Clinical trial NCT04066426
Conditions: Temporomandibular Disorder
Keywords: naproxen sodium codeine phosphate dexamethasone pain temporomandibular joint
Sponsor: Yuzuncu Yıl University
Start date: 2018-03-01; Completion date: 2019-07-15
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Temporomandibular disorders (TMDs) are one of the most common muco-skeletal disorders, seen in the dental clinics. Many factors work together to initiate or aggravate the condition, so it is a multifactorial disorder. The etiology of TMDs may be a result of parafunctional habits such as clenching and bruxism, acute trauma to the jaw, trauma from hyperextension e.g. after a long dental treatment, joint laxity, psychological distress, occlusal disharmony like presence of high crown or free-end saddle leading to joint instability or systemic diseases such as Rheumatoid arthritis or Osteoarthritis. The aim of this study was to evaluate the effects of naproxen sodium+codeine phosphate, naproxen sodium+dexamethasone, and naproxen sodium on pain in patients complaining from temporomandibular pain.

Detailed description:

Arms: arm 1: Naproxen sodium is a propionic acid derivative with analgesic, antipyretic, and antiinflammatory properties. Its mechanism of action relies on the inhibition of prostaglandin synthesis, and significant pain relief and plasma levels can be obtained within 20 minutes following intake. The elimination half-life of naproxen sodium is reportedly around 14 hours, and naproxen sodium is used in doses ranging from 275 to 550 mg in surgical procedures. Codeine phosphate is an opioid analgesic which has similar applications to those of morphine. However, it is significantly less potent as an analgesic and has only mild sedative effects. The drug's principal site of action is at the µ-opioid receptors (MOR) which are distributed in the central nervous system. Peak effect is reached within 2 hours and analgesic action continues for approximately 4 hours. Naproxen sodium (550 mg)+codeine phosphate (30 mg) was used twice daily in this study. arm 2: Naproxen sodium is a propionic acid derivative with analgesic, antipyretic, and antiinflammatory properties. Its mechanism of action relies on the inhibition of prostaglandin synthesis, and significant pain relief and plasma levels can be obtained within 20 minutes following intake. The elimination half-life of naproxen sodium is reportedly around 14 hours, and naproxen sodium is used in doses ranging from 275 to 550 mg in surgical procedures. Naproxen sodium (550 mg) was used twice daily + dexamethasone (8 mg) was used once daily in this study. arm 3: Naproxen sodium is a propionic acid derivative with analgesic, antipyretic, and antiinflammatory properties. Its mechanism of action relies on the inhibition of prostaglandin synthesis, and significant pain relief and plasma levels can be obtained within 20 minutes following intake. The elimination half-life of naproxen sodium is reportedly around 14 hours, and naproxen sodium is used in doses ranging from 275 to 550 mg in surgical procedures. Naproxen sodium (550 mg) was used twice daily in this study. arm 4: Paracetamol is a mild analgesic and antipyretic, and is recommended for the treatment of most painful and febrile conditions, for example, headache including migraine, toothache, neuralgia, colds and influenza, sore throat, backache, rheumatic pain and dysmenorrhoea.
Interventions: intervention 1: naproxen sodium+codeine phosphate, naproxen sodium+dexamethasone, naproxen sodium, paracetamol
Intervention descriptions: intervention 1: NSAID, steroid, opioid, paracetamol and combinations of this drugs can be used in temporomandibular disorders.

Protocol documents:
Prot_SAP_000.pdf: 
17 August 2019 
 
Efficacy of Naproxen-codeine, Naproxen+Dexamethasone, and Naproxen on Myofascial 
Pain 
 
NCT Number: NCT04066426 
Levent Cigerim1, Volkan Kaplan2 
1Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Van Yuzuncu Yil University, Van, 
TURKEY 
2Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tekirdag Namik Kemal University, 
Tekirdag, TURKEY 
 
Authors informations: 
 
Levent Cigerim 
DDS, PhD 
e-mail: levent139@hotmail.com 
ORCID: https://orcid.org/0000-0001-5218-8568 
 
Corresponding Author:  
Volkan Kaplan 
DDS, PhD 
Address: Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tekirdag Namik Kemal 
University, Tekirdag, TURKEY. 
Post Code: 59100 
Fax: + 90 282 250 9935 
Phone: + 90 2822506307 
Mob Phone: + 90 532 504 14 08 
e-mail: dr.volkankaplan61@gmail.com 
ORCID: https://orcid.org/0000-0002-7605-1125 
 
 
 
 
 
 


Study Protocol, Statistical Analysis Plan, and Results 
 
Study Protocol 
This randomized, double-blind prospective clinical study was conducted with 200 
voluntary patients who were selected from the individuals who applied with the complaints of 
myofascial pain to the department of Oral and Maxillofacial Surgery of the Faculty of Dentistry at 
Van Yuzuncu Yıl University between January 2018 and January 2019. 
The voluntary individuals were informed about the study and signed a consent form. The 
study was approved by the Ethics Committee for Clinical Trials of Van Yüzüncü Yıl University 
(Protocol Date/No: 16.02.2018/12). The inclusion criteria included the following: patients with 
myofascial pain that was diagnosed by DC/TMD; patients older than 18 years, who were ASA 1 
or ASA 2 (per ASA Physical Status Classification System, according to the anamnesis); 
complaint of clenching and tooth wear and/or fracture; normal preoperative TMJ MR examination 
and no TMJ sounds (clicking or crepitation); no interventional and/or surgical procedure related 
to TMJ; no use of any drug in the last week; and complaints lasting more than 3 months. The 
exclusion criteria were as follows: smoking; parafunctional habits (determined by asking the 
patient and by clinical examinations); one or more tooth deficiencies; impacted third molar(s) (to 
prevent possible impacted toothache being confused with temporomandibular pain); pregnancy 
or nursing; allergy to study medication; unclear anamnesis; use of different or additional 
medication; non-compliance with the intended drug dosage; and non-compliance with the 
follow-up visits once. 
Following admission to the clinic, patients were referred to open-closed mouth 
temporomandibular joint radiography, panoramic radiography, and magnetic resonance imaging 
for the radiographic evaluation. The clinical evaluation was performed according to the DC/TMD. 
The included patients were randomly divided into four groups. Online software was used for the 
randomization (http://www.graphpad.com/quickcalcs/randomize1.cfm). According to the results 
of the program, closed envelopes containing group numbers were selected by the patients, with 
supervision of auxiliary staff. Only the auxiliary staff knew the patient’s group. Neither the 
investigator nor the patient knew which drug was given. The groups received the following 
treatments: Group A: naproxen sodium 550 mg (Apranax fort 550 mg tablet, BID), Group B: 
naproxen sodium 550 mg + codeine phosphate 30 mg (Apranax plus tablet, BID), Group C: 
naproxen sodium 550 mg + single-dose dexamethasone 8 mg (Apranax fort 550 mg tablet, BID 
+ Kordexa 8 mg tablet, OD), GroupD (control group): paracetamol 500 mg (Parol 500 mg tablet, 
QID). The drugs were prepared and bottled by the auxiliary staff and given to patients following 


the coding process. Before the initiation of the treatment, occlusal splints were produced for all 
patients, and patients were instructed to wear them for 8 hrs daily, along with taking the 
medication. The visual analog scale (VAS) was used for the pain assessment (0 = no pain; 10 = 
unbearable pain). The follow-up examinations were performed before the start of the treatment 
and during the treatment at the first, second, and fourth weeks. Study drugs were administered 
for one week, then patients were instructed to wear the splint for 8 hrs daily and to use only 500 
mg paracetamol as an analgesic if they felt it necessary and not to use any other drug. The 
follow-up of these patients is still ongoing. Thirty-one patients were excluded from the study due 
to 26 patients having been lost to follow-up, 2 patients used different medication, and 3 patients 
did not comply with the intended drug dosage. 
 
Statistical Analysis Plan  
Power analysis was performed using the G*Power (v3.1.7) program to determine the 
number of samples. The power of the study is expressed as 1-β (β = type II error probability) and 
generally, the studies should have 80% power. According to Cohen’s effect size coefficients, 
assuming that the evaluations to be made between two independent groups will have a large 
effect size (d = 0.80), it was determined that there should be at least 34 people in each group to 
obtain 90% power at an α = 0.05 level. Considering the possible losses during the study, the 
groups were formed of 50 people. Descriptive statistical methods (mean, standard deviation, 
median, frequency, percentage, minimum, and maximum) were used for the evaluation of the 
study data. The normal distribution of quantitative data was examined and tested with the 
Shapiro-Wilk test and graphical visualization. The comparison of the normally distributed 
quantitative variables for three and more groups was done with the one-way ANOVA test and, 
for two groups, with the Bonferroni test. The comparison of non-normally distributed quantitative 
variables for three and more groups was done with the Kruskal-Wallis test and, for two groups, 
with the Bonferroni-Dunn test. The Repeated Measures test (variance analysis for repeated 
measurements) was used for the intergroup comparison of the normally-distributed variables; 
paired comparisons were performed with the Bonferroni test; and Pearson’s chi-square test was 
used for the comparison of the qualitative variables. The intergroup comparison of the qualitative 
data was done with the Cochran’s Q test, and the Dunn test was used for the paired 
comparisons. The accepted level of significance was p <0.05. Statistical analyses were done 
with NCSS (Number Cruncher Statistical System) 2007 (Kaysville, UT, USA) software package. 
 
Results 


 A total of 169 patients were included in the study and 132 of them were female while 37 
were male. The groups A, B, C, and D consisted of 42, 40, 40, and 47 patients, respectively. 
Their mean age was 27.04±10.56 years (18-69 years). 35.5% of patients (n=60) were married 
and 64.5% (n=109) were single. Regarding their occupation; 20.1% (n=34) were unemployed, 
13.0% (n=22) were government employees, 29.6% (N=50) were housewives, 10.1% (n=17) 
private-sector employees and 27.2% (n=46) were students.  Regarding the left occlusions of 
patients; 74% (n=106) had class I closure, 18.3% (n=31) class II closure, %7.7 (n=13) class III 
closure. 75.5% (n=108) of right side occlusions consisted of class I closures, 16.0% (n=27) of 
class II closures and 8.9% (n=15) of class III closures.  There was no statistically significant 
difference between the groups for age, gender, marital status, occupation, occlusion type of 
left/right side distributions; Patient Health Questionnaire-9 (PHQ-9) and General Anxiety 
Disorder-7 (GAD-7) scores (p>0.05). Only, there was statistically significant difference between 
the groups for occupation (p<0.05). There was no drug side effect reported by the patients in the 
groups. 
Evaluation of the Baseline VAS Measurements According to the Groups: 
There was a statistically significant difference between the groups regarding the baseline 
VAS measurements (p<0.05). The VAS values in Group D were lower than Group C (p<0.05). 
Other paired comparisons did not reveal any statistically significant difference (p>0.05). 
Evaluation of the Changes in VAS Measurements According to the Groups: 
The evaluation of the changes between baseline and first-week VAS measurements 
showed that the change in Group B was greater than Group A and D, and the decrease in VAS 
values of the subjects in Group B was greater than the subjects in Group A and D (p<0.01). 
Other paired comparisons did not reveal any statistically significant difference (p>0.05). 
The evaluation of the changes between baseline and second-week VAS measurements 
revealed that the change in Group B was greater than Group A, C, and D, and the decrease in 
VAS values of the subjects in Group B was greater than the subjects in Group A, C, and D 
(p<0.01). Other paired comparisons did not reveal any statistically significant difference 
(p>0.05). 
The evaluation of the changes between baseline and fourth-week VAS measurements 
showed that the change in Group B was greater than Group A, C, and D and the decrease in 
VAS values in the subjects of Group B was greater than the subjects of Group A, C, and D 
(p<0.05). In addition, the change in Group A was greater than Group D and, the decrease in 


VAS values in the subjects of Group A was greater than the subjects of Group B (p<0.05). Other 
paired comparisons did not reveal any statistically significant difference (p>0.05). 
According to the evaluation of the changes between the first-week and second-week 
VAS measurements, the change in Group B was greater than Group D, and the decrease in 
VAS values in the subjects of Group B was greater than the subjects in Group D (p<0.01). Other 
paired comparisons did not reveal any statistically significant difference (p>0.05). 
The comparison between the first-week and fourth-week VAS measurements showed 
that the change in Group B was greater than Group C and D, and the decrease in VAS values in 
the subjects of Group B was greater than the subjects of Group C and D (p<0.01). The change 
in Group A was greater than Group D, and the decrease in VAS values in the subjects of Group 
A was greater than the subjects of Group D (p<0.01). Other paired comparisons did not reveal 
any statistically significant difference (p>0.05). 
The comparison between the second-week and fourth-week VAS measurements showed 
that the change in Group A was greater than Group C and D (p<0.01). Besides, the change in 
Group B was greater than Group C and D (p<0.01). Other paired comparisons did not reveal any 
statistically significant difference (p>0.05).