SSRN Id3705177

Title:
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Occlusal Adjustment vs Placebo for Chronic Temporomandibular
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Disorders. The MAP Randomized Clinical Trial
Authors:
López-Cedrún, José Luís. PhD 1
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Santana-Mora, Urbano. PhD 2
Mora-Bermúdez, María Jesús. PhD 2
Collier, Timothy. PhD 3
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Pocock, Stuart J. PhD 3
Santana-Penín, Urbano. PhD 2 *
1 Oral and Maxillofacial Surgery Service, University Hospital of La Coruña, La Coruña,

Spain.
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2 Department of Surgery and Medical-Surgical Specialties, Faculty of Medicine and
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Odontology, University of Santiago de Compostela, Santiago de Compostela, La Coruña,
Spain.
3 Department of Medical Statistics, London School of Hygiene and Tropical Medicine,
London, UK.
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* Corresponding author:
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Prof. Urbano Santana-Penín

Facultade de Medicina e Odontoloxía.
Universidade de Santiago de Compostela.
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C/ Entrerríos s/n. 15782 Santiago de Compostela. SPAIN

Phone: +34 630558265. Fax: +34 981562226
E-mail: urbano.santana@usc.es
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ORCID: 0000-0002-9322-4120.
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This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3705177
Key Points
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Question Can occlusal adjustment treat considerable chronic pain from
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temporomandibular joint disorders?
Findings The phase 3 randomized MAP trial that included 77 adult participants with
chronic temporomandibular joint disorders showed that over the course of 6 months the
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mean reduction in pain score was 1.5 units higher in the occlusal adjustment group than
in the placebo group (median 7/7 at baseline, 2.0/3.5 at 6 months, occlusal
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adjustment/placebo group, respectively; 0-10 scale), a significant difference.
Meaning Occlusal adjustment addressed to recover physiological jaw closure and

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provide alternate chewing function treated chronic temporomandibular joint disorders.
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ABSTRACT
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IMPORTANCE Evidence regarding effective treatments for temporomandibular joint
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disorders (TMDs) is limited.
OBJECTIVE To determine whether occlusal adjustment may reduce the pain intensity
of patients with chronic TMD.
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DESIGN The MAP study was a phase 3 randomized, participant- and assessor-blinded,
placebo-controlled trial of a novel occlusal therapy for chronic TMD over the course of
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6 months. It was carried out from August 4, 2014 to October 25, 2018 (last 6-month
follow-up).
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SETTING Single referral tertiary care hospital. Therapies were performed in a
University Clinic in a different city.

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PARTICIPANTS From 924 adult patients screened diagnosed as TMD, 820 were
excluded (partial tooth loss, no chronic condition, malocclusion); 27 declined to

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participate. Seventy-seven participants underwent randomization; all but one female
participant completed the analysis.

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INTERVENTIONS Participants were randomly (1:1) assigned to occlusal adjustment
therapy (N=39) or similar placebo (N=38) that did not remove any enamel.
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MAIN OUTCOME AND MEASURE Primary outcome (before data collection
began): change in pain score (in a 0-10 points visual analogue scale) from baseline to
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the 3- and 6-month assessments. Because one majority of the 1-month therapy visits
(carried out in a city 70 km away) were delayed nearest the 3-month visit, the actual
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primary outcome was the average pain intensity improvement at 6 months in respect of
the baseline scores (05/05/2016 ISRCTN amendment). Clinical important difference 1.5
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points.
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RESULTS The trial was stopped early for efficacy. This report includes all randomized
participants in their originally assigned group: 39 to occlusal adjustment and 38 to
placebo therapy. Both groups were balanced regarding baseline characteristics. As
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compared with the placebo, occlusal adjustment reduced jaw pain intensity (adjusted
mean difference, -1.54; 95% confidence interval [CI] -.5 to -2.6; P=0.004; ANCOVA
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model).
CONCLUSIONS AND RELEVANCE The occlusal adjustment was effective in

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treating chronic TMD pain and improved limited mouth opening in comparison with the
placebo over a 6-month period. The results of this trial are provisional and should not be
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generalized to patients with different dental conditions, or if the therapies are provided
by less experienced dental professionals.
TRIAL REGISTRATION UTN: U1111-1134-0832, ClinicalTrials.gov number

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NCT02144233, and ISRCTN number ISRCTN61654487.

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Key words. Mesh Terms:

Musculoskeletal Diseases [C05]
Jaw Diseases [C05.500]
Mandibular Diseases [C05.500.607]
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Craniomandibular Disorders [C05.500.607.221]

Temporomandibular Joint Disorders [C05.500.607.221.897]
Temporomandibular Joint Dysfunction Syndrome [C05.500.607.221.897.897]
Occlusal Adjustment [E06.658.578.200]
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Facial Pain [C10.597.617.364]

Chronic Pain [C10.597.617.258]
Mastication [G10.261.326.240.500]
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MAP Trial Graphical Abstract
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Social Science Research Network- SSRN Elsevier
QUESTION Can the occlusal adjustment treat chronic pain from temporomandibular joint disorders?
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CONCLUSIONS The occlusal adjustment therapy significantly reduced the intensity of symptoms or signs of chronic TMDs over the course of 6
months as compared with placebo adjustment. The results of this trial are provisional and should not be generalized to patients with dif ferent dental
conditions or if the therapies are provided by inexperienced dental professionals
POPULATION INTERVENTION FINDINGS

77 Participants The trial was stopped early for efficacy
71 Women 39 randomized 38 Median (IQR) pain intensity scores (0-10 points
6 Men Occlusal adjustment Similar placebo visual analogue scale) at 6 months:
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diamond inactive
bur bur occlusal adjustment
Adults with temporomandibular 2.0 points (.0, 3.0)
disorders with chronic considera-
ble pain, fully dentate clinically 0 10
normal occlusion, did not respond
similar placebo
to previous conservative therapies
3.5 points (1.0, 6.0)
Median age: 29 years Decreasing the excessive
Did not remove enamel 0 10
lateral guidance angle
Between-group difference: -1.5 points
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LOCATIONS PRIMARY OUTCOME
Single referral tertiary care center Reduction in the mean pain intensity from baseline at the (two-sided 95% CI, 0.5 to 2.6, p=0.004; analysis of
6-month assessment (clinical important difference 1.5) covariance models adjusting for baseline values)
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INTRODUCTION
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Chronic TMDs are characterized by preauricular pain (which usually changes with
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function) and restricted mouth opening.1 It affects 10 million people in the USA.2
Although sex is not a major factor for TMDs, 3,4 more women than men ask for therapy.
Chronic forms are disabling and often have comorbidity, such as headache,5 depression
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or suicidal ideation.6 Their etiology is still debated.1 The disorders entail a significant
personal and social cost 7 and are underrecognized,8 distressing9 among clinicians, as the
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therapeutic evidence as reported in systematic reviews is very limited for these
syndromes.10
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Patients with TMD usually have one habitual chewing side;11 which is the location of
the symptoms, with lower lateral guidance (more occlusal contacts) 12 and with higher
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condylar path.13 During mastication the joint on the working side acts as a fulcrum
(static), while the joint on the nonworking side acts as a gliding joint allowing adequate
lubrication and metabolism.

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We hypothesized that an occlusal adjustment that obtained balanced occlusion 14
(distributing loads over the entire dental arch and protecting temporomandibular joints)
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15,16 and decreasing the excessive angle of the lateral guidance typically on the
nonworking side, expecting that increases the number of dental contacts and improve
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chewing function on this side 12,13 (Figure 1), should provide an effective treatment for
TMDs. To test the null hypothesis of no different effect, a randomized clinical trial was
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conducted to determine the efficacy of this novel occlusal adjustment approach for
treating chronic jaw pain.

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Figure 1. Clinical characteristics of a typical chronic (left) temporomandibular disorder.
A, Illustrations showing symptoms, chewing function, increasing eminence height (higher
condylar path) and (B) lower left lateral guidance (green lines, central or right line drawings;
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with more dental contacts, and, thus, better prepared to chew) angle than right lateral guidance
(red lines, left or central line drawings) angle. M, masseter muscle; r, right; l, left; w, working;
b, balancing.
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METHODS
Trial design and oversight

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This phase 3 randomized clinical trial, which had a double-blind design (participants
and evaluators)17 and was placebo-controlled, parallel, and carried out in a single center,
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compared a novel occlusal adjustment with a similar placebo intervention. This trial was
approved by the Regional Human Ethics Committee of Galicia, Spain (approval number
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2009/017, updated November 29, 2013).
The protocol 18-21, the performance, 22,23 and the reporting22-24 of this study were carried
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out in accordance with (Equator Reporting Network) standard guidelines. An
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independent Data and Safety Monitoring Board 25 approved the protocol (Supplement
1) before study began and monitored the trial in real time using a certified online
database (OpenClinica®), implemented to ensure the transparency and accuracy of the
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trial's progress;20 only the service nurse was able to enter data and was also responsible
for storing documents in a locked drawer, which was inaccessible to the researchers.
Eligibility and recruitment
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Adult patients between 18 and 65 years of age, diagnosed with Axis I TMD,26 with
clinically normal occlusion, with pain (reported by the patient) of moderate to severe
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intensity (scores ≥4 and ≤9) 21 on a of 0 to 10 visual analogue scale (where 0=no pain
and 10=worst possible pain) and chronic pain (at least during the previous 6 months)
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were considered eligible. Patients with more than 2 mm of displacement in the
horizontal plane between the cusps and their antagonist fosses between the centric
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occlusion and the maximum intercuspal position were excluded. The full list of
inclusion and exclusion criteria can be found in the study protocol (Item 10 in
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Supplement 1). All participants had previously received occlusal device therapy; most
had also received other conservative or minimally invasive treatments.

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After a complete evaluation, a trial clinician detailed the study design extensively,
orally and in writing, and invited each qualified patient to participate. Once they had
consented to participate, they traveled to the hospital, were enrolled, were numbered
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consecutively, and were registered in Openclinica. The research team was notified, who
then called the patient for treatment (2 to 4 weeks later) reminding them to follow the
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participant instructions. No occlusal adjustment was offered outside the trial.
Randomization and blinding
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Prof. James H. Ware created the random assignment sequence (1:1), which was hidden
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from the researchers and committees, and e-mailed it to the service nurse; she made 4
series of opaque envelopes (female/male, muscular/articular), signed on the flap,
numbered, and stored consecutively; Prof. Ware also sent the therapy code (A/B) to the
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therapy provider, who read it and immediately forwarded it in an opaque, sealed
envelope to the chairman of the monitoring committee, who kept it closed until the
results of the study had been written and approved.
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Trial regimen and procedures
The trial regimen consisted of an occlusal adjustment or a placebo adjustment. The

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occlusal adjustment in this trial (Supplement 2) was designed to obtain balanced
occlusion and alter the lateral guidance to satisfy the equation: right condylar path ×
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left lateral guidance = left condylar path × right lateral guidance. Typically, 90
minutes were required for the adjustment. The therapy was refined in a second session
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one to two months later, which typically required 30 minutes. Placebo treatment was
performed identically to occlusal adjustment but using a noncutting drill that did not
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remove any enamel. Adjustments outside the trial and the use of occlusal splints were
not permitted; other concomitant therapies were strongly discouraged.

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Outcomes and data collection
The primary outcome was reduction in the mean intensity of jaw pain from baseline at
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the 6-month assessment (clinical important difference 1.5 points). Secondary variables
were an increase in maximum unassisted mouth opening (smallest detectable difference
3 mm),27 improvement in the mental component 28 using the validated version in

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Spanish of the Symptoms Check List -90- Revised,29 and the risk of changing the
habitual chewing side. There were 3 data collection periods: baseline, 3 months
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(secondary time for the main variable) and 6 months (primary time for all variables)
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after therapy.
Concealment allocation
At the start of therapy (at the University Dental Clinic), the therapy provider requested
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the therapy code by telephone from the nurse of the University Hospital. The nurse then
wrote the assignment in the on-line file of the participant and the trial number and name
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of the participant in the envelope that was closed, sealed, signed, and stored for
subsequent verification.
Statistical methods er
Using data from an earlier pilot trial (cliniclatrials.gov NCT00899717), we assumed a
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standard deviation of 2.4 for the jaw pain intensity score at 6 months. We determined
that a total of 88 participants (44 per group) would be required to provide 80% power to
detect a difference of 1.5 points (considered clinically important) in the jaw pain
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intensity score.
Baseline characteristics are described by treatment group using frequencies and

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percentages for discrete variables and mean and standard deviation (SD) or median and
interquartile range (IQR) for continuous variables.

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The null hypothesis was that no difference would be found in the studied variables
between the actual and placebo treatment groups. For the primary outcome of change in
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self-reported jaw pain intensity from baseline to 6 months, analysis of covariance
(ANCOVA) was used adjusting for baseline jaw pain intensity and including treatment
group as an explanatory variable. The distribution of change in jaw pain intensity from
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baseline to 6 months was examined and found to be approximately normally distributed.
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A secondary analysis of change from baseline in self-reported jaw pain at the 3-month
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and 6-month visit was carried out using a linear mixed model assuming a constant
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treatment effect across the 2 visits. The secondary continuous outcomes of change in
maximum unassisted mouth opening from baseline to 6 months and change in the
Global Severity Index from baseline to 6 months were analyzed using ANCOVA
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adjusting for the baseline values. The distributions of these variables were examined
and found to satisfy the assumption of normality. The change in the habitual chewing
side was reported descriptively.
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All analyses were conducted using the intention to treat approach. The primary outcome
was also analyzed in the per protocol population as a sensitivity analysis.

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The Data and Safety Monitoring Board was responsible for activating early stopping.
The study used an interim analysis plan with a single interim analysis after 70% of
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participants have completed the six-month follow-up visit. Using the Lan-DeMets
version of the O’Brien-Fleming stopping rule, the critical value for statistical
significance at the interim analysis (under both intention-to-treat and per-protocol sets)
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was +2.438, corresponding to a nominal two-sided P value of 0.0146.

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RESULTS
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Trial population
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This trial was carried out in the Maxillofacial Surgery Service of the University
Hospital of A Coruña, Spain, between August 4, 2014 and October 1, 2018. All the
participants who received randomization (N=77) were included and remained in the
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group to which they were originally assigned: 39 in the occlusal adjustment group and
38 in the placebo group (Figure 2). Both groups under study had similar demographic
and clinical characteristics (Table 1; eTables 1-5 in Supplement 3).
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924 Patients were screened
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820 Did not meet inclusion criteria
27 Declined to participate
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77 Underwent randomization
39 Were assigned to occlusal adjustment grou p 38 Were assigned to placebo group

37 Received assigned regimen 38 Received assigned regimen
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2 participants do not received assig-

ned regimen due to dental hypersensitivity
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39 Were assessed for jaw-pain intensity score 38 Were assessed for jaw-pain intensity score
38 at month 6 38 at month 6
1 at month 3 (leave the study at month 3)
5 Were excluded after randomization. Cause s: 2 Were excluded after randomization.Causes,

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not meet eleigibility:

2 participants did not received assigned thera-
py due to dental hypersensitivity 1 depresion
1 cognitive deficit
2 do not meet eligibility: depresion
1 did not comply with the study protocol: used
splint
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34 Were included in the per-protocol analysis 36 Were included in the per-protocol analysis
39 Were included in the intention-to-treat analysis 38 Were included in the intention-to-treat analysis
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Figure 2. Flow diagram. Screening, Randomization, and Follow-up.
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Table 1: Characteristics of the Participants at Baseline
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Occlusal adjustment Placebo
Characteristic group (N=39) group (N=38)
Female sex ¾ no. (%) 36 (92.3) 35(92.1)
Median age (IQR) ¾ yr 29 (22-38) 30 (25-40)
Affected side/s ¾ no. (%)
Right 10 (25.6) 8 (21.1)
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Left 16 (41) 13 (34.2)
Both 13 (33.3) 17 (44.7)
Median symptoms chronicity (IQR) ¾ months 36 (18-120) 45 (24-79)
Arthralgia (with or without myalgia) ¾ no. (%) 33 (84.6) 29 (76.3)
Myalgia (without arthralgia) ¾ no. (%) 4 (10.3) 7 (18,4)
Internal joint derangement
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Disc displacement with reduction ¾ no. (%) 8 (20.5) 5 (13.2)
Disc displacement without reduction ¾ no. (%) 4 (10.3) 5 (13.2)
Disc degeneration or absence ¾ no. (%) 2 (5.1) 2 (5.3)
Degenerative joint disease ¾ no. (%) 2 (5.1) 1 (2.6)
Condyle hypoplasia ¾ no. (%) er 4 (10.3) 1 (2.6)
Jaw-pain (VAS score)
Median ¾ (IQR) 7 (5-8) 7 (6-7)
Mean ¾ (SD) 6.6 (1.4) 6.5 (1.1)
Mouth opening (mm)
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Limited mouth opening ¾ no. (%) 16 (41) 12 (31.6)
Maximum unassisted jaw opening. Mean(SD) 41.5(8.4) 43.9(7.8)
Habitual chewing side¾ no. (%)
Right 16 (41.0) 14 (36.8)
Alternate 8 (20.5) 13 (34.2)
Left 15 (38.5) 11 (28.9)
Mean Global Severity Index ¾ (SD) 0.9 (0.6) 0.8 (0.5)
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Headache
Prevalence in this trial ¾ no. (%) 34 (87.2) 30 (78.9)
Median intensity VAS ¾ (IQR) 7 (5-8) 5.8 (1-7.6)
Neuropathic facial pain ¾ no. (%) 13 (36.1) 12 (34.3)
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Condylar path angles in relation to Frankfort Plane. Mean ¾ (SD) (degrees)

Right side ¾ (SD) 50.5 (10,7) 47.3 (8.1)
Left side ¾ (SD) 50.1 (10.5) 49.3 (8.6)
Lateral guidance angles in relation to Frankfort Plane ¾ (SD) (degrees)
Right side ¾ (SD) 41 (11.6 40.1 (12.5)
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Left side ¾ (SD) 38 (10.4) 37.3 (10.6)
IQR, interquartile range; SD, standard deviation; VAS, 0- 10-points visual analogue scale
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Efficacy
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Primary efficacy outcome
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The trial was halted prematurely for efficacy on June 11, 2018 by the Monitoring
Committee according to predetermined rules in the protocol. A significant difference
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was found between the groups in the mean change in self-reported jaw pain intensity
from baseline to 6 months, with the decrease in pain being greater in the occlusal
adjustment group (adjusted mean difference 1.5, 95% confidence interval [CI], 0.5 to
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2.6, p=0.004) (Table 2; Figure 3; eTable 8, eFigure 5 in Supplement 3). A significant
mean difference at 6 months was also observed in the per protocol population (adjusted
mean difference 2.0, 95% CI 1.0 to 3.0, p<0.001).

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Table 2: Outcomes at 6 months
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Occlusal
Placebo Mean Differencea P
Adjustment Value
Outcomes (n = 38) (95% CI)
(n = 39)
Jaw-Pain scoreb
Mean (SD) change from baseline -4.4 (2.0) -2.9(2.7) -1.5 (-2.6, -0.5) .004
Maximum unassisted mouth opening-mm
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Mean (SD) change from baseline 6.2 (6.5) 2.5 (0.3) 3.1 (0.4, 5.7) .02
Global Severity Index
Mean (SD) change from baseline -0.4 (0.4) -0.3 (0.3) -0.05 (-0.21, 0.11) .54
Habitual chewing side-N(%)
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Right 6 (15.4) 6 (15.8)

Alternate 25 (64.1) 27 (71.0)
Left 8 (20.5) 5 (13.2)
Change in chewing side¾ N(%) 27 (69.2) 20 (52.6) 1.32c (0.91, 1.90) .14
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Perceived Improvement¾ N(%) 37 (94.9) 23 (67.7) 1.40c (1.10, 1.79) .002

Headache Intensity
Mean (SD) change from baseline -3.0 (3.2) -1.2 (3.5) -0.73 (-1.99, 0.52) .25
Neuropathic Pain¾ N(%) 2 (5.4) 4 (11.4) 0.47c (0.09, 2.42) .36
a mean difference, 95% confidence intervals and p-values from analysis of covariance
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models adjusting for baseline values; b for change in jaw-pain score a negative number
indicates a reduction in pain; c risk ratio and 95% CI.
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Figure 3. Change in pain intensity and in mouth opening range. Mean changes from
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baseline are baseline-adjusted; 95% confidence intervals (I bars) and p values are from analysis
of covariance models adjusting for baseline values in the intention to treat approach. Placebo
Group has been used as the reference group (as control Group). Negative values of jaw-pain
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(Panel A) or positive values in maximum jaw-opening (Panel B) of mean change favors
occlusal adjustment group.
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Secondary efficacy outcomes
The mean change in maximum unassisted mouth opening from baseline to 6 months
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was significantly higher in the occlusal adjustment group (adjusted difference in mean
change from baseline 3.1 mm, 95% CI 0.5 to 5.7, p=0.02) (Table 2, Figure 2). The
majority of participants in both groups referred to chewing alternately at 6 months, and
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no evidence was found of a difference in the change of the chewing side (risk ratio 1.32,
95% CI 0.91 to 1.90, p=0.14) (Table 2). No evidence was found of a difference
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between the groups in change in the Global Severity Index, with similar improvements
from baseline seen in both groups (adjusted mean difference -0.05, 95% CI -0.21 to
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0.11, p=0.54) (Table 2).
Pre-specified efficacy outcomes
The percentage of participants reporting a perceived global improvement at 6 months

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was higher in the occlusal adjustment group (95%) than in the placebo group (68%)
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(risk ratio 1.40, 95% CI 1.10 to 1.79, p=0.002) (eTable 13 in Supplement 3). Belief
about the treatment received was similar in the 2 groups at the time of therapy or at the
6-month assessment. No evidence was found of a difference between the groups in

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change in the headache intensity with improvements from baseline seen in both groups
(adjusted mean difference -0.73, 95% CI -1.99 to 0.52, p=0.25). The percentage of
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patients reporting neuropathic symptoms at 6 months (5% occlusal adjustment, 11%
control) did not differ significantly between the 2 groups (risk ratio 0.47, 95% CI 0.09
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to 2.42, p=0.36). The use of medication was minimal in this trial. One occlusal
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adjustment and 2 placebo group participants used antidepressants, and 1 participant in
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each group used analgesics (for migraine and for jaw pain, respectively).
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Additional information on the results can be seen in Supplement 3.
Safety
There were no serious adverse events. Three participants in the occlusal adjustment
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group reported hypersensitivity, which was treated with topical fluoride application.
DISCUSSION
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The authors are unaware of a previous study that demonstrated that any therapy was
more effective than placebo in treating chronic temporomandibular disorders pain. The
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occlusal adjustment was also more effective than placebo in increasing maximum
unassisted mouth opening (Table 2, Figure 3). No serious adverse effects were
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detected.
The results of this study disagree with systematic review 10 that concluded that occlusal
adjustment was not more effective than a placebo. The occlusal adjustment used in the
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present trial (Supplement 2) was different than traditional 10 approaches, which may
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explain the difference in the results obtained. With the present adjustment, obtaining a
balanced occlusion allowed loads to be distributed over most of the teeth and reduced
loads on the mandibular joints,15,16 while with canine disclusion the stomathognatic
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system behaves like a class 3 lever system (Figure 1-B) during lateral mandibular
movements. Furthermore, reduction of the excessive lateral guidance probably

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facilitated the use of the nonworking side,13 as it increased the number of teeth
contacting on that side, better preparing it for chewing,12 an aspect that has traditionally
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been neglected.1,10 The absence of any therapeutic effect of occlusal adjustment in 2
participants with nasal obstruction was surprising, although it was effective after
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treating this pathology. We suggest that the presence of nasal obstruction should be an
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exclusion criterion in future trials. Most patients experienced pain on only 1 side at
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baseline, which is common and argues in favor of local factors, since one would expect
that if general factors were the only cause, they would mostly affect both sides (joints).
It seems logical to assume a benefit to the teeth and periodontium by treating occlusal
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premature contacts or interferences and avoiding overuse on one side and lack of use of
the other side. In our clinical practice, we have over many years, repeated minimally
invasive occlusal adjustment throughout an individual's life, allowing teeth to last a
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lifetime. The adjustment alters the dental anatomy, although the result is probably
similar to that caused by physiological wear. er

The strengths of this study include the adherence to standard guidelines,18-24 the
homogeneous study population (complete dentition and clinically normal occlusion),

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and the independence and fidelity of the data (by including initial protocol
[Supplement 1] and data in Openclinica at the time of each independent assessment,

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which was accessible to the monitoring committee and inaccessible to trialists);25 efforts
were made to preserve evaluator (JLC) and participant blinding; and an attempt was
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made to systematize the proposed occlusal adjustment procedure (Supplement 2) so
that the study could be replicated by other researchers.

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Limitations
This study has several limitations: few of the participants were male (Table 1),3,4 which
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seems characteristic of tertiary level hospital patients with the condition; the assessment
of the chewing function at the end of the study was biased, probably due to the
information given to participants at the start of the study; the absence of group
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differences in this outcome suggests the participant’s willingness to chew in an
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alternating fashion, which masks the assessment of the possible therapeutic effect; as a
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nonpharmacological trial, it was impossible to blind the therapy provider, who was not
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part of the evaluations or statistical analyses,17 and no psychological evaluation by
experts6 was systematically made during screening, which would have excluded some
participants in both groups because they fell under the exclusion criteria.
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It seems appropriate to report that the outcomes of participants after the trial were
consistent with the main trial outcome; moreover, the rescue occlusal adjustment
significantly reduced pain. One participant reported pain relapse (9/3/5 scores at
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baseline/6 months/3 years, respectively) three years after adjustment and declined new
adjustments. er
This trial most probably underestimated the effect of occlusal adjustment, as the
treatment was always performed systematically during only 2 visits. Other limitations
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were the use of strict intention-to-treat analysis, the failure to fully detect eligibility
criteria, and the lessebo effect.30 The results of this trial are provisional and should not
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be generalized to patients with different dental conditions (severe malocclusions,
missing teeth), or if the therapies are provided by inexperienced dental professionals;

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future pragmatical trials are needed to determine the effectiveness of this treatment in a
more universal setting.

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CONCLUSIONS
The occlusal adjustment was effective in treating chronic TMD pain and improved the
limited mouth opening in comparison with the placebo over a 6-month period. The
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results of this trial are provisional and should not be generalized to patients with
different dental conditions, or if the therapies are provided by inexperienced dental

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professionals.
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Contributors
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Author Contributions: Dr Santana-Penín had full access to all of the data in the study
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and takes responsibility for the integrity of the data and the accuracy of the data
analysis. Drs Santana-Mora and Santana-Penín contributed equally as co–first authors.
Concept and design: López-Cedrún, Mora-Bermúdez, Santana-Mora, Santana-Penín
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Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Santana-Penín, López-Cedrún, Santana-Mora.
Critical revision of the manuscript for important intellectual content: All authors.
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Statistical analysis: Collier, Pocock.
Obtained funding: Mora-Bermúdez, López-Cedrún, Santana-Penín.

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Administrative, technical, or material support: López-Cedrún, Mora-Bermúdez.
Supervision: López-Cedrún, Mora-Bermúdez, Santana-Mora, Santana-Penín.

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Data Sharing Statement: See Supplement 4. Dataset doi:10.5061/dryad.zkh189370.
Conflicts of interest: There are no conflicts of interest to report.

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Funding/Support: Funded by the Ministry of Science and Innovation of the

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Government of Spain and European Regional Development Fund, Grant nº PI11/02507;
“una manera de hacer Europa”.

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Role of the funding source: The funder of the study had no role in study design, data
collection, data analysis, data interpretation, or writing of the report. The corresponding
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author had full access to all the data in the study and had final responsibility for the
decision to submit for publication.

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Additional Contributions: The authors are grateful to James H. Ware, PhD (Harvard
University; posthumously, for his contribution in the study design and statistical
20
analysis plan). The independent monitoring committee: Pentti Alanen, PhD (Turku
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University, Finland), João Carlos Pinho, PhD (Porto University, Portugal), Julián
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Álvarez Escudero, PhD, Maria del Carmen Carollo, PhD (Santiago de Compostela
University, Spain), Francisco Gude, PhD (Santiago de Compostela University Hospital,
Spain). José María Fraga, PhD (Santiago de Compostela University), and Fernanda
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Lorenzo, PhD, as well as Mrs. Teresa Pazos (A Coruña University Hospital, Spain).
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10.1016/0030-4220(94)90031-0.
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7. Durham J, Shen J, Breckons M, Steele JG, Araujo-Soares V, Exley C, Vale L.
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treatments in temporomandibular disorders: a qualitative systematic
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11. Diernberger S, Bernhardt O, Schwahn C, Kordass B (2008) Self-reported
chewing side preference and its associations with occlusal,
temporomandibular and prosthodontic factors: results from the
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population-based Study of Health in Pomerania (SHIP-0). J Oral Rehab.

2008; 35(8): 613–620.
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12. Hildebrand Y. Studies in mandibular kinematics. Dent Cosmos 1936; 78(5):

449–458.
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13. Santana-Mora U, López-Cedrún J, Mora MJ, Otero XL, Santana-Penín U.

Temporomandibular disorders: the habitual chewing side syndrome. PLoS
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14. Jablonski S. Jablonski’s dictionary of dentistry. Krieger Publishing Company.

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15. Minagi S, Watanabe H, Sato T, Tsuru H. Relationship between balancing-

side occlusal contact patterns and temporomandibular joint sounds in
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Craniomandib Disord. 1990;4(4):251–6.
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16. del Palomar AP, Santana-Penín U, Mora-Bermúdez MJ, Doblaré M.
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Clenching TMJs-loads increases in partial edentates: a 3D finite element
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9487-y.
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17. Elwood JM. Critical appraisal of epidemiological studies and clinical trials.
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18. World Medical Association. World Medical Association Declaration of
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19. Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining
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200–7. doi: 10.7326/0003-4819-158-3-201302050-00583.
20. Chan AW, Tetzlaff JM, Gøtzsche PC, et al. SPIRIT 2013 explanation and
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e7586. doi: 10.1136/bmj.e7586.
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21. Dworkin RH, Dennis TC, Peirce-Sandner S, et al. Research design

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considerations for confirmatory chronic pain clinical trials: IMMPACT

recommendations. PAIN. 2010; 149: 177–193.
22. Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010
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trials. BMJ 2010;340: c332. doi: 10.1136/bmj.c332.
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23. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and
elaboration: updated guidelines for reporting parallel group randomised
trials. Int J Surg. 2012; 10(1): 28–55. doi: 10.1016/j.ijsu.2011.10.001.
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24. Bauchner H, Golub RM, Fontanarosa PB. Reporting and Interpretation of
Randomized Clinical Trials. JAMA. 2019;322(8):732-735. doi:
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10.1001/jama.2019.12056.
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25. DAMOCLES Study Group, NHS Health Technology Assessment Programme.
A proposed charter for clinical trial data monitoring committees: helping
them to do their job well. Lancet. 2005; 365 (9460): 711–22.
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26. Schiffman E, Ohrbach R, Truelove E, et al. Diagnostic Criteria for
Temporomandibular Disorders (DC/TMD) for Clinical and Research
Applications: Recommendations of the International RDC/TMD
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Consortium Network and Orofacial Pain Special Interest Group. J Oral
Facial Pain Headache. 2014;28(1): 6–27. doi: 10.11607/jop.1151.
27. Kropmans TJ, Dijkstra PU, Stegenga B, Stewart R, de Bont LG. Smallest
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detectable difference in outcome variables related to painful restriction of
the temporomandibular joint. J Dent Res. 1999; 78(3): 784–9.
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28. Derogatis LR, Rickels K, Rock AF. The SCL-90 and the MMPI: a step in the
validation of a new self-report scale. Br J Psychiatry 1976; 128: 280–9.
29. Derogatis LR. SCL-90-R Symptom Checklist 90 Revised. Spanish

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adaptation. González de Rivera JL. Cuestionario de 90 síntomas. TEA Ed.

S.A. Madrid, 2002.
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30. Mestre TA, Shah P, Marras C, Tomlinson G, Lang AE. Another face of
placebo: the lessebo effect in Parkinson disease: meta-analyses. Neurology.
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2014;82(16):1402–9. doi: 10.1212/WNL.0000000000000340.

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24
SUPPLEMENT 1.
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MAP TRIAL PROTOCOL
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Title page
MAP Protocol. Restoring physiological jaw closure and MAsticatory function as
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treatment for chronic facial Pain: a randomized clinical trial
Public title: Improving chewing function to treat chronic pain
ACRONYM: MAP
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Universal Trial Number (UTN): U1111-1134-0832
ClinicalTrials.gov Identifier: NCT02144233
International Standard Randomized Controlled Trial Number Register (ISRCTN Register):
ISRCTN61654487 - http://www.controlled-trials.com/ISRCTN61654487/
Protocol number: 4 (final)

Protocol date: 2016 May 4th
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Authorized signature
Name: Professor Urbano Santana-Penín

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(Chair of Trial Steering Committee for final protocols and amended final protocols)
Trial Steering Committee

Urbano Santana-Penín (USP)
José López-Cedrún (JLC),
María J. Mora (MJM)
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Urbano Santana-Mora (USM)
Key words. Mesh Terms:

Musculoskeletal Diseases [C05]
Jaw Diseases [C05.500]
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Mandibular Diseases [C05.500.607]

Craniomandibular Disorders [C05.500.607.221]
Temporomandibular Joint Disorders [C05.500.607.221.897]
Temporomandibular Joint Dysfunction Syndrome [C05.500.607.221.897.897]
Occlusal Adjustment [E06.658.578.200]
Facial Pain [C10.597.617.364]
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Chronic Pain [C10.597.617.258]

Mastication [G10.261.326.240.500]
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MAP TRIAL
Name of person authorized to sign final protocol and protocol amendments for the sponsor (Chair of Trial
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Steering Committee)
Name: Prof Dr Urbano Santana-Penín urbano.santana@usc.es
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Professor and chair, Tel Instit.: +34 881812350
Orofacial Pain and Prosthodontics Department Tel: +34 647 344 093
Faculty of Medicine and Dentistry Fax: +34 981 562226
Santiago de Compostela University
C/ Entrarríos s/n
15782 SANTIAGO DE COMPOSTELA, SPAIN
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Principal Investigators in bold and Investigators responsible for the conduct of the MAP Trial
Dr José López-Cedrún (JLC),

lopezcedrun@centromaxilofacial.com
Head of the Oral and Maxillofacial Surgery Department Tel: +34 981178000 Ext 292021
Complejo Hospitalario Universitario A Coruña Fax: 0034 981178052
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Calle Jubias 84, 15006 A CORUÑA, Spain
Professor María J. Mora (MJM) mariajesus.mora@usc.es

Head of the Stomatology Unit
University Hospital Complex of Santiago de Compostela, and Tel: +34 981951919
University of Santiago de Compostela, A Coruña, Spain
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Dr Urbano Santana-Mora (USM). Clinical Instructor.

urbanoalejandro.santana@rai.usc.es
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Orofacial Pain and Prosthodontics Department Tel: +34 881812350
Faculty of Medicine and Dentistry Fax: +34 981 562226
Santiago de Compostela University
C/ Entrarríos s/n
Dr Javier Collado López (JCL)

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Oral and Maxillofacial Surgery Department jcolmax@gmail.com

Complejo Hospitalario Universitario A Coruña 981 178000
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Dr María Pombo Castro (MPC)

Oral and Maxillofacial Surgery Department mariacorme@hotmail.com
Dr Fernanda Lorenzo Franco (FLF)
Oral and Maxillofacial Surgery Department JMbares@terra.com
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Dr Rocío P. García. Clinical Instructor. rochi_perez@hotmail.es
Facultad de Medicina y Odontología Fax: +34 981 562226
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Universidad de Santiago de Compostela

C/ Entrerríos s/n
Dr Iria L. Darriba. Clinical Instructor. irialopezdarriba@gmail.com

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Facultad de Medicina y Odontología Fax: +34 981 562226

Universidad de Santiago de Compostela
C/ Entrerríos s/n
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Trial manager and monitor
Urbano Santana-Mora (USM)
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Protocol Steering Committee:
Same as the Trial Steering Committee (see title page)
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Data management team:
Teresa Pazos Fernández (TPF), JLC
Dr María Pombo Castro (MPC)
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Trial Management Committee:
JLC, USP
Other individuals or groups overseeing the trial:

Prof. James H. Ware (JHW)
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Written (committed) Chair:
USP
Serum Utilization Committee:

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Ms Teresa Pazos Fernández (Nurse), Dr Rivas Lombardero (Head of Lab) and JLC.
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Data and Safety Monitoring Board (DSMB): (please see item 21a)
Prof. Dr. Pentti Alanen (Chair). alanenpentti@gmail.com

Prof. Dr. Julián Álvarez Escudero (Expert in Pain Medicine) julian.alvarez.escudero@sergas.es
Prof. Dr. Joao C. Pinho (Expert in TMD). pinhojc@gmail.com
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Prof. Dr. Carmen Carollo (Statistician). mdelcarmen.carollo@usc.es

Dr. Francisco Gude (Statistician). francisco.gude.sampedro@sergas.es
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Index
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Summary 8
Administrative information 10
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Title (Item 1)
Trial registration (Item 2)
Protocol version (Item 3)
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Funding (Item 4)
Roles and responsibilities (Item 5)
Introduction 14
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Background and rationale (Item 6)
Objectives (Item 7)
Trial design
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Methods 16
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Participants, interventions, and outcomes
Study setting (Item 9)
Eligibility criteria (Item 10)
Interventions (Item 11)

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Outcomes (Item 12)
Participant timeline (Item 13)

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Sample size (Item 14)
Recruitment (Item 15)

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Assignment of interventions
Allocation: sequence generation, allocation, concealment

mechanism Implementation (Item 16)
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Blinding (masking) (Item 17)
Data collection, management, and analysis
Data collection methods (Item 18)

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Data Management (Item 19)
Statistical methods (SAP) (Item 20)

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Monitoring:
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Data monitoring (Item 21),
Harms (Item 22),
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Auditing (Item 23)
Ethics and dissemination 40
Research ethics approval (Item 24)
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Protocol amendments (Item 25)
Consent or assent (Item 26)
Confidentiality (Item 27)
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Declaration of interests (Item 28)
Access to data (Item 29)
Ancillary and post-trial care

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Dissemination policy (Item 31)

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References 47
Tables and figures 51
Appendices 55
WHO Trial Registration Data Set

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Informed consent materials (Item 32)
Biological specimens (Item 33)

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Information sheet for prospective participants 58
Informed consent form 64

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Data collection forms and Information sheet for prospective

participants 65
Information sheet for prospective participants (Spanish) 79

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Data collection forms and Information sheet (Spanish) 86
Ethics approval 111
Conflict interest statement of DSMB 113

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Minutes (before participant’s enrollment and after 13 participants

completed follow-up) of the DSMB and the TSC meetings, 114
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Minute of the DSMB and the TSC of the MAP: trial termination,
11th June, 2018 119
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List of Amendments
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January 29th, 2015 122
October 16th, 2015 123
May 4th, 2016 124
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Trial Coordinator and Sponsor's Representative
Prof Dr Urbano Santana-Penin
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Facial Pain and Prosthodontics, Faculty of Medicine and Dentistry, University of Santiago de Compostela,
C/ Entrerrios s/n. 15782 Santiago de Compostela, Spain.
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Tel: +34 647344093.
Fax: +34 981562226.
E-mail: urbano.santana@usc.es
Principal Coordinating Investigator
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Dr José López-Cedrún
Head of the Oral and Maxillofacial Surgery Department, University Hospital Complex of A Coruña,
Calle Jubias 84, 15006 La Coruña, Spain.
Phone: +34 981178000 Ext 292021.
FAX: +34 981178052
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E-mail: lopezcedrun@centromaxilofacial.com
Trial Statistician
Prof. James H. Ware
Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, US.
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E-mail: ware@hsph.harvard.edu
PASSED AWAY
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ABSTRACT
Background
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Chronic temporomandibular joint (TMJ) disorders (TMD) are the main cause of facial pain, and the
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second cause of musculoskeletal pain after low-back pain. The cause of TMD is unknown and therapy is
usually empirical. Systematic reviews have shown that more research is needed to elucidate the benefits
of occlusal adjustment for TMD. The risk factors for chronic unilateral TMD include dental (occlusal)
premature contacts and habitual chewing on the affected side; therefore, a new occlusal therapy is
proposed to restore physiological jaw closure and chewing function.
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Aims
The primary endpoint will be the average change in pain score from baseline to the six-month
assessments. Efficacy will be demonstrated by superior pain relief with the active treatment compared
with the placebo.
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Methods
Study design
A phase 3, randomized, single (extensible to up three) centre, 6-month parallel-group, patient- and
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observer-blinded, placebo-controlled clinical trial to assess the efficacy of occlusal adjustment on
recovery of physiological jaw closure and chewing function in patients with TMD.
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Study population
Inclusion criteria: TMD patients, aged 18-65 years with full dentates and normo-occlusion suffering
significant pain (pain scores ≥4 and ≤9; method: 0 to 10 visual analogue (VAS) and/or 0 to 10 numerical
rating scale (NRS); 0 = no pain, 10 = worst imaginable pain). Main exclusion criterion is the requirement
of excessive enamel removal to equilibrate the dental articulation (occlusion).
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Intervention
Active therapy will consist of the elimination of premature tooth contacts and the reduction of the steeper
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lateral anterior guidance. Placebo therapy will be conducted in a manner identical to the active
adjustment, but no enamel will be removed.
Outcomes
Main outcome: change in self-reported pain intensity on the affected side measured by the VAS scale at 6
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months with respect the baseline. Secondary outcomes: change in maximum comfortable mouth opening
(using a Boley gauge), chewing function (interview and observed on the habitual chewing side,
dichotomized, 0=no change, 1=change) and mental component using self-administered tests. Time frame:
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baseline, 3 months (secondary time point) and 6-months (primary time point) follow-up.
Sample size estimation

Based on data from a previous study, we assume a standard deviation of 2.4 for this variable. We will
test the null hypothesis of no treatment effect at the two-sided 0.05 level. With a fixed sample size
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design, a total sample size of 88 subjects (extended to 110 for drop-outs) with complete follow-up would
provide power of 0.8 to detect changes in pain score of 1.5 units between the active and placebo treatment
groups.
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Analysis plan
To test the null hypothesis of no group (occlusal adjustment vs placebo) differences in the studied
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variables analysis of covariance (ANCOVA) will be used adjusting for baseline scores and including
treatment group as an explanatory variable. Change in chewing side will be explored using Fisher’s exact
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test.
Interim analysis plan and stopping rules

The Data and Safety Monitoring Board will be responsible for activating early stopping. The study will
employ an interim analysis plan with a single interim analysis after 70% of planned sample have completed
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the six-month follow-up visit. Using the Lan-DeMets version of the O’Brien-Fleming stopping rule, the
critical value for statistical significance at the interim analysis (under both intention-to-treat and per-
protocol sets) will be +2.438, corresponding to a nominal two-sided P value of 0.0146.
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Sponsor
University of Santiago de Compostela, Praza Obradoiro s/n, 15782 Santiago de Compostela, Spain
Funder
Ministry of Science and Innovation of the Government of Spain (Grant nº PI11/02507).
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European Development Fund (EDF). Fondo Europeo de Desarrollo Regional (FEDER) . “Una manera de
hacer Europa”
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Autonomic Committee of the Research Ethics of Galicia: CAEI approval number 2009/017; updated
on November 29, 2013).
Date trial started

11th August 2014.
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Expected end date

July 2018.
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The authors state that there are no conflicts of interest to report.

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The MAP protocol
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[According to the SPIRIT statement (Chan et al., 2013a,b); additionally, according to the
CONSORT Statement for trials of nonpharmacological treatment (Boutron et al., 2008)].
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Section/Item Item Number Description
Administrative information
Title 1 Descriptive title identifying the study design, population,
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interventions, and, if applicable, trial acronym
The MAP Trial: Restoring MAsticatory function as treatment for

chronic Pain: a randomized clinical trial
Trial 2a Trial identifier and registry name. If not yet registered, name of
registration intended registry.
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International Standard Randomized Controlled Trial Number
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ISRCTN61654487 - http://www.controlled-
trials.com/ISRCTN61654487/
2b All items from the World Health Organization Trial Registration
Data Set
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Please see Appendix I, Page 42.
Protocol 3 Date and version identifier
version
Protocol version-2
Issue date: October 16th, 2015
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Authors: USP, JLC, MJM, USM

This protocol version was designed according to the SPIRIT
2013 Statement: Standard Protocol Items for Clinical Trials
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(Chan et al., 2013a,b).

Funding 4 Sources and types of financial, material, and other support
Carlos III Institute of Health of the Ministry of Science and

Innovation of the Government of Spain (Grant Number
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PI11/02507)
European Development Fund (EDF). Fondo Europeo de
Desarrollo Regional (FEDER) . “Una manera de hacer Europa”
Time period of support: 2012–June 2016.
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Funding for this trial covers diagnostic devices (acquired),

consumables, and statistical and editing costs for publication of
the protocol and study results.
The design, management, analysis and reporting of the study are
entirely independent of the Carlos III Institute of Health.
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Roles and 5a Names, affiliations, and roles of protocol contributors

responsibilities
Urbano Santana-Penin (USP; University of Santiago de
Compostela), Jose Lopez-Cedrun (JLC; University Hospital
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Complex of A Coruña), Maria J Mora (MJM; University
Hospital Complex of Santiago de Compostela), Urbano Santana-
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Mora (USM; University of Santiago de Compostela).
James H. Ware (JHW; Harvard School of Public Health, USA)
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Pentti Alanen (PA; Turku University. Finland).
Authors’ contributions
USP and JLC conceived the study. USM, MJM initiated the
study design and USP and JLC helped with implementation.
MJM, JLC and USP are grant holders.
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All authors contributed to refinement of the study protocol and
approved the final manuscript.
Overseers contributions
PA provided methodological expertise in clinical trial design.
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JHW conducted the primary statistical analysis plan and the
sample size calculation.
5b Name and contact information for the trial sponsor
Trial sponsor: Urbano Santana-Penín

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Contact name: Urbano Santana-Penín.
Address:
Universidad de Santiago de Compostela, Facultad de Medicina y
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Odontología, C/ Entrerrios s/n 15782 Santiago de Compostela,
Spain. Tel: +34 647344093. E-mail: urbano.santana@usc.es
5c Role of study sponsor and funders, if any, in study design;
collection, management, analysis, and interpretation of data;
writing of the report; and the decision to submit the report for
publication, including whether they will have ultimate authority
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over any of these activities
The University of Santiago de Compostela and the Ministry of

Science and Innovation had no role in the study design; the
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collection, management, analysis, and interpretation of data;

writing of the report; or the decision to submit the report for
publication, and they will not have the ultimate authority over
any of these activities.
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5d Composition, roles, and responsibilities of the coordinating

center, steering committee, endpoint adjudication committee,
data management team, and other individuals or groups
overseeing the trial, if applicable (see Item 21a for the data
monitoring committee)
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Principal investigators and research physician (see steering

committee):
Design and conduct of MAP protocol
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Preparation of protocol and revisions

Preparation of investigators brochure (IB) and case report forms
(CRFs)
Organizing steering committee meetings
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Managing clinical trial registry
Publication of final study results
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Roles during the study phases:
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1. Screening and enrollment phases (coordinated by Dr JLC
):
1.1.Screening: Drs JCL, MPC, FLF
1.2. Enrolment and determination of complete baseline
outcomes: JCL, MPC, FLF. Graphic recordings: Prof MJM, Dr
USM. All outcomes measures at baseline will be obtained before
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allocation and assignment procedures.
2. Randomization
2.1. Allocation: Prof JHW
2.2. Assignment of participants to therapy X/Y Groups: Ms TPF
(blinded).
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3. Therapy phase
Therapy provider: Prof USP.
4 Follow-up
Follow-up outcome measures: Dr JLC will provide the forms
and the self-administered tests to each patient and will take the
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measurement of the maximum mouth opening at the 3- and 6-
month follow-up visits. He is unaware of any patient’s assigned
Group and does not have access to the patient’s data.
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Therapy session (Dr USP): therapy will be performed in a quiet
room with only the clinician and the patient present, with the
door open to ask for any advice from nurses. No other member
of the trial team can be present. This session is the first contact
between the therapist and the participant, and is independent of
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all other sessions, that were/will be conducted by a different

investigator, and in a different room or day. The clinician will
refine the therapy one month later and he will not see the
participant at any other time. Thus, the only visits and contacts
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between the therapist and the patients will be the two therapy
sessions: the main session (typically 1 h ± 30 min) and one
second session (typically 15 min) 1 month later to refine the
therapy. The therapist will not visit any participant either before
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or after.
Steering committee (SC)

All lead investigators will be steering committee members.
(see title page for members)
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JLC is the coordinator.

Agreement of final protocol
Oral and maxillofacial surgeon specialists (JCL, MPC and FLF)
will recruit patients and liaise with the principal investigator
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(JLC); JLC and/or MPC and/or FLF will perform independent

measurements of the maximum mouth opening, and experts in
kinesiography and axiography (MJM, USM) will perform
recordings for diagnostic and therapy planning, and perform
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intraoral exploration and tooth row measurement in order to
implement the exclusion criteria.
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The steering committee will review the progress of the study and
if necessary agree changes to the protocol.
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Trial management committee (TMC)
Principal investigator (JLC), research physician (MJM), nurse
(TPF).
Study planning
Organization of steering committee meetings
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Provision of annual risk report of adverse events, according to
the WHO scale, to the CAEI.
Provision of reports of any serious unexpected suspected adverse
events to the Data and Safety Monitoring Board (DSMB).
Responsible for trial master file
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Advise lead investigators
Audit 6-monthly feedback forms and decide when site visit will
occur.
Assist with international review, board/independent ethics
committee applications
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Data verification
Main Statistician: Prof. James H. Ware
Organization of central serum sample Collection (Dr Rivas
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Lombardero, Head of Hospital Lab; TPF)
Data manager
(TPF) Maintenance of trial IT system and data entry. Data
verification.
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Lead investigators
Lead investigators JLC (Coordinator), JCL, MPC, FLF: they
will be responsible for identification and recruitment. Lead
investigators USM and MJM will perform independent data
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collection and completion of CRFs (including measuring and

recording condylar path (CP) and lateral guidance (LG) angles),
along with following up study patients and ensuring adherence
to study protocol. Drs JLC, USM and MJM are responsible for
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the final enrolment; this requires the evaluation of dental

articulation and the indication for minimally invasive occlusal
adjustment (see item 10: Exclusion Criteria number 2.12).
Dr USP will perform patient therapy, and no other contact will
be maintained with patients or outcomes assessors during the
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trial, except for participation in the DSMB opening sessions. Dr

USP will perform the therapy sessions; when initiating the
therapeutic procedure he will telephone the administrative
coordinator (TPF) and ask for the therapy code (A/B). All
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patients will remain in their assigned group; depending on this

assignation, the clinician will choose the diamond (active) or the
inactive (placebo) instrument.
37
INTRODUCTION
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Background and 6a Description of research question and justification for
rationale undertaking the trial, including summary of relevant
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studies (published and unpublished) examining benefits
and harms of each intervention
Background
Introduction: Temporomandibular joint (TMJ) disorder
(TMD) is a collective term that encompasses a number of
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clinical problems involving the masticatory muscles,
TMJ, and adjacent structures; they are considered a
subgroup of musculoskeletal disorders and have been
identified as a major cause of orofacial pain of non-dental
origin (De Leeuw and Klasser, 2013). The NIDCR web-
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site states that TMDs are second only to low back pain
among disabling musculoskeletal conditions; affecting
approximately 5 to 12% of the population, with an annual
direct cost estimated at $4 billion. About half to two-
thirds of those with TMJ disorders will seek treatment.
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Etiology: TMD is regarded as a chronic disease; except
for cases of traumatic origin, the cause of TMD is
unknown (Hylander 2006, Scrivani et al., 2008; Tanaka et
al., 2008; De Leeuw and Klasser, 2013).
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Existing knowledge: Relief of approximately 90% of
TMD-pain symptoms can be achieved using counseling
(de Freitas et al., 2013) and/or other conservative
therapies. However, it has been reported that there is no
difference between conservative therapies (drugs,
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splinting) and control (“no treatment”) groups (Minakuchi

et al., 2001).
Systematic reviews have concluded that currently there is
no evidence that occlusal adjustment have any therapeutic
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or preventive effect on TMD (Forssell et al., 1999,

Tsukiyama et al., 2001, Koh and Robinson, 2003; List,
2010). However, these reviews also indicate (1) that
evidence to the contrary has not been provided and (2)
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that more research is needed to elucidate whether there is

any benefit of occlusal adjustment treatment for TMD.
Studies to date have been limited, focusing mainly on
removing interferences to achieve occlusal harmony.
Need for a trial: It has been shown that the TMD side is
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the side that presents a steeper condylar path (CP), flatter

lateral anterior guidance (LG) and is the habitual chewing
side (Santana-Mora et al., 2013). The CP is that path
traveled by the mandibular condyle in the
temporomandibular joint (TMJ) during various
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mandibular movements; LG is the influence of the

contacting surfaces of anterior teeth on tooth limiting
mandibular movements (GPT, 2005).
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Over 30 years, the researchers have performed the
proposed occlusal therapy: restoring physiological jaw
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closure and chewing function; the results showed a
probable therapeutic effect (pain relief was achieved in
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most TMD-pain subjects who had not responded to more
than 6 months of conservative therapies). However, this
clinical observation could be overestimated. The best
approach to assess the efficacy of a therapy is the
randomized controlled trial (Antczak et al., 1986); thus,
this study is needed in order to demonstrate that
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customized occlusal therapy can have a beneficial effect
on the dynamics and functioning objectives of the
chewing apparatus rather than anatomical occlusal
modifications in order to achieve relief of signs and
symptoms.
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6b Explanation for choice of comparators
Choice of comparator
It was difficult to choose a therapeutic approach against
which our occlusal adjustment should be compared
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because, at present, there is no a “gold standard” therapy,
and the efficacy of most treatment approaches for TMDs
is unknown; moreover, the superiority of such methods
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over placebo controls or untreated controls remains
undetermined (Forssell et al., 1999; Minakuchi et al.,
2001). Placebo occlusal adjustment can be beneficial for
many TMD patients, perhaps because the response of a
patient with TMD to any form of therapy is based on a
complex interaction between the patient, the doctor, and
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the treatment, rather than on a simple cause-and-effect

phenomenon (Goodman et al., 1976). In consequence, the
comparison to placebo (also called “mock” or “dummy”
therapy) therapy seems reasonable, as in previous reports
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(Goodman et al., 1976; Tsolka et al., 1992; Kirveskari et

al., 1998; Forssell et al., 1999; Minakuchi et al., 2001).
Objectives 7 Specific objectives or hypotheses
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1 Research hypothesis
That the restoration of physiological jaw closure and
impaired chewing function by occlusal adjustment therapy
will relieve chronic TMD-pain. Efficacy will be
demonstrated by showing significantly superior pain relief
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(and increasing maximum mouth opening when limited)

at the 6-month visit with active treatment as compared
with placebo.
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2 STUDY OBJECTIVES
2.1 Primary objective
The primary endpoint will be the average pain-intensity of
chronic unilateral TMD on the affected side at 6 months
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minus the baseline value, i.e., the average of the
improvements at 6 months relative to baseline. Treatment
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efficacy will be assessed by comparing pain relief in the
active treatment arm as compared with placebo.
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2.2 Secondary objectives
2.2.1 Key secondary objectives
To determine the effect of occlusal adjustment (OA)
therapy on maximum mouth opening, on quality of life
and the risk of changing the habitual chewing side.
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2.2.2 Other secondary objectives
To assess the effect of OA on other outcomes, such as the
duration and dimensions of pain episodes and other
peripheral factors (see eTable 3 pre-specified outcomes).
Trial design 8 Description of trial design including type of trial (e.g.,
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parallel group, crossover, factorial, single group),
allocation ratio, and framework (e.g., superiority,
equivalence, non-inferiority, exploratory)
The MAP trial is designed as a randomized, controlled,

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parallel-group, two-arm (real or placebo therapy), trial,
measuring treatment efficacy and superiority, which is
outcome assessor and patient blinded, single-center, with
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a primary endpoint of pain-intensity reduction at 3 and 6
months after treatment with respect to the baseline scores;
randomization will be performed by permuted block
randomization of random sizes with a 1:1 allocation.
Participation of up 2 other public academic hospitals
within the European Union is welcome in order to
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perform a multicenter study.

METHODS To detect any intervention-related differences in pain
intensity with the desired power, the baseline incidences
at the sites must be sufficiently high. We chose one
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academic hospital (A Coruña), which covers one area of

over 1,000,000 people including rural and urban areas.
Eligible participants seeking treatment from the Santiago
de Compostela University Orofacial Pain Unit will be
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invited to participate; data will be stored at the La Coruña

Hospital. Almost all adult patients will be Caucasian and
mainly females. Treatment will be performed at the
Santiago de Compostela University.
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Participants, interventions, and outcomes

Study setting 9 Description of study settings (e.g., community clinic,
academic hospital) and list of countries where data will be
collected. Reference to where list of study sites can be
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obtained
The University Hospital Complex of A Coruña, Spain.

(Main Center for recruitment). This is the public hospital
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reference center.
Address: Servicio de Cirugía Maxillofacial. Complejo
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Hospitalario Universitario de A Coruña, Calle Jubias 84,
15006 A Coruña, Spain.
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Email: lopezcedrun@centromaxilofacial.com
Phone: 0034 981178000 Ext 292021. FAX: 0034
981178052
Faculty of Medicine and Dentistry, University of Santiago

de Compostela. Spain.
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Address: Facultad de Medicina y Odontología, C/
Entrerrios s/n 15782 Santiago de Compostela, Spain. Tel:
+34 647344093. Fax: 0034 981562226. E-mail:
urbano.santana@usc.es
Eligibility 10 Inclusion and exclusion criteria for participants. If
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criteria applicable, eligibility criteria for study centers and
individuals who will perform the interventions (e.g.,
surgeons, psychotherapists)
Patients must provide written, informed consent before any

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study procedures occur (see Appendix II for sample
Informed Consent Form). Main eligibility criteria have
been chosen according to the IMMPACT recommendations
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for chronic pain trials (Turk et al., 2003; Dworkin et al.,
2010)
1 Inclusion Criteria
Pre-screened patients satisfying the TMD-pain instrument
(Gonzalez et al., 2011); TMD-pain diagnosis requires each
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of two findings: pain of sufficient frequency across a recent

period and modification of the pain by jaw function.
Assessors (JLC, FLF, MPC) will apply this instrument for
eligibility. Moreover, each participant must comply with
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all of the following at randomization:

1.1 Patients suffering TMD-pain (Joint and/or Muscle pain)
according to DC/TMD (Schiffman et al., 2014) (eTable
2).
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1.2 Aged 18–65 years.

1.3 Completely dentate adults with normal (or adequately
restored with fixed crowns or bridges) occlusion.
1.4 Suffering from significant TMD-pain (≥4 and ≤9
scores, in a 0–10 visual and/or numerical analogue
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scale-VAS/NRS; 0 = no pain to 10 = worst possible

pain).
1.5 Had requested therapy for TMD-pain, referred to the
Hospital/University Service
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1.6 After more than 6 months of treatment with

conservative therapies.
2 Exclusion Criteria
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2.1 Psychosis
2.2 Major depression
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2.3 Substance abuse
2.4 Cognitive impairment
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2.5 Addiction to morphine or derivatives
2.6 Litigation or asking for disability/retirement
compensation for chronic pain.
2.7 Dental care professionals
2.8 Orthodontic therapy during the last 2 years
2.9 Degree 2 to 3 of tooth mobility
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2.10 Patients with any pain that is more severe, in the same
location as, or cannot be clearly distinguished from TMD
pain.
2.11 Individuals for whom minimally-invasive occlusal
adjustment could not achieve occlusal equilibration
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(assessed by the experts in occlusion, Drs. USM, MJM), to
minimize tissue removal. Over 2 mm of difference between
the maximal intercuspal position and the centric occlusion;
and/or over 4 mm (2 mm on any side) of difference
between upper and lower arches measured: between the
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mesial fossae of the first upper premolars with respect to
the cusps of the first lower premolars; and the mesiopalatal
cusp of the first upper molars with respect to the central
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fossae of the first lower molars. A Boley gauge
(Beerendonk, nº REF 042-750-00; Dentaurum GmbH &
Co., KG, Ispringen, Germany) will be used for these
intraoral measurements.
No periodontal disease (except for chronic severe cases

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with grade 3 mobility), fibromyalgia nor neuropathic pains

are exclusion criteria.
Study Network, Training, and Responsibilities

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The therapy provider (USP) has expertise (over 30 years)

in TMD diagnosis and occlusal adjustment (OA) therapy.
The basic source of learning is the study of Schuyler
(1935), and from the practical viewpoint, the occlusal
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adjustment of complete dentures and clinical full mouth

rehabilitation after wax-up study in a semiadjustable
articulator.
Trial center standard equipment requirements:
Dental lamp and chair with dynamic rotary instruments.
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Restorative material (adhesive composite; Herculite , Kerr)

Topical professional fluorides.
Axiograph (Gerber facebow, Gerber Condylator Service;
Zürich, Switzerland). Kinesiograph (K7 Evaluation system;
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Myotronics Inc., Kent, WA, US).

Interventions 11a Interventions for each group with sufficient detail to allow
replication, including how and when they will be
administered
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Enrolled participants will be randomized in equal
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proportions between active or placebo occlusal adjustment
therapy.
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1 Active therapy. Therapy should be customized for each
participant’s condition. The bases for occlusal adjustment
(OA) were first described by Schuyler in 1935 and are
currently in general use. The subtractive procedure is
limited by the thickness of the enamel. The first step will
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consist of the elimination of premature tooth contacts
during retruded jaw closure. Unlike in Schuyler’s
procedure, the decision was made to grind the mandibular
or maxillary tooth marks to preserve quality contacts (no
interferences or hyper balance) on the nonworking side
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during lateral motion. This will be carried out even on the
nonworking side to protect the TMJ. The second step will
include reduction of the steeper lateral anterior guidance;
the magnitude of this alteration will be estimated by the
following equation:
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(right CP)  (left LG) = (left CP)  (right LG)
Recordings and measurements of condylar path (CP; using
conventional axiograph) and lateral guidance (LG, using
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electronic kinesiograph, Myotronics K7® device) angles
will be performed using a previously described method
(Santana-Mora et al., 2013).
The first step will be achieved when: 1) most (if not all)
teeth are in contact with their antagonists during jaw
closure; 2) habitual jaw closure in maximal intercuspal
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position can be performed without any jaw deflective

movements from the centric relation; and 3) the jaw
muscles are relaxed, allowing jaw closure with no
spontaneous resistance against jaw manipulation performed
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by an experienced clinician.
Regarding the second step, if the reduction of the steeper
LG angle is not enough to change the side used to chew, a
composite, placed mainly in the canine tooth, can be used
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to increases the flatter LG on the habitual chewing side.

Overcorrection is expected to compensate for a masticatory
preference on the opposite side to the handedness.
Blue articulating ribbon (200 µm, BK1, Dr. Jean Bausch
KG, Köln, Germany) will be used to discern contact
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between any of the teeth in question. A diamond rotary

instrument will be used (ISO 909, Komet Instrument; Gebr.
Brasseler GmbH & Co., Lengo, Germany).
Therapy outside the trial will not be offered for any eligible
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participant.
2 Placebo therapy. Placebo occlusal adjustment will take

place in a manner identical to the real occlusal adjustment.
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However, a specially fabricated inactive rotary instrument
will be used, and no enamel will be removed.
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The clinician (Dr USP) will always act as if the real
therapy was being delivered, and all participants will
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receive the same counseling and management, mainly to
achieve the placebo effect and avoid the nocebo effect and
inter-subject differences (van Laarhoven et al., 2011).
All participants should say that they felt better and had
more dental contacts at the end of the therapy sessions,
suggesting that all participants considered that they had
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received real OA.
All participants will be reevaluated and treated

(refinement) one month later, and independently assessed
at the 3-month and 6-month post-therapy visit.
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11b Criteria for discontinuing or modifying allocated
interventions for a given trial participant (e.g., drug dose
change in response to harms, participant request, or
improving/worsening disease)
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A participant’s doubts about the usefulness of treatment, or
dental pain elicited by OA therapy, will be the criteria for
discontinuing the allocated intervention for a given trial
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participant.
11c Strategies to improve adherence to intervention protocols,
and any procedures for monitoring adherence (e.g., drug
tablet return; laboratory tests)
Face-to-face adherence reminder sessions will take place at

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the initial product dispensing-session and at each study

visit thereafter.
Intensive professional topical fluoridation will be
administered at post-therapy, 3-month and 6-month follow-
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up visits.
11d Relevant concomitant care and interventions that are
permitted or prohibited during the trial
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Concomitant analgesics or other therapies are not

prohibited but are advised against in this trial.
Maneuvers requiring extended jaw-opening, such as
extensive dental therapy sessions or excessively painful
jaw-opening (for example for pharyngeal explorations) are
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discouraged during the trial.

All patients attending the Service were informed about
normal jaw function and that overuse, misuse, or
parafunction could provoke or worsen their complaints
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(Crane et al., 2012). They received instructions on keeping

the jaw muscles relaxed and avoiding nonfunctional tooth
contacts and excessive mouth opening. This information
will be provided at any visit for the trialist responsible for
44
assessments (except by the therapy provider). After
therapy, all participants were encouraged to chew
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alternately, or on the more comfortable side, avoiding the
conscious, deliberate use of a given side.
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Prohibited Concomitant therapies
Splint therapy (owned or new) and/or additional
adjustments outside of the trial are prohibited.
Outcomes 12 Primary, secondary, and other outcomes, including the
specific measurement variable (e.g., systolic blood
pressure), analysis metric (e.g., change from baseline, final
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value, time to event), method of aggregation (e.g., median,
proportion), and time point for each outcome. Explanation
of the clinical relevance of chosen efficacy and harm
outcomes is strongly recommended
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1. Primary Outcome Measures
1. Self-reported affected-side pain-intensity across the trial
on a 0–10 numerical rating (NRS) and/or visual analogue
(VAS) scales (0 = no pain, 10 = worst possible pain)
(Huskisson, 1974; Dworkin et al., 2005). Time frame:
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baseline, 1-month, 3-month and 6-month follow-up.
Efficacy will be demonstrated by showing significantly
superior pain relief at the 6-month visit with the active
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treatment as compared with placebo.
2. Secondary Outcome Measures

1. Maximum unassisted jaw opening, using a Boley gauge.
Limited if ≤38 mm (females) or ≤40 mm (males).
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2. Chewing function (alternate vs. one habitual chewing

side):
2.1.a. Clinically observed habitual chewing side (if at
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least 7/10 almonds by the same side);

2.1.b. alternately, observing the lateral bolus of chewing-
gum placement the chewing tests at 7 masticatory
sequences each of 15 s duration: consistent right and left
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side bolus placement is defined as either right or left side

bolus placement in a total of three consecutive observations
in a single participant; e .g., right/right/right. Predominant
right or left side bolus placement is either right or left side
bolus placement in two of three consecutive observations
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in a single subject; e.g. right/right/left (Christensen &

Radue, 1985).
2.2. Interview: actual and retrospective chewing function
(Diernberger et al., 2008).
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3. Quality of life (mental component) assessed by the self-

administered Spanish validated questionnaire SCL-90-R
(Derogatis et al., 1976; González de Rivera et al., 1989).
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Pain-intensity and maximum comfortable, and full,
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unassisted jaw opening are the most relevant outcomes
regarding efficacy and harms. These are the main
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complaints, main therapy objectives, and pain intensity was
used to determine the sample size and the early stopping
rules.
3. Other Pre-specified and Diagnostic-Related Outcome

Measures: Please See eTable 3.
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Participant 13 Time schedule of enrolment, interventions (including any
timeline run-ins and washouts), assessments, and visits for
participants. A schematic diagram is highly recommended.
The main outcomes of interest are the pain-intensity and
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maximum unassisted mouth opening improvement and
time-therapy interaction. Enrolled participants will be
assessed using the full battery of instruments (eTable 3)
before allocation (baseline outcomes). Time between
enrollment and allocation-assignment-therapy day will
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vary from 7 to 14 days; eFigure 1 shows timeline of events
for the study. eFigure 2 shows a schematic flow diagram of
the study.
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Sample size 14 Estimated number of participants needed to achieve study
objectives and how it was determined, including clinical
and statistical assumptions supporting any sample size
calculations
The primary endpoint will be the average change in pain

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score from baseline to the six-month assessments. Based

on data from our previous study, we assume a standard
deviation of 2.4 for this variable. We will test the null
hypothesis of no treatment effect at the two-sided 0.05
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level. With a fixed sample size design, a total sample size

of 88 subjects with complete follow-up would provide
power of 0.8 to detect a difference with a change in pain
score of 1.5 units between the real and placebo treatment
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groups.
To guard against the possibility of large treatment effects
that call for early termination of the study, the study will
employ an interim analysis plan with a single interim
analysis after 70% of participants have completed the six-
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month visit. Using the Lan-DeMets version of the O’Brien-

Fleming stopping rule, the critical value to declare
statistical significance at the interim analysis will be
+2.438, corresponding to a nominal two-sided P value of
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0.0146. The total sample size for this design is 44 per

treatment group. To guard against loss of power because of
loss to follow-up of up to 20% of participants, the target
46
sample size for the study will be 55 per treatment group or
110 in total.
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Those responsible for the interim analysis will have the
option of stopping the study early without compromising
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statistical validity if results at the interim analysis meet the
criterion for a statistically significant difference between
the treatment and placebo groups.
Recruitment 15 Strategies for achieving adequate participant enrolment to

reach target sample size
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The subjects screened to achieve the target sample size will
include mainly females, as this symptomatology affects
mainly females (4:1 ratio; De Leeuw and Klasser, 2013).
The enrollment period will extend over 12 months. The
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clinical center involved in the MAP (occlusal therapy for
chronic TMD-pain) was chosen based on documentation of
patient availability, among other things. Patients are
recruited for MAP at the University Hospital of A Coruña
(Spain) through two primary mechanisms: (1) patients
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currently suffering from TMD referred to the Hospital
requesting therapy for their symptoms (main source of
participants); and (2) identification in the TMD patient
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registry (hospital database). The hospital patient registry
(database) has been maintained since 1990 and currently
contains over 5,000 TMD patients. It is estimated that over
500 new TMD patients are seen each year, while a smaller
number become inactive due to relocation, change of
health care provider, etc. Once identified in the database,
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patients potentially eligible for inclusion in the MAP study

will be contacted by the nurse coordinator who will explain
the study and ascertains the patient’s interest. If interested,
the patient will be seen at the University Hospital of A
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Coruña where more detailed evaluations will be performed.

Subjects will not receive financial compensation to
participate.
Assignment of interventions
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Allocation
Sequence 16a Method of generating the allocation sequence (e.g.,
generation computer-generated random numbers) and list of any
factors for stratification. To reduce predictability of a
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random sequence, details of any planned restriction (e.g.,

blocking) should be provided in a separate document that
is unavailable to those who enroll participants or assign
interventions
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Participants in this open label trial will be randomly

assigned to either the placebo or the experimental group
with a 1:1 allocation as per a computer generated
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randomization schedule using permuted blocks of random
sizes. The block sizes will not be disclosed, to ensure
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concealment. To match the main characteristics of patients
and disease and balance the number of patients in each
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group, the randomization included stratification by sex and
by muscular-/joint-pain. The purpose of this stratification
was to increase the study validity and comparability
between active and placebo therapy groups.
An independent statistician from the Harvard School of
Public Health (Prof. James H. Ware) generated the
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treatment assignment schedule using 1:1 blind
randomization and sent it to the administrative coordinator
and nurse (Ms. Teresa Pazos Fernández) in the Department
of Oral and Maxillofacial Surgery who hold the
randomization schedule in a locked file.
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TPF made 4 envelope series (female articular, female
muscular, male articular, male muscular) introducing on
each envelope the treatment the corresponding code
according to assignment schedule in a numbered
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consecutive manner. The envelopes are closed and signed
by TPF; after this, USP also signed all envelopes.
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Prof JHW sent codes directly to the therapy caregiver. This
code will be known only by the therapy provider (USP).
The code was immediately sent to the Chair of the DSMB
and will remain in a closed envelope during the trial. This
envelope could be opened by the DSMB in the case of an
unexpected adverse event or a serious urgent reason for it.
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A new therapy code R/S would then be used if the ultimate

decision was to continue the trial.
A code A/B for the study treatments active/placebo (or
placebo/active) therapy will be assigned by Ms TPF, and
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stored in closed sealed envelopes by the administrative

person (blinded) responsible for the locked study data.
Allocation 16b Mechanism of implementing the allocation sequence (e.g.,

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concealment central telephone; sequentially numbered, opaque, sealed

mechanism envelopes), describing any steps to conceal the sequence
until interventions are assigned
The researchers will obtain informed consent for assess

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eligibility, will present the study to a participant eligible for

enrolment, will obtain signed informed consent for MAP
trial, perform all baseline outcome measures, and then will
obtain the treatment assignment.
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The administrative coordinator in the Department of Oral

and Maxillofacial Surgery will provide treatment
assignments at the moment the therapy is initiated. Ms.
Pazos, for later verification, will write the participants
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assigned to code group A/B therapy in the schedule
correlatively.
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All persons, participants, researchers and administrators are
blinded to the allocation and assignment procedure. All
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these people but the therapist are unaware of the study
group to which trial participants have already been
assigned, upon study group assignment and beyond; the
DSMB, data handler (administrative person) and data
analysts are blinded with respect to the assignment. Data
will be managed as participant from A or B group (instead
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of the type of therapy).
Implementation 16c Who will generate the allocation sequence, who will enroll
participants, and who will assign participants to
interventions
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Trial investigators will strive for complete separation of the
individuals involved in the steps before enrolment
(sequence generation process and allocation concealment
mechanism) from those involved in the implementation of
study group assignments.
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The sequence is unpredictable and will be locked away
from all trialists and even the person who generated it. The
assignment schedule will be accessed only by the
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coordinating nurse, who will receive careful instructions to
avoid showing it to any other person until the study is
finalized.
Allocation will take place after all baseline measurements
have been completed.
Four groups of 60 envelopes each were made (following
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stratification: female/male and join/muscular pain); the

group description (female-muscle / female-articular /
muscular male / male joint pain) was written on each
envelope; also were numbered consecutively from. Miss
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Pazos wrote the corresponding schedule therapy-code on a

card and covered it with another card that was opaque to
light. She closed each envelope and signed it as a precint
on the flap. At the start of therapy, Mss Pazos will open the
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corresponding envelope (correlated ascending numbering

and group), she will see the therapy code and write it in the
form of the patient and she will inform the clinician. The
card containing the code will be reintroduced in the
envelope and will be back sealed with personal patient's
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identifier adhesive sticker of the official national health

system; Ms Pazos and Dr Santana-Penin jointly will sign as
precinct the closed envelope; envelopes were kept by Ms
Pazos, until the end of the study to audit and verify the data
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later (only opened in an open session of the DSMB and

TSC and persons that oversee trial).
All participants will remain in the therapy-group to which
they were originally assigned.
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Most visits are performed at the University Hospital of A
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Coruña. However, most first or main procedures (main
therapy visit) will be performed at the University Dental
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Clinic of the Santiago de Compostela University; the
reason is that placement of composite is anticipated in
some participants, and the university clinic is the adequate
setting (Surgery Service have not instrumental and
materials for operative dentistry). After each participant’s
enrolment, when he/she is lying on a dental chair for
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receive therapy procedure, the therapy provider ask by
telephone to Miss Pazos the therapy code corresponding to
the particular participant and their group (female/male and
articular/muscular).
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Miss Pazos upload the therapy code at the corresponding
enrolled participant thorough the Openclinica files; In
addition, resave the code on the envelope, close, sign, and
writes out the name of the participant; finally returns to
store the envelope in the locked locker.
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Blinding 17a Who will be blinded after assignment to interventions (e.g.,
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(masking) trial participants, care providers, outcome assessors, data
analysts) and how
To protect the study against bias, and achieve objective

assessment of the therapeutic effect of the intervention
(Ergina et al., 2009), the therapy provider will be separate
ot
from all post-therapy patient assessments; they will also

play no part in baseline measurements, eligibility criteria,
randomization, allocation and assignment procedures.
Assessments regarding clinical recovery will be conducted
tn
by assessor/s blinded to treatment allocation and

calibrated-training with the therapist. The main assessor
(Dr JLC) is an experienced clinician with over 25 years of
experience assessing and treating TMD patients, and will
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be responsible for the determination of the maximum

unassisted jaw-opening; a second measure will be
performed by the other calibrated specialists of the
Hospital Service (JCL, MPC and FLF). The assessment of
kinesiography and axiography recordings and
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measurements will be performed by experienced clinicians

(Prof MJM and Dr USM). The administrative coordinator
(Miss Pazos ) outside the research team, will feed a file
with most relevant/safety data (specifically pain-intensity,
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maximum unassisted mouth opening and unexpected

adverse events, including time-frame) into the computer in
separate datasheets; this file will be accessible to the
DSMB in a numbered form and with no modifiable files.
50
Data can only be completed by the administrative person,
before storage in a locked database.
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All researchers, even the person responsible for the
allocation, will have no access to information about the
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allocation (codes A/B); the therapy code will be known
only by the therapy provider.
Therapeutic procedures will be performed by the clinician
and the participant in a quiet room with the door open. Any
persons who enter the room cannot look into the mouth of
the patient or at the instruments, and must avoid any
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comment or question regarding the therapeutic procedure.
The auxiliary persons will be able to verify the physician-
patient relation but will not be able to discern the type of
therapy performed.
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17b If blinded, circumstances under which unblinding is
permissible and procedure for revealing a participant’s
allocated intervention during the trial
To maintain the overall quality and legitimacy of the MAP

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trial, code breaks should occur only in exceptional
circumstances when knowledge of the actual treatment is
absolutely essential for further management of the patients.
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Investigators are encouraged to discuss with the DSMB
and Ethics Committee physician if they believe that
unblinding is necessary. Due to the characteristics of the
study, this possibility is extremely unlikely. The
investigators are encouraged to maintain the blind as far as
possible. The actual allocation must NOT be disclosed to
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the patient and/or other study personnel including other site

personnel, monitors, corporate sponsors or project office
staff; nor should there be any written or verbal disclosure
of the code in any of the corresponding patient documents.
tn
The Investigator must report all code breaks (with reason)

as they occur on the corresponding CRF (case report form,
eTable 4).
Data collection, management, and analysis
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Data collection 18a Plans for assessment and collection of outcome, baseline,
methods and other trial data, including any related processes to
promote data quality (e.g., duplicate measurements,
training of assessors) and a description of study
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instruments (e.g., questionnaires, laboratory tests) along

with their reliability and validity, if known. Reference to
where data collection forms can be found, if not in the
protocol
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TMD-pain condition, according to RD/TMD criteria

(Schiffman et al., 2014) will be diagnosed by the
experienced clinicians of the Hospital Service.
51
1. Primary outcome:
1. Pain-intensity of the affected side will be measured by
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self-administered questionnaire using a validated visual
analogue scale (VAS) Huskisson, 1974). Time frame:
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baseline, 3-month and 6-month follow-up. The primary
outcome will be the average pain intensity improvement at
6 months in respect of the baseline scores. Clinical
important difference 1.5 units (Dworkin et al., 2010).
2. Secondary outcomes:
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2.1. Maximum comfortable jaw opening, using a Boley
gauge (including overbite). Defined as limited if ≤38 mm
(females) or ≤40 mm (males). Calibrated interobserver
reliability should yield an intraclass correlation coefficient
(ICC) of .95. Two independent calibrated observers will
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assess this outcome during the baseline and at the 6-month
visits; discrepancies of over 1 mm will be resolved by
discussing results, performing a new measurement or
consulting a third clinician.
2.2. Chewing function (alternate vs. one habitual chewing
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side): Clinically observed habitual chewing side: if at least
7/10 almonds are chewed on the same side
(Paphangkorakit et al., 2006); (or) the side where the
chewing-gum are placed first cicle and at 15, 20, 25, 30,
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35, 40 ane 45 s (if at least 6 of the 8 is placed on the same
side). Interview: actual and retrospective chewing function
(Diernberger et al., 2008): Do (and did) you prefer one side
for chewing?; answers: No—yes, the left side—yes, the
right side—I do not know.
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2.3 Quality of life assessed by the self-administered

Spanish validated questionnaire SCL-90-R (Derogatis et
al., 1976; González de Rivera et al., 1989).
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The examiners neither know (or guess the group) nor

examine the occlusion when evaluating the TMD status of
the subjects at any phase, also not during the possible re-
treatment after 6 months. Effort is made to carefully ensure
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that Dr Lopez-Cedrun and Ms Pazos make/record their

registrations independently.
3. Other Pre-specified Outcome Measures:

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Please see eTable 3 for outcomes, measurement method

and time frame.
Training and certification plans

Each researcher has been trained in the study requirements,
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clinical examination, standardized measurement of

maximum mouth opening, performing axiographic and
kinesiographic recordings and measurements, and
52
requirements for laboratory specimen collection including
serum samples, counseling for adherence to therapy and
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the eliciting of information from study participants in a
uniform reproducible manner.
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The data to be collected and the procedures to be
conducted at each visit will be reviewed in detail.
Each of the data collection forms and the nature of the
required information will be discussed in detail on an item
by item basis. Entering data forms, responding to data
discrepancy queries and general information about
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obtaining research quality data will also be covered during
the training session.
Serum samples (3 mL) at baseline and after 6-month
follow-up will be frozen in liquid nitrogen and stored in an
identifiable (but not named) manner until the end of the
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study. Data from the laboratory will be securely
transmitted in batches and quality controlled; i.e. data will
be entered and verified in the database at the Hospital with
a subset later selected for additional quality control.
Appropriate edit checks will be in place at the key entry
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(database) level.
All self-administered tests used (NRS/VAS-pain scale,
McGill pain, SDN4, SCL-90-R questionnaires) have been
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validated in several studies.
Axiography and kinesiography are reproducible (Santana-
Mora et al., 2013) and three sets of recordings will be
performed routinely.
The interobserver/researchers measures agreement for
maximum unassisted mouth opening was assessed before
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the study began between Drs. JLC and USP, yielding an

intraclass correlation coefficient (ICC) of .95 (TMD-pain
patients) and .97 in healthy adults, in a series of over 50
people.
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18b Plans to promote participant retention and complete

follow-up, including list of any outcome data to be
collected for participants who discontinue or deviate from
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intervention protocols
Retention
As with recruitment, retention addresses all levels of
participation.
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Study investigators and staff:

• Provide verbal and/or written feedback to all participants
about the results of the screenings.
• Maintain interest in the study through materials, mailings
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and/or telephone calls.

• Send letters/mail/’phone calls to all participants prior to
the final data collection, reminding them of the upcoming
53
data collection, treatment refinement, prophylactic
fluoridation and dental hygiene.
d
• Be as flexible as possible with study schedule and
proactive in resolving any questions or problems.
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Participant Evaluations in the Case of Treatment
Discontinuation or Study Withdrawal
All randomized participants completing the 6-month
evaluation schedule will have fulfilled the clinical and
laboratory evaluation requirements for the study.
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All randomized participants who are prematurely
discontinued from the MAP study will be considered off
study therapy/on study and will follow the same schedule
of events as those participants who continue study
treatment except for the adherence assessment. All of these
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participants will be followed through 6 months as
scheduled, and will have the following clinical and
laboratory evaluations performed.
Randomized participants prematurely discontinued from
the study at any time after therapy evaluation will have the
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complete last visit clinical (at any time) and laboratory (if
more than 3 months alter therapy) evaluations performed.
If a participant reveals their intention to discontinue the
trial, they will be invited to an assessment of “final data” if
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at least 1 month has elapsed after the initial therapy; these
data will be used as the final data according to the
intention-to-treat principle. If the participant does not agree
or if less than a month has elapsed after therapy, the
participant will be excluded from the final analysis.
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Participant Retention
Once a participant is enrolled or randomized, the study site
will make every reasonable effort to follow the participant
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for the entire study period. It is projected that the rate of

loss-to-follow-up on a complete study basis will be at most
10%. Study site staff will be responsible for developing
and implementing local standard operating procedures to
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achieve this level of follow-up.
Participant Withdrawal
Participants may withdraw from the study for any reason at
any time, while retaining the right to receive conventional
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treatment. The investigators also may withdraw

participants from the study in order to protect their safety
and/or if they are unwilling or unable to comply with
required study procedures after consultation with the
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Protocol Steering Committee, Statistical and Data

Management Center, Protocol Statisticians, and DSMB.
54
Participants also may be withdrawn if the study sponsor or
government or regulatory authorities terminate the study
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prior to its planned end date.
Note: Early study discontinuation due to economy or
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motivation of researchers is not a reason for withdrawal
from the study.
Data 19 Plans for data entry, coding, security, and storage,

management including any related processes to promote data quality
(e.g., double data entry; range checks for data values).
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Reference to where details of data management procedures
can be found, if not in the protocol.
Data Forms and Data Entry

In the MAP trial [Restoring MAsticatory function as
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treatment for chronic Pain: a randomized placebo-
controlled trial], all data from all clinical instruments
(physical) will be entered physically and electronically.
This will be carried out at the participating site where the
data originated. er
Original study forms will be entered and kept on file at the
University Hospital of A Coruña (CHUAC). A subset will
be requested later for quality control; when a form is
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selected, the participating site staff will pull that form.
Participant files are to be stored in numerical order and
stored in a secure and accessible (only to the administrative
coordinator) place and manner. Participant files will be
maintained in storage for a period of 4 years after
completion of the study.
ot
Data for the DSMB include pain-intensity (and the percent

of time suffering severe pain) on the both sides, maximum
unassisted jaw-opening and adverse events; a file in excel
format containing these outcomes at baseline and at the 3-
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and 6-month follow-up assessments will be created and

posted in a OpenClinica® folder accessible under password
by the DSMB in a non-modifiable and blinded manner;
data can be entered only at the CHUAC by the
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administrative coordinator (Ms Teresa Pazos).

Openclinica sent passwords automatically to the e-mail of
DSMB members.
Data will consist of the exact transcripts of the signed
forms of self-administered instruments and the maximum
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mouth opening, recorded by an independent researcher,

usually JLC, or other independent calibrated expert trialist.
Although very unlikely to occur, minor (for material error)
modifications can be carried out, and a report of any
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changes and causes should be recorded.
Data Transmission and Editing
55
The data entry screens will resemble the paper forms
approved by the steering committee. Data integrity will be
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enforced through a variety of mechanisms.
Referential data rules, valid values, range checks, and
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consistency checks against data already stored in the
database (i.e., longitudinal checks) will be supported.
The option to choose a value from a list of valid codes and
a description of what each code means will be available
where applicable. Checks will be applied at the time of
data entry into a specific field and/or before the data is
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written (committed) to the database.
Modifications to data written to the database will be
documented through either the data change system or an
inquiry system. Data entered into the database will be
retrievable for viewing through the data entry application
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system. The type of activity that an individual user may
undertake is regulated by the privileges associated with
his/her user identification code and password.
Data Discrepancy Inquiries and Reports to overseeing

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persons
Additional errors will be detected by programs designed to
detect missing data or specific errors in the data. These
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errors will be summarized along with detailed descriptions
for each specific problem in Data Query Reports, which
will be sent to the Data Managers, to the Steering
Committee and to the DSMB.
The data manager who receives the inquiry will respond by
checking the original forms for inconsistency, checking
ot
other sources to determine the correction, modifying the

original (paper) form entering a response to the query. Note
that it will be necessary for data managers to respond to
each inquiry received in order to obtain closure on the
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queried item.
The main researcher (JLC) together with the administrative
coordinator at the CHUAC will be responsible for making
appropriate corrections to the original paper forms
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whenever any data item is changed. Written documentation

of changes will be available via electronic logs and audit
trails.
Biochemistry reports will be sent via e-mail (to Ms. Pazos)
when data are received from the Hospital Lab; these items,
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planned only for ancillary reports, will be entered only at

the end of the study.
Security and Back-Up of Data

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All forms, including printed and digital storage systems

related to study data, will be kept in locked cabinets.
Access to the study data will be restricted to the
administrative coordinator alone.
56
A password system will be utilized to control access to the
DSMB only for lecture use and overseeing collaborators.
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These passwords will be changed on a regular basis. All
reports will be prepared such that no individual subject can
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be identified.
A complete back-up of the database will be performed
monthly; the previous documents will be stored for the
duration of the study for data verification. Discs containing
photographs and video will be stored off-site in a climate-
controlled facility and will be retained indefinitely.
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Incremental data back-ups will be performed on a daily
basis. Back-ups of periodic data analysis files will also be
kept. These discs will be retained at the off-site location
until the study is completed and the database is published.
In addition to the system backups, additional measures will
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be taken to back-up and export the database on a regular
basis at the database management level.
Study status reports

The Data Management Team will send every 6-Months
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email reports with information on missing data, missing
forms, and missing visits, to the chair of the DSMB.
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Description of Hardware at DCC
For maximum programming efficiency, the Excel database
management system within a Google drive support will be
employed for this study. Integrity will be checked through
a variety of mechanisms including stored procedures,
stored triggers, and declarative database integrity for
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between table verifications. Security will be enforced using

passwords and may be assigned at different levels to
groups and individuals. The DSMB and researchers will
have access for use in lectures only.
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Statistical 20a Statistical methods for analyzing primary and secondary

methods outcomes. Reference to where other details of the
statistical analysis plan can be found, if not in the protocol.
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For analysis of baseline characteristics, qualitative

variables will be expressed as frequencies and percentages
(25th–75th percentiles) and continuous variables as means
(standard deviation). Fisher´s exact test or McNemar test
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will be used to compare the distributions of binary

variables; Student’s t-test will be used to compare
normally-distributed variables, and the Wilcoxon or Mann-
Whitney U test for non-normally distributed continuous
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variables.
For the primary and secondary endpoints, we will test the
hypothesis that the average reduction in self-reported pain-
intensity from baseline to 6 months are greater in the
57
treated than in the placebo arm, and the increase in
maximum spontaneous mouth opening (and maximum
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unassisted jaw opening) and the reduction of psychological
distress (SCL-90-R test), we will test for a treatment effect
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by analysis of covariance, with the baseline value of the
outcome as a covariate. Time, treatment group, and time by
treatment interaction, will be entered stepwise as fixed
effects. These effects will remain in the model if their
parametric coefficients are significant or the model fit is
increased significantly (in terms of Akaike (AIC) or
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Schwarz (BIC) criteria). Moreover, in all cases, random
effects will be explored for the intercept (patient) and slope
(time and patient).
Fisher’s exact test will be used to assess the change in the
chewing side (binary variable: 0 = no change, 1 = change-
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favorable).
We will examine the residual to assess model assumptions
and goodness-of-fit. We will calculate Relative Risk (RR)
and RR Reductions (RRR) with corresponding 95%
confidence intervals to compare dichotomous variables,
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and difference in means will be used for additional analysis
of continuous variables. P-values will be reported to one
decimal places with P-values less than 0.001 reported as P
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< 0.001. For all tests, we will use two-sided P-values with
a level of significance of alpha 0.05.
We propose to test therapeutic efficacy using two analysis
sets; the intention-to-treat and the “per protocol” analysis.
Criteria for determining the “per protocol” group
assignment were established by the Steering Committee
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and approved by the DSMB before the trial began; per

protocol analyses will exclude all those patients who had
no completed the treatment originally allocated in the MAP
trial, main therapy study visit and the refinement therapy
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one month later, do not meet eligibility or do not adhere to

protocol. Given our expectation that very few patients will
cross over or be lost to follow-up, these analyses should
agree very closely.
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We propose declaring that the treatment provides

therapeutic efficacy, only if the results are shown to be
significant using both the “intention to treat” and the “per
protocol” analysis sets.
The software R version 2.15.0 (R Development Core
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Team) including the nlme (for linear mixed models) and

the Design packages (for logistic regression models)
available at http://www.R-project.org, or IBM SPSS last
version will be used.
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20b Methods for any additional analyses (e.g., subgroup and

adjusted analyses)
58
We plan to conduct one subgroup analysis, both with a
strong biological rationale and possible interaction effects.
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• Subgroups with therapy completed vs. uncompleted
(hypersensitivity)
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A secondary analysis of the primary endpoint will adjust
for those pre-randomization variables, which might
reasonably be expected to be predictive of favorable
outcomes.
• TMD condition: Joint pain vs. muscle pain.
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• Degree of psychosocial dysfunction.
• Sex and age
• Handedness preference (Edinburg inventory)
• Hemimandibular retrognathia side
• Affected vs. unaffected sides.
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A tertiary analysis will include subgroups combining two
complementary outcomes:
• Baseline vs. 6-month follow-up pain-intensity related to
percent of time suffering from significant pain.
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• Responders: patients with a reduction ≥30% or ≥50 % of
pain-intensity at the 6-month follow-up with respect to
baseline.
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20c Definition of analysis population relating to protocol
nonadherence (e.g., as-randomized analysis), and any
statistical methods to handle missing data (e.g., multiple
imputation)
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Outcomes could be missing for patients who withdraw

from the trial. We will report reasons for withdrawal for
each randomization group and compare the reasons
tn
qualitatively. The effect that any missing data might have

on results will be assessed via sensitivity analysis of
augmented data sets. Dropouts (essentially, participants
who withdraw consent for continued follow-up) will be
included in the analysis, using modern imputation methods
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for missing data.

The main feature of the approach is the creation of a set of
clinically reasonable imputations for the respective
outcome for each dropout. This will be accomplished using
a set of repeated imputations created by predictive models
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based on the majority of participants with complete data.

The imputation models will reflect uncertainty in the
modeling process and inherent variability in patient
outcomes, as reflected in the complete data.
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After the imputations are completed, all of the data

(complete and imputed) will be combined and the analysis
performed for each imputed-and-completed dataset.
Rubin’s method of multiple (i.e., repeated) imputation will
59
be used to estimate treatment effect. We propose to use an
odd number to allow use of one of the datasets to represent
d
the median analytic result).
These methods are preferable to simple mean imputation,
or simple “best-worst” or “worst-worst” imputation,
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because the categorization of patients into clinically
meaningful subgroups, and the imputation of their missing
data by appropriately different models, accords well with
best clinical judgment concerning the likely outcomes of
the dropouts, and therefore will enhance the trial’s results.
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Monitoring
Data 21a Composition of the data monitoring committee (DMC);
monitoring summary of its role and reporting structure; statement of
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whether it is independent from the sponsor and competing
interests; and reference to where further details about its
charter can be found, if not in the protocol. Alternatively,
an explanation of why a DMC is not needed
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A Data and Safety Monitoring Board (DSMB) has been
established.
The DSMB is independent of the study organizers. During
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the period of recruitment to the study, interim analyses will
be supplied, in strict confidence, to the DSMB, together
with any other analyses that the committee may request.
This may include analyses of data from other comparable
trials. In the light of these interim analyses, the DSMB will
advise the TSC (trial steering committee) if, in its view: the
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active intervention has been proved, beyond reasonable

doubt, to be different from the control (placebo
management) for all or some types of participants. The
TSC can then decide whether or not to modify intake to the
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trial. Unless this happens, however, the TSC, PMG [Project

management group], clinical collaborators and study office
staff
(except those who supply the confidential analyses) will
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remain ignorant of the interim results.

The frequency of interim analyses will depend on the
judgement of the Chair of the DSMB, in consultation with
the TSC. However, we anticipate that there might be one
interim analyses after 70% of participants have completed
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the six-month follow-up visit, and one final analysis.

The data and safety monitoring board (DSMB) consists
of:
1. Chair of DSMB. Investigator with expertise in
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current clinical trials (temporomandibular joint

disorders) conduct and methodology: Professor
Pentti Alanen. Turku University, Finland.
60
2. Prof. Dr. Julián Álvarez Escudero. Professor and
chair and Head of the Anesthesiology and Pain;
d
University Hospital and University of Santiago de
Compostela, Spain.
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3. Biostatisticians:
3.1. Professor Mª Carmen Carollo, Department of
Statistics, University of Santiago de Compostela,
Spain.
3.2. Dr Francisco Gude, Head of Statistics Service,
University Hospital Complex of Santiago de
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Compostela, Spain.
4. Expert in the clinical aspects of the disease being
studied: Joao Carlos Pinho. Associate Professor.
Head of Occlusion and Orofacial Pain Unit. School
of Dentistry. University of Porto. Portugal.
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The DSMB will meet the criteria and responsibilities of the
NIH guidelines. The DSMB is responsible for ensuring that
the intervention does not have unanticipated adverse
effects. The stopping rule would be applied to the primary
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outcome, in this case, pain-intensity.
Decisions/recommendations for extending recruitment
(based on whether actual control arm response rates are
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different from those predicted rather than on emerging
differences) or for extending follow-up will be open to the
DSMB.
Statement of whether it is independent from the sponsor
and competing interests (page 79).
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N.B. Dr. Florencio Monje did not attend the meetings. He

will not be invited to the next meetings of the DSMB.
Instead, Professor Julián Álvarez-Escudero will be invited.
21b Description of any interim analyses and stopping
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guidelines, including who will have access to these interim

results and make the final decision to terminate the trial.
To guard against the possibility of large treatment effects

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that call for early termination of the study, the study will
employ one interim analysis plan with a single interim
analysis after 70% of participants have completed the 6-
month follow-up visit. Using the Lan–DeMets version of
the O’Brien-Fleming stopping rule, the critical value to
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declare statistical significance at the interim analysis will

be +2.438, corresponding to a nominal two-sided P value
of 0.0146. The total sample size for this design is 44 per
treatment group. To guard against loss of power because of
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loss to follow-up of up to 20% of participants, the target

sample size for the study will be 55 per treatment group or
110 in total.
61
Those responsible for the interim analysis will have the
option to stop the study early without compromising
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statistical validity if results at the interim analysis meet the
criterion for a statistically significant difference between
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the treated and placebo groups. The DSMB will have
access to these interim results, unidentified participants and
blinded to the therapy code A/B; however, the trial steering
committee will have the final decision to terminate the
trial, in accordance with the CAEI.
Harms 22 Plans for collecting, assessing, reporting, and managing
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solicited and spontaneously reported adverse events and
other unintended effects of trial interventions or trial
conduct
Unexpected adverse events will be reported individually
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(Turk et al., 2003) following the criteria of the Common
Terminology Criteria for Adverse Events v4.0 (NIH,
2009).
An adverse event refers to an untoward occurrence during
the trial, which may or may not be causally related to the
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intervention or other aspects of trial participation. An
adverse effect is a type of adverse event that can be
attributed to the intervention. In this study we can made
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distinctions between adverse events that are anticipated
versus unanticipated. The possibility of an increase in pain
intensity, reduction in maximum opening range, worsening
of the impaired chewing function, or dental
hypersensitivity are anticipated, although mainly in the
placebo therapy group, as can happen due to spontaneous
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evolution of the illness, typically fluctuant; In our study an

adverse event will be defined as any untoward medical or
dental occurrence in a subject without regard to the
possibility of a causal relationship. Reports of adverse
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events will be collected after the subject has provided

consent and enrolled in the study. If a subject experience
an adverse event after the informed consent document is
signed (entry) but the subject has not started to receive
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study intervention, the event will be reported as not related

to study therapy. All adverse events occurring after entry
into the study and until the end of the study will be
recorded. An adverse event that meets the criteria for a
serious adverse event (SAE) between enrollment and the
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end of the study will be reported to the DSMB and to the

Ethics Committee as an SAE.
A serious adverse event for this study is defined as any
untoward medical occurrence that is believed by the
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investigators to be causally related to study-therapy and

results in any of the following: life-threatening condition
(that is, immediate risk of death, which will never be
expected in this study); severe or permanent disability,
62
prolonged hospitalization, or a significant hazard as
determined by the DSMB.
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For these outcomes, binary measures, e.g. mortality and
complications, logistic regression will be used to test the
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intervention effect, controlling for covariates when
appropriate.
All harms will be reported to relevant groups (sponsor,
Steering Committee, CAEIC, DSMB), which is an
important process that is subject to local regulation. Key
considerations include the severity of the adverse event,
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determination of potential causality, and whether it
represents an unexpected or anticipated event.
Auditing 23 Frequency and procedures for auditing trial conduct, if

any, and whether the process will be independent from
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investigators and the sponsor
The researchers and the DSMB and all overseeing persons

will discuss the protocol in detail and identify and clarify
any areas of weakness. At the start of the trial, the
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administrative coordinator and the steering committee will
conduct a tutorial on the web-based data entry system. The
coordinators will practice entering data so that the monitors
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can confirm that the coordinators are proficient in all
aspects of data entry, query response, and communication
between the steering committee and the DSMB, and, if
necessary, with the Ethics Committee (CAEI). They will
audit the overall quality and completeness of the data,
examine source documents, interview investigators and
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coordinators, and confirm that the clinical center has

complied with the requirements of the protocol. The
steering committee will verify that all adverse events have
been documented in the correct format, and are consistent
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with protocol definition; the steering committee will

review the source documents as needed, to determine
whether the data reported in the web-based system are
complete and accurate; the chair of the DSMB and the
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secretary of the CAEI will have access to the data on-line.

Source documents are defined as medical charts or
information, associated reports and records including initial
hospital admission reports and the complete set of
diagnostic outcomes and adverse events and effects.
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The monitors will confirm that the regulatory binder is

complete and that all associated documents are up to date.
The regulatory binder should include the protocol and
informed consent (all revisions), regional review board
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(CAEI) approvals for all of the above documents, CAEI

correspondence, case report forms, investigator’s and
DSMB’s agreements.
63
Scheduling monitoring visits will be a function of patient
enrollment, site status and other commitments. The CAEI
d
and the DSMB will notify the site in writing at least three
weeks prior to a scheduled visit. The investigators will be
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available to meet with the monitors, DSMB, CAEI, or
representatives of the Institutional or Regional Health
Service. Although notification of the visits will include the
list of patients scheduled to be reviewed, the monitors
reserve the right to review additional TMD patients.
If a problem is identified during the visit (i.e., poor
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communication with the above mentioned persons,
inadequate or insufficient staff to conduct the study,
missing study documents) the steering committee or one of
the principal investigators will assist in resolving the
issues.
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The focus of the visit/electronic monitoring will be on
source document review and confirmation of adverse
events. The monitor will verify the following variables for
all patients: initials, date of birth, sex, signed informed
consent, eligibility criteria, date of randomization,
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treatment assignment (coded), adverse events, and
endpoints.
Ethics and dissemination
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Ethical issues
World Medical Association Declaration of Helsinki (2013).
Organic Law 15/1999, of the 13 of December on the
protection of information of a personal nature.
Royal Decree 1716/2011, of 18 November, regulating the
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treatment of human biological samples.
Research ethics 24 Plans for seeking REC/IRB approval

approval
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This protocol and the template informed consent forms

contained in Appendix II were reviewed and approved by
the sponsor and the applicable IRBs/ECs [institutional
review boards/ethical committees] with respect to scientific
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content and compliance with applicable research and

human subjects regulations.
The protocol, site-specific informed consent forms (local
languages and English versions), participant education and
recruitment materials, and other requested documents—and
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any subsequent modifications— also were reviewed and

approved (approval number 2009/017; updated on
November 29, 2013) by the Autonomic Committee of the
Research Ethics of Galicia (COMITÉ AUTONÓMICO DE
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ÉTICA DE LA INVESTIGACIÓN DE GALICIA: CAEI).

Subsequent to initial review and approval, the responsible
ethical committees (CAEI) will review the protocol at least
annually. The principal investigator will provide safety and
64
progress reports to the CAEI at least annually and within
three months of study termination or completion. These
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reports will include the total number of participants
enrolled, dropouts and causes, serious adverse events and
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effects and summaries of each DSMB review of safety
and/or efficacy or futility.
Protocol 25 Plans for communicating important protocol modifications
amendments (e.g., changes to eligibility criteria, outcomes, analyses) to
relevant parties (e.g., investigators, RECs/IRBs, trial
participants, trial registries, journals, regulators)
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Modification of the Protocol
Any modifications to the protocol which may impact on
the conduct of the study, potential benefit to the patient or
may affect patient safety, including changes of study
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objectives, study design, patient population, sample sizes,
study procedures, or significant administrative aspects will
require a formal amendment to the protocol. Such
amendment will be agreed upon by the DSMB, and
approved by the Ethics Committee (CAEI) prior to
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implementation and, when indicated, notified to the health
authorities in accordance with local regulations.
Administrative changes to the protocol are minor
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corrections and/or clarifications that have no effect on the
way the study is to be conducted. These administrative
changes will be agreed upon by the DSMB, and will be
documented in a memorandum. The CAEI may be notified
of administrative changes at the discretion of the steering
committee.
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Consent or 26a Who will obtain informed consent or assent from potential
assent trial participants or authorized surrogates, and how (see
item 32)
tn
One of the main researchers will introduce the trial to each

patient regarding the main aspects of the trial. Patients will
also receive information sheets (Appendix III) in both
Galician and Spanish languages. They will discuss the trial
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with patients in light of the information provided in the

information sheets. Additionally, if a patient asks for
additional information, the researcher will show images of
the mouth of patients before and after therapy, from the
university linked archive; this could include static
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presentation and video reports. Patients will then be able to

have an informed discussion with the participating
consultant.
The participant will provide their written consent that they
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are willing to participate in the trial at least 24 hours later.

Information sheets (Appendix II) and consent forms
(Appendix III) are provided for all participants involved in
the trial.
65
26b Additional consent provisions for collection and use of
participant data and biological specimens in ancillary
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studies, if applicable
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Samples for Biorepositories
Additional biological serum samples (3 mL) will be
obtained to be stored for use in future studies on the
pathology of the stomatognathic system. Serum samples, at
baseline and after 6 months of follow-up, will be collected
and frozen in liquid nitrogen. TMD-related biomarkers
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represent a recent topic; thus, the precise choice of
biomarkers and their determination will be carried out at
the end of the study. Consent will be obtained after specific
information has been provided, and will be included in the
information for prospective participants; this outcome will
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be recommended but not mandatory to include subjects in
the study. The data and specimens will be coded and
identifiable and used specimens and data derived from
them cannot be withdrawn.
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Instructions for Preparation of Requests for an
Ancillary Study
A signed consent form (please see page 52) must be
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obtained from every participant in the ancillary study, if the
data collection/request is not covered in the original
informed consent process for the main MAP Trial.
If a separate consent form is required for the ancillary
study, a copy of the signed ancillary study consent form for
each study participant must be included in the MAP trial
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record. A data file tracking all signed ancillary consent

forms must be maintained by the ancillary study and an
electronic copy of that file must be delivered to the DSMB.
Confidentiality 27 How personal information about potential and enrolled
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participants will be collected, shared, and maintained in

order to protect confidentiality before, during, and after
the trial
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Confidentiality
All study-related information will be stored securely at the
A Coruña University Hospital. All participant information
will be stored in locked filing cabinets in areas with limited
access. All laboratory specimens, reports, data collection,
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process, and administrative forms will be identified by a

coded ID (identification) number only, to maintain
participant confidentiality. All records that contain names
or other personal identifiers, such as locator forms and
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informed consent forms, will be stored separately from

study records identified by code number. All local
databases will be secured with password-protected access
systems. Forms, lists, logbooks, appointment books, and
66
any other listings that link participant ID numbers to other
identifying information will be stored in a separate, locked
d
file in an area with limited access. A notebook with 26
sheets including screening, baseline, postherapy 3-months
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and 6-months follow-up forms was prepared for each
participant (n=110). The administrative coordinator is the
main person responsible for the generation of on-line data,
and can only access them simultaneously with the
clinician, ensuring patient safety and data accuracy. The
data will be transmitted to the steering committee and
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DSMB by virtual private network internet transmission.
All test results will be kept strictly confidential, all
counseling and blood draws will be conducted in private
rooms, and study staff will be required to sign agreements
to preserve the confidentiality of all participants.
re
Participants’ study information will not be released outside
of the study without the written permission of the
participant, except as necessary for monitoring by
government and regulatory authorities.
Declaration of 28 Financial and other competing interests for principal
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interests investigators for the MAP trial
The principal investigators state that they have no

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competing interests to declare.
Trips for members of the DSMB will be funded by a grant
from the Ministry of science and investigation to the MAP
trial
Access to data 29 Statement of who will have access to the final trial data set,
and disclosure of contractual agreements that limit such
ot
access for investigators
According to the World Medical Association, the trial

investigators retain the right to access data.
tn
Intra-Study Data Sharing

The Data Management Coordinating Committee (jointly,
the administrative coordinator (blinded)) will oversee the
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intra-study data sharing process. Project data sets will be

housed on the Project Accept web site and/or the file
transfer protocol site created for the study, and all data sets
will be password protected.
One web page was created to offer on-line information to
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the DSMB of the MAP trial. Only the administrative

coordinator will have complete acces; however, all input or
change will be recorded. Members of the DSMB will have
only-read access to on-line data but having no possibility
Pr
for modifications. One certification will be done at the

endo of the study to ensure safety of data and use.
OpenClinica® (© 2004-2010 Akaza Research LLC and
collaborators) will be used for this pourpose.
67
Ancillary and 30 Provisions, if any, for ancillary and post-trial care, and for
post-trial compensation to those who suffer harm from trial
d
care participation
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The trialists, sponsors and principle investigators will
provide the best possible care for participants’ healthcare
needs that arise as a direct consequence of trial
participation (e.g., intervention-related harms). The
participants are dependent on the research team but also on
the National Health Care Service. Although subsequent
vie
access to the interventions is limited by cost or lack of
availability a priori, this study includes post-study access
by study participants to interventions identified as
beneficial in the study with no payment, or access to other
appropriate care or benefits according to local laws.
re
Patients will not receive any financial compensation for
participation. Liability insurance (MAPFRE, Number
0971370090602; from Dec 2013 to Dec 2016) was
obtained before approval by the Ethics Committee to
protect patients from any harm as a result of treatment.
er
Dissemination 31a Plans for investigators and sponsor to communicate trial
policy results to participants, health care professionals, the
public, and other relevant groups (e.g., via publication,
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reporting in results databases, or other data-sharing
arrangements), including any publication restrictions
Publications
Data analysis and release of results

ot
The aim of the principal researchers is to protect the

integrity of the major objectives of the study; data that
break the blind will not be presented prior to the release of
mainline results. No abstracts will be presented at any
tn
meetings during the study.

Data from a preliminary study assessing the same main
outcomes after performing the same therapy in a sample of
21 patients could be included (Thabane et al., 2010). The
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abstract of these results is not yet published although it is

posted at the clinicaltrials.gov Registry (NCT00899717).
Review process
The main paper will be discussed by the Publication
Subcommittee (JLC, USP, MJM, JHW and USP), and with
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the chair of the DSMB.
Primary outcome papers

The primary outcome papers of the MAP trial are papers
Pr
that present outcome data on pain intensity on the affected

side, maximum unassisted mouth opening, the habitual
chewing side and the patient’s quality of life (SCL-90-R
scores). The determination of whether or not a particular
68
analysis represents a primary outcome will be made by the
Steering Committee on the recommendation of the
d
Publications Subcommittee.
we
Other study papers, abstracts and presentations
All papers must be approved by the Publications
Subcommittee before they are submitted.
Close-out Procedures
MAP may terminate at the planned target of 1 year after
vie
the last participant has been randomized, or at an earlier or
later date if the circumstances warrant modification.
Regardless of the timing and circumstances of the end of
the study, close-out will proceed in two stages:
• Interim period for analysis and documentation of study
re
results.
• Debriefing of participants and dissemination of study
results.
A. Interim
Every attempt will be made to reduce to an absolute
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minimum the interval between the completion of data
collection and the release of the study results. We expect to
take about 6 months to compile a report of the final results
pe
for an appropriate journal.
B. Reporting of study results
The study results will be released to the participating
physicians, referring physicians, patients and the general
medical community.
We plan to publish the results independently of whether
ot
positive or negative (non-significant) findings are obtained.

All investigators are aware and motivated to committing to
the ethical responsibility to disclose unbiased information,
mainly by avoiding overestimation of benefits,
tn
underestimation of harms, or any detrimental impact on

patient care and research. Any restrictions are imposed a
priori for the MAP trial.
Since the pathology which was the focus of this study is
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often seen initially by pediatricians and general

practitioners, we intend to make our results known through
journals devoted to disseminating results of MAP in the
field of biomedicine.
ep
31b Authorship eligibility guidelines and any intended use of

professional writers
Assignment of Writing Committees

Pr
Topics suggested for presentation or publication will be

circulated to the PIs (principal investigators) of the MAP
trial. The PI of an ancillary study should be considered for
lead author of material derived from this study. Disputes
69
regarding authorship will be settled by the study chair after
consultation with the chair of the steering committee.
d
Reports of the FSGS-CT: Classes of Reports
we
There are four classes of reports of the MAP:
A. Reports of the major (primary and secondary) outcomes
of the study.
B. Reports addressing in detail some aspects, or other pre-
specified tertiary outcomes of the MAP, but in which the
data are derived from the entire study.
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C. Systematic review of TMD pain conditions, diagnostic
and/or therapeutic; this can be submitted/published during
the trial period.
D. Relevant case report/s.
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Authorship Policy
The authors of MAP publications will be listed as detailed:
JLC, USM, MJM, JHW, USP.
The FSGS participant box will list all professionals that
have participated in the FSGS-CT for a minimum of one
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year after the decision of the steering committee.
31c Plans, if any, for granting public access to the full
protocol, participant-level data set, and statistical code
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Data sharing statement
No later than 3 years after the collection of the 6-month
post-randomization interviews, we will deliver a
completely de-identified data-set to an appropriate data
archive for sharing purposes.
ot
Appendices
Informed 32 Model consent form and other related documentation given
consent to participants and authorized surrogates
materials
tn
Sample patient informed consent (please see Appendix II;

Pages 45, 51 and 60).
Biological 33 Plans for collection, laboratory evaluation, and storage of
specimens biological specimens for genetic or molecular analysis in
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the current trial and for future use in ancillary studies.

Serum samples will be collected at baseline and after the 6-
month follow-up visit for future use in ancillary studies on
TMD-related circulating biomarkers.
ep
Pr
70
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75
eTable 1. Characteristics of traditional vs. proposed active therapy
Traditional Proposed
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Interarch Contacts
Centric Position Only posterior teeth All (if possible)
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Lateral eccentric
Working side Canines All (if possible)
Nonworking side No dental contacts All posterior teeth (if
possible)
Masticatory function Not evaluated Diagnosis of the habitual
chewing side
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Goal - Masticatory function
rehabilitation
Lateral dental guidance Not evaluated Steepness diagnosis
Goal - Reduce steepness
Condylar path Not evaluated Steepness diagnosis
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Goal - Influence on lateral anterior
guidance reduction
Procedure Occlusal reshaping Occlusal reshaping (and/or
composite addition)
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eTable 2. Patient’s classification of TMD pain according to the Diagnostic Criteria for
Temporomandibular Joint (TMJ) Disorders (DC/TMD) (Schiffman et al., 2014)
I. TEMPOROMANDIBULAR JOINT Right Left

DISORDERS
1 Joint pain
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A. Arthralgia
B. Arthritis
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II. MASTICATORY MUSCLE DISORDERS

1. Muscle pain
A. Local myalgia
B. Myofascial pain
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A. Myofascial pain with referral
Patients could present in the I and/or II TMD group, or with other TMD signs, including internal TMJ-
derangement.
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eTable 3. Outcomes’ assessment and STUDY PERIOD
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TIMEPOINT
Name of the outcome Method of measurement Baseline Post-therapy 3-Mo 6-Mo
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Primary outcome
Pain intensity, affected 0–10 VAS/NRS (Huskisson,
* * * *
side 1974; Dworkin, 2005)
Secondary outcomes
Maximal unassisted mouth
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Boley gauge (mm) * * * *
opening
Chewing function Observed. Interview * * *
Quality of life SCL-90-R Questionnaire * *
Other Pre-specified Outcome Measures:
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Maximal comfortable Boley gauge (mm) * * * *
mouth opening
Assisted mouth opening Boley gauge (mm) * * * *
Patient’s perception of
0-10 point Likert scaleer * * * *
reduced movement
Max. lateral / protrusive
Kinesiography * *
jaw displacement
% time in severe pain 0–100 (%) NRS * * *
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Pain severity Von Korff et al., 1992 * * *
Pain-intensity on the
0–10 VAS/NRS * * *
initially unaffected side
Pain-dimensions McGill Pain Questionnaire
* *
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Neuropathic pain DN4 Questionnaire

* *
(Bouhasira et al., 2005)
Patient impression 7 point Likert scale
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Circulating biomarkers Blood levels (Slade et al., * *

2011)
Occlusal pressure Fuji dental prescale® * *
Radiographic defect
Periodontal disease (if Probing depth
* *
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indicated) Clinical attachment level

Tooth mobility (periotest®)
(Diagnosis-therapy related outcomes)
Lateral Guidance angles
Kinesiography * * *
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Lateral shift opening

Condylar Path angles Axiography * *
Laterality Oldfied, 1971 (10 items) *
Credibility test Borkovec & Nau (1972) * *
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Sociodemography Elliott et al., 2005 * *

Physicians and patients Interview (yes, not)
*
blinding
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Adverse Events WHO scale * * *
VAS, visual analogue scale; NRS, numerical rating scale; MFIQ, mandibular function impairment
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questionnaire; OHIP, oral health impact profile.
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eTable 4. Participant’s Form for DSMB. Participant MAP-Number: ………..
Allocated therapy: A B
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Outcome Baseline 3-months 6-months
Affected side: Rigth; Left, Bilateral
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Pain-intensity ritght side (0–10 VAS/NRS)
Pain-intensity left side (0–10)
% time in severe pain (0–100, NRS)

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Maximum comfortable opening
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Maximum unassisted jaw opening
(Specify event, causes, and date of presentation)

Unexpected Adverse Events
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eFigure 1. Study design: timeline of events for the study.
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Assessed for eligibility (n>1000)
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Excluded (n= …)
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• Not meeting inclusion criteria (n= )
• Declined to participate (n= )
• Other reasons (n= )
Enrollment
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R andom ized (88≤n≤110)
Allocation
Allocated to A intervention (44≤n≤55) Allocated to B intervention (44≤n≤55)
• Received allocated intervention (n= ) • Received allocated intervention (n= )
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Follow-up
Discontinued intervention (n= ) Discontinued intervention (n= )
Causes: Causes:
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Interim analysis
Com pleted analysed (n ≤ 31) Com pleted analysed (n ≤ 31)

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Analysis
Com pleted analysed (44≤n≤55) Com pleted analysed (44≤n≤55)

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eFigure 2. Study design: flow diagram of participants.

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APPENDIX I
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WHO Trial Registration Data Set (Version 1.2.1)
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1. Primary Registry and Trial Identifying Number
clinicaltrials.gov, ID number:
2. Date of Registration in Primary Registry

Date when trial was officially registered in the Primary Registry.
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3. Secondary Identifying Numbers
Other identifiers besides the Trial Identifying Number allocated by the Primary Registry, if any. These
include:
o Universal Trial Number (UTN): U1111-1134-0832
o Current Controlled Trials ISRCTN Number:
o Sponsor name and Sponsor-issued trial number: Urbano Santana-Penín
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4. Source(s) of Monetary or Material Support
Institute of Health Carlos III of the Ministry of Science and Innovation of the Government of Spain
(PI11/02507).
5. Primary Sponsor
o Urbano Santana-Penín. Email address: urbano.santana@usc.es ; Telephone number: +34
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647344093; Postal address: Facultad de Medicina y Odontología, C/ Entrerríos s/n 15782 Santiago
de Compostela, A Coruña, Spain.
The individual, organization, group or other legal entity which takes responsibility for initiating,
managing and/or financing a study. The Primary Sponsor is responsible for ensuring that the trial is
properly registered. The Primary Sponsor may or may not be the main funder.
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6. Secondary Sponsor(s)
Have agreed with the primary sponsor to take on responsibilities of sponsorship, and act as the Primary
Sponsor’s legal representative in relation to some or all of the trial sites.
o Jose López-Cedrún. Head of the Oral and Maxillofacial Surgery Department. Complejo
Hospitalario Universitario A Coruña. Calle Jubias 84, 15006 La Coruña, Spain. E-mail:
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lopezcedrun@centromaxilofacial.com Tel: +34 981178000 Ext 292021; Fax: 0034 981178052

o María J. Mora (MJM). Head of the Stomathology Unit, University Hospital Complex of
Santiago de Compostela, and Professor of the University of Santiago de Compostela. 15782
Santiago de Compostela, A Coruña, Spain. E-mail: mariajesus.mora@usc.es Tel:
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7. Contact for Public Queries

Email address: urbano.santana@usc.es ; Telephone number: +34 647344093; Postal address: Facultad
de Medicina y Odontología, C/ Entrerríos s/n 15782 Santiago de Compostela, A Coruña, Spain.
8. Contact for Scientific Queries
There must be clearly assigned responsibility for scientific leadership to a named Principal
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Investigator. The PI may delegate responsibility for dealing with scientific enquiries to a scientific
contact for the trial. This scientific contact will be listed in addition to the PI.
o Urbano Santana-Penín. Professor and chair of Orofacial Pain and Prosthodontics. Email
address: urbano.santana@usc.es ; Telephone number: +34 647344093; Postal address: Facultad de
Medicina y Odontología, C/ Entrerríos s/n 15782 Santiago de Compostela, A Coruña, Spain.
o Jose López-Cedrún. Head of the Oral and Maxillofacial Surgery Department, Complejo
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Hospitalario Universitario A Coruña, Calle Jubias 84, 15006 La Coruña, Spain. E-mail:
lopezcedrun@centromaxilofacial.com Tel: +34 981178000 Ext 292021; Fax: 0034 981178052
9. Public Title
Title intended for the lay public in easily understood language.
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Trial of treatment for chronic facial pain.
10. Scientific Title

Scientific title of the study as it appears in the protocol submitted for funding and ethical review.
Include trial acronym if available.
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The MAP Trial: Restoring Masticatory function as treatment for chronic Pain: a randomized
clinical trial.
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11. Countries of Recruitment
The countries from which participants will be, are intended to be, or have been recruited at the time of
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registration.
Spain. Other centers (Public Academic Hospitals) from the European Union countries will be
welcome to participate; the therapy provider will be available to perform the same therapies.
12. Health Condition(s) or Problem(s) Studied

Primary health condition(s) or problem(s) studied (e.g., depression, breast cancer, medication error).
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Chronic Unilateral Temporomandibular Joint Disorder (TMD) Pain. (Joint-pain and/or
muscle-pain).
13. Intervention(s)
Intervention Name: For drugs use generic name; for other types of interventions provide a brief
descriptive name.
o Occlusal adjustment therapy (OA)
Intervention Description:
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o Therapy intervention (Active arm). Therapy consists of the elimination of premature tooth
contacts during retruded jaw closure, and reduction of the steeper lateral anterior guidance angle;
the magnitude of this alteration will be estimated by the following equation:
(right condylar path)  (left anterior guidance) = (left condylar path)  (right anterior guidance)
o
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Control intervention (Placebo arm). Placebo occlusal adjustment will take place in a
manner identical to the real adjustment. However, no enamel will be removed.
14. Key Inclusion and Exclusion Criteria

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Inclusion and exclusion criteria for participant selection, including age and sex. Other selection criteria
may relate to clinical diagnosis and co-morbid conditions; exclusion criteria are often used to ensure
patient safety.
Inclusion Criteria. Patients suffering joint and/or muscle pain, according to DC/TMD (Schiffman et
al., 2014) (eTable 1). Completely dentate adults (18–65 years old) with normal occlusion suffering
from significant (≥4 and ≤9 scores, on a 0–10 visual analogue scale-NRS; 0 = no pain to 10 = worst
possible pain) (Huskisson, 1974; Dworkin, 2005) chronic (over 6 months) pain for which they had
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requested therapy, referred to the Hospital Service, after more than 6 months of conservative therapies
(Greene, 2010; De Leeuw and Klasser, 2013; Freitas et al., 2013). Subjects suffering disc derangement
will be included if the aforementioned symptoms are also present. Almost-completely dentate patients
will be included if they were treated before enrollment by a conventional or implant-supported fixed
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partial prosthesis allowing similar potential comfortable chewing on both sides.

Exclusion Criteria. Psychosis, major depression, substance abuse, cognitive impairment, addiction to
morphine or derivates (Turk et al., 2003). Litigation or asking for disability/retirement compensation
for chronic pain. Dental care professionals. Patients who underwent orthodontic therapy during the last
2 years. Degree 2 to 3 of tooth mobility (Miller, 1950). Patients with any pain that is more severe, in
the same location as, or cannot be clearly distinguished from TMD pain. Bilateral symptoms (scores of
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over 4 on the “less” affected side). Individuals for whom minimally-invasive occlusal adjustment could
not achieve occlusal equilibration.
15. Study Type

Study type consists of:
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o Study interventions
Study design including:
o Method of allocation: randomized (1:1)
o Masking: participants, data collectors, outcomes assessors, statisticians, DSMB, and all
researchers and personnel except the therapy provider (whom it is impossible to blind). The therapy
provider will not assess any study outcomes and will not see the patient after therapy is performed
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and refined one month later.

o Assignment: parallel.
o Purpose. Therapeutic efficacy.
o Phase 3
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o Treatment allocation will be determined by an independent statistician using the method of
randomized permuted blocks (Akobeng, 2005) and with a code A/B. Block sizes will vary from 2 to
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6 as determined by the statistician and will not be disclosed to other investigators. The treatment
assignment schedule will be sent from the statistician to the administrative staff of the Hospital
Service and will be maintained in a locked file. A code A/B for active or placebo therapy will be
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assigned using 1:1 randomization; this code will be only known to the therapist, and will be stored
in a sealed envelope by the member of staff responsible for the locked study data. Assignments of
enrolled participants to active or placebo treatment will be done independently by the Hospital
administrative coordinator of the study.
16. Date of First Enrollment

o Anticipated date of enrolment of the first participant: May 31st, 2014.
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17. Target Sample Size
o Number of participants that this trial plans to enrol in total: 110.
18. Recruitment Status
Recruitment status of this trial:
o Pending: participants are not yet being recruited or enrolled.
19. Primary Outcome(s)
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Outcomes are events, variables, or experiences that are measured because it is believed that they may
be influenced by the intervention.
o Name of the outcome: self-reported spontaneous affected-side pain-intensity across the trial.
This Primary Outcome was used in sample size calculations, and will be the main outcome used to
determine the effects of the intervention.
Method of measurement used: a 0–10 visual analogue scale (0 = no pain, 10 = worst possible pain)
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(Huskisson, 1974).
The timepoints of primary interest: baseline, 3-month and 6-month follow-up.
20. Key Secondary Outcomes
o Name of the outcome: Maximum unassisted jaw opening.
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Method of measurement used: using a Boley gauge (including overbite).
Jaw opening is defined as limited if ≤38 mm (females) or ≤40 mm
(males).
The timepoints of primary interest: baseline, 3-month and 6-month follow-up.
o Name of the outcome: Chewing function (alternate vs. one habitual chewing side).
Method of measurement used: Clinically-observed habitual chewing side: a) if at least 7/10 chewin-
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gum are chewed on the same side; b) the side used first during gnatographic recordings while
chewing gum. Interview: actual and retrospective chewing function (Diernberger et al., 2008).
The timepoints of primary interest: baseline, and 6-month follow-up.
o Name of the outcome: Quality of life.
Method of measurement used: self-administered Spanish validated questionnaire SCL-90-R
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(Derogatis et al., 1976; González de Rivera et al., 1989).

The timepoints of primary interest: baseline, 6-month follow-up.
21. Analysis plan
o A linear mixed model analysis will be performed for comparisons of most variables and a
logistic regression model will be used for measuring the probability/risk of change of the chewing
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side between baseline and six months; additionally, McNemar’s test could be used.
22. Interim analysis plan and stopping rules
o The data and safety monitoring board will be responsible for activating early stoppage. The
study will employ an interim analysis plan with a single interim analysis after 70% of participants
have completed the six-month visit. Using the Lan–DeMets version of the O’Brien-Fleming
stopping rule, the critical value to declare statistical significance at the interim analysis (under both
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intention-to-treat and per-protocol sets) will be +2.438, corresponding to a nominal two-sided P-

value of 0.0146.
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APPENDIX II
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INFORMATION SHEET (for prospective participants)
For prospective participants in the research study entitled “MAP Protocol: Restoring
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physiological jaw closure and masticatory function as treatment for chronic pain: a
randomized clinical trial”
PRINCIPAL RESEARCHERS AND PROMOTERS: Dr. José López-Cedrúm, Chief of the Maxillofacial
Surgery Service of the University Hospital Complex of A Coruña and Dr Mª Jesús Mora and Dr. Urbano
Santana-Penín, University Professors, Faculty of Medicine and Dentistry, University of Santiago de
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Compostela.
This document aims to offer information about an objective investigative study designed to evaluate the
usefulness of a clinical procedure for patients who suffer pain and/or limitation of mouth opening.
Patients are invited to participate in a six-month clinical trial, submitting themselves to treatment under
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the conditions explained in this document. This study is being carried out in the University Hospital
Complex of A Coruña and in the Faculty of Medicine and Dentistry of the University of Santiago de
Compostela and was approved by the Clinical Research Ethics Committee of Galicia (Ref.: 2009/017;
updated on November 2013).
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If you decide to participate in this study, you will receive personalized information from the researchers,
which you must read carefully beforehand. You should ask any and all questions necessary to understand
the details of the study. If you prefer, you may take this document and review it with others, taking the
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necessary time to decide whether or not to participate.
Participation in this study is completely voluntary. You may decide not to participate or, if you agree to
participate, you may change your mind, revoking consent at any time without the obligation to give any
explanation. We assure you that this decision will not affect your relationship with your doctor nor the
medical attention you have the right to.
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Mouth and facial pain and/or the limitation of mouth opening appear to be due to a disease that can manifest
itself in different ways in each person. Commonly referred to as temporomandibular disorders (TMD),
it includes different diseases of the temporomandibular joint, chewing muscles, or both. Both
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manifestations of this disorder - pain and the limitation of mouth opening - can be highly disabling and
dramatically affect quality of life.
The cause of TMDs, as in your case, has still not been scientifically established; as such, it is considered
unknown. For this reason, all treatments are empirical. In light of previous controlled studies, it appears
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that it is as effective to do nothing as it is to use known procedures such as medication, splints, and
acupuncture. This is because it is a benign disease, and approximately 80% of cases evolve favorably even
when no treatment is provided. Even so, sometimes the disease evolves unfavorably and becomes chronic,
causing severe pain and/or limitation in jaw mobility. Often the mouth cannot be fully opened, and eating
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is difficult.
Although simply touching the affected area can induce pain, it can present spontaneously or, in particular,
when trying to eat. The pain can be minor, but sometimes patients describe it as the worst pain imaginable.
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Another problem is the limitation of mouth opening. A person without a disorder of the chewing apparatus
will, on average, be able to open the mouth a distance of over 40 (± 3) mm (females open somewhat less
than males) and can open as much as 65 mm. Limited jaw opening of less than 38 mm is generally not very
problematic. However, when the ability to open is limited to less than approximately 28 mm, chewing
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becomes difficult and usually painful and important functions such as using a spoon to eat or brushing the
teeth on the tongue-facing surfaces cannot be completed correctly. The provision of necessary dental
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treatment may also be impeded, especially in the posterior areas of the mouth. Medical procedures such as
intubation, where surgical interventions are necessary, can also be problematic. We consider the limitation
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of opening capability to be a variable in itself and believe everyone should be able to regularly open the
mouth within normal limits.
The treatment we propose, as clinicians and researchers, is the normal procedure employed at the University
of Santiago de Compostela for more than 30 years. This treatment has long been used in dentistry, but it is
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difficult to carry out and requires a high level of specialization or specific training. Thus, the researchers
are not proposing that you receive a new treatment without knowing the effect that it will have on the
evolution of your condition. Rather the researchers are convinced that this treatment is appropriate in your
case. It is recommended only after detailed observation of your case and in the belief that you will benefit.
The treatment is painless.
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This treatment requires a diagnosis of the form and function of the structures that compose the chewing
apparatus and the establishment of a possible cause of your disorder and the probabilities of success
(recovery or minimization and avoidance of further damage).
The treatment consists of a highly precise grinding of the dental enamel. Only the minimum necessary
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reduction will be made in order to prevent those teeth which first come into contact from forcing the jaw
into abnormal displacement so that the rest can come into contact. By lightly grinding away the excess, the
jaw is permitted to close without having to change its own path of centered closing. Consequently, the teeth
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receive all the force of the elevating chewing muscles of the jaw (150 Kg or more) but not other joints that
are not designed to receive those forces. By way of example, imagine stepping on a pebble that forces you
to place your foot in an irregular or uncomfortable position, and in order to correctly support the foot you
end up twisting the whole leg. Physically you can understand that if instead of receiving the full force on a
couple of antagonist teeth, the force is distributed across the entire dental arch - 14 pairs of teeth - then the
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force received on each tooth is less. Therefore, the potentially traumatic and detrimental effect on the tooth
(which can provoke reflexes and damaging effects in the rest of the chewing apparatus and even in the head
and neck) would be eliminated since those forces would be applied over a surface many times larger, over
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all or almost all the teeth.
Perhaps an example such as the following will help us understand the possible cause of your condition and
why and how we intend to correct it. If we stand on an irregular surface, such as when a pebble gets stuck
under our foot, it requires us to compensate for this irregularity. Consciously or subconsciously, we resort
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to exerting more or less force with this leg, and we may even try not to use it at all if we are going to be in
this position for a long time. As long as the pebble remains under the foot, compensating mechanisms allow
us to manage, but at times we may notice problems in the heel for example, or the knees or hips. Obviously
removing the pebble will allow the body to return to a more normal position avoiding damage to muscles
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elsewhere. Excessive dental contacts can have a similar effect on the chewing apparatus that may explain
some of the symptoms of your condition. Imagine now that the pebble gets stuck to your shoe or to the
bottom of your foot and that you begin to walk. Probably your walking will be difficult, and you may even
do damage to your hips or back. If we reach the conclusion that there is something that doesn’t allow us to
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properly support the foot and that persists when walking, it would seem logical to attempt to eliminate the
impediment. In the same way, interferences or the excessive or premature contact of a tooth could damage
your chewing mechanism and it would be reasonable to try to eliminate those interferences
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Hence, both from a static point of view and from a functional one, the difficulty may be resolved by grinding
down the impediment. Therefore, the closing of the jaw in normal conditions of rest, or when clenching the
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teeth or swallowing, as well as from the functional point of view, may achieve an improvement in chewing.
This disorder, in the opinion of some specialists, tends to appear in individuals who prefer to use only one
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side of the mouth when eating. The treatment aims to allow you to eat comfortably on either side of the
mouth. Occasionally, and temporarily, we may change the preference for chewing from one side to the
other until the more painful and affected side is rehabilitated. Ultimately, a unilateral but alternating
chewing pattern should be possible.
The teeth can detect increments (“grit”) of only 5 microns. For this reason, small discrepancies can have an
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adverse effect, but small corrections can have a very positive effect. The amount of wear needed cannot be
established beforehand; ultimately the nervous and muscular systems guide the clinician as to when a
sufficient amount has been ground down. On occasion we may indicate the possibility of slightly increasing
part of any lost dental tissue if it is necessary to establish correct harmony of the dental contacts. For this
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we may use materials common to the treatment of dental restorations or fillings.
Expected effect, prognosis: the elimination or significant reduction of pain and/or alteration of limited
mouth opening; creation of the conditions necessary to return the joint to its normal position (not always
achieved) and to prevent an increase in joint, muscular, and dental damage.
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It has been reported and we know from experience that some patients stop experiencing pain after some
work has been done and that on occasion pain disappears entirely when a procedure has been performed
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to simulate dental wear. We cannot explain this from a scientific point of view but will try to evaluate this
fact while allowing you to benefit from it. If you were to be “cured” or “not cured” upon receiving this
simulated procedure, it would be your decision whether to submit yourself or not to the actual treatment
afterwards. There are no objective studies that support this procedure as effective, which is one reason this
study is being proposed in this way. The specialist who carries out the procedure is convinced of the positive
impact of the real procedure and has wide experience in carrying it out.
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“Randomization” will be random and participants will be chosen to receive treatment of sufficient
minimal selective grinding of the tooth enamel, or to receive a similar procedure but without grinding down
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the enamel (placebo) in such a way that you will not know if you received real treatment or placebo (blind).
An independent specialist (Dr López-Cedrún), who will not know what type of treatment was received,
will evaluate the data after the treatment (blind assessment). Thus, neither you nor the evaluating clinician
will know the type of treatment that is being evaluated.
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The researchers will offer treatment with the real procedure to those participants who, having received the
placebo, continue to have symptoms and who upon receiving the information, wish to undergo it.
Inclusion in this study does not prohibit you from continuing your normal treatment if you consider it
beneficial. The treatment is intended to be curative. Generally, it will be recommended that you dispense
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with normal treatment and that you avoid the use of a splint since it could modify dental contacts in an
unpredictable way.
Generally this study seeks to achieve the following goals: 1. Do no harm; 2. Correct the cause and thus
remedy the participants’ pathology, particularly painful ones; 3. Avoid other alternative treatments, some
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of them ostensibly more invasive and unpredictable; 4. Act in an ethical and methodologically rigorous
manner and make available in a scientific way the results obtained in this study, whether they be positive,
indifferent, or negative and publish these internationally; 5. Carry out new similar studies, if the results are
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encouraging, with other researchers so as to be able to reach a new paradigm or treatment modality that can
cure in a predictable way those patients who suffer from this pathology. Consequently, we hope to add a
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therapeutic option that currently is not available to the Health Sciences in the field of TMDs.
In reality, for this reason we are not dealing with a new study, in the sense of using patients as participants
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in a study of an unknown or previously untried procedure. On the contrary, the procedure has been used
for many years and will be carried out by a very experienced specialist. Both principal researchers possess
experience in the field of health research.
The work of the research team goes unpaid. The treatment is free for the participants in the study.
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You are being invited to participate because you fit the criteria described in the research protocol.
Basically, following observations made during your visit to the Hospital Service, you may be cured through
simple adjustment of the occlusion (by the selective grinding of the dental enamel).
Given the character of this study and keeping in mind other similar studies, we hope for 29 participants per
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group so that significant conclusions may be obtained.
Participation will consist of undergoing an initial interview in which an attempt will be made to reach
diagnostic and prognostic conclusions about your pathology. This will include the completion of auxiliary
tests such as radiography and occasionally resonance testing, when possible and called for, and non-
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invasive examinations such as the study of jaw mobility and chewing function.
Afterwards, if you are selected, you will be randomly included in one of the two study groups: the treatment
group or the control group (treated with the placebo). In either case you will also be asked to complete a
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psychological test typical of these studies, which seeks to understand the effect that the disorder and pain
has on the state of mind. It will be confidential, as will all your medical history, and will be evaluated by a
psychologist to understand what effect the treatment has on your state of mind and quality of life.
The anticipated treatment will be carried out in two separate visits: the first (main) one typically requires 1
h and a second visit to refine the therapy takes about 15 min. All patients will be informed about the
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treatment (occlusal adjustment) to be received in exactly the same way. You must appear for treatment and
further visits, and you must not require special care. You must agree to the topical application of fluoride
with mouthwashes and daily use of dental pastes for as long as possible. This is beneficial for teeth even if
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no treatment is undergone.
Progress will be evaluated in all cases at 3 months and at 6 months after the main treatment visit. Your
participation will last approximately one year. To benefit the health of the general public, the researchers
carrying out the study, and above all else you as a patient, we will try to evaluate your progress or carry out
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possible readjustments over the next two or three years, as long as you are willing.
The research team could decide to end the study before the expected date or interrupt your participation
because of the appearance of new and relevant information. This information will be shared with the
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participants so they can share in the decision, for safety reasons, or because of a breach in the procedures
of the study.
The only risks or inconveniences appear to be from the grinding down of the enamel, which is irreversible.
Hypersensitivity could appear during the treatment. If this were to occur, your treatment would be stopped
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immediately. Because you would not be able to eat in a vigorous manner, which is what is hoped for, the
treatment could be ineffective.
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This secondary effect will be minimized to the extent possible. You should keep in mind that this enamel
wear, including into the dentine, commonly occurs spontaneously with this pathology, being much more
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aggressive than that which is practiced as part of the therapy whose goal is to reduce or stop this
spontaneous pathological wear or auto abrasion. Fluoride will be the recommended treatment in these cases,
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as will be the avoidance of acidic foods such as vinegar and acidic fruits. As long as the dental
hypersensitivity persists, such foods should only be ingested through a straw and prolonged contact with
dental surfaces should be avoided.
This study is experimental from a formal viewpoint, and as such the normal guidelines for attendance will
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be modified to observe what happens.
Participants will not obtain any direct economic benefit from their participation in this study. Also, they
will not receive any payment for transport to the treatment center.
Scientifically we do not know if the intervention is beneficial, and it is for this reason that we wish to
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study it. The only benefit sought is an evaluation of its future application in the cure and prevention of TMJ,
a pathology that causes facial pain and/or alters jaw movement in the population at large.
Pregnancy and lactation in themselves do not exclude an individual from this treatment. Even so, as
access to radiographs is desirable, the study will exclude women in gestation unless they have had x-rays
taken previously.
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The most frequently used alternatives to this treatment are not specific and not directly curative since
a causal treatment does not exist. The alternatives are occlusal splints, medication (pain relievers, muscle
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relaxants, central nervous system depressants, antipsychotics, anticonvulsants, neuromuscular blockers),
physical therapy, acupuncture and closed or open surgery, including the elimination of the affected
articulation and its replacement with artificial prosthetics. The researchers will inform you in detail about
them. Nevertheless, none of them are considered predictable, and they don’t appear to offer any statistical
improvement when they are compared with no treatment. Other researchers have recently described the
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ineffectiveness of surgical interventions in certain cases and the necessity of further interventions with
unpredictable results.
Remember that normal jaw function and that overuse, misuse, or parafunction could enhance or provoke
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their complaints and you should to keep the jaw muscles relaxed, and to avoid non-functional tooth contacts
and excessive mouth opening.
You will receive a summary of the information that is obtained from the study if you so wish. You
may also receive the results of the tests that are carried out if you so request. As these results may not have
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a clinical application or a clear interpretation, you should discuss them with the doctors carrying out the
study.
The results of this study will be published if accepted by scientific biomedical journals; however, no
information that could lead to the identification of the participants will be included.
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The confidentiality of your data will be protected in accordance with the Organic Law 15/1999, of the
13th of December on the protection of information of a personal nature. At all times, you may access your
information, correct it, or delete it. Only the clinician (Dr Santana-Penín), the study’s monitors, and the
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health authorities, all of whom have the obligation to maintain confidentiality, will have access to all the
data collected in the study. Information that cannot be identified may be transmitted to third parties. In the
case that any information is transmitted to other countries, it will be carried out with a level of protection
of personal information at least equivalent to that demanded by the legislation of our country.
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Serum samples (3 mL) at baseline and at the 6-month follow-up will be obtained and stored identifiably
(but not named) until the end of the study. Laboratory data will be securely transmitted in batches and
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quality controlled; i.e. data will be entered and verified in the hospital database with a subset later selected
for additional quality control.
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Your associated information will be kept in an identified or identifiable form, which means that the
information will include name, initials or surname, clinical history number, etc. The person responsible for
the custody of this information is a member of the administrative personnel, and the information will be
blindly stored in closed envelopes in the archive of the Clinical Hospital of A Coruña for the period of time
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necessary to finalize the study. No researchers will have access to the trial data (except if any unexpected
adverse event should occur, for your safety) during the trial. Following the protocol employed for patients
who use the hospital service, this will be approximately 2 years.
If you agree, these tests will be preserved for future investigative studies related to the present one, with
the same person in charge of them, for 5 years, and in an identifiable manner.
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No negative consequence is expected from participation. The possibility of harm caused by participation
is almost non-existent if we keep in mind that only the loss of a fraction of dental enamel is involved. This
reduction is always kept to the minimum needed to be effective. Other possibilities for harm only appear
possible as a result of unforeseen accidents. We will make every effort to ensure the safety of participants.
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If, as a direct consequence of the treatments carried out in this study, some harm were to come to the
participants, the current legislation would be Law 14/2007 regarding biomedical research.
The Carlos III Institute of Health of the Ministry of Science and Innovation of the Government of Spain
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fund this study. The performance of the researcher's work is non-remunerative. The suggested procedure
and necessary tests will be free for patients.
The benefits of commercial products or patents derived from the study, if there were any, would not be
passed to the patient.
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More information can be given to you by
Dr López-Cedrún at the usual telephone number where you request appointments for the Maxillofacial
Surgery Service of the University Hospital of La Coruña; E-mail: lopezcedrun@centromaxilofacial.com;
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and also by Professor Santana-Penín in the Medicine and Dentistry Faculty of the University of Santiago
de Compostela, Entrerríos s/n 15782 Santiago de Compostela. Email: urbano.santana@usc.es, Telephone:
+34 647 34 40 93
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N.B.: If you prefer a Galician version is also available.

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APPENDIX III
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Informed consent form
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The person who appears in this document
SURNAMES________________________________NAME ___________________AGE________
is a patient who suffers a painful facial pathology that is included in the diagnostic group
“temporomandibular disorders,” in this case more prominent on the ___________ side and in this case
characterized by:
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_________________________________________________________________________
declares that he/she has been INFORMED by the specialist:
Dr. Jose López Cedrún, registration nº 425 (Region X, A Coruña). Maxillofacial surgeon. Chief of
services—University Hospital Complex of La Coruña, and/or
Dr Urbano Antonio Santana Penín. Dental registration nº 28008065 (1st Region, Madrid). Stomatologist,
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Professor of the University of Santiago de Compostela.
Regarding the research project entitled: “MAP Protocol: Restoring physiological jaw closure and
masticatory function as treatment for chronic pain: a randomized clinical trial”
Treatment that will be received and the objective sought: minimal grinding of the dental enamel necessary
to avoid excessive, damaging dental contact, permitting muscle rest and improvement in chewing function.
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Expected effect and prognosis: significant reduction or elimination of pain. A recovery of the ability to
open the mouth within the normal limits (more than 40 mm) where this opening was limited. In summary,
to eliminate the cause that provokes damage of the painful joint and return it to normal function, which is
not always possible, and also to prevent an increase in dental, muscle, and joint damage.
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Special circumstances:
_____________________________________________________________________
Upon receiving this information, I as the patient, or the father, mother or legal representative,
DECLARE that I
• have read and adequately understood the content of the information provided prior to the consent.
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• am satisfied with the information received and, where required, have obtained explanations from
the clinician responsible for the project about the questions raised.
• am aware of the possibility of revoking the consent given, at any time, without need to express a
reason, and without affecting in any way my/his/her later treatment.
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• have received a copy of the informed consent document.

In A Coruña, on the ____ day of _________________, 201...
THE PATIENT, THE SPECIALIST,
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Signed: Dr López-Cedrún or Dr Santana-Penín

Note: You may contact the clinics and researchers at 647 344 093 or by email urbano.santana@usc.es, or
directly at the Maxillofacial Surgery Service at the University Hospital of A Coruña, or the Faculty of
Dentistry (Prosthetics and Orofacial Pain) of the University of Santiago de Compostela, Santiago de
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Compostela at any time during the course of the study,

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APPENDIX IV. DATA COLLECTION FORMS
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Investigators brochure (IB) and CRFs [case report forms]
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Participant I – SCREENING Date: 201… / …..… /
…
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Phone: E-mail:
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Could we explore to you to asses if you can participate in a prospective clinical trial to treat facial pain?:
NO (causes) ……………………………… Yes: If you agree, please continue:
What is your chief complaint?:
……………………………………….…………………………………………
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X=pain, global.
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Z=pain in the
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worst moment
…...………… Treatment for TMD:

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When symptoms started?:

…………………………………………………
Indemnities, retirement, legacy:
….………………………………………………………………………………
Intraoral examination
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Fixed partial prosthesis/implants 

………………………………………………………………………...
Occlusion:
…………………………………………………………….………………………………………
Periodontal disease: ……………………………………….…Tooth mobility (over 3): teeth
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………………
Caries, teeth loosening:  ……………………..…….. Restorable: 
……….…….…………………...
Prosthesis/implants 
………………………………………………………….….……..…………………
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Exclusion criteria?: explain

……………………………………………………….……………………………
Immediate restoration commitment 
...............................................................................................................
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Potentially enrollable: YES ;NO . If subject is not excluded at this time:
Written study inform, lecture, explanation . Invitation for an extensive diagnosis: ACEPT: YES . NO
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Participant signature: Dr signature:
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Participant …………………………. II - Baseline condition 201.. / ………… /
…
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Tel: E-mail:
MRI, CBCT, Panoramic (OPG) Rx:
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………………………………………………………………………………
Patient’s TMD condition according to DC/TMD (Schiffman et al., 2014)
I. TEMPOROMANDIBULAR JOINT DISORDERS
1 Joint pain Right TMJ Left TMJ
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A. Artrhralgia
B. Arthritis

1. Muscle pain Right side Left side
A. Local myalgia
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B. Myofascial pain
Patients could present I and/or II TMD group, and other TMD signs, including internal derangement.
10 Almonds (R/L): … /…
Maxim
Comfort (without pain): ….. / …..
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Full, unasissted: .…. / …..
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Assisted: ….. / …..
opening
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Describe R / L where the gum at all times
1º ciclo 15s 20s 25s 30s 35s 40s 45s
Do (and did) you prefer one side for chewing?: No ; yes, left side; yes, right side; I do not
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know.
Splint?: No; yes
…………………………………………………………………………………...………
Orthodontics?: No; yes:Fixed; Orthopedics.
………………………………………………………..
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Intraoral exploration
1. Maximal mouth opening: comfortable(without pain): …. /Unassisted: …. /Assisted: .… (mm).
2. Hemimandib. retrognathia (midline, Angle class): Symmetric ; right , left .
3. Occlusal Quality:............….……………………………………………………
4.1. Probing deep over 3mm:  : …..………………..………....................
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4. Perio.
4.2. Periodontal Activity  ……………………….…….……..........…...
4.3. Radiographic defect depth  : ...…………..…..…..............................
4.4. Tooth mobility 0-3): : .......………..…….……...…………..…........
5. Dental decay: :
…....……………………………….……………..……….……................................
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6. Fixed partial prosthesis/implants 

…………………………………….…………….………………
7. Graphic recordings. 7.1. Axiography

7.3. Prescale
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8. Video/ photographic images.

9. Implementation of self-administered questionnaires. SCL-90-R ; McGill: DN4
Questionnaire (including clinical exploration); MFIQ; Oral Health Impact Profile. Credibility
test
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Participant signature:
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…
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X=pain, global.
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Z=pain in the
worst moment
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During what proportion of time do you experience severe pain?:

0% 1 20% 30% 40% 50% 60% 70% 80% 90% 100%
0
%
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0% = never in severe pain 100% = always in severe pain

Headache intensity in recent weeks (If any)
0 1 2 3 4 5 6 7 8 9 10
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0 = no pain worst possible pain=10
Other painful Areas?  : ………………………….………….…………………

How much can you open your mouth?
0 1 2 3 4 5 6 7 8 9 10
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0 = nothing perfectly =10
Chewing funtion, interview:

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Do you prefer one side for chewing? No ; yes, the left side ; yes, the right side ; I do not know .
Did you previously prefer other side? No ; yes, the left side ; yes, the right side ; I do not know
.
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Participant signature: …………………………. Trialist signature:

……………………………
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…
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Please put an X to signal the score that best represents your opinion:
1. How logical does this type of treatment seem to you?
0 1 2 3 4 5 6 7 8 9 10
0 = NOTHING 10 = TOTALLY
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2. How confident would you be that this treatment would be successful in
eliminating your pain and/or limited mouth opening?
0 1 2 3 4 5 6 7 8 9 10
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3. How confident would you be in recommending this treatment to a friend who
was suffering from TMD pain? er
0 1 2 3 4 5 6 7 8 9 10
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4. If you were extremely anxious for TMD pain, would you be willing to
undergo such treatment?
0 1 2 3 4 5 6 7 8 9 10
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5. How successful do you feel this treatment would be in decreasing a different

pain; for example, headache?
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0 1 2 3 4 5 6 7 8 9 10
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How would hurry over time?

0 1 2 3 4 5 6 7 8 9 10
0=extremely slowly extremely fast=10
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Sociodemography (Elliott et al., 2002)

Level of education: Higher education Secondary school No qualifications
Marital status: Never married Currently married No longer married
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Housing tenure: Owned or mortgaged Council rented Privately rented and

other
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Employment status: Employed Retired Unable to work due to illness Others
not employed
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…
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Chronic pain severity. (Von Korff et al., 1992)
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Pain intensity ítems
1. How would you rate your facial pain on a 0-10 scale at the present time, that is
right now?, where 0 is “no pain” and 10 is “pain as bad as could be”
no pain pain as bad as could be
0 1 2 3 4 5 6 7 8 9 10
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2. In the past 6 months, how intense was your worst facial pain rated on a 0-10
scale?, where 0 is “no pain” and 10 is “pain as bad as could be”
0 1 2 3 4 5 6 7 8 9 10
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3. In the past 6 months, on the average, how intense was your facial pain rated on a
0-10 scale?, where 0 is “no pain” and 10 is “pain as bad as could be”? (That is, your
usual pain at times you were experiencing pain.)er
0 1 2 3 4 5 6 7 8 9 10
Disability items
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4. About how many days in the last 6 months have you been kept from your usual
activities (work, school or housework) because of facial pain?
Disability days:
5. In the past 6 months, how much has facial pain interfered with your daily
activities rated on a 0-10 scale where 0 is “no interferente” and 10 is “unable to carry on
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any activities”?
0 1 2 3 4 5 6 7 8 9 10
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6. In the past 6 months, how much has facial pain pain changed your ability to take
part in recreational, social and family activities where 0 is “no change” and 10 is
“extreme change”?
no change extreme change
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0 1 2 3 4 5 6 7 8 9 10
7. In the past 6 months, how much has facial pain changed your ability to work
(including housework) where 0 is “no change” and 10 is “extreme change”?
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no change extreme change

0 1 2 3 4 5 6 7 8 9 10
Do you want to participate in this study? Please answer the next day.
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EDINBURGH HANDEDNESS INVENTORY
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Please indicate your preferences in the use of hands in the following activities by
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putting + in the appropriate column. Where the preference is so strong that you
would never try to use the other hand unless absolutely forced to, put + +. If in any
case you are really indifferent put + in both columns.
Some of the activities require both hands. In these cases the part of the task, or
object, for which hand preference is wanted is indicated in brackets.
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Please try to answer all the questions, and only leave a blank if YOU have no
experience at all of the object or task.
LEFT RIGHT
1 Writing
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2 Drawing
3 Throwing
4 Scissors
5 Toothbrush
6 Knife (without fork)
7 Spoon
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8 Broom (upper hand)
9 Striking Match (match)
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10 Opening box (lid)
I Which foot do you prefer to kick with?

II Which eye do you use when using only one?
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L.Q. Leave these blank spaces Decil

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…
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Serum samples (If enrolled, not mandatory) 

………………………………………………………………
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Participant III - Therapy-1. TEMPLATE 201.. / ........... /
….
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Signed informed consent?:
NO : cause/s: …………………………………………..…………
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YES : ENRROLLED-MAP Nr: …
Gnatography: lateral guidances, lat maximal, from Centric to MIP, maximal unassisted opening.
Right Therapy template Left
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Condylar path
Lateral guidance
Pain
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Internal derangement of TMJ/s
Hemimandibular retrognathia
Habitual chewing side
Handedness preference
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Comments:
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………………………………………………………………………………………..…
……………………………………………………………………………………………………
……………………………………………………………………………………………………
……………………………………………………………………………………………………
………
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Participant III - Therapy-1. After 201.. / ........... /
….
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Received allocated intervention?: YES :
…………………………………………………………………
NO  cause
……………………………………………………………………………….……………………
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After therapy (independent assessor):
Adverse
events?...................................................................................................................................................
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Maxim
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opening
10 Almendras (R/L): … /..
Escribir D / I en donde se encuentra el chicle

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1º ciclo 15s 20s 25s 30s 35s 40s 45s
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(Self-administered)
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Do you prefer one side for chewing? No ; yes, the left side ; yes, the right side ; I do not know .
How would you rate your mouth opening on a 0-10 scale at the present time, where 0 is “I can nothing
open my mouth” and 10 is “I can open completely”
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I can nothing open my mouth I can open completely

0 1 2 3 4 5 6 7 8 9 10
How would you rate your facial pain on a 0-10 scale at the present time, that is right now?, where 0 is “no
pain” and 10 is “pain as bad as could be”
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0 1 2 3 4 5 6 7 8 9 10
Patient global impression (improved)

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Very Much Much Minimally No Change Minimally Much Very Much

Improved Improved Improved Worse Worse Worse
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What kind of treatment have you received?: REAL  ; PLACEBO ; I do not know 
Patient signature: Dr signature:

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Comments:
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……………………………………………………………………………………………
…………………………………………………………………………...………………………
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Participant IV – Terapy-2. BEFORE 201.. / ........... / ….
Adverse Events: ………..…………………………………………………
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10 Almendras (R/L): … / …
R / L, on which side is the chewing gum?
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1º ciclo 15s 20s 25s 30s 35s 40s 45s

Maxim
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opening
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X=pain, global.
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Z=pain in the
worst moment
How much can you open your mouth?
0 1 2 3 4 5 6 7 8 9 10
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0 = nothing perfectly =10

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0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
0% = never in severe pain 100% = Always in severe pain
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0 1 2 3 4 5 6 7 8 9 10
0=No pain worst possible pain=10
Do you prefer one side for chewing?: No ; yes, left side; yes, right side; I do not know.
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Comments:
……….……………………………………………………………………………………...……
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Participant V: 3-Months 201.. / ………... /…..
Adverse Events: NO ; YES ………….………………………….
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Side used to chew (chewing gum)
1º cicle 15s 20s 25s 30s 35s 40s 45s
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Maxim
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opening
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X = pain,
global.
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worst moment
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Do you use one side to chew?: N0, Alternate; Yes, the right ; Yes, the left; I don’t know
Do you received any other therapy for your facial pain?:
……………………………………………
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
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0 1 2 3 4 5 6 7 8 9 10

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0 1 2 3 4 5 6 7 8 9 10
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Comments:
……….……………………………………………………………………………….…
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Participant name VI: 6-Months Date 2010 / 0000 /
00
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Dr, Type of treatment performed?: Real; placebo; I don’t know
Adverse Events: NO ; YES :
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…………………………….………
R / L, chewing side Comfort (without pain): ….. / …..
Maxim
1º cicle 15s 20s 25s 30s 35s 40s 45s Full, unasissted: .…. / …..
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opening
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X = pain,
global
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worst moment
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Do you use one side to chew?: N0, Alternate; Yes, the right ; Yes, the left; I don’t know
Do you received any other therapy for your facial pain?:
……………………………………………
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0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
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0 1 2 3 4 5 6 7 8 9 10
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0 1 2 3 4 5 6 7 8 9 10

Comments:
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……….……………………………………………………………………………….…
…………………
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This last visit included the same assessment and tests as baseline, the
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credibility tests, and the adverse events evaluation.
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Patient name ……………………..………………...………………………………... 201 / mes /
día

very much much minimally no change minimally much worse very much
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improved improved improved worse worse
Patient’s blinding: What kind of therapy have you received?: Real  Placebo  I don’t know 
Adverse events:
…………………………………………………………………….………………………..……
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Participant signature: ..............................................................
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Patient name VII – POSTSTUDY. REEVALUATION /
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THERAPY?
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201 / m / d
Timeline of after-study evaluation/therapy to better care of each one participant:

After study ended, and statistical analyses were carried out, therapy codes are disclosed, and results were
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discussed, the TSC proceed to the explanation of therapy received. Participants, Staff and outcome’s
assessors will remaing blinded until the end of the study.
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One assessment 6-Mo after the completion of MAP Trial (one year after therapy) is warranted. Additional
patient's monitoring until five years after treatment is expected.
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APPENDIX V.
SPANISH version of participant’s INFORMATION and DATA
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COLLECTION FORMS
HOJA DE INFORMACIÓN A LA/AL PARTICIPANTE EN EL ESTUDIO DE
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INVESTIGACIÓN TITULADO
NB.: Si lo prefiere, una versión en gallego esta disponible.
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MAP Trial. Efectividad de una nueva terapéutica oclusal
en los desórdenes temporomandibulares crónicos. Ensayo
clínico aleatorizado controlado.
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INVESTIGADORES PRINCIPALES:
Dra. Mª Jesús Mora Bermúdez. Odontóloga del Complejo Hospitalario Universitario

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de Santiago de Compostela. Dedicación exclusiva. Profesora Titular de la Universidad
de Santiago de Compostela.
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Dr. José López-Cedrún Cembranos. Jefe del Servicio de Cirugía Maxilofacial del
Complejo Hospitalario Universitario de A Coruña.
Dr. Urbano Santana Penín. Catedrático de universidad. Facultad de Medicina y
Odontología. Universidad de Santiago de Compostela.
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Este documento tiene por objeto ofrecerle información sobre un estudio de

investigación de tipo experimental (ensayo clínico) en el que se le invita a participar.
Este estudio se esta realizando en el Complexo Hospitalario Universitario de A Coruña
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y en la Facultade de Medicina e Odontoloxía de Santiago de Compostela, y fue

aprobado por el Comité Ético de Investigación Clínica Humana de Galicia.
Si decidiese participar en el mismo, debe recibir información personalizada del
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investigador, leer antes este documento y hacer todas las preguntas que precise para
comprender los detalles sobre el mismo. Si así lo desea, puede llevarse este documento,
consultarlo con otras personas, y tomar el tiempo necesario para decidir si participar o
no.
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La participación en este estudio es completamente voluntaria. Vd. puede decidir no

participar o, si acepta hacerlo, cambiar de parecer retirando el consentimiento en
cualquier momento sin obligación de dar explicaciones. Le aseguramos que esta
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decisión no afectará a la relación con su médico ni a la asistencia sanitaria a la que Vd.

tiene derecho.
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La patología dolorosa de boca y cara (y/o las alteraciones del movimiento-limitación de
la apertura bucal) tiene un nombre común para señalar diferentes patologías de las
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articulaciones temporomadibulares, musculatura masticatoria o ambas: desórdenes
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temporomandibulares (DTM). Los principales síntomas son el dolor y/o la limitación
de la movilidad de la boca. El dolor puede ser muy invalidante, y constituye un motivo
relevante de absentismo laboral en las sociedades avanzadas.
La causa de los DTM, como ocurre en su caso, aun no se ha establecido
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científicamente. Por tanto, se considera desconocida. Por este motivo, todos los
tratamientos que se aplican para tratar los síntomas son empíricos pareciendo, a la luz
de estudios controlados previos, que tanto da emplear un procedimiento cualquiera de
los conocidos (medicación, férulas, acupuntura y otros), como no hacer nada. La ventaja
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es que habitualmente evoluciona de modo favorable aunque no se emplee ningún
tratamiento, por ser una enfermedad de tipo benigno. Ahora bien, a veces evoluciona de
modo tórpido y se cronifica provocando dolor severo y/o limitación de la movilidad
mandibular y dificultad para comer principalmente. Esto puede afectar dramáticamente
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la calidad de vida del paciente.
El tratamiento que, como clínicos e investigadores, le proponemos es el procedimiento
habitual empleado en la Universidad de Santiago de Compostela desde hace más de 25
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anos. Es indoloro.
Este tratamiento se base en un diagnóstico de la posición y movimientos mandibulares y
articulares, determinación del tipo de masticación que el sujeto presenta, así como del
análisis de los datos -como la morfología de las superficies articulares, pero también de
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las dentarias y la asimetría del tercio inferior de la cara- que pueden indicar la
preferencia del lado de masticación actual e incluso a lo largo del desarrollo del
paciente.
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El tratamiento consiste en un desgaste selectivo del esmalte dentario mínimo

necesario para obtener un reparto de las cargas generadas por la musculatura; por otra
parte, e implícitamente en el mismo procedimiento, se pretende rehabilitar la función
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masticatoria, en el sentido de favorecer la masticación unilateral alternante de modo

natural o espontáneo, o lo que es lo mismo, evitar emplear de modo preferente un solo
lado para masticar. Especulamos una causa común y diferentes estadios de alteración,
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que puede ir, de estadios iniciales como dolor myofascial a la artropatía degenerativa
con inversión de cúpula y degeneración o perforación del disco articular; el tratamiento
propuesto no pretende actuación directa sobre las estructuras articulares, sino
simplemente evitar sobrecargas y facilitar una dinámica, esencial para una correcta
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lubricación de los compartimentos articulares, principalmente mediante la rehabilitación

funcional masticatoria. En este estudio el tratamiento es el mismo, independiente del
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tipo de desorden temporomandibular que sufra. No obstante aclaramos que dadas las
características del estudio, los criterios de elegibilidad de los participantes y los centros
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de referencia en los que pretende desarrollarse, basándonos en la revisión de la
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experiencia acumulada, especulamos que aproximadamente un 80% de los pacientes
presentarán signos de afectación articular, mayoritariamente desplazamientos de disco;
bien es cierto que no ha sido/será siempre posible obtener imágenes de resonancia
nuclear magnética, por lo que esta información es meramente posibilista, al menos de
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casos documentados.
Efecto esperado, pronóstico: eliminación o reducción significativa del dolor y/o de la

alteración o limitación de la apertura bucal. Crear las condiciones para recuperar la
normalidad articular, lo cual no siempre se logra, y prevenir un aumento del daño
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articular, muscular y dentario.
La aleatorización consistirá en la decisión por azar de recibir el tratamiento de

mínimo desgaste suficiente del esmalte de los dientes, selectivo, o bien por el contrario,
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recibir un procedimiento semejante pero sin desgaste del esmalte (placebo), de tal modo
que el paciente no conocerá si recibe un tratamiento real o un placebo (ciego). Un
especialista independente, que non sabrá qué tipo de tratamiento recibió, hará la
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determinación de los datos tras el tratamiento. Así, ni el paciente ni el clínico evaluador
conocerá el tipo de tratamiento que evalúa (doble ciego).
Los investigadores le ofrecerían la posibilidad de tratarse mediante el procedimiento

real a aquellos pacientes, si fuese el caso, que, habiendo recibido un placebo siguiesen
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con la sintomatología en la revisión 6 meses después y, tras recibir la información,

deseasen someterse a el.
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Incorporarse a este estudio no excluye que el paciente pueda seguir con el tratamiento
usualmente llevado a cabo, si lo considerase beneficioso, aunque debido a que el
tratamiento pretende ser curativo y no se espera este efecto de ningún otro tratamiento,
de modo genérico se recomendará prescindir de el/los.
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En general este estudio persigue los siguientes objetivos: 1, no dañar a los pacientes;
2, corregir la causa y por tanto curar la patología del paciente, principalmente la
dolorosa o la imposibilidad de abrir correctamente la boca si este fuese su caso; 3, evitar
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otros tratamientos alternativos, algunos sensiblemente más invasivos, y no predecibles;

4, actuar de modo ético y metodológicamente riguroso y poner de manifiesto de modo
científico los resultados obtenidos en este estudio, independientemente de si fuesen
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positivos, indiferentes o negativos y lograr la difusión internacional de éstos; 5, poder

realizar nuevos estudios, si los resultados fuesen alentadores, semejantes por otros
investigadores para poder llegar a un posible nuevo paradigma o modalidad de
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tratamiento que pueda curar de modo predecible a los pacientes que sufren esta
patología; de esta manera pretendemos aportar una opción terapéutica de la que en el
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momento carecen las Ciencias de la Salud en el campo de los DTMs.
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En realidad, por tanto non se trata de una investigación nueva, en el sentido de emplear
a los pacientes como destinatarios de un procedimiento desconocido o no probado
previamente, si no que por el contrario lleva muchos años de aplicación, y será
realizado por un especialista con gran experiencia en la ejecución del procedimiento
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clínico. Ambos investigadores principales poseen experiencia en el campo de la
investigación sanitaria.
Este estudio no esta financiado por ninguna entidad de modo específico. Por tanto la
actuación por parte del equipo de investigación tiene carácter no remunerativo. El
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procedimiento sugerido será gratuito para los pacientes.
Se le ofrece participar a Vd. Debido a que cumple los criterios que están descritos en
el protocolo de investigación. Básicamente porque tras a observación en su visita al
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Servicio Hospitalario, podría ser curado mediante un simple ajuste de la oclusión.
Dado el carácter de este estudio, y teniendo en cuenta otros estudios de naturaleza
similar, esperamos que participen 50 personas para que pudiésemos obtener
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conclusiones significativas.
Mi participación consistirá en someterme a una entrevista inicial en la que se intentará

obtener unas conclusiones diagnósticas y pronósticas de su patología. Incluirá la
realización de pruebas auxiliares como a radiografía y ocasionalmente resonancia,
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cuando este indicada y sea posible, y registros no cruentos como estudio de la movilidad
mandibular . Posteriormente, si resulta seleccionado, se sorteará su incorporación a uno
de los dos grupos de estudio: grupo tratado realmente y grupo control o tratado
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mediante placebo.
En otra visita se aplicará el tratamiento previsto; todos los pacientes serán tratados
desde el punto de vista informativo, con respecto al tipo de tratamiento (tallado)
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recibido, como si fuesen tratados realmente. El sujeto que participe, debe acudir para
realizar el tratamiento y las visitas posteriores. No requiere cuidados especiales.
Se evaluará la evolución en todos los casos, sobre todo de modo clínico con una
periodicidad de 1 a 3 meses. Su participación tendrá una duración total estimada de un
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año.
El equipo investigador podría decidir finalizar el estudio antes de lo previsto o
interrumpir su participación por aparición de nueva información relevante que será
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trasladada a los pacientes para que participen en la decisión, por motivos de seguridad,
o por incumplimiento de los procedimientos del estudio.
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Los riesgos o inconvenientes parecen ser solamente los derivados del desgaste del
esmalte, que es irreversible. Podría aparecer hipersensibilidad durante el tratamiento; si
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así fuese, el tratamiento se detendría en el mismo momento, ya que de no ser así, podría
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ser un tratamiento ineficaz debido a que el paciente no podría comer de modo vigoroso,
como se espera que haga.
Este efecto secundario será minimizado en lo posible. Debe tenerse en cuenta que el
desgaste del esmalte, incluso después de la dentina es frecuente que ocurra de modo
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espontáneo en esta patología, siendo mucho más agresivo que lo que se practica
terapéuticamente, y que pretende reducir o detener el desgaste patológico espontáneo o
autoabrasión.
El estudio es experimental desde un punto de vista formal, por tanto, la pauta normal de
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la asistencia será modificada para observar que ocurre.
No obtendrá beneficio económico directo por participar en el estudio.
Desconocemos científicamente si la intervención será beneficiosa, y por eso se

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quiere investigar. El único beneficio buscado, por tanto, es descubrir su posible utilidad,
con la esperanza de que en el futuro tenga aplicación para curar e incluso prevenir la
patología que cursa con dolor de la cara y/o las alteraciones del movimiento da
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mandíbula.
El embarazo y la lactancia no exluyen este tratamiento per se. No obstante, siendo

deseable disponer de radiografías, el estudio excluirá la participación de mujeres en
estado de gestación, a no ser que se disponga de las pruebas previamente, caso que si
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podría incluirse.
Las alternativas a este tratamento más utilizados son inespecíficas, no curativas

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directamente, ya que no existe un tratamiento causal. Son: las férulas oclusales,

medicación (antidolorosa, relajantes muscular, depresoras del sistema nervioso central;
antipsicóticos, anticonvulsivantes, bloquentes neuromusculares, …), fisioterapia,
acupuntura y ciruxía, incluso con la eliminación de la articulación/es afectada/s
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sustituyéndose por prótesis artificales. Los investigadores le informarán detalladamente

sobre ellos. Non obstante, ningno se considera predecible, y parecen no ofrecer ninguna
mejora estadísticamente cando se comparan con simplemente no hacer nada.
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Recuerde que la función normal de la mandíbula requiere una masticación variada y

normal durante las 3 o 5 comidas principales y que el uso excesivo, mal uso o
parafunciones podría aumentar o provocar a sus quejas y usted debe mantener los
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músculos de la mandíbula relajada y evitar contactos dentarios no funcionales y

apertura excesiva de la boca.
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Recibiré un resumen de la información que se obtenga del estudio si Vd. lo desea.
También podrá recibir los resultados de las pruebas que se le practiquen si así lo
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solicita. Estos resultados pueden no tener aplicación clínica ni una interpretación clara,
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por lo que, si quiere disponer de ellos, deberían ser comentados con los médicos que
llevan a cabo el estudio.
Los resultados de este serán publicados si fuesen admitidos en revistas científicas,

pero non se transmitirá ningún dato que pueda llevar a la identificación de los
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participantes.
Se protegerá la confidencialidad de mis datos, conforme a lo dispuesto por la Ley

Orgánica 15/1999, de 13 de diciembre, de protección de datos de carácter personal. En
todo momento, Vd. podrá acceder a sus datos, corregirlos o cancelarlos. Solamente el
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equipo investigador, los monitores del estudio, y las autoridades sanitarias, que tienen el
deber de gardar la confidencialidad, tendrán acceso a todos los datos recogidos en el
estudio. Podrá transmitirse a terceros la información que no pueda ser identificada. En
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el caso de que alguna información sea transmitida a otros países, se realizará con un
nivel de protección de los datos equivalente, como mínimo, al exigido por la normativa
de nuestro país.
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No se obtendrán muestras orgánicas. Aunque no es esencial para participar en el
estudio, le pediremos que nos permita realizar análisis de sangre (5cc) dos veces (antes
de comenzar el estudio y después de finalizado), para determinar proteinas (citokinas),
no realizando pruebas genéticas y destruyendo posteriormente las muestras. La
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finalidad de este análisis es valorar si existen cambios en la presencia de algunas proteinas

que podrían indicar el beneficio/perjuicio a nivel sanguíneo, ya que estas determinaciones
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se han aconsejado por algunos estudios científicos. Al finalizar el estudio las muestras
serán destruidas.
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Se realizarán sistemáticamente tests, pruebas y registros gráficos indirectos,

imprescindibles para un correcto diagnóstico y planificación terapéutica.
Sus datos asociados serán guardados de forma identificadas o identificable, que quiere
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decir que los datos incluirán el nombre, iniciales de apellidos, número de historia
clínica, etc. El responsable de la custodia de los datos es el Dr. López Cedrún, y serán
almacenados en el archivo del Hospital Clínico da Coruña durante el tempo necesario
para finalizar el estudio, que son 2 anos aproximadamente, y siguiendo el protocolo
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empleado para los pacientes que acuden al Servicio.
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Si Vd. accede, estas pruebas serán conservadas para futuros estudios de investigación
relacionados con el presente, con mismo responsable del lugar, durante 5 años y de
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manera identificable.
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No se espera ninguna consecuencia negativa da participación. La posibilidad de
daños derivados por la participación son casi inexistentes, si consideramos que el único
es la perdida de una fracción del esmalte dentario. Siempre se trata de reducir este
desgaste al mínimo suficiente para que sea efectivo. Otras posibilidades de daño
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solamente parecen posibles de tipo accidental no previsibles. En todo caso, pondremos
todos los medios necesarios para eliminar o minimizar los daños derivados de la
participación.
Los beneficios de los productos comerciales o patentes derivadas del estudio, si se
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lograsen, no repercutirán en el paciente.
Me puede dar más información el Dr. López Cedrún en el teléfono habitual donde
solicito las visitas al Servicio de Ciruxía Maxilofacial del Complejo Hospitalario
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Universitario de A Coruña.
También el Profesor Urbano Santana Penín, en el tfno 881812349, o personalmente

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(Tfno: 647344093) en el edificio de Odontoloxía de la Facultad de Medicina y
Odontología de la Universidad de Santiago de Compostela. C/ Entrerríos s/n. 15782
SANTIAGO DE COMPOSTELA.
Muchas gracias por su colaboración.

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Phone: E-mail:
Participant I - SCREENING 201 /
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oooo / 00 Queja principal:
………………………………………………..…
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¿Nos permite valorar si puede participar en un ensayo clínico
para tratar el dolor facial?: NO; SÍ. Si esta de acuerdo,
continue.
Aumenta su dolor al palpar los temporales?: Sí, No. Moviendo la mandíbula?Sí, No.
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X = dolor
promedio
re
Z = el mometo
de más
er intensidad
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Cuándo comenzaron sus síntomas?:

…………………………………..……………………………
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Llevó ORTODONCIA?: Fija Removible; Duración: …………… A los …… de edad.

Usa FÉRULA OCLUSAL?  INICIO: …………. Durante: ……………años/meses
Ha solicitado discapacidad o litiga por algún motivo?:
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.......................................................................
Si necesitase tratamiento dental lo haría YA?: 
................................................................................
Intraoral examination Manualidad: R

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L
- Occlusion: ................................................................................................. Retrognatia: R, L,
C
-Caries, ausencias dentarias:  …………..….. Tratable: 
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……….…...................................
- Prótesis/implants  ................................................................................
ELEGIBLE?: NO POR: ……………………………………………………………………
SÍ: Información sobre el estudio, lectura, explicación y discusión .
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Desea que realicemos un diagnóstico más completo para determinar si puede ser enrolado y
tratado en el estudio? NO; SI  (citación para BASAL):
……………………………………………..
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Firma del participante: Firma del Dr:
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Observations:
…...…………………...…………………...…..………………………………………
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……………………………………………………………………………………………………
…..
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Participant II-Baseline 201 / mes / día
Phone: E-mail:
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MRI, CBCT, Panoramic (OPG) Rx: …………………………………………………
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Patient’s TMD condition according to DC/TMD (Schiffman et al., 2014)
I. TEMPOROMANDIBULAR JOINT DISORDERS
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1 Joint pain Right TMJ Left TMJ
A. Artrhralgia
B. Arthritis
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1. Muscle pain Right side Left side
A. Local myalgia
B. Myofascial pain
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Patients could present I and/or II TMD group, and/or internal derangement:
Suele masticar por un mismo lado?: N0, alterno; Si, por la DCHA; Sí, por la IZDA. No lo sé .
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Ortodoncia?: fija ; removible: momento y duración:
…………………..………………………
Usa FÉRULA OCLUSAL?  INICIO: …………. Durante: ……………años/meses
Exploración Intraoral
1. Hemimandib. Retrognathia (midline, Angle class): Symmetric ; right , left .
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2. Occlusal Quality:
............….………………………………………………….……………
3. Periodontal disease. 3.1. Probing (over 3mm):  :
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…..……………………………..............
3.2. Periodontal Activity 
……………………….….………………
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3.3. Radiographic defect depth  :

.……..............................................
3.4. Tooth mobility 0-3): :
.......………..…….……...……………..
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4. Dental decay: :
…....……………………………..……….….................................................
5. Fixed partial prosthesis/implants 
………………………………………………………......
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7.2. Gnatography
7.3. Prescale
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8. Implementation of self-administered questionnaires. SCL-90-R ; McGill: DN4 Questionnaire
(including clinical exploration); Credibility test.
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Firma del participante: Firma del especialista:
Observaciones:…...…………………...…………………...…..…………………………………
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……………………………………………………………………………………………………
……
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Participante II-Baseline 201 / mes / día
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X = dolor
promedio
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Z = el mometo
de más
intensidad
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¿Durante cuánto tiempo suele tener el dolor facial importante?:
0% 10% 20% 30% 40% 50% er 60% 70% 80% 90% 100%
0%=Nunca tengo dolor severo 100%=Siempre tengo dolor severo
¿Qué desencadena su dolor?:

….................……………………………………….………………….......
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Mareos: Sí No . Vértigo: Sí , No . A veces le cuesta tragar: Sí No .
Dolor de cuello: Sí No . Otras áreas dolorosas: ……………………………………………………
Tiene dolor/disconfort al masticar; en dientes : dcha, izda. Encías : dcha, izda
¿Cómo calificaría su capacidad para abrir su boca, en una escala de 0 a 10?:

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0 1 2 3 4 5 6 7 8 9 10
0=No puedo abrirla nada Puedo abrirla del todo perfectamente=10
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INTENSIDAD del dolor de CABEZA durante las últimas semanas (Si lo tuviese)
0 1 2 3 4 5 6 7 8 9 10
0=Ningún dolor El peor dolor imaginable=10
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¿Su medico le diagnosticó la causa de su dolor de cabeza?: No. Sí, ………………………………

¿El dolor de cabeza cambia cuando mmueve la mandíbula?: Sí, No.
Firma del participante: Dr.:
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INVENTARIO DE EDIMBURGO
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Por favor indique qué mano usa para realizar las siguientes actividades poniendo +
en la columna apropiada. Si su preferencia es my clara, ponga ++. Si le resulta
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indiferente ponga + en las dos columnas.
Alguna actividad requiere las dos manos. En este caso parte de la tarea u objeto, la
mano que marca la preferencia se indica entre paréntesis.
IZQUIERDA DERECHA
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1 Escribir
2 Dibujar
3 Lanzamiento (pelota, piedra)
4 Tijeras
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5 Cepillo de dientes
6 Cuchillo (sin tenedor)
7 Cuchara
8 Escoba (la mano más arriba)
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9 Raqueta (match)
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10 Abrir una caja (la tapa)
I ¿Con qué pie tira mejor una pelota?

II ¿Con qué ojo mira cuando guiña uno?
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L.Q. Deje estos espacios en blanco Decil

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Sociodemografía al inicio del estudio (Elliott et al., 2002)

Nivel de educación: Educación superior (Estudios universitarios y Formación Profesional de grado
superior) Educación secundaria postobligatoria (Bachillerato y Formación Profesional de grado
medio) Enseñanza obligatoria 
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Estado matrimonial: Soltero/a Actualmente casado/a Divorciado/a

Vivienda: Propia o hipotecada Arrendamiento público Arrendamiento privado y otras
Situación laboral: Trabajador Retirado Incapacitación por enfermedad Otras causas de
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desempleo
Firma del participante:
121
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Severidad del dolor crónico. (Von Korff et al., 1992)
Elementos de intensidad del dolor
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1. ¿Cómo calificaría EN ESTE MOMENTO, su dolor facial en una escala de 0 a 10? Donde
0 es “no dolor” y 10 es “el peor que podría ser”
No dolor El peor dolor que podría ser
0 1 2 3 4 5 6 7 8 9 10
2. En los últimos 6 meses, ¿cuál fue la intensidad, en una escala de 0 a 10, DEL PEOR
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DOLOR FACIAL QUE PADECIÓ? Donde 0 es “no dolor” y 10 es “el peor que podría ser”
0 1 2 3 4 5 6 7 8 9 10
3. En los últimos 6 meses, GLOBALMENTE, ¿cuál fue la INTENSIDAD DE SU DOLOR

FACIAL en una escala de 0 a 10? Donde 0 es “no dolor” y 10 es “el peor que podría ser” (Es
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decir, su grado de dolor habitual en los momentos en los que padecía dolor)
0 1 2 3 4 5 6 7 8 9 10
Elementos discapacitantes
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4. ¿Alrededor de cuántos días, en los últimos 6 meses, no ha podido realizar sus actividades
habituales (trabajo, escuela o tareas del hogar) por culpa del dolor facial?
Días discapacitantes
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5. En los últimos 6 meses, ¿cuánto el dolor facial interfirió en sus actividades diarias, en una
escala de 0 a 10 ? Donde 0 es “no interferencia” y 10 “incapacidad para realizar cualquier
actividad”
0=No interferencia Incapacidad para realizar cualquier actividad=10
0 1 2 3 4 5 6 7 8 9 10
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6. En los últimos 6 meses, ¿cuánto el dolor facial HA CAMBIADO SU CAPACIDAD

PARA PARTICIPAR EN ACTIVIDADES RECREATIVAS, sociales o familiares actividades
diarias, en una escala de 0 a 10 ? Donde 0 es “no cambio” y 10 “cambio extremo”
No cambio Cambio extremo
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0 1 2 3 4 5 6 7 8 9 10
7. En los últimos 6 meses, ¿cuánto el dolor facial HA CAMBIADO SU CAPACIDAD

PARA TRABAJAR (incluyendo las tareas del hogar), en una escala de 0 a 10? Donde 0 es “no
cambio” y 10 “cambio extremo”
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0 1 2 3 4 5 6 7 8 9 10

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Listado de síntomas de los desórdenes temporomandibulares
Los problemas de la mandíbula pueden causar múltiples dificultades de formas diferentes. De la
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siguiente lista, indique con que problemas está teniendo dificultades (rodee con un círculo “si “o
“no”; varias respuestas de “si” son posibles):
Dolor de mandíbula si
no
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Ruidos en mi mandíbula cuando muevo la boca si
no
Mi mandíbula está bloqueada y no puedo abrirla ni cerrarla si
no
Otros problemas mandibulares – por favor descríbalos
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.......................................................................
..........................................................................................................................................................
.....
Por favor, señale con una X el valor que mejor representa su opinión er
1. ¿Le parece lógico este tipo de tratamiento?
0 1 2 3 4 5 6 7 8 9 10
0 = Nada totalmente=10
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2. ¿Qué tan segura/o esta usted de que este tratamiento podría tener éxito para eliminar
sus síntomas?
0 1 2 3 4 5 6 7 8 9 10
0 = Nada totalmente = 10
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3. ¿Recomendaría este tratamiento a un amigo que sufriese síntomas similares?

0 1 2 3 4 5 6 7 8 9 10
0 = seguro que NO seguro que SI = 10
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4. Si usted sufriese estos síntomas, ¿estaría usted dispuesta/o a someterse a ese

tratamiento?
0 1 2 3 4 5 6 7 8 9 10
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5. ¿Percibe que el éxito de este tratamiento puede reducir otros síntomas, como el dolor
de cabeza?
0 1 2 3 4 5 6 7 8 9 10
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¿Cómo de prisa percibe que le pasa el tiempo?

0 1 2 3 4 5 6 7 8 9 10
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0=Extremadamente lento Extremadamente rápido=10

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Escala Tampa de Kinesiofobia: Desordenes temporomandibulares
Para cada una de las frases siguientes , por favor indique el grado de acuerdo/desacuerdo
empleando la siguiente escala:
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1 2 3 4
Muy en desacuerdo(NO) Algo en desacuerdo Algo de acuerdo Muy de
acuerdo(SI)
1. Tengo miedo de hacerme daño si muevo la mandíbula. 1 2 3 4
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2. Si no pienso en mis síntomas mandibulares, se pondrán peor. 1 2 3 4
3. Mi mandíbula me está diciendo que algo va seriamente mal en ella. 1 2 3 4
4. Mis síntomas mandibulares probablemente mejorarían si moviese
1 2 3 4
más la mandíbula.
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5. Otra gente no se toma mis síntomas mandibulares lo suficientemente
1 2 3 4
en serio.
6. Mis síntomas mandibulares han puesto en riesgo mi salud para el
1 2 3 4
resto de mi vida.
7.
8.
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Mis síntomas mandibulares significan que he dañado mi mandíbula.
Aunque algo agrave mis síntomas mandibulares no me voy a hacer
1 2 3 4
1 2 3 4
daño.
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9. Tengo miedo de dañar mi mandíbula accidentalmente. 1 2 3 4
10. La manera más segura de evitar que mis síntomas empeoren es tener
1 2 3 4
cuidado y no mover mi mandíbula más de lo necesario.
11. No tendría tantos síntomas en la mandíbula si no estuviese
1 2 3 4
sucediendo algo potencialmente dañino .
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12. Aunque tengo síntomas mandibulares me encontraria mejor si

1 2 3 4
siguiese usando mi boca con normalidad.
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13. Mis síntomas mandibulares me permiten saber cuando dejar de

1 2 3 4
mover mi mandíbula de tal modo que no me haga daño a mi mismo/a.
14. No es seguro para alguien con mi situación mandibular usar mucho la
1 2 3 4
boca.
rin
15. No puedo hacer todo lo que hace otra gente porque es muy fácil que
1 2 3 4
me haga daño en la mandíbula.
16. Aunque hacer algo agrave mis síntomas mandibulares, no creo que
1 2 3 4
sea perjudicial.
ep
17. Nadie debería tener que mover su mandíbula cuando tiene un

1 2 3 4
problema mandibular.
18. Tengo miedo a abrir mucho la boca ya que puede que no consiga
1 2 3 4
cerrarla otra vez.
Pr
124
Participant II-Baseline 201.. / mes / día
Cuestionario de dolor McGill.
d
Por favor, marque con una X los cuadros que mejor describen su dolor
we
Valor de intensidad sensorial Valor de intensidad afectiva
Temporal 1 Temor
Como pulsaciones Temible
Como una sacudida Espantoso
vie
Como un latigazo Horrible
Térmica Autonómica / Vegetativa

Frío Que marea
Caliente Sofocante
re
Ardiente
Presión constrictiva Castigo

Entumecimiento Espasmo er Que atormenta
Como un pellizco Retortijón Mortificante
Agarrotamiento Opresivo Violento
Calambre
pe
Presión puntiforme / incisiva Tensión / Cansancio
Pinchazo Extenuante
Punzante Agotador
Penetrante Incapacitante
Agudo
ot
Presión de tracción gravativa Cólera / Disgusto

Pesado Incómodo
tn
Tirante Que irrita

Como un desgarro Que consume
Tenso
Espacial Pena / Ansiedad

rin
Superficial Interno Deprimente

Difuso Profundo Agobiante
Que se irradia Que angustia
ep
Fijo Que obsesiona

Desesperante
Viveza Valor de intensidad evaluativa
Temporal 2
Adormecido
Pr
Picor Momentáneo
Hormigueo Intermitente
Como agujetas Creciente
125
Escozor Constante
Como una corriente Persistente
d
Valor de intensidad actual
we
Intensidad
Firma del/la participante:
Sin dolor Intenso
Leve Fuerte
Molesto Insoportable
vie
re
er
pe
ot
tn
rin
ep
Pr
126
Participant II-Baseline 201.. / mes / día
CUESTIONARIO DN4
d
Por favor complete este cuestionario marcando una respuesta para cada número
en las 4 preguntas: ponga una X
we
ENTREVISTA
Pregunta 1: ¿Tiene el dolor una o más de las siguientes características?

SI NO
vie
1- Quemazón
2- Frío doloroso
3- Calambres eléctricos
re
Pregunta 2: ¿Está asociado el dolor con uno o más de los siguientes
síntomas en la misma zona?
4- Hormigueo
5- Alfileres y agujas
er
6- Entumecimiento
pe
7- Picazón
EXAMEN FÍSICO (Rellenar por el Doctor)
Pregunta 3: ¿Está el dolor localizado en una zona donde el examen físico

puede mostrar una o más de las siguientes características?
ot
8- Hipoestesia al tacto
9- Hipoestesia a pinchazos
tn
Pregunta 4: En la zona dolorosa, el dolor es causado o incrementado por:
10- Cepillado suave de la piel

Por cada respuesta positiva asigne un punto, por cada respuesta negativa
rin
asigne un valor de 0 (cero). Sume los puntos; si es mayor o igual a 4 se

considera que hay dolor neuropático.
Puntuación del paciente: /10
ep

SI RESULTA ENROLADO: Extracción sanguínea.
Pr
127
BASAL DATA for OPENCLINICA:
d
we
Participant Date: 2015 / mes / día
MAP-Number: ….
vie
Affected side:
o Right
o Left
re
o Bilateral
Pain-intensity right side:

Pain-intensity left side: er
% time in severe pain:
Maximal comfortable opening:
pe
Maximal unassisted opening:
Gender:
o Female
o Male
ot
TMD:
o Articular
tn
o Muscular
rin
ep
Pr
128
d
DOCUMENTO DE CONSENTIMENTO PARA A PARTICIPACIÓN NUN ESTUDO DE
INVESTIGACIÓN (In Galician)
we
TÍTULO: 201 / mes / día
▪ Bases para o diagnóstico etiolóxico e tratamento da dor facial: ensaio de procedimiento
clínico aleatorizado controlado-placebo.
Eu, ......................................................................................................., ......................,
vie
▪ Lin a folla de información ao participante do estudo arriba mencionado que se me
entregou, puiden conversar con a Dra Mª Xesús Mora ou con o Dr. López-Cedrún ou
con o Dr. Santana Penín (indistintamente) e facer todas as preguntas sobre o estudo
necesarias para comprender as súas condicións e considero que recibín suficiente
información sobre o estudo.
re
▪ Comprendo que a miña participación é voluntaria, e que podo retirarme do estudo cando
queira, sen ter que dar explicacións e sen que isto repercuta nos meus coidados médicos.
▪ Accedo a que se utilicen os meus datos nas condicións detalladas na folla de información
ao participante. er
▪ Presto libremente a miña conformidade para participar no estudo.
Respecto á conservación e utilización futura dos datos detallada na folla de información ao participante,
NON accedo que os meus datos sexan conservados unha vez terminado o presente
pe
estudo
Accedo que os meus datos se conserven unha vez terminado o estudo, sempre e cando
sexa imposíbel, mesmo para os investigadores, identificalos por ningún medio
SI accedo que os datos se conserven para usos posteriores en liñas de investigación
relacionadas coa presente, e nas condicións mencionadas.
ot
En canto aos resultados das probas realizadas,

DESEXO coñecer os resultados das miñas probas
tn
NON DESEXO coñecer os resultados das miñas probas
O/a participante, O/a investigador/a,

rin
Asinado.: Asinado.:
Nota: é posible poñerse en contacto coas clínicas e os investigadores no Servizo de Cirurxía Maxilofacial
ep
do Hospital Universitario da Coruña, ou en 647 344 093 ou por correo electrónico urbano.santana @
usc.es, ou directamente a Facultade de Odontoloxía (Prótese e Dor Orofacial) da Universidade de
Santiago de Compostela, en calquera momento durante o curso do estudo.
Pr
129
Participant III – Therapy-1. TEMPLATE 201 / OOO /
00
d
we
¿Consentimiento informado?: SI : Enrolled MAP Nº:
…
NO  causas:
…………………………………………………………………………
……………..…………
vie
Right Therapy template Left
Condylar path
re
Lateral guidance
Pain
TMJ internal derangement
er
pe
Comments: ………………………………………………………………………………………..
ot
……………………………………………………………………………………………………
……………………………………………………………………………………………………
……………………………………………………………………………………………………
tn
………………………
rin
ep
Pr
130
Participant III – Therapy-1. AFTER 201 / 00000 /
d
00
we
Máxima Apertura (mm):
Comfort (sin dolor): ..… / ...…
No asistida: ..… / ...…
vie
Asistida: ..… / ...…
¿Ha recibido la Tx-2?:
SI 
NO  (Causas)
Efectos adversos:
re
¿Cómo calificaría en la actualidad, es decir, en este momento, su dolor facial en una escala
de 0 a 10? Donde 0 es “no dolor” y 10 es “el peor que podría ser”
No dolor er El peor dolor que podría ser
0 1 2 3 4 5 6 7 8 9 10
¿Cómo calificaría en este momento, su capacidad para abrir su boca en una escala de 0 a
pe
10? Donde 0 es “no puedo abrirla nada” y 10 es “puedo abrirla del todo perfectamente”
No puedo abrirla nada Puedo abrirla del todo perfectamente
0 1 2 3 4 5 6 7 8 9 10
Señale con un círculo la frase que mejor describe la evolución de su queja después del tratamiento
ot
Mejoré Mejoré Mejoré NO Empeoré Empeoré Empeoré

muchísimo mucho algo Cambió algo mucho muchísimo
Qué tratamiento ha recibido?: Real  ; Placebo ; No lo sé 

tn
Firma del paciente: Firma del Dr:
Comments:
………………………………………………………………………………………….……
rin
……………………………………………………………………………………………………
……………………………………………………………………………………………………
………………
ep
Pr
131
Participant IV –Therapy-2. BEFORE 2010 / 00000 /
d
00
Efectos Adversos: NO SI:
we
Confort (sin dolor): …… /
……
No asistida: …… / ……
Asistida: …… / ……
vie
………………………………………..……………………
1º ciclo 15s 20s 25s 30s 35s 40s 45s
re
10 Almendras:
(R/L): … /..
er
X = dolor
pe
global
Z = el mometo
de más
intensidad
ot
¿Durante cuánto tiempo suele tener el dolor facial importante?:

0 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
%
tn
Señale con un círculo la frase que mejor describe la evolución de su queja

¿Cómo calificaría su capacidad para abrir su boca, en una escala de 0 a 10?:
0 1 2 3 4 5 6 7 8 9 10
rin
0 1 2 3 4 5 6 7 8 9 10
ep

Otros tratamientos:
………………………………………………….………………………………………………
Mastica habitualm por un solo lado?: N0, alterno ; Si, por la DCHA ; Sí, por la IZDA . No lo sé 
Firma participante: Dr:
Pr
Observaciones:
…...………………………………...…………………...…..………………………………………
132
Participant IV –Therapy-2. AFTER 2010 / 00000 / 00
d
Right THERAPY TEMPLATE Left
we
Condylar path
Lateral guidance
Pain
vie
TMJ internal derangement
re
¿Ha recibido la Tx-2?:
SI 
NO  (Causas)
Efectos adversos:
er
pe
ot
tn
rin
ep
Pr
133
AUTOADMINISTRADA:
d
¿Cómo calificaría en la actualidad, es decir, en este momento, su dolor facial en una escala
de 0 a 10? Donde 0 es “no dolor” y 10 es “el peor que podría ser”
we
No dolor El peor dolor posible
0 1 2 3 4 5 6 7 8 9 10
¿Cómo calificaría en este momento, su capacidad para abrir su boca en una escala de 0 a
10? Donde 0 es “no puedo abrirla nada” y 10 es “puedo abrirla del todo perfectamente”
vie
No puedo abrirla nada Puedo abrirla del todo perfectamente
0 1 2 3 4 5 6 7 8 9 10
Señale con un círculo la frase que mejor describe la evolución de su queja después del tratamiento
re
Firma del paciente: Firma del Dr:
Comments:
………………………………………………………………………………………….……
er
pe
ot
tn
rin
ep
Pr
134
Participant V - 3-Mo 201 / mes
/ día
d
Efectos Adversos: NO SI: …………………… Confort (sin dolor): …… /
we
……
1º ciclo 15s 20s 25s 30s 35s 40s 45s
No asistida: …… / ……
Asistida: …… / ……
vie
re
X = dolor
global
er
Z = el mometo
de más
pe
intensidad
Suele masticar por un mismo lado?: N0, alterno; Si, por la DCHA; Sí, por la IZDA. No lo sé
ot
¿Recibe algún tratamiento o férula para el dolor facial?: NO ; SI :

.................................................................
tn
¿Durante cuánto tiempo suele tener el dolor facial severo?:

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

rin
Mejoré Mejoré Mejoré Empeoré Empeoré Empeoré

NO Cambió
muchísimo mucho algo algo mucho muchísimo
0 1 2 3 4 5 6 7 8 9 10
ep
¿Cómo calificaría su capacidad para abrir su boca, en una escala de 0 a 10? Donde:
0 1 2 3 4 5 6 7 8 9 10
Pr
Firma del/a participante: Dr.:
135
Participante VI. 6-Mo 201 / mes /
día
d
¿Dr, Qué tratamiento recibió?: Real, Placebo, No lo sé)
Efectos Adversos: NO SI:
we
Confort (sin dolor): …… / ……
No asistida: …………
Asistida: …………
………………………………………..……………………
vie
1º ciclo 15s 20s 25s 30s 35s 40s 45s
re
10 Almendras:
(R/L): … /...
er X = dolor
global
pe
Z = el mometo
de más
intensidad
ot
tn
Suele masticar por un mismo lado?: N0, alterno; Si, por la DCHA; Sí, por la IZDA. No lo sé
¿Durante cuánto tiempo suele tener el dolor facial severo?:

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
rin

Mejoré Mejoré Mejoré Empeoré Empeoré Empeoré
NO Cambió
muchísimo mucho algo algo mucho muchísimo
ep
0 1 2 3 4 5 6 7 8 9 10
Pr
¿Cómo calificaría su capacidad para abrir su boca, en una escala de 0 a 10? Donde:
0 1 2 3 4 5 6 7 8 9 10
Qué tratamiento ha recibido?: Real ; Placebo ; No lo sé 
136
Firma del/a participante: Dr.:
Cita para la exploración completa y ANALÍTICA
d
we
vie
re
er
pe
ot
tn
rin
ep
Pr
137
Patient name ……………………..… VI. 6-Mo 201 / mes / día
d
(por otros investigadores independientes)
Confort (sin dolor): …… / ……
we
No asistida: …………
Asistida: …………
vie
Después de nuestro tratamiento, recibe/ió otro diferente?:
…………………………………
Mastica habitualmernte por un mismo lado?: N0, alterno ; Si, por la DERECHA; Sí, por la
IZQUIERDA. No lo sé 
re
Exploración Intraoral
9. Occlusal Quality: ............….………………………………………………….……………
10.Periodontal disease. 4.1. Probing (over 3mm):  :
…..…………………………….............. er
4.2. Periodontal Activity 
……………………….….………………
4.3. Radiographic defect depth  :
pe
.……..............................................
4.4. Tooth mobility 0-3): :
.......………..…….……...……………..
11.Dental decay: :
…....……………………………..……….….................................................
ot
12.Fixed partial prosthesis/implants 

………………………………………………………......
tn
7.2. Gnatography
7.3. Prescale
15. Implementation of self-administered questionnaires. SCL-90-R; McGill: DN4 Questionnaire
rin
(including clinical exploration); Credibility test.
Firma del participante: Firma del especialista:

Observaciones:…...…………………...…………………...…..…………………………………
……………………………………………………………………………………………………
……
ep
Pr
138
Patient name ……………………..………… VI. 6-Mo 201 / mes / día
d
Severidad del dolor crónico. (Von Korff et al., 1992)
we
Elementos de intensidad del dolor
8. ¿Cómo calificaría EN ESTE MOMENTO, su dolor facial en una escala de 0 a 10? Donde
0 es “no dolor” y 10 es “el peor que podría ser”
0 1 2 3 4 5 6 7 8 9 10
vie
9. En los últimos 6 meses, ¿cuál fue la intensidad, en una escala de 0 a 10, DEL PEOR
DOLOR FACIAL QUE PADECIÓ? Donde 0 es “no dolor” y 10 es “el peor que podría ser”
0 1 2 3 4 5 6 7 8 9 10
re
10. En los últimos 6 meses, GLOBALMENTE, ¿cuál fue la INTENSIDAD DE SU DOLOR
FACIAL en una escala de 0 a 10? Donde 0 es “no dolor” y 10 es “el peor que podría ser” (Es decir,
su grado de dolor habitual en los momentos en los que padecía dolor)
0 1 2 3 4 5 er 6 7 8 9 10
Elementos discapacitantes
11. ¿Alrededor de cuántos días, en los últimos 6 meses, no ha podido realizar sus actividades
habituales (trabajo, escuela o tareas del hogar) por culpa del dolor facial?
Días discapacitantes
pe
12. En los últimos 6 meses, ¿cuántas veces el dolor de espalda, de cabeza o facial interfirió en
sus actividades diarias, en una escala de 0 a 10 ? Donde 0 es “no interferencia” y 10 “incapacidad
para realizar cualquier actividad”
0=No interferencia Incapacidad para realizar cualquier actividad=10
0 1 2 3 4 5 6 7 8 9 10
ot
13. En los últimos 6 meses, ¿cuántas veces el dolor facial HA CAMBIADO SU CAPACIDAD
PARA PARTICIPAR EN ACTIVIDADES RECREATIVAS, sociales o familiares actividades
diarias, en una escala de 0 a 10 ? Donde 0 es “no cambio” y 10 “cambio extremo”
tn

0 1 2 3 4 5 6 7 8 9 10
14. En los últimos 6 meses, ¿Cuántas veces el dolor facial HA CAMBIADO SU

rin
CAPACIDAD PARA TRABAJAR (incluyendo las tareas del hogar), en una escala de 0 a 10?
Donde 0 es “no cambio” y 10 “cambio extremo”
0 1 2 3 4 5 6 7 8 9 10
ep
¿El dolor de cabeza cambia cuando mueve la mandíbula?: Sí, No.

Pr
139
Patient name ……………………..…………… VI. 6-Mo 201 / mes / día
d
Listado de síntomas de los desórdenes temporomandibulares
Los problemas de la mandíbula pueden causar múltiples dificultades de formas diferentes. De la
we
siguiente lista, indique con que problemas está teniendo dificultades (rodee con un círculo “si “o
“no”; varias respuestas de “si” son posibles):
Dolor de mandíbula si
no
Ruidos en mi mandíbula cuando muevo la boca si
vie
no
Mi mandíbula está bloqueada y no puedo abrirla ni cerrarla si
no
Otros problemas mandibulares – por favor descríbalos
.......................................................................
re
..........................................................................................................................................................
.....
Por favor, señale con una X el valor que mejor representa su opinión
1. ¿Le parece lógico este tipo de tratamiento?

0 1 2 3 4 5
er 6 7 8 9 10
0 = Nada totalmente=10
pe
2. ¿Qué tan segura/o esta usted de que este tratamiento podría tener éxito para eliminar
sus síntomas?
0 1 2 3 4 5 6 7 8 9 10
0 = Nada totalmente = 10
ot
3. ¿Recomendaría este tratamiento a un amigo que sufriese síntomas similares?

0 1 2 3 4 5 6 7 8 9 10
tn
4. Si usted sufriese estos síntomas, ¿estaría usted dispuesta/o a someterse a ese

tratamiento?
0 1 2 3 4 5 6 7 8 9 10
rin
5. ¿Percibe que el éxito de este tratamiento puede reducir otros síntomas, como el dolor
de cabeza?
0 1 2 3 4 5 6 7 8 9 10
ep
¿Cómo de prisa percibe que le pasa el tiempo?

0 1 2 3 4 5 6 7 8 9 10
0=Extremadamente lento Extremadamente rápido=10
Pr
140
Patient name ……………………..…… VI. 6-Mo 201 / mes / día
Escala Tampa de Kinesiofobia: Desordenes temporomandibulares
d
Para cada una de las frases siguientes , por favor indique el grado de acuerdo/desacuerdo
empleando la siguiente escala:
we
1 2 3 4
Muy en desacuerdo Algo en desacuerdo Algo de acuerdo Muy de acuerdo
1. Tengo miedo de hacerme daño si muevo la mandíbula. 1 2 3 4

2. Si no pienso en mis síntomas mandibulares, se pondrán peor. 1 2 3 4
vie
3. Mi mandíbula me está diciendo que algo va seriamente mal en ella. 1 2 3 4
4. Mis síntomas mandibulares probablemente mejorarían si moviese
1 2 3 4
más la mandíbula.
5. Otra gente no se toma mis síntomas mandibulares lo suficientemente
1 2 3 4
en serio.
re
6. Mis síntomas mandibulares han puesto en riesgo mi salud para el
1 2 3 4
resto de mi vida.
7. Mis síntomas mandibulares significan que he dañado mi mandíbula. 1 2 3 4
8.
daño.
er
Aunque algo agrave mis síntomas mandibulares no me voy a hacer
1 2 3 4
9. Tengo miedo de dañar mi mandíbula accidentalmente. 1 2 3 4

pe
10. La manera más segura de evitar que mis síntomas empeoren es tener
1 2 3 4
cuidado y no mover mi mandíbula más de lo necesario.
11. No tendría tantos síntomas en la mandíbula si no estuviese
1 2 3 4
sucediendo algo potencialmente dañino.
12. Aunque tengo síntomas mandibulares me encontraria mejor si
ot
1 2 3 4
siguiese usando mi boca con normalidad.
13. Mis síntomas mandibulares me permiten saber cuando dejar de
1 2 3 4
mover mi mandíbula de tal modo que no me haga daño a mi mismo/a.
tn
14. No es seguro para alguien con mi situación mandibular usar mucho la

1 2 3 4
boca.
15. No puedo hacer todo lo que hace otra gente porque es muy fácil que
1 2 3 4
rin
me haga daño en la mandíbula.

16. Aunque hacer algo agrave mis síntomas mandibulares, no creo que
1 2 3 4
sea perjudicial.
17. Nadie debería tener que mover su mandíbula cuando tiene un
1 2 3 4
ep
problema mandibular.
18. Tengo miedo a abrir mucho la boca ya que puede que no consiga
1 2 3 4
cerrarla otra vez.
Pr
141
Patient name …………………… VI. 6-Mo . 201 / mes / día
Cuestionario de dolor McGill.
d
Por favor, marque con una X los cuadros que mejor describen su dolor
Valor de intensidad sensorial Valor de intensidad afectiva
we
Temporal 1 Temor
Como pulsaciones Temible
Como una sacudida Espantoso
vie
Como un latigazo Horrible
Térmica Autonómica / Vegetativa

Frío Que marea
Caliente Sofocante
re
Ardiente
Presión constrictiva Castigo

Entumecimiento Espasmo Que atormenta
Como un pellizco Retortijón er Mortificante
Agarrotamiento Opresivo Violento
Calambre
Presión puntiforme / incisiva Tensión / Cansancio

pe
Pinchazo Extenuante
Punzante Agotador
Penetrante Incapacitante
Agudo
ot
Presión de tracción gravativa Cólera / Disgusto

Pesado Incómodo
Tirante Que irrita
tn
Como un desgarro Que consume

Tenso
Espacial Pena / Ansiedad

rin
Superficial Interno Deprimente

Difuso Profundo Agobiante
Que se irradia Que angustia
Fijo Que obsesiona
ep
Desesperante
Viveza Valor de intensidad evaluativa
Temporal 2
Adormecido
Picor Momentáneo
Pr
Hormigueo Intermitente
Como agujetas Creciente
Escozor Constante
142
Como una corriente Persistente
d
Valor de intensidad actual
we
Intensidad
Firma del/la participante:
Sin dolor Intenso
Leve Fuerte
Molesto Insoportable
vie
re
er
pe
ot
tn
rin
ep
Pr
143
Patient name ……………………..… VI. 6-Mo 201 / mes / día
d
CUESTIONARIO DN4
Por favor complete este cuestionario marcando una respuesta para cada número en las 4 preguntas:
we
ponga una X
ENTREVISTA
Pregunta 1: ¿Tiene el dolor una o más de las siguientes características?
SI NO
1- Quemazón
2- Frío doloroso
vie
3- Calambres eléctricos
Pregunta 2: ¿Está asociado el dolor con uno o más de los siguientes síntomas en la misma
zona?
SI NO
4- Hormigueo
5- Alfileres y agujas
re
6- Entumecimiento
7- Picazón
EXAMEN FÍSICO (Rellenar por el Doctor)

Pregunta 3: ¿Está el dolor localizado en una zona donde el examen físico puede mostrar
una o más de las siguientes características?
er SÍ NO
8- Hipoestesia al tacto
9- Hipoestesia a pinchazos
Pregunta 4: En la zona dolorosa, el dolor es causado o incrementado por:
pe
SI NO
10- Cepillado suave de la piel
Por cada respuesta positiva asigne un punto, por cada respuesta negativa asigne un valor de
0 (cero). Sume los puntos; si es mayor o igual a 4 se considera que hay dolor neuropático.
Puntuación del paciente: /10
ot
Sociodemografía al inicio del estudio (Elliott et al., 2002)

Nivel de educación: Educación superior (Estudios universitarios y Formación Profesional de grado
superior) Educación secundaria postobligatoria (Bachillerato y Formación Profesional de grado
medio) Enseñanza obligatoria 
tn
Estado matrimonial: Soltero/a Actualmente casado/a Divorciado/a

Vivienda: Propia o hipotecada Arrendamiento público Arrendamiento privado y otras
Situación laboral: Trabajador Retirado Incapacitación por enfermedad Otras causas de
desempleo
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SI COMPLETÓ EL ESTUDIO: Extracción sanguínea.

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POST ESTUDIO
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Patient name ……………………..………………...………………………………... 201 / mes /
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REEVALUACIÓN / TRATAMIENTO?
Una vez completado el estudio, realizados los análisis estadísticos, los códigos de terapia se dieron a
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conocer y se discutieron los resultados, de acuerdo con el DSMB:
Explicación del tratamiento recibido por y a cada paciente y, si procede:
Refinamiento
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Información post-estudio a los participantes; tratamiento si lo desean (en este caso, crear nueva carpeta).
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Ethics approval
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Updated ethics approval
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Appendix VI. Statement of whether DSMB is independent from the sponsor and competing interests
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CONFIDENTIAL
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NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE OF DENTAL AND
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CRANIOFACIAL RESEARCH
Data and Safety Monitoring Board (DSMB)
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Conflict of Interest Statement
MAP Protocol: Restoring physiological jaw closure and MAsticatory

function as treatment for chronic Pain: a randomized clinical trial
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1. The following situations may pose a possible Conflict of Interest.
▪ Serving as a part-time, full-time, paid, or unpaid employee of any organizations: (a) that
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are involved in the study under review, (b) whose products or services will be used or
tested in the study under review, or (c) whose products or services would be directly
and predictably affected in a major way by the outcome of the study;
▪ Serving as an officer, member, owner, trustee, director, expert advisor, or consultant of
such organizations; and
▪ Having financial interests or assets – of my own or those of my spouse, dependent
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children, or organizations with which I am connected – in any organizations meeting

the above criteria.
2. PLEASE CHECK (ü) THE APPLICABLE ITEM BELOW.
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☐ I do not have any of the above interests to report.

☐ I have the following (or attached) interests to report.
____________________________________________________________________________
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3. I will notify the Director of the Office of Clinical Trials Operations and Management, NIDCR
promptly if: a change occurs in any of the above during the tenure of my responsibilities, or I
discover that an organization with which I have a relationship meets the criteria for a conflict of
interest.
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4. I am aware of my responsibilities for: maintaining the confidentiality of any non-public

information that I receive or become aware of through this activity, and for avoiding using such
information for my personal benefit, the benefit of my associates, or the benefit of organizations
with which I am connected or with which I have a financial involvement.
5. Acceptance of this invitation to serve on the DSMB confirms that: I do not have any financial or
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other interest with any of the collaborating or competing pharmaceutical firms or other
organizations involved in the study that constitute a potential conflict of interest.
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Member’s Name Signature Date
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NIDCR Reviewer’s Name Signature Date
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Minute of the DSMB and the TSC of the MAP trial open session, before participant’s enrollment
Date: July 11th, 2014
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At the Faculty of Medicine and Dentistry,
University of Santiago de Compostela.
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Ref.: MAP Protocol: Restoring physiological jaw closure and MAsticatory function as treatment for
chronic facial Pain: a randomized clinical trial
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Data and Safety Monitoring Board (DSMB): (please see Protocol item 21a)
Prof. Dr. Pentti Alanen (Chair)* alanenpentti@gmail.com
Prof. Dr. Joao C. Pinho (Expert in TMD) pinhojc@gmail.com
Dr. Florencio Monje (Expert in TMD) fmonje@oralmaxilofacial.com
Prof. Dr. Carmen Carollo (Statistician) mdelcarmen.carollo@usc.es
Dr. Francisco Gude (Statistician) Francisco.Gude.Sampedro@sergas.es
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Urbano Santana-Penín (USP) urbano.santana@usc.es
José López-Cedrún (JLC) lopezcedrun@centromaxilofacial.com
María J. Mora (MJM) mariajesus.mora@usc.es
Urbano Santana-Mora (USM) urbanoalejandro.santana@rai.usc.es
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*, presents at this on-line open and closed sessions.
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In an open session, the DSMB and the TSC of the MAP trial declares:
The DSMB of MAP trial adheres to the National Institutes of Health (NIH) and
The National Institute of Dental and Craniofacial Research (NIDCR) guidelines.
DSMB members should be independent and constructively critical of the ongoing trial, but also
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supportive of aims and methods of the trial.
The TSC declares that all members of the DSMD, the TSC, and persons overseeing the trial have been
considered the MAP trial protocol, and make constructive criticism, and all them accepted the final
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version #1, before enrollment started.
DSMB meets before the trial starts using simultaneous e-mail in a closed session. The purpose of the first
meeting is to allow the members to get to know one another, to consider the protocol in detail, and to
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discuss how the committee might respond to hypothetical situations.
Same day DSMB is meeting with TSC on same approach.
Consideration should be given to an initial "dummy" report, including the use of shell (empty) tables, to
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familiarize the DMC members with the format that will be used in the reports.
Issues specific to the disease under study should be described. MAP trial was designed to assess the
therapy efficacy of the restoring physiological jaw-closure and impaired chewing function by occlusal
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adjustment therapy to treat TMD-pain. Efficacy will be demonstrated by superior pain relief with the
active treatment compared with the placebo.
Relationships. An advisory rather than executive function for DSMB was favored in all parts of the
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project. The surveys and interviews with the experienced DSMB members was for the Chair to report the
recommendations of a DSMB to the principal investigators (Drs Lopez-Cedrún and/or Santana-Penín), on
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the basis that the trial organizers are ultimately responsible for the conduct of the trial. All members of
the DSMB are in direct contact to discos any issue; each member of the DSMB can be directly address
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any concern directly to the principle investigators, although discussion with the Chair of the DSMB is the
preferred system; statisticians of the DSMB could directly ask for data at the time that independently
decide if it is interesting.
The Chair of the DSMB should know the adverse events and, if they are relevant, according to the
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DSMB, the CAEI should be informed by the TSC.
Open sessions with the trial investigators, sponsors, or both to discuss general issues, such as recruitment
rates, were deemed useful, and a combination of open and closed sessions will be held by TSC and/or
DSMB or the Chair’s initiative. At less, the DSMB will be meeting one year after study is running, and
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after interim analysis if relevant.
MAP trial data will be kept confidential and accessible on-line but restricted to the DSMB.
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These persons decided to meet in a closed session with the five DSMB members to discuss any concern
in relation to the MAP trial study and protocol in order to recommend the modification or authorize the
initiation of the trial. The Chair of the DSMB will inform via e-mail the decision of the committee to the
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trialists:
List of participants: Mª Carmen Carollo, Joao Carlos Pinho, Maria J. Mora, Jose Lopez-Cedrún, Urbano
Santana-Penín.
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Invited attendants: Victor A. De la Peña, Iria L. Darriba, Rocío P. García.
Signed: Prof. Dr. Pentti Alanen

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Minute of the DSMB and the TSC of the MAP trial closed followed by an open
session, one year after study is running.
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Date: October 16th, 2015.
At the Faculty of Medicine and Dentistry, University of Santiago de Compostela.
Ref.: MAP Protocol: Restoring physiological jaw closure and MAsticatory function as treatment for
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chronic facial Pain: a randomized clinical trial
ISRCTN61654487 - http://www.controlled-trials.com/ISRCTN61654487/
Data and Safety Monitoring Board (DSMB): (please see Protocol item 21a)
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Prof. Dr. Pentti Alanen (Chair)* alanenpentti@gmail.com
Prof. Dr. Joao C. Pinho (Expert in TMD) pinhojc@gmail.com
Prof. Dr. Julián Álvarez Escudero (Pain Medicine) NEW * julian.alvarez.escudero@sergas.es
Prof. Dr. Carmen Carollo (Statistician) mdelcarmen.carollo@usc.es
Dr. Francisco Gude (Statistician) francisco.gude.sampedro@sergas.es
Dr. Florencio Monje (Expert in TMD). fmonje@oralmaxilofacial.com
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Urbano Santana-Penín (USP) urbano.santana@usc.es
José López-Cedrún (JLC) lopezcedrun@centromaxilofacial.com
María J. Mora (MJM) er mariajesus.mora@usc.es
Urbano Santana-Mora (USM) urbanoalejandro.santana@rai.usc.es
*, presents at this on-line open and closed sessions.

N:B: Main aspects of trial ongoing were discussed previously by the TSC and the Chair of the DSMB.
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In a closed session, the DSMB of the MAP trial declares:
Attendants: Prof. Dr. Joao Carlos Pinho, Prof. Dr. Mª Carmen Carollo, Dr Francisco Gude; by e-mail:
Prof. Dr. Pentti Alanen and Prof. Dr. Julián Á. Escudero.
DSMB meets on October 16th 2015 in Santiago de Compostela University using simultaneous e-mail in a
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closed session. The purpose of the second meeting is to consider the MAP’s follow-up regarding
participant’s safety (including possible harms, unexpected adverse events) the protocol adherence and
possible alterations in detail, and to discuss how the committee might respond to hypothetical/real
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situations.
Dr Monje showed unavailability previously.
A proposal by the TSC, the DSMB supports a new member Dr. Julian Alvarez Escudero, Professor and
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Chair, Head of the Pain Unit at the University Hospital of Santiago de Compostela.
The DSMB declares that each member can proceed to the Openclinica database on-line. According to
Openclinica data, MAP trial is ongoing without relevant problems regarding the patients’ care. No
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unexpected/relevant events have been mentioned neither occurred.
The DSMB declares that all members had considered the MAP trial protocol #2, and made constructive
criticism, and all of them accepted this version #2, which has been implemented from almost the begining
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of this study (september 5th, 2014), as shown on the Openclinica database.
Alterations of this #2 version respect to the first version #1 are:
1. The pain-intensity of the “affected side” (because pain could move to the opposite side) for
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Openclinica was changed and now we use the specification:
1.1. The affected side is defined as: “right”, “left” or “bilateral”. This discrimination is based
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on the participant’s chief complaint and the scores on each side (4 ≤ global pain ≥ 9).
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1.2. Scores on each of any side are displayed in Openclinica. Specifically: maximum
comfortable and maximum unassisted jaw opening.
2. “Maximum spontaneous opening” was changed and completed; the data for Openclinica
includes now two variables: “maximum confortable” and “maximum unassisted” mouth opening.
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3. The OHIP and the MFIQ scales were eliminated. Cause: 1, most questions are repetition of other
implemented tests, and 2, to reduce excesive time consuming procedures during the baseline-diagnostic
and ending sessions. It was reduced from 120 to 90 minutes aproximatelly. Data from these 2 tests will
not be used in the main nor ancillary reports realted to MPA-trial.
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4. To contribute to blinding of all of the trialists, the letters “A” and “B” (group code) where
removed from all the documents; A/B remained accessible only in the Openclinica Database (to Ms.
Teresa Pazos) and they are known exclusively by the therapy provider.
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After participants ending the study, the TSC act in a blind manner and no information, regarding the type
of therapy performed, was/is/will be offered to participants, until the study is completed:
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5. For the better care of participants after study ending, when pain remained, they are invited to
“complete the therapy” or to adhere the CHUAC protocol (please see flow-diagram, page 106 of this
protocol #2 version).
The DSMB consider alterations in the Protocol-2 contribute of progressing and improve blinding of the
study and patient’s care; thus, this version 2 is approved by all members of this Committee.
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The TSC meet at same time in a separate room.

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After this meeting, same day DSMB is meeting with TSC on same approach.
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In a open session, the DSMB and the TSC of the MAP trial declares:
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Issues specific to the disease under study should be described. MAP trial was designed to assess the
therapy efficacy of the restoring physiological jaw-closure and impaired chewing function by occlusal
adjustment therapy to treat TMD-pain. Efficacy will be demonstrated by superior pain relief with the
active treatment compared with the placebo at 6-Months follow-up. According to the recommendations
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of the Chief of the DSMB, participants with facial pain that have not received splint therapy received
prescription for it use (usual approach in CHUAC) before enrollment, with the exception of the
participant’s concerns against it’s use, or for economical reasons, according to public health laws in
Spain. Patients with acute jaw-pain (less that 6 months) receive same prescription of splint therapy and
were/are re-cited when evolution of pain, if it remains, exceed 6-Month before enrollment.
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Relationships. An advisory rather than executive function for DSMB was favored in all parts of the
project. The surveys and interviews with the experienced DSMB members was for the Chair to report the
recommendations of a DSMB to the principal investigators (Drs Lopez-Cedrún and/or Santana-Penín), on
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the basis that the trial organizers are ultimately responsible for the conduct of the trial. All members of
the DSMB are in direct contact to discus any issue; each member of the DSMB can be directly address
any concern directly to the principle investigators, although discussion with the Chair of the DSMB is the
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preferred system; statisticians of the DSMB could directly ask for data at the time that independently
decide if it is interesting.
The Chair of the DSMB should know the adverse events and, if they are relevant, according to the
DSMB, the CAEI should be informed by the TSC.
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Open sessions with the trial investigators, sponsors, or both to discuss general issues, such as recruitment
rates, were deemed useful, and a combination of open and closed sessions will be held by TSC and/or
DSMB or the Chair’s initiative. At less, the DSMB will be meeting one year after study is running, and
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after interim analysis if relevant.
Recruitment status (N participants):
Enrolled: 45.
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Completed 6-Mo follow-up: 13.
Treated. Two therapy sessions: 17. One therapy session: 5.

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Enrolled, not assigned: 10.
MAP trial data were/are/will be kept confidential and accessible on-line but restricted to the DSMB.
These persons decided to meet in a closed session with the five DSMB members to discuss any concern
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in relation to the MAP trial study and protocol in order to recommend the modification or authorize the
continuation of the trial. The Chair of the DSMB will inform via e-mail the decision of the committee to
the trialists:
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DSMB decided the MAP trial protocol version 2 clearance and authorize the continuation of the trial.
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List of participants: Mª Carmen Carollo, Francisco Gude Sampedro, Joao Carlos Pinho, María J. Mora
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Bermúdez, Jose Lopez-Cedrún, Urbano Santana-Penín, Urbano Santana Mora and Teresa Pazos
Fernández; attendants simultaneously by e-mail: Pentti Alanen, Julián Álvarez Escudero.
Signed:
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Prof. Dr. Pentti Alanen
Prof. Dr Mª J. Mora
Dr. JL López-Cedrún
Prof. Dr Urbano Santana
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Meeting date: 11th June, 2018. MINUTE
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AMENDMENTS
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January 29th, 2015.
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Rescue therapy plan:
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October 16th, 2015
1. The affected side is defined as: “right”, “left” or “bilateral”. This discrimination is based on the
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participant’s chief complaint and the scores on each side (4 ≤ global pain ≥ 9). Scores on each of any side
are displayed in Openclinica.
2. “Maximum spontaneous opening” was changed and completed; the data for Openclinica
includes now two variables: “maximum comfortable” and “maximum unassisted” mouth opening.
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3. The OHIP and the MFIQ scales were eliminated. Cause: 1, most questions are repetition of other
implemented tests, and 2, to reduce excessive time consuming procedures during the baseline-diagnostic
and ending sessions. It was reduced from 120 to 90 minutes approximately. Data from these 2 tests will
not be used in the main nor ancillary reports related to MPA-trial.
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4. To contribute to blinding of all of the trialists, the letters “A” and “B” (group code) where
removed from all the documents; A/B remained accessible only in the Openclinica Database (to Ms.
Teresa Pazos) and they are known exclusively by the therapy provider.
5. After participants ending the study, the TSC act in a blind manner and no information, regarding
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the type of therapy performed, was/is/will be offered to participants, until the study is completed:
6. For the better care of participants after study ending, when pain remained, they are invited to
“complete the therapy” or to adhere the CHUAC protocol (please see flow-diagram, page 78).
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04/05/2016
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International Standard Randomized Controlled Trial Number Register (ISRCTN Register):
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https://doi.org/10.1186/ISRCTN61654487
Study hypothesis
Current hypothesis as of 04/05/2016:
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That the restoration of physiological jaw closure and impaired chewing function by occlusal adjustment
therapy will relieve chronic TMD-pain. Efficacy will be demonstrated by showing significantly superior
pain relief at the 6-month visit with active treatment as compared with placebo.
Previous hypothesis:
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The primary endpoint will be the average change in pain score from baseline to the 3- and 6-months
assessments. Efficacy will be demonstrated by superior pain relief with the active treatment compared
with the placebo.
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Supplement 2: Occlusal adjustment therapy in this trial
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Trial of occlusal adjustment for chronic jaw pain. A Randomized
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Clinical Trial
Authors:
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Urbano Santana-Mora,
José Luís López-Cedrún,
María Jesús Mora-Bermúdez,
Urbano Santana-Penín
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TABLE OF CONTENTS
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Trial regimen and procedures
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Preliminary statements ……………….……………………………………………………………………….… 3
Occlusal adjustment in this trial …………………….……………………………………….… 4

Phase 1. Adjustment of jaw closure …………………………….…………………………………. 9
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The buccal cusp of the second mandibular premolar ………..……………………..…… 9
The lingual cusp of the second maxillary premolar. ………………...……………...….… 10
The lingual cusp of the first maxillary molar. ……………………….…………..……..…… 11
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The mesio-lingual cusp of the first maxillary molar. ………………………………...…… 13
Occlusal adjustment of the canines during jaw closure. …………….………………..… 14
Phase 2. Adjustment of the mandibular literalities ………………………..…..……..… 16
Occlusal adjustment of the canines during lateral jaw movement……….………… 16
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Occlusal adjustment of interferences in premolars and molars
during the lateral movement of the mandible. ……………………………..……………… 21
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Working side ……………………………………………………….……………………….…….. 21
Balancing side ……………………………………………………………………………………... 22
The importance of an appropriate arch shape …………………………………………….. 25
Occlusal adjustment of the lingual surfaces of the maxillary incisors …………… 27
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REFERENCES …………………………………..……………………………………………………..….………. 30
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ADDITIONAL INFORMATION for the MAP trial
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TRIAL REGIMEN AND PROCEDURES
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Preliminary statements
This overview of occlusal adjustment is not intended to cover all possible occlusal
adjustment options in dentistry. It is only intended to describe the procedure that is
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applicable in the specific case of a clinically normal or quasi-normal dental
occlusion so that the clinician can be informed about the details of the procedure,
should they wish to replicate the study. In these patients, a minimally invasive
adjustment can achieve the goals of improving muscle activity and masticatory
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function.
Occlusal adjustment when pathological mesiodistal or transverse relationships are

clearly evident, such as for patients with skeletal class II or III or other anomalies
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such as excessive overbite and/or crossbite, is not described in this document.
Surgical, rehabilitative, orthopedic or orthodontic correction may be indicated
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before occlusal adjustment. Occlusal adjustment when the occlusion is normal or
quasi-normal should always be avoided by optimizing dental contacts through
orthodontics. The problem is that orthodontics usually does not achieve occlusal
correction to the micrometer level, so it is difficult to completely eliminate the
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requirement for occlusal adjustment. However, the teeth are likely to undergo
physiological wear throughout life; a correctly planned and executed occlusal
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adjustment should replicate the natural dental anatomy appropriate to the patient's
age.
Successful treatment requires the patient be able to chew comfortably and

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vigorously on each side alternately. This requires a correct and complete oral
anatomy and the absence of dental or gingivo-periodontal pathology; correct
interdental contacts are also necessary to avoid food packing (mainly fibrous type)
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and the consequent discomfort or pain, as this would limit the use of that location
for chewing.
A good long-term prognosis also depends on the use made of the masticatory
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apparatus; a diet based on excessively soft or crushed foods will probably not favor
the correct development and evolution of the masticatory apparatus.
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Occlusal adjustment in this trial
Concept, objectives, and rationale. Occlusal adjustment or reshaping is any change in the
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occlusion intended to alter the occlusal surfaces of the teeth or restorations to change their
shape (GPT-9; Schuyler, 1935; Dawson, 1989). The occlusal adjustment implemented in
this study (see item 11a of the study protocol) was designed to recover the closure of the
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mandible and physiological masticatory function. By adjusting the centric occlusion, the
aim was to reduce the activity of the masticatory musculature during rest and also to
reduce the intensity and frequency of clenching and non-functional tooth grinding. By
adjusting the lateral excursions, the aim was to establish vigorous, unilateral and
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alternating physiological mastication. The achievement of both objectives is necessary to
provide a theraputic masticatory apparatus for these patients. If the musculature becomes
fatigued because of hyperactivity not related to mastication, the masticatory musculature
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may undergo fatigue, expressed as tension or pain. If mastication is not adequate, habitual
mastication on one side being one of the main pathologies, it may also negatively affect
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muscular coactivation during non-chewing periods. Occlusal prematurities can generate
chronic dento-periodontal trauma with damage to the tooth or teeth involved and
secondarily lack of muscle coordination. Automatically or subconsciously, the patient
may seek to eliminate these prematurities by grinding the teeth, which may be associated
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with the etiology of bruxism. This pathophysiological mechanism may be caused by

prematurity and/or occlusal interference during mandibular excursions. It does not seem
sufficient to eliminate prematurities, but it also seems logical to eliminate interferences
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in general. Structurally and dynamically, our adjustment was intended to obtain a

balanced occlusion, defined in the Jablonski dictionary (Jablonski, 1992) as Dental
occlusion in which the occlusal contact of the teeth on the working side of the jaw is
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accompanied by the harmonious contact of the teeth on the opposite (balancing or

nonworking) side. Note that it does not include the protrusion movement. When there is
balanced occlusion, the protrusive movement always discludes the posterior teeth;
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enabling incising food or a thread without being impeded by the posterior teeth.
In our experience, neuromuscular relaxation is achieved clinically immediately after

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adjustment of the closure of the mandible into the centric position; the alternating
masticatory function must be achieved by adjusting the mandibular laterality movements:
reduction of the increased lateral guidance that often exists on the habitual nonworking
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side is usually required. Figure 1 in the main manuscript shows the occlusal
characteristics of a patient who usually chews on the left side and suffers chronic pain on
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that same left side (Santana-Mora et al., 2013); in the upper part, the initial situation is
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observed, and, in the lower part, the occlusion is shown after the occlusal adjustment. The
upper and central image show mandibular closure in maximum intercuspation; in the
upper left image, the canines are the only teeth that contact when making the right
mandibular lateral movement, which requires a more vertical movement (red arrow) than
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the movement towards the opposite side (black arrow in the upper right image). In the
movement towards the left side, in addition to being more horizontal, there is a greater
number of contacting teeth, allowing for more efficient chewing, which contributes to
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this being the habitual chewing side (Hildebrandt, 1936). The lower part of this figure
shows the result of the occlusal adjustment; although the occlusal closing alteration in
central occlusion (central images) is not perceptible in the figure nor during left lateral
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movement (right images), the increased horizontal movement is evident. The figure also
showsd the increased number of dental contacts during right lateral movement (lower left
image) with respect to right lateral movement before treatment (upper left image).
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Before
right lateral jaw motion maximal intercuspal position left lateral jaw motion
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After centric occlusion

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Figure S1. Pictures showing a characteristic occlusion from a patient suffering from left symptoms
(upper part) and therapy (lower part). The main objective was to achieve centric occlusion concordant
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with maximal intercuspal position and reduce the highest right lateral guidance (left pictures) to reco-
ver alternate chewing function.
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Blue articulating paper (200 µm, BK1, Dr. Jean Bausch KG®, Cologne, Germany) was
used to discern contacts between the teeth. The use of this type of articulating paper has
not usually been recommended by other authors. The reason stated has been that the
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occlusal adjustment requires a precision of a few micrometers, greater than that provided
by this paper (200 µm). One reason is that, because it is relatively rigid, it is easier to
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place between arches; the articulating paper must be placed simultaneously on both sides
to help the patient close in a centric position; if the paper is placed on only one side, the
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patient tends inappropriately to move the jaw towards the side where the paper is placed.
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When there is an interference, the paper is usually perforated (the paper must be checked),
and the mark on the tooth has a central area without ink, surrounded by a marked blue
area, indicating the contact area that should be considered for removal. In this technique,
the decision to grind the mark on the maxillary or mandibular tooth was taken after
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observing the lateral jaw motion to preserve all light contacts during lateral jaw motion
on the working and the nonworking sides by following the concept of the protection of
the nonworking side temporomandibular joint.5 To grind enamel, we used mainly a
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diamond rotary instrument (ISO 909, Komet instrument; Gebr. Brasseler GembH & Co.,
Lengo-Germany), although some surfaces can be adjusted using cylindrical diamond
rotary instruments.
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The occlusal adjustments in this study were performed by balancing the centric occlusion
and subsequently both lateral excursions of the mandible. The adjustment was carried out
by eliminating a minimal amount of enamel from the premature contacts, repeating the
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process as many times as necessary; contacts of other dental pairs were obtained
successively until they were generalized in the arches. Adjustment of the centric
occlusion should be stopped when (i) the muscle contracture disappears, allowing the jaw
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to be easily manipulated and all or most of the teeth to come into contact in a balanced
manner; and (ii) when the patient is asked to squeeze their teeth together and the jaw does
not make any movement from centric occlusion to achieve maximum intercuspation
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(there is no "centric slide"). This indicates that it is the most closed position, since any
movement would imply a certain degree of jaw opening or displacement. This probably
reinforces the physiologically closed position proprioceptively, avoiding the need to look
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for other positions that would involve pathogenetic parafunctional movements. Tooth
contact should not be sought systematically, as, if one is undercut or incorrectly
positioned, it may require excessive adjustment of the other teeth. The correct chewing
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function will likely allow the correct occlusion to develop spontaneously at a later date;
consequently, dental contacts and the inclination of the occlusal plane should be
improved. The second step consists of reducing the higher lateral guidance; the magnitude
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of this alteration was estimated by the following equation: right condylar path × left
lateral guidance = left condylar path × right lateral guidance.
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There are 4 main differences in our occlusal adjustment compared with traditional
occlusal adjustment (Schuyler, 1935; Dawson, 1989; Okeson, 2012):
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1. Balance the occlusion to obtain centrically balanced occlusion during jaw
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closure in centric position and in both lateral excursions of the mandible. This
objective requires that lateral excursions be considered right from the beginning
of the centric occlusion adjustment.
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2. Reduce the greatest lateral guidance, usually the nonworking side which is
usually the non-symptomatic side.
3. Use restorative material, when indicated, to alter the dental morphology,
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minimizing the removal of dental tissue.
4. Obtain a class I ratio of canines on both sides, both in centric relation and during
lateral excursion (working side).
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Therapy should be re-evaluated and re-treated (refined) one month later and several times
more if needed, although this was not done in this trial. The first session typically required
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90 to 120 min, including kinesiography monitoring. Factors related to the patient’s
occlusion and muscular coactivation influenced the time of this first session. The second
and subsequent sessions required from 15 to 30 min. Dental pain elicited by therapy was
the criterion for discontinuing the intervention. Other concomitant therapies should not
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be used. After therapy, all participants should be encouraged to chew on the more
comfortable side, avoiding the conscious, deliberate use of a given side. In the usual
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clinical context, the observation of the presence of one habitual chewing side after first
and subsequent therapy is important in order to help with the occlusal corrections.
The procedure is explained in the following figures. We do not attempt to dictate how to
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perform occlusal adjustment for each patient. These are simply a series of remarks in an
attempt to systematize the technique in these almost clinically normal mouths, which
require a minimal invasive procedure in a predictable way. Moderate Angle class II can
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also be functionally corrected. Occlusal adjustment therapy should allow a correct

intercuspal position during jaw closure in centric position; Figure 2 shows a typical dental
articulation with a very narrow lower dental arch: occlusal adjustment is absolutely
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contraindicated in these cases.
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eFigure 2-S2. Picture from a patient with buccal lower cusps are lingualized more
than 2 mm (red arrows) in respect the antagonists’ fosses during centric occlusion:
Occlusal adjustment is absolutely prohibited in these cases.
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Because functional rehabilitation was a primary objective of this trial, conditions such as
tooth loosening or pain during chewing associated with dental caries or inadequate
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interdental contacts had been previously treated, or the patients were not recruited for this
trial.
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The goal of balanced occlusion during lateral jaw movement was only achieved when the
occlusal plane was correctly adjusted. A typical sequence of occlusal adjustment
performed in this trial is presented below.
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Phase 1. Adjustment of jaw closure.
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How can balanced contacts be obtained in centric relationship in clinical practice?
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The buccal cusp of the second mandibular premolar.
The first premature contact during jaw closure usually occurs between the premolars on
one side, commonly between the buccal cusp of the second mandibular premolar and the
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lingual cusp of the second maxillary premolar during retrusive jaw closure. When the
paper marks identify the interference between the lingual cusp of the second maxillary
premolar and the buccal cusp of the second mandibular premolar, it normally contacts the
mesial surface of the maxillary premolar and the distal surface of the mandibular premolar
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in an intermediate area of the cusp (Figure S2, upper part). Is the lingual cusp of the
second maxillary premolar or the buccal cusp of the second mandibular premolar
adjusted? In this trial, the decision was made to adjust a tooth or its antagonist after
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assessing the occlusal relationship in the balancing position. The balance position in these
situations is more important than the working position. The working position is easier to
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adjust, as each cusp works with the same antagonist tooth than in the centric position. The
balance is a more complex relationship as it requires contacts between the antagonist teeth
in the centric position with the neighboring teeth in the balancing position. If the buccal
cusp of the second mandibular premolar interferes in centric and also in balancing
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positions, in this case with the lingual cusp of the first maxillary premolar (Figure S2,
left), the mandibular buccal cusp must be reduced. The reason for this decision is based
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on the objective of obtaining adequate contacts in both centric and balancing positions;
by adjusting only one cusp (only its slope) the objective is achieved, but if the maxillary
cusp is adjusted, only correct contacts in the centric position would be achieved. and it
would be necessary later to reduce the lingual cusp of the first maxillary premolar and
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also the entire excursion of the mandibular buccal cusp on the maxillary lingual, thus
requiring substantially greater removal of dental tissue. If the mandibular buccal cusp
moves away from its antagonist during balancing (Figure S2, right), this cusp must not
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be adjusted, and the lingual cusp of the second maxillary premolar will be reduced.
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The lingual cusp of the second maxillary premolar.
Sometimes, it is the height of the lingual cusp of the second maxillary premolar that
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prematurely contacts the distal fossa or the distal marginal ridge of the second mandibular
premolar (top panel in Figure S3). In this case, a check should be made to see if during
lateral excursion the maxillary lingual cusp interferes with the mesiobuccal cusp of the
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first mandibular molar; if it interferes in centric and also in balancing contact (Figure S3,
left side), the cusp of the maxillary premolar should be reduced; if, however, it only
contacts in the centric position but not in the balancing position (Figure S3, right side),
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the mandibular fossa and/or marginal ridge should be reduced.
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In premolars, the most important cusps, are the mandibular buccal cusps on account of
their dual supporting and working function. If a borderline situation or doubts exist about
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which premolar cusp should be adjusted between the maxillary lingual cusps or the
mandibular buccal cusps, in general, the maxillary cusps should be selected.
The lingual cusp of the first maxillary molar.

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In general, the most important cusps in the molars are the lingual cusps. In particular, the
mesiolingual cusp of the first molar is considered the key to occlusion. It errupts at 6
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years of age, appearing behind the deciduous arch without replacing any deciduous teeth;
the maxillary and mandibular molars appear simultaneously. Generally, after the
elimination of prematurity in the premolars, the mesiolingual cusp of the first maxillary
molar contacts the central fossa of the first mandibular molar (upper part of Figure S4).
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The decision to remove this interference by adjusting the maxillary cusp or mandibular
fossa, as in the premolar procedure, requires the exploration of the lateral excursion to
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the opposite side; this will reveal the dynamic relationships of the mesiolingual cusp of
the first maxillary molar with the occlusal surface of its antagonist, the first mandibular
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molar. The maxillary cusp should contact slightly with the mesio-lingual slope of the
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disto-buccal cusp of the first mandibular molar. If this lateral movement interferes during
its excursion (lower images on the left side of figure S4), the mark on the lingual cusp of
the maxillary cusp should be reduced. If it does not contact and is separated (lower images
on the right side of figure S4), the central fossa of the first mandibular molar should be
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deepened. It may happen that contacts are established on the slopes of the cusps; in that
case, the reasoning shown in figure S6 applies. It is important that this cusp maintain light
contacts during balancing.
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The prior decision to alter the lateral guidance may partially depend on the criteria
referred to above. By reducing the existing guidance on a given side, the balancing
contacts on the opposite side may increase, achieving balancing contacts when they did
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not previously exist. However, these may turn previously light contacts into an
interference. This must be verified beforehand, and in exceptional situations, a lingual
cusp of a maxillary molar can be adjusted even if there is only a slight contact in
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balancing, which should suggest a preferrance for adjusting the mandibular fossa.
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The mesio-lingual cusp of the first maxillary molar.
This cusp can interfere centrally with the distal fossa of the second mandibular premolar
or with the distal marginal ridge of the first mandibular molar. In the same way, it is
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necessary to evaluate the occlusal relation during balancing, which will now include the
mesial slope of the mesio-buccal cusp of the second mandibular molar. This implies the
inclination of the occlusal plane; if it is correct, there will be light contacts; if it is
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incorrect, there will be a complete absence (posterior descending plane) or interference

(posterior elevated plane), adjusting following similar principles with this cusp as with
the mesio-lingual cusp of the first maxillary molar.
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The same procedure is applied to the second molars. Because the adjustment should
require minimal removal of tooth tissue, this removal should contribute in the same
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proportion to improving the patient's occlusal plane.
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Occlusal adjustment of the canines during jaw closure.
The first premature contacts never appear in the canines, unless they are in malocclusion.
Premature contacts may appear when the adjustment of the centric occlusion is being
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completed and are an important prognostic factor. They are probably the most important
teeth in the mouth due to their anterior position in the arch, their primary function in
mandibular lateral guidance, their large size (especially their long root) and the large
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number of mechanoreceptors on their extensive periodontium. Figure S5 shows the
adjustment of an interference between canines when, at the same time, the aim is to reduce
the lateral guidancee (left part of figure S5) or when, on the contrary, it is intended to
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increase the lateral guidancee (right part of figure S5). In this case, the vertical dimension
in centric occlusion, which is higher than the maximum intercuspation, is slightly
reduced; the adjustment is generally halted when a stable maximum intercuspation is
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reached that will coincide with the centric occlusion in the same vertical dimension as the
patient's initial maximum intercuspation.
The centric adjustment of the incisors is similar to that of the canines, and they should
contact in centric occlusion and also during mandibular lateral excursion. Briefly, if the
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incisal edge of a mandibular incisor interferes in centric occlusion and in working

excursion, the incisal edge is reduced. If it only interferes in centric occlusion but does
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not contact in working excursion, the lingual fossa of the maxillary incisor is deepened.
Once the first phase of adjustment of the centric occlusion has been completed, the lateral
movements are evaluated and adjusted.
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Phase 2. Adjustment of the mandibular lateral excursion.
Occlusal adjustment of the canines during lateral excursion of the jaw.
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In clinical practice, the contacts of the canines after centric adjustment can present
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different situations. We will consider three possible situations: (i) adequate centric contact
(Figure S6); (ii) excessive contact surfaces (although not in height, as the centric
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occlusion is adjusted) typically facets on the labial surface of the mandibular canines
(Figure S7 left side of the figure or right side of the patient) and (iii) centric contact is
lacking (Figure S7, right side of the figure or left side of the patient); another rare situation
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may occur, when it is necessary to increase the lateral guidance and it is not desirable to
add composite resin to the maxillary canine: the incisal edge of the mandibular canine
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can be increased and centric occlusion can be readjusted by subsequently adjusting the
lingual surface of the maxillary canine. In the first situation (i), it may not be necessary
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to alter any canine in question if the lateral guidance is adequate; it may be necessary to
adjust the slope of the maxillary canine if decreasing the ipsilateral guidance is indicated
(Figure S6, left side) or to increase the slope of this canine by adding restorative material
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if it is necessary to increase the angle of the lateral guidance. (Figure S6, right hand side).
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In the second situation (ii), which may have been corrected at least partially during centric
occlusion adjustment, although the mouth is balanced in this situation, it may be
necessary to decrease the right lateral guidance, which is currently higher ("R1," in the
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left part of figure S7) until it becomes more horizontal than the left lateral guidance, which
is currently too horizontal ("L1" and right part of Figure S. In this situation, there is
excessive wear on the canines on the left side, and satisfying the proposed equation would
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require extensive adjustment also on the right side. This means that the reduction will be
the maximum possible within the limits of the tooth enamel, performed on the mandibular
177
canine first, eliminating the lateral contact surface, which is often a facet of recognizable
wear. The lower edge of this facet must be maintained so as not to lose centric contact.
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This reduces the angle of the guidance towards the right side ("R2" in figure S7). This
lateral guidance can be further reduced by removing part of the lingual-mesial slope from
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the cusp and from the edge of the maxillary canine ("R3" in figure S7). On the left side,
there is separation of the canines (iii), and it is convenient to add dental material to make
contacts in the centric occlusion position, so restorative material should be added to the
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cusp of the mandibular canine to achieve contact in centric occlusion and also to increase
the left lateral guidance ("L2" in figure S7). Additionally, it may be indicated to incresse
the height of the maxillary canine to slightly increase the left lateral guidance ("L2" in
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figure S7), which should be slightly greater than the right lateral guidance to promote
change in the habitual chewing side. The addition of composite resin on the left side
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mandibular canine will make it possible to recover the contacts of the canines in the
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centric position and a slight increase in the lateral guidance; it prevents the need for
extensive adjustment on the opposite side. On the right side, the contact should be reduced
during centric adjustment.
Canines are probably the most important teeth from the point of view of dental occlusion.
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The Angle class I position is important during mandibular closure, but it is even more so
during lateral excursion, as it promotes the anterior movement of the mandible during
working excursion. If during lateral excursion, the canines are in a Class II relationship,
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the movement of the mandible will tend to be delayed, resulting in the compression of
the retrodiscal tissues of the temporomandibular joint. If the correct centric and working
relationship cannot be achieved by straightforward adjustment, restorative material
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should be added with the aim of obtaining class I centric and working relationships.
Although the centric relation appears to be class I, Figure S8 shows how, during lateral
excursion, the working side is in class II and can be adjusted by remodelling (left side of
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figure S8); the distal insisal edge of the mandibular canine and then the mesial incisal
edge of the maxillary canine. It is usually necessary to reduce the height of the distal
incisal edge until the wear facet of the labial surface, if any, is eliminated to facilitate
lateral excursion. This wear facet typically appears when there is excessive overbite
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The right side of Figure S8 shows how a class II relationship can be converted into class
I during mandibular lateral excursion when class II contacts are also centrally located
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(Figure S8, right side): the distal part of the distal proximal surface is reduced, composite
resin is added to the mesial proximal surface of the canine and then the mesial surface of
the maxillary canine is adjusted. If it is necessary to increase the lateral guidance,
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composite resin is added to the distal of the maxillary canine, or the mesial proximal
surface of the mandibular canine is increased by reducing the contact that would appear
in the center of the maxillary canine. This decision often depends on the lingual position
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of both canines.
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Occlusal adjustment of premolar and molar interferences during the lateral excursion
of the mandible.
WORKING SIDE
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On the working side, there may be an interference between the mandibular and maxillary
buccal cusps (Figure S9, left side); or between the maxillary lingual cusps and the
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mandibular lingual cusps (Figure S9, right side). These interferences during the working
excursion can appear, although between the same teeth that contact in centric. The
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maxillary buccal cusps should be adjusted in the first case, and the mandibular lingual
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cusps in the second case. In this way, the centric contacts are not altered, maintaining the
occlusal vertical dimension.
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BALANCING SIDE
Most of the adjustment of the excursive interferences has already been carried out
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during the centric adjustment in the described procedure. However, occlusal
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interferences may occur on the balancing side: these are usually the lingual cusps of the
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maxillary jaw with the mesiolingual slopes of the mandibular buccal cusps. This is
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usually adjusted by increasing the grooves from the central fossae (without deepening
them) in a disto-buccal direction, allowing light contact with the maxillary lingual cusps
during the lateral excursion (Figure S10). In the case of the premolars, the mandibular
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cusps are not adjusted, and their excursive interferences are usually adjusted on the
lingual cusps of the maxillary premolars.
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Elimination of balancing side interferences in maxillary molars or premolars
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Before the occlusal adjustment of the lateral contacts, it is important to note that once the
centric occlusion has been adjusted, the contacts supporting the centric occlusion must
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not be further reduced. If the centric contacts were to be adjusted, the centric contacts
would be lost (an iatrogenic action). The essential supports of the occlusion, which should
not be lost after centric adjustment, are the following: the incisal edges of the incisors and
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of the mandibular canines; the buccal cusps of the mandibular premolars; and the lingual
cusps of the maxillary molars (Figure S11). Secondarily the buccal cusps of the
mandibular molars should not be further adjusted, unless required instead of the lingual
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cusps of the maxillary molars.

The resulting morpholgy should be surfaces or facets and not pointed cusps or sharp
antagonist grooves.
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The importance of an appropriate occlusal plane orientation and the arch shape.
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A balanced occlusion can only be achieved during lateral movement if there is correct
inclination of the occlusal plane. Furthermore, the posterior sectors should not be V-
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shaped, but U-shaped. If the arch is V-shaped, the maxillary lingual cusps tend to be
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separated from the mandibular buccal cusps during balancing excursion, running distally
over the central grooves of the mandibular molars. (Figure S12).
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If the arch is U-shaped, the maxillary lingual cusps tend to approach or contact the
mandibular buccal cusps during balancing excursion (Figure S13); Similarly, the
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mandibular buccal cusps tend to be directed anteriorly over the maxillary central grooves
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without being able to contact (if the arches are V-shaped) or to approach or contact the
maxillary lingual cusps (if the arches are U-shaped).
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Occlusal adjustment of the lingual surfaces of the maxillary incisors

The final adjustments are made on the lingual surfaces of the maxillary incisors if they
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interfere with the occlusion (Figure S14). Only the surfaces adjacent to the incisal edges
should be adjusted, mainly towards the inciso-distal angle of the lingual surfaces
following the marks of the articulating paper. The surface that contacts the antagonist
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incisal edge should not be adjusted so as not to lose the centric contacts. An exception is
the presence of contact surfaces of the mandibular incisors, which can form a facet and
not a linear contact. In this case, the height of the mandibular incisors can be reduced to
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the limit of the facet or mark of the articulating paper. In this way, the amount of wear on
the maxillary incisors can be reduced.
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Protrusive marks must never be removed after centric and lateral adjustment; otherwise,
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the working side contacts would be lost.
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Ideally, a graphic record should be obtained of the mandibular lateral guidances and of
the condylar paths and condylar angle measurements in order to be able to carry out an
optimal treatment plan. The values obtained, if symmetrical, should guide the suspicion
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of a change of the habitual side of chewing instead of suspecting the use of only one side
throughout the life of the patient. If the affected side presents greater lateral guidance
and/or smaller condylar angle, pathology that inhibited the use of the habitual side, such
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as food packing, an inadequate proximal contact, or dental caries should be suspected. In

these circumstances, the observed (current) chewing side may not coincide with the
symptomatic side. These criteria tend to be more complex to assess when symptoms are
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similar on both sides; in short, generally, in these patients, the therapeutic lateral guidance
should tend to be approximately symmetrical. If a condylar slope is clearly higher on one
side, the anterior lateral guidance should probably be more horizontal on the opposite
186
side, favouring chewing on the more horizontal condylar path side, complying with the
equation proposed in the main manuscript. Previous studies and our experience suggest
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that the mandibular midline moves as a consequence of hemimandibular retrognathia
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towards the habitual working side during development. If so, it is plausible that on that
side the condylar slope increases. In an adult, the habitual chewing side may remain the
same (lower lateral guidance and higher condylar path), exaggerating this asymmetry. If,
however, the side changes in an adult after the developmental period, the condylar slope
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increases in the same way as on the working side. However, it starts from a previous
flattening and, therefore, this increase is not observed unless very long periods of time
elapse. For this reason, the formula implemented in this study should be taken with some
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caution, especially in patients with mandibular asymmetry and bilateral symptoms. We
will describe the condition that occurs in most patients, which is unilateral mastication,
in a patient with unilateral pathology.
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This study also considered the possibility that hemispheric dominance may favor ipsilateral
chewing. The assumption was made that if both lateral guidances are perfectly symmetrical and
all other factors are also symmetrical, the patient will tend to chew on the hemispherical
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dominance side. Therefore, the need to lower the lateral guidance on the non-dominant side of
the hemisphere was emphasized when the aim was for the patient to prefer using the non-
dominant side (as it is asymptomatic in these patients).
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REFERENCES
Dawson PE. Evaluation, diagnosis and treatment of occlusal problems. 2nd ed. St Louis:
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CV Mosby; 1989. p. 434-456.
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GPT-9. The Glossary of Prosthodontic Terms: Ninth Edition. [No authors listed]. J
Prosthet Dent. 2017;117(5S):e1-e105. doi: 10.1016/j.prosdent.2016.12.001.
Hildebrand Y (1936) Studies in mandibular kinematics. Dental Cosmos 78 Issue 5:449-

458.
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Okeson JP. Management of Temporomandibular Disorders and Occlusion. 7 th ed. Mosby,
Inc. 2012.
Schuyler CH. Fundamental principles in the correction of occlusal disharmony, natural
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and artificial. JADA 1935 (July);1193-1202.
Santana-Mora U, López-Cedrún J, Mora MJ, Otero XL, Santana-Penín U.

Temporomandibular disorders: the habitual chewing side syndrome. PLoS One. 2013 Apr
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8;8(4):e59980. doi: 10.1371/journal.pone.0059980.
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Supplement 3: Additional information: Diagnosis and Results
Trial of occlusal adjustment for chronic jaw pain
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A Randomized Clinical Trial
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Authors:
Urbano Santana-Mora,
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Timothy Collier,
Stuart Pocock,
José Luís López-Cedrún,
María Jesús Mora-Bermúdez,
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Urbano Santana-Penín
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189
TABLE OF CONTENTS
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Baseline characteristcs of trial participants……………………………………………………….….…….. 3
Sociodemography ……………………………………………………………………….………………..…… 3
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Chewing function ……………………………………………………………………….………..….….…….. 4
Condylar path angles ………………………………………………………………….…………..…..…….. 5
Lateral guidance angles …………………………………….………………………………..………..…….. 6
EFFICACY (additional information)
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Main outcome:
Jaw pain intensity reduction at month 6 ………………….…………………….……………...…… 8
Main outcome in important subgroups…………………………..……………………………… 15
Secondary outcomes
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Chewing function ………………………………………………………………………….… 16
Maximum unassisted mouth opening ……………………………………….……..…….………….. 17
Psychological Distress: Global Severity Index scores ……………………….……………..…… 20
Correlation between the change in psychological distress and pain relief……………….……
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Pre-specified outcomes
Headache intensity ………………………………………………………………………….. 23
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Neuropathic symptoms …………………………………………………………...…………. 24
Awareness of trial-group assignment ………………………………………………………. 25
Global perceived effect ……………………………………………………………………… 27
Disability ……………………………………………………….…………………………… 28
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Confidence in the procedure ………………………………………………………………… 29
REFERENCES …………………………………..……………………………………………….…. 30
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BASELINE CHARACTERISTCS OF TRIAL PARTICIPANTS (additional data)
The sociodemographic characteristics (Elliott et al., 2002) of the participants at baseline is shown in eTable
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1; at month 6, these characteristics only varied for a minimal number of participants in each group; one
placebo group participant moved from the community; one married occlusal adjustment group participant
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no longer married.
eTable 1. Sociodemographic characteristics of participants.
Occlusal Adjustment Placebo group

Characteristic
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Group (N =39) (N =38)
Level of education N % N %
Higher 21 53.8 26 68.4
Secondary 12 30.8 9 23.7
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No qualifications 6 15.4 3 7.9
Marital status
Never married er 26 66.7 27 71.1
Currently married 11 28.2 9 23.7
No longer married 2 5.1 2 5.3

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Housing tenure
Owned or mortgaged 17 43.6 21 55.3
Council rented 2 5.1 1 2.6
Privately rented 8 20.5 6 15.8

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Other 12 30.8 10 26.3
Employment status
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Employed 25 64.1 24 63.2
Retired 1 2.6 0 0
Unable to work due to illness 0 0 0 0

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Not employed for other reasons 13 33.3 14 36.8

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CHEWING FUNCTION
The proportion of participants with one habitual chewing side was balanced between the trial groups (Table
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1 in the main manuscript). Consistent one-side chewing requires observed (Kazazoglu et al., 1994),
kinesiographic and interview test coincidence (Varela et al., 2003). At baseline, participants with unilateral
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symptoms chewed significantly on the affected side (eFigure 1); Fisher exact test, P<0.001.
Chewing side at baseline

25
right alternate left
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Number of Participants
20
15
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right both left
affected side
eFigure 1. Bar chart showing the side used to chew by participants with unilateral symptoms at baseline
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Condylar path angles
Condylar path angle measurements (Santana-Mora et al., 2013) were repeatable (ICC=0.89, 95%CI 0.85 to
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0.92; P<0.001 (N=141 joint recordings) and did not reveal any differences in terms of side or sex (eTable
2).
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eTable 2. Mean (SD) of condylar path angles (degrees) on each side and sex of overall
participants.
mean differences (95%

side right-hand left-hand CI) P value
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48.5±9.7 50.1±9.4 -1.5 (-3.8 to 0.8) 0.2
sex Female male
49.3±9.7 49.2±7.1 0 (-6.8 to 7) 1.0
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In the group with unilateral symptoms, condylar path angles were lower on the non-affected side (46.6±7.8;
N=48) than on the affected side (51.8±10.6; N=39); unadjusted mean differences 5.3, 95%CI 2.7 to 7.8,
P<0.001; two-tailed paired t test (9 tracings were excluded due to aberrant morphology); there were no side
differences of condylar path angles in participants with bilateral symptoms (eTable 3).
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eTable 3. Mean (SD) of condylar path angles in participants with unilateral or bilateral
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symptoms.
Subgroup of participants (N=49) with unilateral symptoms
Mean differences (95% CI)

Side P value
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affected side non-affected side
51.9±10.8 46.6±8.0 5.3 (2.7 to 7.9) <0.001

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Subgroup of participants (N=28) with bilateral symptoms
right-hand side left-hand side P value
48.9±9.6 50.2±9.0 -1.2 (-4.7 to 2.2) 0.5

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Lateral guidance angles
The lateral guidance angle measurements (Santana-Mora et al., 2013) were repeatable (ICC=0.984; 95%
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CI 0.978 to 0.988, P<0.001; n=150 recordings); there were between-sides differences (41.5±10.6 vs
37.8±10.4 degrees, right- and left-side, respectively (P=0.01; N=75); there were no sex differences for
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lateral guidance angles (eTable 4).
eTable 4. Mean (SD) values of the lateral guidance angles (degrees) of participants (N=77)
(female/male: 72/5) before therapy.
Side right-hand side left-hand side mean differences (95% CI) P value
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41.5±10.6 37.8±10.4 3.7 (0.9 to 6.4) 0.01
Sex Female Male
39.3±10.6 40.7±14.4 1.3 (-5.7 to 8.3) 0.7
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The lateral guidance angles were lower on the affected side (35±9.8) than on the non-affected side
(44±10.9) (N=49); unadjusted mean difference -8.9; 95%CI, -12.4 to -5.4; P<0,001. There were no side
differences for lateral guidance angles in participants with bilateral symptoms (eTable 5).
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eTable 5. Mean (SD) values of lateral guidance angles (degrees) at baseline in the subgroup
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of participants with unilateral and participants with bilateral symptoms.
Subgroup of patients with unilateral symptoms (N=49)
affected side non-affected side mean differences (95% CI) P value
35±9.8 44±10.9 -8.9 (-12.4 to -5.4) <0.001

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Subgroup of patients with bilateral symptoms (N=28)
right-hand side left-hand side

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40.8+11.9 39+9.8 1.8 (-2.5 to 6.2) 0.4
The lateral guidance angles (degrees) were significantly decreased on the non-affected side (adjusted mean
differences 8; 95%CI, 4.9 to 11.1; P<001) by occlusal adjustment but were not significantly altered on the
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affected side (adjusted mean differences -1.4, 95%CI, -4 to 1.2; P= 0.3) (eTable 6).
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eTable 6. Occlusal adjustment alteration of lateral guidance angles in participants with
unilateral symptoms (N=26).
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after occlusal mean differences (95%
baseline adjustment CI) P value
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non-affected side 43.7±11 35.7±12.4 8 (4.9 to 11.1) <0.001
affected side 34.7±9.9 36.1±11.9 -1.4 (-4 to 1.2) 0.3
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In the occlusal adjustment group, in participants with both sides affected (N=13), the lateral
guidance angles were not significantly altered therapeutically on either side; (adjusted mean
differences 1, 95%CI -2.4 to 4.4; P=0.6 on the right side and (adjusted mean differences 1.7,
95%CI -2.6 to 6.1; P= 0.4) on the left side (eTable 7).
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eTable 7. Occlusal adjustment alteration of lateral guidance angles in participants with
bilateral symptoms (N=13).
after occlusal mean differences (95%

baseline adjustment CI) P value
right-hand side
left-hand side
40.8+11.9
38.9+9.9
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39.7±9.5
37.2±8.6
1 (-2.4 to 4.4)
1.7 (-2.6 to 6.1)

0.6
0.4
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EFFICACY (additional information).
Main outcome: Jaw pain intensity reduction at month 6. The forms for the patients included an analog
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scale of pain and a numerical pain-rating scale so that each participant could choose the one they understood
better. Both are equally capable of measuring pain (Dworkin et al., 2010). The eFigure 16 shows histogram
of jaw pain variables.
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The percentage of reduction in pain intensity was significantly different between the two trial groups:
unadjusted score, 68.627.4% in the active group and 42.840.4% in the placebo group; adjusted mean
difference, 25.8%; 95% CI, 10.1 to 41.6, P=0.002.
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eTable 8: Pain outcome at 6 months
Pain score Occlusal adjustment Placebo group P-Value

group
Median (IQR) 2.0 (0.0, 3.0) 3.5 (1.0, 6.0)
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Mean (SD) change from baseline -4.45 (2.0) -2.86 (2.7)
Mean Difference (95% CI) -1.54 (-2.56, -0.51) Reference 0.0038

Mean difference, 95% confidence intervals and p-values are from analysis of covariance (ANCOVA)
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models adjusting for baseline values.
Group 2 has been used as the reference group (as I assume this is the control group!). For the pain
score outcome, because we are talking about change in pain, a negative number is good. So the
interpretation of -1.54 is that mean reduction in pain score is 1.54 (units) higher in group 1 compared
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to group 2.
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Raw Values Change from Baseline
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eFigure 2. Distribution of pain scores – raw scores and change from baseline
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eFigure 3. Scatter plot of 6 month versus baseline pain scores with regression lines from
ANCOVA model. The red and blue lines are the fitted values from the ANCOVA model for
Group 1(occlusal adjustment) and Group 2(placebo) respectively. The vertical separation between
the two lines represents the mean difference in pain score at 6 months (1.54) between the groups
adjusting for the baseline pain score. Note: as it is possible for more than one individual to have
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the same pain score at baseline and month 6, the marker symbols are frequency weighted i.e.
larger size = more observations at that point.
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eFigure 4.: Individual patient pain score trajectories (baseline to month 6) and overall mean pain
score (dark line) by treatment group. Group 1, occlusal adjustment; Group 2, placebo.
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eFigure 5.: Time course of jaw-pain intensity according to trial group.
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eFigure 6. Box plot of change in pain score by treatment group. The white centre line
represents the median and the boxes the interquartile range. This shows the shift in distribution of
the change in pain score. Group 1, occlusal adjustment; Group 2, placebo.
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Although pain score and global severity index are both quite strongly positively skewed, the change from
baseline for each of these outcomes is approximately normally distributed. See histograms on final pages.
Maximum mouth opening is approximately normally distributed. So ANCOVA adjusting for baseline
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values is appropriate. For the pain score outcome at 6 months I have also carried out a two-sample t-test
on (i) pain scores at 6 months and (ii) change in pain scores from baseline at 6 months. The mean
difference, 95% CI and p-values are shown below.
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eTable 9: Pain outcome at 6 months
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Mean Difference (95% CI) P-Value
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Pain score at 6 months 1.5 (0.50,2.5) 0.005
Change in Pain score -1.5 (-0.5, -2.6) 0.004
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eTable 10. Cross-tabulation of 30% responders* on each group at month 6.
Account occlusal
adjustment placebo total P value
non responders 4 15 19
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responders 35 23 58
total 39 38 77 0.004
*30% responders are participants showing over 30% of pain relief.

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In comparison with the placebo, a higher number of participants receiving occlusal therapy
were 30% responders (with over 30% of pain relief; Fisher exact test, P=0.004).
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eTable 11. Cross-tabulation of 50% responders* in each group at month 6.
Account occlusal
adjustment placebo total P value
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non responders 7 19 26
responders 32 19 51
total 39 38 77 0.004
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*50% responders are participants showing over 50% of pain relief.

In comparison with the placebo, a higher number of participants receiving occlusal therapy
were 50% responders (Fisher exact test, P=0.004).
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Consistency of the main outcome in important subgroups (Pocock and Stone, 2016) (pre-specified in
the initial protocol):
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UNILATERAL vs BILATERAL subgroups
Pain in patients with UNILATERAL symptoms (N=48): Adjusted mean difference 1.2, 95% CI -
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0.1 to 2.6, P= 0.09 (per protocol adjusted mean difference 1.6, 95%CI, 0.2 to 3.0, P=0.03).
Pain in patients with BILATERAL symptoms (N=29): Adjusted mean difference 2.0, 95% CI 0.2
to 3.7, P= 0.03 (per protocol adjusted mean difference 2.6, 95% CI 0.6 to 4.6, P=0.01).
ARTHRALGIA subgroups
Subgroup comparisons were previously specified for arthralgia (with or without myalgia). The
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arthralgia group was the largest in this study (86%, 66/77). Significant differences were found in
jaw pain improvement between the two groups (adjusted mean difference 1.7; 95%CI 0.6 to 3.0,
P=0.04).
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Secondary outcomes
Chewing function
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Chewing function (Varela et al., 2003) at the start and end of the study (eTable 10).
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eTable 12. Cross-tabulation of change in chewing side across the trial (Fisher’s exact test;
P=0.1).
Account ⎯ no. (%) group
Change in chewing side Occlusal
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adjustment Placebo total P value
Not changed 11 (14.3) 18 (23.4) 29 (37.7)
Changed 28 (36.4) 20 (26.0) 48 (62.3)
Total 39 (50.6) 38 (49.4) 77 (100) 0.1
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MAXIMUM UNASSISTED MOUTH OPENING
eFigure 17 shows the distribution of maximum mouth opening – raw scores and change from baseline.
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Raw values Change from Baseline
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eFigure 7. Distribution of Maximum Mouth Opening – raw scores and change from baseline
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eTable 13: Maximum unassisted mouth opening
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Maximum unassisted mouth opening Occlusal adjustment
Placebo group P-Value
score (mm) group
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Median (IQR) 47.69 (8.4) 46.37 (7.7)
Mean (SD) change from baseline 6.22 (6.5) 2.46 (5.7)
Mean Difference (95% CI) 3.06 (0.45, 5.66) Reference 0.022
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Mean difference, 95% confidence intervals and p-values are from analysis of
covariance (ANCOVA) models adjusting for baseline values.
Group 2 has been used as the reference group (as the statistician assumed this is
the control group)
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Maximum mouth opening is one of the chief complaints associated with this disorder. Recovering a
normal opening range (>40 mm) in patients who have limited opening (≤40) at baseline is an important
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therapy goal. Minimally important difference 3 mm. Occlusal adjustment therapy significantly reduced
the number of participants with limited mouth opening with respect to the placebo at month 6 (Chi square
test, P=0.02) (eTable 11).
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eFigure 8. Scatter plot of 6 month versus baseline maximum mouth opening (mm) with regression lines
from ANCOVA model. The red and blue lines are the fitted values from the ANCOVA model for Group
1 and Group 2 respectively. The vertical separation between the two lines represents the mean difference
in maximum mouth opening (mm) at 6 months between the groups adjusting for the baseline value.
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eFigure 9. Individual patient maximum mouth opening (MMO) trajectories (baseline to month 6) and
overall change in MMO (dark line) by treatment group. Group 1, occlusal adjustment; Group 2, placebo.
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eTable 14. Cross-tabulation of change in maximum unassisted mouth opening (MMO)
across the trial: MMO 40 vs >40 mm. Chi Square test.
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Account ⎯ no. (%) Group
Change in MMO Occlusal

adjustment Placebo total P value
improved 11 (14.3) 2 (2.6) 13 (16.9)

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no change 27 (35.1) 33 (42.9) 60 (77.9)
worsened 1 (1.3) 3 (3.9) 4 (5.2)

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Total 39 (50.6) 38 (49.4) 77 (100) 0.02
Improved: changed from limited to normal opening. worsened: changed from normal to limited
opening. No change: at 6 months continued the same as at the beginning of the study.
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PSYCHOLOGICAL DISTRESS
eFigure 18 shows the histogram of Global Severity Index – raw scores and change from baseline.
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Raw Values Change from Baseline
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eFigure 10. Distribution of Global Severity Index – raw scores and change from baseline
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eFigure 11. Scatter plot of 6 month versus baseline Global Severity Index (GSI) with regression lines
from ANCOVA model. The red and blue lines are the fitted values from the ANCOVA model for Group
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1 and Group 2 respectively. The vertical separation between the two lines represents the mean difference
in GSI at 6 months between the groups adjusting for the baseline value.
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eFigure 12. Individual patient GSI trajectories (baseline to month 6) and mean GSI (dark line) by
treatment group.
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No significant between-group differences were found in changes in the mental component (continuous
variable) assessed with the Symptoms-Checklist Revised (SCL-90-R) instrument (Derogatis, 1989, 2002)
at 6 months in relation to the baseline (except for the phobia subscale: adjusted mean differences 0.21;
95%CI, 0.03 to 0.39; P= 0.003).
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Correlation between the change in psychological distress and pain relief.

A significant correlation was found between the improvement in pain and improvement in psychological
distress in the placebo group (Pearson correlation, P=0.03), but not in the occlusal adjustment group
(Pearson correlation, P=0.7) (Figure S19). This suggests an influence of the psychological factor in the
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placebo group and a lack of influence in the occlusal adjustment group; therefore, the effect should be
attributed to the occlusal adjustment.
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occlusal adjustment placebo
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10
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8
Jaw-pain intensity: baseline minus 6-months scores
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*x
.94
5 +2
2.1
6 y=
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y=4.52-0.21*x
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-2
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-.5 .0 .5 1.0 1.5
Global severity index: baseline minus 6-months scores
eFigure 13. Plot showing the correlation between the improvement of global severity
index and reduction of jaw pain.
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Positive values (of the dif ference) indicate an improvem ent at 6 months in both variables.
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PRESPECIFIED OUTCOMES
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HEADACHE INTENSITY
No evidence was found of a difference between the groups in change in the headache intensity at 6 months
(adjusted difference in mean change -0.73, 95% CI -1.99, 0.52, p=0.25). (Table 2 in the Main Manuscript;
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eFigure 14)
Occlusal adjustment Placebo
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4.0
Mean change at 6 months: -0.73
95% CI: -1.99, 0.52
p value: 0.25
3.0
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Mean change in headache intensity
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1.0
0.0
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0 1 2 3 6
Months since randomization
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eFigure 14. Mean change in headache intensity during the trial according to trial group.
Mean change in headache intensity (in a 0-10 numerical pain-rating scale; 1.5 points are clinical
important change) with 95% confidence intervals over time using ANCOVA model, adjusted to
baseline scores.
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First Occlusal Adjustment Second Occlusal Adjustment

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Neuropathic symptoms
The number of participants showing neuropathic symptoms (Bouhassira et al., 2005) at baseline
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was reduced in both groups at month 6 (eTable 12):
eTable 15. Neuropathic pain symptoms. Number of participants (%).
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Risk Ratio
Acount Occlusal adjustment Placebo (95% CI) P Value
Neuropathic
symptoms
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At baseline 13 12
At month 6 2 (5.4) 4 (11.4) 0.47 (0.1, 2.4) 0.4

Neuropathic pain refers to over 4 scores in a 0-10 point DN4 Questionnaire.
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Awareness of the trial-group assignment
The lack of awareness of the trial group assignment was maintained during the trial (eTable 13, eFigure
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21).
eTable 16. Participants’ awareness of trial-group assignment after therapy and at month
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6. Number of participants (%).
Account group
Confident of Occlusal adjustment Placebo
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After allocated therapy Real Therapy 24 (61.5) 27 (71.1)
I don’t know 15 (38.5) 11 (28.9)
Placebo 0 (0.0) 0 (0.0)
At month 6 Real Therapy 26 (66.7) 21 (55.3)
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I don’t know 12 (30.8) 14 (36.8)
Placebo 1 (2.6) 3 (7.9)
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After the therapy session, 24 of the occlusal adjustment group participants correctly guessed their group
assignment, and 15 responded ‘I don’t know’; 27 placebo group participants incorrectly guessed their group
assignment after the therapy session and 11 responded ‘I don’t know.’ At month six, 26 participants in the
occlusal adjustment group correctly guessed their group assignment, 12 participants responded ‘I don’t
know,’ and 1 participant incorrectly guessed the group assignment; 21 participants in the placebo group
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incorrectly guessed their group assignment, 14 responded ‘I don’t know,’ and 3 participants correctly
guessed their group assignment.
The clinical assessor was also quizzed after each evaluation, including at 3 and 6 months and at follow-up.
They never identified any awareness of the type of trial therapy.
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Global perceived effect (improvement).
The global perceived effect after therapy at 6 months was assessed on an ordinal scale (Very much better,
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Much better, Minimally Improved, No Change, Minimally worse, Much worse, Very Much Worse). Post
hoc comparisons used dichotomization: improvements vs no change. No change included the only
participant that reported minimal worsening. eTable 14 shows that the participants’ overall perception of
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improvement at month 6 was better in the occlusal adjustment group than in the placebo group (Fisher’s
exact test, P=0.004).
eTable 17. Cross tabulation of perceived effect (improvement) at month 6.
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Group
Account
Occlusal
adjustment Placebo Total
Perceived effect No change 2 11 13
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improved 37 23 60
Total 39 34 73*
* Data from 1 occlusal adjustment and three placebo group participants were not available.
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More participants of the occlusal adjustment group than placebo group reported subjective
improvement at month 6 (Fisher exact test, P=0.004).
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Disability
The overall improvement of disability scores (Von Korff et al., 1992) at month 6 in each group (except for
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the disability days) was not related with the type of therapy (eTable 15).
eTable 18. Disability scores across the trial.
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1. About how many days in the last 6 months have you been kept from your usual
activities (work, school, or housework) because of facial pain? Mean±SD.
Outcome/Time Point At baseline At month 6 95% CI P value
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Overall participants 3.9±13.4 3.7±13.1 -4.4 to 4.8 0.9
Occlusal adjustment Placebo 95% CI
Adjusted mean differences 1,1±12,7 -0,8±24 -8 to 11.7 0.7
2. In the past 6 months, how much has facial pain interfered with your daily
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activities rated on a 0-10 scale, where 0 is “no interference” and 10 is “unable to carry
on any activities”?
Outcome/Time Point At baseline At month 6
Overall participants 4.9±2.7er 3±2.8 1 to 2.7 <0.001
Adjusted mean differences 2.0±3.6 1.7±3.8 -1.4 to 2.1 0.7

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3. In the past 6 months, how much has facial pain pain changed your ability to take
part in recreational, social, and family activities, where 0 is “no change” and 10 is
“extreme change”?
Overall participants 4.6±2.9 2.5±2.8 1.2 to 3.0 <0.001

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4. In the past 6 months, how much has facial pain changed your ability to work
(including housework), where 0 is “no change” and 10 is “extreme change”?

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Overall participants 4.1±3.2 2.2±2.6 1.0 to 2.8 <0.001

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Positive values of adjusted mean differences indicate lower disability at 6-month assessment
or favors occlusal adjustment group.
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Confidence in the procedure
The participants’ confidence (Borkovec and Nau, 1972) in the procedure was high and was maintained
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during the trial in each group (eTable 16). Is it possible that the placebo group was more suggestible?
eTable 19. Mean±SD credibility scores (on a 0-10 numerical rating scale, with 0=not at
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all, 10= totally) during the trial.
95% CI P1 P2
Subscale / time point Active Placebo Diff
Lower
upper
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How logical does this type of treatment seem to you?
At baseline 9.1±1.1 8.9±1.3 0.2 -0.36 0.74 0.5
At month 6 8.7±1.6 8.8±1.6 -0.1 -0.88 0.66 0.8
differerences 0.4±1.5 -0.1±1.9 0.5 -0.32 1.39 0.2
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How confident would you be that this treatment would be successful in eliminating
your pain and/or limited mouth opening?
At baseline 8±1.8 8. 3±1.3 -0.3 -1.02 0.4 0.4
At Month 6 8±1.9 7.6±2.6
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differerences -0.0±2.3 0.6±2.6 -0.54 -1.73 0.65 0.36
How confident would you be in recommending this treatment to a friend who was
suffering from TMD pain?
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At baseline 8.3±1.7 8.4±1.5 -0.15 -0.88 0.58 0.7
At month 6 8.6±1.6 8.8±1.9 -0.17 -1.01 0.67 0.7
differerences -0.4±1.9 -0.4±2.4 -0.01 -1.07 1.06 0.9
If you were extremely anxious about TMD pain, would you be willing to undergo such
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treatment?
At baseline 9.3±1.1 9. 5±1.9 -0.18 -0.9 0.54 0.6
At month 6 9±1.6 9.2±1.5 -0.31 -1.06 0.45 0.4
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differerences 0.4±1. 7 0.1±1.9 0.41 -0.45 1.28 0.34

How successful do you feel this treatment would be in decreasing a different pain, for
example, headache?
At baseline 8.3±1.9 8.8±1.3 -0.54 -1.33 0.24 0.2
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At month 6 7±2.8 8.5±2.2 -1.52 -2.7 -0.4 0.02

differerences 1.5±3 0.5±2.6 1.03 -0.3 2.4 0.1
P1 denotes P values of differences between placebo and occlusal adjustment groups
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P2 denotes P values of (intra-individual differences) group differences between baseline and 6-month
assessments.
Data from 7 participants were not available.
Only one item shows statistical (not clinical) significance: as compared with occlusal adjustment group,
placebo group was more confident that therapy improved other associated symptoms at month 6 (such
as cervical pain, headache, …).
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SUPPLEMENT 4
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Data Sharing Statement
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Data
Data available: Yes
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Data types: Deidentified participant data, Data dictionary
How to access data: Data will be provided on reasonable request to
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corresponding author Urbano Santana-Penín (urbano.santana@usc.es)
When available: With publication
Supporting Documents
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Document types: Informed consent form, templates of forms used in data collection
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from participants.
How to access documents: Supporting documents will be provided

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on reasonable request to corresponding author Urbano Santana-Penín
(urbano.santana@usc.es)
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When available: With publication
Additional Information
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Who can access the data: researchers whose proposed use of the
data has been approved

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Types of analyses: meta-analysis
Mechanisms of data availability: with investigator support after

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approval of a proposal
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Title:

López-Cedrún, José Luís. PhD 1

1 Oral and Maxillofacial Surgery Service, University Hospital of La Coruña, La Coruña,

Prof. Urbano Santana-Penín

C/ Entrerríos s/n. 15782 Santiago de Compostela. SPAIN

in the placebo group (median 7/7 at baseline, 2.0/3.5 at 6 months, occlusal

Meaning Occlusal adjustment addressed to recover physiological jaw closure and

of patients with chronic TMD.

University Clinic in a different city.

excluded (partial tooth loss, no chronic condition, malocclusion); 27 declined to

participate. Seventy-seven participants underwent randomization; all but one female

participant completed the analysis.

INTERVENTIONS Participants were randomly (1:1) assigned to occlusal adjustment

MAIN OUTCOME AND MEASURE Primary outcome (before data collection

participants in their originally assigned group: 39 to occlusal adjustment and 38 to

placebo therapy. Both groups were balanced regarding baseline characteristics. As

CONCLUSIONS AND RELEVANCE The occlusal adjustment was effective in

by less experienced dental professionals.

TRIAL REGISTRATION UTN: U1111-1134-0832, ClinicalTrials.gov number

NCT02144233, and ISRCTN number ISRCTN61654487.

Key words. Mesh Terms:

Craniomandibular Disorders [C05.500.607.221]

Facial Pain [C10.597.617.364]

POPULATION INTERVENTION FINDINGS

lubrication and metabolism.

We hypothesized that an occlusal adjustment that obtained balanced occlusion 14

treating chronic jaw pain.

Trial design and oversight

2009/017, updated November 29, 2013).

database (OpenClinica®), implemented to ensure the transparency and accuracy of the

Eligibility and recruitment

had also received other conservative or minimally invasive treatments.

participant instructions. No occlusal adjustment was offered outside the trial.

series of opaque envelopes (female/male, muscular/articular), signed on the flap,

results of the study had been written and approved.

The trial regimen consisted of an occlusal adjustment or a placebo adjustment. The

not permitted; other concomitant therapies were strongly discouraged.

Outcomes and data collection

were an increase in maximum unassisted mouth opening (smallest detectable difference

3 mm),27 improvement in the mental component 28 using the validated version in

Baseline characteristics are described by treatment group using frequencies and

interquartile range (IQR) for continuous variables.

self-reported jaw pain intensity from baseline to 6 months, analysis of covariance

baseline to 6 months was examined and found to be approximately normally distributed.

side was reported descriptively.

was also analyzed in the per protocol population as a sensitivity analysis.

was +2.438, corresponding to a nominal two-sided P value of 0.0146.

and clinical characteristics (Table 1; eTables 1-5 in Supplement 3).

39 Were assigned to occlusal adjustment grou p 38 Were assigned to placebo group

2 participants do not received assig-

5 Were excluded after randomization. Cause s: 2 Were excluded after randomization.Causes,

not meet eleigibility:

Figure 2. Flow diagram. Screening, Randomization, and Follow-up.

Condylar path angles in relation to Frankfort Plane. Mean ¾ (SD) (degrees)

Left side ¾ (SD) 38 (10.4) 37.3 (10.6)

Committee according to predetermined rules in the protocol. A significant difference

mean difference 2.0, 95% CI 1.0 to 3.0, p<0.001).

Right 6 (15.4) 6 (15.8)

Perceived Improvement¾ N(%) 37 (94.9) 23 (67.7) 1.40c (1.10, 1.79) .002

majority of participants in both groups referred to chewing alternately at 6 months, and

Pre-specified efficacy outcomes

The percentage of participants reporting a perceived global improvement at 6 months

6-month assessment. No evidence was found of a difference between the groups in