Comparison of amitriptyline with stabilization splint and placebo in chronic TMD patients: a pilot study.

Abstract

Objective of work

The authors conducted a clinical study to evaluate the effectiveness of amitriptyline in treatment of chronic TMD patients and to compare treatment results with stabilization splint.

Materials and Methods

Twenty-one patients with chronic TMD were included and randomly distributed into 3 groups: patients in Group A received amitriptyline, patients in Group B received placebo, and those in Group C were treated with stabilization splint. Treatment outcomes (pain assessed by a visual analogue scale (VAS), maximal comfortable mouth opening (MCO) and oral health related quality of life (OHIP-14)) were taken at baseline (before treatment), and at 1^st, 6^th and 12^th week of treatment.

Results

No statistically significant differences between the groups at baseline were found (p>0.05). VAS scores improved significantly in Group A (F=11.326, p=0.002, effect size =0.791) and in group C (F=7.343, p=0.005, effect size=0.647). Mean OHIP-14 scores decreased significantly only in Group A (F=4.417, p=0.036, effect size =0.596). In Group B, VAS and OHIP-14 scores did not change significantly over time. Subjects in Group C had a significant change in MCO relative to Group A and Group B.

Conclusion

From this pilot study it can be concluded that the use of low doses of amitriptyline for a period of 12 weeks is effective for pain management and quality of life improvement in chronic TMD patients. Stabilization splint demonstrated superiority in the management of limited mouth opening during the same period.

Introduction

Temporomandibular disorders (TMDs) are considered the most common orofacial pain conditions of non-dental origin. The current perspective regarding TMD is multidimensional, meaning that many psychological, physical and social factors may have a role in the development of this disorder (1). If the pain becomes chronic, it can have great impact on social and emotional behavior of patient. Taking this into account, certain pieces of evidence prove the validity of the statement that patients suffering from chronic TMD may also have reduced quality of life (2).

In the absence of clear knowledge of the etiological mechanisms that are underlying this disorder, the main goal in TMD management, apart from relieving pain and restoring mandibular function, is to improve oral health related quality of life. When treating patients with chronic orofacial pain, not only is it necessary to evaluate the impact of pain on the quality of life but also the effect of treatment on overall quality of life improvement (3, 4).

A conservative treatment, including occlusal splint, medication, self-care strategies and physical therapy, are considered the first choice for TMJ treatment. The most frequently used therapeutic option is a stabilization splint (5, 6), although a variety of other full-arch and partial oral appliances have been in use. It is generally believed that wearing an occlusal splint alters the peripheral sensory input from receptors in the masticatory muscles, periodontal tissues and oral mucosa (7), and decreases the intra-articular pressure in TMJ (8).

Tricyclic antidepressants (TCA) act by inhibiting serotonin reuptake in the posterior horn of spinal cord, and thus successfully decreasing the speed at which pain information is transmitted to the brain. There is some evidence that low doses of amitriptyline daily significantly reduce the pain of chronic TMD without producing side effects (9), but patients were evaluated only for a short period of time.

So far, numerous studies have investigated the role of stabilization splint in TMD management (10-12). However, the use of TCA in the treatment of TMD has not been fully explored, particularly regarding its impact on oral health related quality of life. Accordingly, the objective of this pilot study was to evaluate the effectiveness of amitriptyline in treatment of chronic TMD patients and to compare the obtained treatment results with stabilization splint. The null-hypothesis was that there would be no difference between treatment options in a 12-week treatment period.

Materials and Methods

Subjects

This clinical trial was carried out at the Department of Prosthodontics, School of Dental Medicine, University of Zagreb. The subjects were recruited from patients seeking treatment for non-odontogenic orofacial pain who had not been previously treated. The patients were diagnosed using Research Diagnostic Criteria for temporomandibular disorders (RDC/TMD) (diagnostic categories I or II in the RDC/TMD) (13, 14). The data regarding participant's age, gender, current marital status and duration of pain were collected by a questionnaire. Exclusion criteria were: 1) periodontal disease, 2) removable dentures or complete fixed prosthodontic restorations, 3) ongoing orthodontic treatment, 4) pain due to temporomandibular joint osteoarthritis (diagnostic category III in the RDC/TMD) 5) other orofacial pain conditions, 6) mental or neurological disorders, 7) pain due to systemic disease, 8) pregnancy, 9) cardiac disease and 10) known intolerance to amitriptyline.

At the baseline (T0) all patients were evaluated by the clinician (R.B.B.) who was well trained in diagnosing TMD.

Standardizations of the examiner

To estimate the intra-examiner reproducibility, a clinical examination was made on two separate occasions by the same clinician, on 10 subjects, different from those included in the study. The intra-examiner error was not statistically significant (ICC>0.9). No significant differences between the first and second measurement were found (p=0.85-0.89, paired t-test).

Ethical approval

This study was approved by the Ethics Committee of the School of Dental Medicine, University of Zagreb. Written informed consent was received from all individual patients included in the study. All experimental procedures were conducted in accordance with ethical standards of the Helsinki Declaration.

Study protocol

Twenty-seven patients met the conditions and 21 of them were finally included in the study. The principle reason for patients declined participation in the study was that they thought that participation in the study would take up too much of their time. Prior to randomization all patients were informed about the possible side-effects of amitriptyline. After that they signed written consent form.

The randomization was performed using Microsoft Excel software after the codification of each patient. The patients were allocated into three treatment groups: Group A received 25 mg of amitriptyline), Group B received placebo pill of the same size and appearance (made at MAGDIS d.o.o., A. Šenoe 37, Mala Gorica, 10431 Sv. Nedjelja) and Group C was treated with stabilization splint (Figure 1).

Figure 1.

Flowchart illustrating the selection and distribution of the participants into the study groups

Treatment procedure

Patients undergoing pharmacological treatment were instructed to take one pill at bedtime, during 12 weeks. Patients in the stabilization splint group were instructed to wear the splint only during sleep. All therapies were delivered by the same clinician (I.A.).

The maxillary stabilization splint was made on stone cast in ARTEX articulator. It was a hard acrylic splint (Resilit-S, Erkodent, Siemensstraße 3, 72285 Pfalzgrafenweiler, Germany), with a thickness of 1.5 mm at the level of the first molar. The same dental technician made all splints. The clinician (I.A.) adjusted the splint so that the simultaneous and symmetric contacts were obtained in maximum intercuspation. The same clinician adjusted the splint at follow up appointments if there was a need for it.

Outcome measures

The baseline examiner (R.B.B.), blind to a type of therapy, performed clinical examination of each patient at follow up appointments at 1^st (T1), 6^th (T2) and 12^th (T3) week after treatment initiation.

VAS-pain

VAS was used to evaluate the patient's pain at rest or during function in the last 7 days. The VAS is a 100 mm-long line, with left endpoint indicating “no pain at all” and right endpoint representing “worst pain imaginable”.

Maximal comfortable mouth opening

Maximal comfortable mouth opening (MCO), the maximum distance the patient could open his/her mouth without feeling pain, was evaluated as the distance between the edges of the maxillary and mandibular incisors.

Oral health-related quality of life evaluation

The Croatian OHIP-14 questionnaire was used to evaluate oral health-related quality of life. Patients expressed their level of agreement with 14 questions about the oral health- related quality of life, by choosing one of the answers: 0-never, 1- hardly ever, 2-sometimes, 3 fairly often -and 4-very often. Possible OHIP-14 scores ranged from 0 to 56. The potential validity of the OHIP for evaluation of TMD patients and its previous usage for this purpose (15) contributed to the adoption of this previously validated version in the present study (16).

Statistics

Preliminary analyses consisted of descriptive statistics, normality tests and tests for homogeneity of variances. A repeated-measurements analysis of variance was used to test the differences in VAS and OHIP-14 scores at baseline-T0, T1, T2 and T3. The eta squared (η²) was used to estimate the size of the effect. Changes in maximally comfortable mouth opening were analyzed with ANOVA, followed by the post hoc Bonferroni tests.

The data were analyzed using statistical software SPSS 17.0 (Chicago, IL, USA). A value of p < 0.05 was considered statistically significant.

Results

Baseline scores

Eight patients dropped out of the study. Hence, 13 participants (4 in amitriptyline group, 4 in placebo group and 5 in stabilization splint group) completed the study. The Table 1 summarizes the participant’s baseline characteristics, according to treatment group. The mean age for the amitriptyline group was 57.25±8.13 years, for placebo group 46.5±18.15 years, and for stabilization splint group 42.8±12.45 years. The mean pain duration for the amitriptyline group was 9.8±2.8 months, for placebo group 19.5±13.3 months, and for stabilization splint group 16.8±7.8 months. No significant differences in baseline characteristics between groups were found (p >0.05).

Table 1. Demographics and baseline data of participants.

	amitriptyline Group A (n=4)	placebo Group B (n=4)	Stabilization splint Group C (n=5)	F (p)
Age (years)	57.25±8.13	46.5±18.15	42.8±12.45	3.417 (0.099)
Initial pain (VAS)	80.25±14.15	72.75±21.71	70.0±12.5	0.459 (0.645)
Pain duration (months)	9.8±2.8	19.5±13.3	16.8±7.8	1.832 (0.210)
Initial OHIP-14	23.5±5.06	23.7±11.26	27.00±9.92	2.487 (0.134)
Initial MCO	40.00±8.20	30.75±4.64	30.80±7.15	2.497 (0.132)

Treatment effectiveness

The change patterns for pain in each group are shown in Figure 2. We checked the variable pain at four points: baseline (T0), 1^st week (T1), 6^th week (T2) and 12^th week (T3). Pain decreased continuously over time in amitriptyline group (Group A) and in stabilization splint group (Group C); the difference was significant for Group A (F=11.326, p=0.002, effect size =0.791) and for group C (F=7.343, p=0.005, effect size =0.647) (Figure 2).

Figure 2.

Changes in pain (VAS) from baseline to 12th week of the therapy

Changes in OHIP-scores from baseline to 12^th week of the therapy are shown in Figure 3. We checked the variable oral health-related quality of life at four points: baseline (T0), 1^st week (T1), 6^th week (T2) and 12^th week (T3). A significant improvement in the quality of life during the treatment period was found only in Group A (F=4.417, p=0.036, effect size =0.596).

Figure 3.

Changes in OHIP-score from baseline to 12th week of the therapy

In placebo group (Group B), VAS and OHIP-14 scores did not change significantly over the treatment period (p>0.05).

The subjects in all three groups had an increased MCO at the final visit comparing with baseline (Figure 4). A between group comparison showed that in Group C a significant change in MCO relative to Group A and Group B was found (p>0.05).

Figure 4.

The effectiveness of therapeutic interventions was evaluated by assessing the change in maximal comfortable mouth opening following 12 weeks treatment

At the final visit subjects in Group A and group C had greater, but not significant, change in VAS scores (Figure 5), as well as greater OHIP reduction (Figure 6), than patients in group B.

Figure 5.

The effectiveness of therapeutic interventions was evaluated by assessing the change in VAS scores following 12 weeks treatment

Figure 6.

The effectiveness of therapeutic interventions was evaluated by assessing the change in OHIP-14 scores following 12 weeks treatment 1. Rogulj AA, Richter I, Brailo V, Krstevski I, Boras VV. Catastrophizing in Patients with Burning Mouth Syndrome. Acta stomatologica Croatica. 2014;48 (2):109-15. Epub 2014/06/01.

Discussion

Currently, the stabilization splint represents the “gold standard” for treatment of temporomandibular disorders. However, many other treatment modalities for TMD have been tried over time. Experimental evidence, based on randomized clinical trials, is controversial and till today no single treatment has been proven to be better than any other for TMD. The present study evaluated the effectiveness of amitriptyline compared to stabilization splint and placebo in chronic TMD patients.

Our preliminary data support the use of low doses of amitriptyline over a period of 12 weeks for the management of the pain caused by chronic TMD. Administration of amitriptyline resulted in 56.68% reduction in the VAS scores. This result is in agreement with several other studies (17-20). However, as with any other medication, the use of amitriptyline may increase the risk of adverse effects.

Tricyclic antidepressant amitriptyline has been found to be better than placebo for some chronic pain conditions (21, 22). In the study of Plesh et al. (20), the reduction of pain intensity was observed when using 30 mg of amitriptyline. Furthermore, patients who received amitriptyline combined with CBT continued to improve according to the VAS even when therapy was discontinued (19). The findings of Sharav et al. (21) showed that there is no difference in analgesic effect between low (30 mg) and high (150 mg) dose of amitriptyline but there was a significant reduction in pain intensity among amitriptyline and placebo. In the first study of McQuay et al. (17), the use of 25 mg of amitriptyline resulted in a significant reduction of pain intensity after 3 weeks versus placebo group. In the second study, McQuay et al. (18) compared low (25 mg) and high (75mg) doses of amitriptyline versus placebo and showed that high dose has a greater effect. However, the size of sample was relatively small. The findings of Rizzati-Barbosa et al. (9) showed a significant reduction in pain intensity after administering 25 mg of amitriptyline versus placebo group after 2 weeks of treatment. Our findings showed that the placebo effect on pain was high only at early periods of drug administration. After the third follow up visit, no further improvement in the placebo group was found, while amitriptyline and stabilization splint group had significant decrease in pain intensity during the entire study.

Certain pieces of evidence prove the validity of the assumption that patients who suffer from temporomandibular disorders may also have a reduced oral health-related quality of life. In the study of Almoznino et al. (2) OHIP-14 scores were worse for patients with TMD than in normal population. Blanco-Aguilera et al. (23) showed that perception of oral health is worse in patients who suffer from chronic pain for a longer period of time. According to a systematic review (24), it appears that many treatment modalities led to an improvement in the quality of life in TMD patients. The present results revealed a significant improvement in OHIP-14 score in amitriptyline group, a slight, but not statistically significant improvement in stabilization splint group, while in placebo group OHIP-14 scores did not change significantly over time.

Of all the treatment options, only the stabilization splint had a significant effect on the amount of mouth opening, whereas patients treated with stabilization splint had a significantly greater change in the comfortable mandibular opening relative to amitriptyline and placebo group. Patients in amitriptyline and stabilization splint groups showed better reduction in VAS and OHIP-14 scores, although the differences, when compared to placebo group, were not statistically significant.

The present pilot study has certain limitations that reduce the strength of our conclusions, the biggest limitation being a small sample size. However, this pilot study encourages execution of a full scale study since our results are favorable. The outcome measures of orofacial pain treatment are very subjective, which warrants the adherence to strict clinical protocol involving blinding. Execution of those protocols is very cumbersome and the recruitment process is time consuming. For this reason, we feel that the results of our preliminary pilot study are valuable, although the number of patients is small.

Conclusion

Even with the abovementioned limitations, the results of this pilot study show that amitriptyline and stabilization splint may be effective in decreasing the intensity of pain, thus improving quality of life of patients with chronic TMD. The stabilization splint showed superiority in the management of limited mouth opening during the same period. Further research using adequate sample size would be of value.