Upper, medium, and lower thirds of the
masseter muscle (three points) and the
anterior region of the temporalis muscle
(one point)

Medicine Vidor et al, 31 16 15 RDC/TMD Over a 4‐wk period (28 d), oral medications
(melatonin) 2013 20‐4o yo 32.27 (4.65) yo 29.47 (5.01) Myofascial pain were administered at bedtime (5 mg
Brazil 100% 100% yo (group I.a and melatonin tablets)
100% I.b)

Splints Zhang et al, 36 18 18 RDC/TMD Occlusal splints for 1 mo

2013 37.8 ± 11.4 yo 31.4 (9.00) yo 31.3 (8.3) yo Myofascial pain
China 66.66% NR NR (group I.a and
I.b)

Acupuncture Zotelli et al, 40 20 20 RDC/TMD The acupoints used were: ST6, ST7, SI18,
2017 36.5 (8.6) yo 38 (8.7) 35.1 (8.5) Muscular or mixed GV20, GB20, BL10 and LI4, during treatment
Brazil 72.5% yo yo TMD, with or performed for four weekly sessions
90% 70% without opening
mouth limitation

Abbreviations: AMP, amitriptyline; BTX‐A, Botulinum toxin A; CBT, Cognitive Behaviour Therapy; Cicl, Cyclobenzaprine; Clo, Clonazepam; DD,
Disc Displacement; NR, Not Reported; NRS, Numerical Rating Scale; NSAIDs, Non‐steroidal Anti‐inflammatory Drugs; TMD, Temporomandibular
Disorder; TMJ, Temporomandibular Joint; USA, United States of America; VAS, Visual Analogue Scale; yo, years old.

,23,26,33,36,39,41,50,53,56
13 as unclear20,27,30,37,38,48-51,54,55,59,61 and 20 as
21,24,25,28,29,31,32,34,40,42-47,52,57,58,60,62
high risk of bias.
of bias was reporting bias. Some studies provide unclear information
about blinding outcome evaluators to knowledge of group allocation
against detection bias, and many of them did not provide descrip-
tions about all measurements in terms of means and standard devia-
tion. The complete item list is presented in Figure 2 and Table S3.
3.4 | Synthesis of results
The higher risk
A meta‐analysis was conducted over 26 of the selected studies
(Figures 3 and 4). The heterogeneity between the studies was high
on this meta‐analysis because the results were from different types
of therapy, so a random effect was considered. To facilitate interpre-
tation of the results, the studies were clustered into two different

F I G U R E 2   Risk of bias results from

the Cochrane Collaboration's tool for
assessing risk of bias [Colour figure can be
viewed at wileyonlinelibrary.com]
PORPORATTI et al. |
      875

Information about
placebo therapy Pain measurement Results Main conclusion

Injections with sterile VAS 0‐100 Consequently, the mean VAS difference after TMJ pain
normal saline 2 and 5 min after the Ultracain injection was 12.8 (SD = 23.5) and the perception after injection of an anaesthetic agent does differ from
injection mean VAS difference after placebo injection was the perception after placebo injection.
4.5 (SD = 15.0). This difference between VAS
scores before and after Ultracain and placebo
injections was statistically significant.

Laser which emitted no VAS 0‐10 There was no statistically significant difference The treatments were efficient in the reduction of muscular pain in
energy) observed in the study within groups for placebo patients with TMD, for both groups, active or placebo. However,
groups using dose 25 and 60 J/cm2. there was a sharper and more lasting reduction of pain in the
experimental groups.

The tablets were manu- VAS 0‐10 The melatonin group had significantly lower pain This study provides additional evidence supporting the analgesic
factured in such a way VAS scores than the placebo‐treated group (Table effects of melatonin on pain scores and analgesic consumption
that the placebo and 2) at the end of treatment. The melatonin‐treated in patients with mild‐to‐moderate chronic myofascial TMD pain.
active treatment were group, when compared with the placebo group,
identical demonstrated a mean pain reduction of 44%.

non‐occluding palatal VAS 0‐100 89% of group active either completely recovered Occlusal splint could eliminate or improve the signs and symptoms
splints (39%) or clinically improved (50%) while only 22% of TMD patients with myofascial pain.
of group placebo had a spontaneous improvement.

Placebo acupuncture VAS 0‐10 No decrease in pain in the Treatment Group when Acupuncture points used were equally effective in reducing pain
in the same acupoints compared with the Placebo Group. in both groups.
with a 0.3030‐mm
sham needle

meta‐analyses: (a) placebo differences between TMD subtypes as
observed:
1. All groups (26 studies, sample = 585): This meta‐analysis
indicated that for placebo therapy, mean change in pain
intensity was higher on laser acupuncture with 45.5  mm
point reduction, followed by avocado soya bean extract
with 36.0  mm, laser with 34.0  mm and ozone therapy with
33.0  mm reduction.
2. Muscular TMD (13 studies, sample = 248): Mean change in pain
intensity for placebo therapy was higher on ozone therapy with
33.0 mm point reduction, followed by 5 J/cm2 laser with 28.0 mm,
tender point injection of granisetron with 23.0  mm and splints
with 15.0 mm reduction.
3. Articular TMD (seven studies, sample = 210): Mean change in
pain intensity for placebo therapy was higher on intra‐ar-
ticular Ultracain with 36.0  mm, followed by medicines such as
Clonazepam 0.5 mg and Glucosamine 400 mg with 20.0 mm re-
duction both.
4. Mixed TMD (six studies, sample = 127): For placebo therapy, mean
change in pain intensity was higher on laser acupuncture with
45.5 mm, followed by laser 6 J/cm2 with 34.0 mm reduction.
5. Relative differences for all groups (26 studies, placebo sample = 585):
Placebo therapy presented a percentage of pain reduction about
60%‐75% for laser 6 J/cm2 and laser acupuncture, about 40%‐60%
with laser acupuncture and laser 5 J/cm2, avocado soya bean ex-
tract, ozone therapy, acupuncture and tender point injections of
granisetron. A reduction of 40% with medicines as Clonazepam
0.5 mg and Cyclobenzaprine 10 mg was found (Figure 4).
A possible nocebo effect was found only for intra‐articular injec-
tion of local anaesthetic Ultracain with about 8% pain increase after
placebo application.
(b) Placebo differences between TMD therapies as observed:
1. Medicines (12 studies, sample = 215, I2= 58%): Mean change in
pain intensity was 15.95 (95% CI 12.8‐19), promoting a 19.3%
of placebo improvement.
 |
876       PORPORATTI et al.
PORPORATTI et al.
F I G U R E 3   Forest plot for overall mean differences of placebo therapies. A, Different TMD subtypes. B, Different TMD therapies. Graphs
generated with Review Manager 5.3 (RevMan 5.3, The Nordic Cochrane Centre, Copenhagen, Denmark)
2. Laser (eight studies, sample = 140, I2= 88%): Mean change in pain in-
tensity was 13.55 (95%CI 5.9‐21.1), promoting a 28.9% of placebo
improvement.
2
3. Other Therapies (13 studies, sample = 230, I = 80%): Mean change
in pain intensity was 14.91 (95%CI 7.4‐22.4), promoting a 26.4% of
placebo improvement.
In addition, funnel plot graph was completed and presented no report
bias detected as observed in Figure 5.
3.5 | Risk of bias across studies
The selected studies had a placebo‐controlled design. Pain at base-
line was not always compared between groups and how dropouts
happened were not constantly described. The main methodological
problem was concerning assessment of outcomes and selection of
the reported result. Most of the selected studies featured system-
atic errors in measuring the outcome, not providing standard devia-
tions for the mean results.
4 | D I S CU S S I O N
The aim of this systematic review and meta‐analysis was to investi-
gate the available evidence on the placebo and possible nocebo ef-
fect for different therapies for TMD‐related pain. To the best of our
knowledge, this is the first study that reviewed systematically these
2
approaches studies altogether. Laser 6 J/cm and laser acupuncture
provided a placebo effect of about 60% and 75% pain reduction,
followed by laser 5 J/cm2 with almost 60%, avocado soya bean ex-
tract and ozone therapy with around 50%, tender point injections of
granisetron with 40% and medicines with about 19%. Also, a possi-
ble nocebo effect of about 8% was found for intra‐articular injection
of Ultracain.
The use of placebos in clinical trials is explained by the assump-
tion that a supposed active drug or treatment effect should be su-
perior to an inert drug or treatment. However, placebo effect is a
key phenomenon of self‐control over pain. Placebos elicit definite
biological as well as behavioural responses from patients within a
wide variety of medical conditions, and it could be attributed to dif-
ferent psychological mechanisms including conditioning, expecta-
tion, learning, memory, motivation, somatic focus, reward, anxiety
reduction and meaning.63
Expectation is fundamental for placebo responses in pain con-
trol.64 Greater placebo‐induced pain relief is correlated with stron-
ger prefrontal cortex (PFC) and periaqueductal grey (PAG) activation
during anticipation of pain, which is consisting with opioid releas-
ing within the brainstem and the influence of the descending pain‐
modulatory system to regulate pain perception during the placebo
|
      877
response. Contextual factors, which include a variety of verbal and
non‐verbal elements, including empathy by doctor and staff, easing
of anxiety by proper diagnosis and treatment, and suggesting ge-
neric healthy regimens of diet, exercise, rest and anxiety control also
modulated the placebo response.65
There was a great variability in the magnitude of placebo re-
sponse across the various therapeutics’ approaches (10%‐75%).
Comparable results were also documented in meta‐analysis done in
other pain conditions. In one study with fibromyalgia, the pooled es-
timate of a 50% pain reduction by placebo was 18.6%.66 Expectation,
therapeutic encounter particularities and contextual factors could
explain why placebo effect in laser therapy studies was larger than
other therapies in TMD pain control.67 These studies included tech-
nical devices and higher number of sessions, which could optimise
the interaction between health providers and patients and thus the
placebo response.
Placebo response could also be influenced by gender. Some
studies showed differences in placebo response between men
and women, not only because of biological characteristics but also
because of the perception, expression and tolerance of pain that
are likely influenced by a variety of social and psychological pro-
cesses.66,68 This fact could not be explored in this review as the
sampling methods were not representative for gender differences,
as women comprehended between 60% and 100% of the samples
and several studies of TMD pain demonstrated a higher prevalence
in women than men across the lifespan.69
The differences in meaning and interpretation of pain experi-
ence and, consequently, in placebo response could be influenced by
culture, which may affect the verbal description of pain experience
and responses to both active and placebo interventions through
biologic predispositions and behaviour interacting with develop-
mental history.11 This could explain the higher rates of placebo re-
sponse obtained in studies done in Brazil when compared with other
countries. 23,28,30
Nocebo effect is a negative expectation of pain. The neurobio-
logical mechanisms of the nocebo effect have been less investigated.
The expectation of pain or of stronger pain than is actually presented
could bias the perception towards hyperalgesia, that is exacerbated
pain as a result of noxious stimuli. In this review, only one study
showed a possible nocebo effect. This study used a cross‐sectional
design where the patient received both therapies (anaesthesia injec-
tion or saline).53 The information given to the patient and knowledge
about the anaesthesia effects could have influenced these results
(expectation). Many therapies can have side effects; this is not the
same thing as nocebo. Ultracain injection, independently of anaes-
thesia solution used, the injection itself may cause some discomfort
and thereby increase in pain.
The results from this study should be seen with caution as it
is limited by differences in therapeutic approaches, sample size,
 |
878       PORPORATTI et al.

F I G U R E 4   Percentage of pain alteration after different therapies for placebo groups

PORPORATTI et al. |
      879

F I G U R E 5   Funnel plot for overall

mean differences of placebo therapies,
related to different TMD therapies.
Graph generated with Review Manager
5.3 (RevMan 5.3, The Nordic Cochrane
Centre, Copenhagen, Denmark) [Colour
figure can be viewed at wileyonlinelibrary.
com]

gender, age, number of sessions, country, diagnosis and placebo considered in future studies to tease out the mechanisms involved
technic. Moreover, the GRADE level of evidence is very low, thus on this fascinating aspect of human physiology.
leading to cautionary statements in the interpretation of this re-
view's findings. In this systematic review, 37 studies were excluded
by using a non‐validated diagnostic tool other than RDC/TMD or 5 | CO N C LU S I O N S
DC/TMD. Furthermore, new studies applying valid diagnostic crite-
ria such, and with representative samples, would certainly provide Based on the available data, the placebo response could play a major
robust evidence. effect on TMD pain management and may be responsible from 10%
In this review, none of the included papers presented a con- to 75% of pain relief. Laser acupuncture avocado soya bean and ami-
trol group without any intervention, so it is not possible to sup- triptyline promoted the higher placebo effect. Laser showed a 29%
port that we really measured the magnitude of placebo effect. of placebo effect, as well medicine with 19% and other therapies
Spontaneous fluctuations of TMD signs and symptoms, regres- with 26%. Possible nocebo effect was found only for Ultracain injec-
sion towards the mean pain intensity and reporting biases can tion with 8%. Clinicians could apply such evidence in order to opti-
influence the placebo intervention. Thus, the authentic placebo mise pain management and judgement about treatment efficacy and
effect is only possible to be established when these non‐spe- researches may find it useful when designing their investigations.
cific factors are taken into account. Therefore, the RCT methods
should consider the comparison between placebo and no treat-
AC K N OW L E D G M E N T S
ment group. This is essential to confirm and quantify whether
placebo is indeed significantly and relevantly better than any pain The authors declare they received no funding for this investigation.
treatment.11 On the other hand, ethical issues should also be con-
sidered and the institutional review board would need to weigh
C O N FL I C T O F I N T E R E S T
the potential benefit of the scientific knowledge to be gained
against the potential harm that could derive from withholding ac- The authors declare they have no potential conflicts of interest with
tive treatment.70 respect to the authorship and/or publication of this article.
For better RCT design, some factors must be taken into con-
sideration: multicentric design needs to be applied to control for
E T H I C A L A P P R OVA L
culture differences. Despite it is not ethical keep a patient without
treatment, the establishment of a “no treatment” group is important This article does not contain any studies with human participants or
on RCT designs. In addition, pain assessment should involve other animals performed by any of the authors.
aspects, rather than the sensory discriminative dimension of pain,
for example quality of life, disability and function; and Initiative
I N FO R M E D C O N S E N T
on Methods, Measurement, and Pain Assessment in Clinical Trials
(IMMPACT) recommendations.71 Finally, open placebo trials can be For this type of study, formal consent is not required.
 |
880       PORPORATTI et al.
ORCID
André Luís Porporatti  https://orcid.org/0000-0003-4379-9695
Yuri Martins Costa  https://orcid.org/0000-0002-7658-5020
Juliana Stuginski‐Barbosa  https://orcid.
org/0000-0002-7805-5672
Ana Míriam Velly  https://orcid.org/0000-0003-3125-1884
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https​://doi.org/10.1111/joor.12827​
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