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Table of Contents   
ORIGINAL RESEARCH  
Year : 2011  |  Volume : 22  |  Issue : 3  |  Page : 404-409
Analgesic efficacy of diazepam and placebo in patients with temporomandibular disorders: A double blind randomized clinical trial


1 Department of Oral Medicine and Radiology, Bapuji Dental College and Hospital, Davangere, India
2 Department of Oral Medicine and Radiology, M.M. College of Dental Sciences & Research, Mullana (Ambala), Haryana, India
3 Department of Oral Medicine and Radiology, U.P. Dental College, Lucknow, Uttar Pradesh, India
4 Department of Oral Medicine and Radiology, BVU Dental College & Hospital, Pune, India

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Date of Submission14-Apr-2010
Date of Decision16-Jul-2010
Date of Acceptance11-Oct-2010
Date of Web Publication3-Nov-2011
 

   Abstract 

Aim: The aim of the study was to evaluate and compare the analgesic efficacy of placebo and diazepam in patients with temporomandibular disorder.
Materials and Methods: Thirty-five patients were recruited with a diagnosis of temporomandibular disorder based on standard clinical diagnostic criteria for temporomandibular disorder. The patients were put in to one of the two groups: placebo or diazepam at random. The average pain intensity was recorded with visual analog scale (VAS) at pretreatment, at weekly interval till the completion of a three-week trial and at post-treatment visit on the eighth week from baseline. The secondary outcome measures were changes in masticatory muscle tenderness, viz. massater muscle, lateral pterygoid muscle, medial pterygoid muscle and temporalis muscle and changes in mouth opening.
Statistical Analysis: Intra-group comparison for analgesic efficacy and mouth opening was carried out by Wilcoxon's signed ranked test. Inter-group comparison for analgesic efficacy was also carried out using Mann-Whitney's test.
Results: A statistically significant (P<0.01) decrease in temporomandibular disorder pain in the placebo group (65%) and statistically highly significant (P<0.001) decrease in the diazepam group (72%) were observed on VAS after three weeks of treatment. The inter-group comparison demonstrated no statistically significant difference between the groups.
Conclusion: This study suggests that the placebo can give near similar results as diazepam can. So the role of placebo should also be considered as one of the important management strategies. In the short term, reduction in the masticatory muscle tenderness and significant improvement in the mouth opening in both the groups were observed.

Keywords: Analgesic efficacy, diazepam, double-blind randomized clinical trial, placebo, temporomandibular disorders

How to cite this article:
Pramod G V, Shambulingappa P, Shashikanth M C, Lele S. Analgesic efficacy of diazepam and placebo in patients with temporomandibular disorders: A double blind randomized clinical trial. Indian J Dent Res 2011;22:404-9

How to cite this URL:
Pramod G V, Shambulingappa P, Shashikanth M C, Lele S. Analgesic efficacy of diazepam and placebo in patients with temporomandibular disorders: A double blind randomized clinical trial. Indian J Dent Res [serial online] 2011 [cited 2019 Jul 20];22:404-9. Available from: http://www.ijdr.in/text.asp?2011/22/3/404/87062
What makes pain such an important clinical problem is the unpleasantness associated with it. The urge to obtain relief from pain and escape from its cause are the prime factors motivating patients to seek medical treatment. [1] A common chronic pain problem of the oro-facial region is temporomandibular disorder (TMD), a musculoskeletal disorder.

Temporomandibular disorder is a collective term which embraces a number of clinical problems that involve the masticatory musculature, the temporomandibular joint (TMJ) and associated structures or both. [2]

The etiology of TMD is often multifactorial and complex. [3],[4] Symptoms and signs of different diagnostic categories of TMD may overlap and more than one problem can be present at the same time.

Many different therapeutic modalities have been proposed based on the etiology of TMD. However, no clear consensus exists within the dental and medical community as to what constitutes the treatment of choice for this condition.

Despite a heap of literature on therapeutic modalities, a few studies have evaluated pharmacologic treatment of TMD in well-controlled studies. A meta-analysis of more than 4,000 references on TMD, published from 1980 to 1992, found that approximately only 1% (n=55) was randomized controlled studies, with only five of these evaluating pharmacological agents. [5]

Diazepam, a benzodiazepine, has been advocated for many years for TMD patients. A few clinical trials involving TMD patients, however, point out a need for more such clinical trials involving diverse populations. [5]

Placebo, an inactive preparation, is given to satisfy patient's symbolic need for drug therapy, and is used in controlled studies to determine the efficacy of medicinal substances. The power and ubiquitous nature of the placebo effects are well documented. A good knowledge of the placebo effect may improve our ability to understand patient's responses to treatment, particularly those with chronic conditions. Therefore, the understanding and the use of the placebo effect in the correct therapeutic environment may improve effective management.

This clinical trial was an attempt to evaluate and compare the analgesic efficacy of placebo and diazepam in patients with TMD.


   Materials and Methods Top


The study groups comprised patients above 15 years and below 60 years of age of both sexes. Diagnosis of TMD in these patients was made using Truelove's standard criteria. [6]

The following patients were included in the study:

  • Daily pain in the pre-auricular region at least of three months duration.
  • Muscle tenderness to palpation in one or more muscle of mastication.
  • Those who were diagnosed as TMD earlier, but not treated with diazepam.
  • Patients being treated with some other medication were included provided a washout period of 15 days was allowed before inclusion in this study.


Limited mouth opening and the presence of clicking were not necessary for inclusion, if first three criteria were met.

The following patients were excluded from the study group:

  • Those with evident changes in TMJ detected on radiographic examination.
  • Pain attributable to recent facial trauma, dental surgery, or placement of a dental appliance.
  • Other local causes of pain (dental abscess, trigeminal neuralgia or migraine)
  • The presence of other disorder that required ongoing treatment with analgesics, muscle relaxants, or mood altering drugs, which would confound the evaluation of TMD pain.
  • Allergy or other contraindications to the study drugs
  • Patients taking medication for other medical conditions during the last 15 days.


Ethical committee approval was taken prior to initiating the clinical trial. Only those patients who had given a signed informed consent on institutionally approved document participated in the study. Based on inclusion and exclusion criteria, 35 patients were included in the study.

Study design

This study design was a double blind randomized clinical trial to evaluate analgesic efficacy in patients with TMD. The allocation was concealed from the doctor (who assessed the patients) as well as patients during all stages of the study. The allocation sequence was known only to another staff in the department, who dispensed the tablets along with the detailed instructions. A record of all dispensed medications was maintained by the same staff.

The dosage of the drug under study was consistent with common clinical practice. Patients were randomly assigned to one of the following groups: Group 1 (placebo) or Group 2 (diazepam).

The patients of Group 1 were instructed to take one placebo tablet in the morning after breakfast. The placebo tablets were formulated to have the same appearance as active drug. Neither the doctor nor the patients were aware of the treatment given until completion of the interventions.

The patients of Group 2 were instructed to take one diazepam (5 mg) tablet daily in the evening after a small meal and were also instructed to avoid driving and working on or near machinery after taking tablet.

The patients in both the groups had received treatment for three weeks and were recalled at an interval of one week. A post treatment follow-up was done after five weeks (i.e., after eight weeks from baseline).

The data collection was by recording of demographic data, general history, TMD history and physical examination. It was carried out in a systematic manner at the baseline visit. Trans-cranial radiographs of TMJ on both sides were made. The following three parameters were recorded at baseline and post-baseline visits:

  • Pain intensity on VAS (in mm)
  • Masticatory muscle tenderness viz. in masseter, medial pterygoid, lateral pterygoid and temporalis
  • Mouth opening (in mm)
The pain in masticatory muscles and TMJ specific regions was assessed by the methods explained by Dworkin. [7] Similarly, TMJ sounds were auscultated. Mouth opening was measured with a divider and a scale.

Statistical analysis

Intra-group comparison for analgesic efficacy and mouth opening was carried out by Wilcoxon's signed ranked test. Inter-group comparison for analgesic efficacy and mouth opening between two groups was carried out using Mann-Whitney's test. Inter-group comparison for changes in the masticatory muscle tenderness was carried out using Chi-square test.


   Results Top


The final sample consisted of 21 women and 14 men [Table 1].
Table 1: Age and sex wise distribution of patients

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Analgesic efficacy

On intra-group comparison for analgesic efficacy [Table 2] [Figure 1], there was a statistically significant (P<0.01) decrease in TMD pain in placebo group (65%) and statistically highly significant (P<0.001) decrease in TMD pain in diazepam group (72%) was observed with treatment for three weeks. On the eighth week visit, reduction in pain score was better in the diazepam (72%) than the placebo group (67%).
Figure 1: Pain intensity at different interval on visual analog scale

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Table 2: Comparison of pain intensity on VAS in study groups at different intervals

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There was no statistically significant difference between the two study groups, when an inter-group comparison for analgesic efficacy was made.

Muscle tenderness

In the intra-group comparison for masticatory muscle tenderness, there was tenderness reduction in both placebo and diazepam groups with treatment for three weeks and five weeks after cessation of treatment [Table 3]a and b. But masseter muscle in diazepam group was the only exception where it showed a slight increase in tenderness after five weeks of cessation of treatment.
Table 3a: Comparison of masticatory muscle tenderness at different time intervals
Table 3b: Comparison of masticatory muscle tenderness at different time intervals


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The inter-group comparison for muscle tenderness in all masticatory muscles was of no statistical significance.

Mouth opening

The intra group comparison for changes in the mouth opening at different intervals [Table 4], [Figure 2] revealed that the mean mouth opening increased in the placebo group with treatment for three weeks (13%) and without treatment for five weeks from cessation of treatment (16.5%), and this was highly significant (P<0.001). In the diazepam group, the mean mouth opening increased with treatment for three weeks (30%) and it remained the same after five weeks after cessation of treatment (30%), and this was also highly significant (P<0.001).
Figure 2: Comparison of mouth opening in different groups at different intervals

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Table 4: Comparison of mouth opening in different groups at different intervals (mm)

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The inter-group comparison for changes in the mouth opening in both the groups at different intervals [Table 4] was done using Mann-Whitney's test. On the third week visit (with treatment) and the eighth week visit (five weeks from cessation of treatment) from baseline, increase in mouth opening was better seen in the diazepam group than in the placebo group. The difference between both the groups was statistically significant (P<0.01).


   Discussion Top


Evaluation of pain

All the 35 patients in our study reported pain as their chief complaint. On the third week visit after completion of treatment, it was found that reduction in pain score was better in the diazepam group (72%) than in the placebo group (65%). On the eighth week i.e., after five weeks of treatment free period, reduction in pain score was better in the diazepam (72%) than in the placebo group (67%). However on inter-group comparison, there was no statistically significant difference between two groups on the third and the eighth week visits.

There are only a few studies evaluating the efficacy of diazepam on pain reduction in temporomandibular disorders. Our observation is similar to the observation made by Basmajian [8] and Singer and Dionne [5]

Basmajian [8] has compared cyclobenzaprine with diazepam and placebo for patients with skeletal muscle spasm in lumbar and neck region. A clinical improvement in signs and symptoms was observed for both medications and the placebo, and there was no statistical difference between the three treatment groups. Singer and Dionne [5] in their clinical trial on chronic oro-facial muscle pain patients observed significant decrease in pain symptoms in groups treated with diazepam alone and diazepam and ibuprofen combination.

The improvement in the patients treated with diazepam may be due to the underlying anxiety and spasm of muscles of mastication. But this data does not differentiate whether the improvement with diazepam was the result of its muscle relaxant property, its anxiolytic property, or non-specific central nervous system depression.

In the present study, there was significant pain reduction in the placebo group also. A similar observation is made by Singer and Dionne [5] Basmajian, [8] Herman et al., [9] Dionne. [10]

Dionne [10] have observed that the analgesic efficacy of ibuprofen 2400 mg / day for four weeks could not be separated from the placebo in chronic orofacial pain patients. Herman et al. [9] have also observed that there was no significant difference in pain reduction between clonazepam (active drug) and placebo in their study on myofascial pain patients. Epstein JB [11] has observed that the placebo effect was significant for symptoms of chronic conditions including pain.

In contrast to the present result, Ekberg et al. [12] have found a response rate of only 31% for the placebo group and 44% in diclofenac sodium group. They also observed that the placebo seems to be more effective when the painful or stressful condition was severe and its potency seems to be greater when the pain was acute rather than chronic. Greene and Laskin [13] in their study have observed that 58% reported improvement with meprobamate and only 31% after taking placebo tablets.

When a patient responds to therapy, there may be several reasons accounting for the improvement. The specific treatment rendered may have been effective in reducing pain and promoting in healing or the condition may have run its natural course and treatment may have been coincidental, or pain relief may be due to the placebo effect. [14]

Highly anxious patients appear to show the greatest placebo response; this may be associated with reduction in anxiety and associated suffering. But how a placebo works is still unanswered. In addition to the obvious physiologic effects, the placebo response could be psychological. Under the right circumstances, any patient may experience a positive response to placebo. While the placebo effect is short-lived, the power of placebo for therapeutic should not be underestimated by the clinician - it is another important tool in management. [15]th

In the present study, it was observed that both diazepam (active drug) and placebo drugs are useful in relieving TMD pain. Overall, the results were better for diazepam than placebo. From this study, we suggest that all three factors namely inflammatory mediators, anxiety and spasm play a vital role in the etiology of TMD.

In addition to the evaluation of pain, other parameters like muscle tenderness and mouth opening were also studied.

Masticatory muscle tenderness

In group 1 (placebo), only marginal reduction in tenderness was observed in first two weeks, but after three weeks of treatment and five weeks after cessation of treatment, there was a mild to moderate decrease in muscle tenderness. In group 2 (diazepam), there was a gradual, but a significant decrease in tenderness in all the masticatory muscles. The decrease in the muscle tenderness was better in the diazepam group than in the placebo group but was not statistically significant.

There are only a few studies on diazepam evaluating its efficacy on masticatory muscle tenderness. In contrast to our results, Ekberg et al. [12] have observed that placebo was less effective in relieving muscle tenderness than the active drug (diclofenac sodium). Singer and Dionne [5] have observed no significant improvement in muscle tenderness to palpation in their comparative study with ibuprofen and diazepam in chronic orofacial pain patients.

Mouth opening

At the end of three weeks of treatment in group 1 (placebo), the mean mouth opening increased by only 13%, but in group 2 (diazepam), the increase was 30%. After five weeks from cessation of treatment, there was further significant increase in mouth opening in group 1 (placebo) by 16.5% but there was no change in group 2 (diazepam).

In the present study the improvement in the mouth opening was significantly better in the diazepam group when compared to the placebo.

In contrast to the present study, Singer and Dionne [5] have observed no significant improvement after treatment for inter-incisal opening in their comparative study with ibuprofen and diazepam in chronic orofacial pain patients. They thought it could be due to the mean opening that was within normal range for all patients. Ekberg et al. [12] have observed no increase in maximum mouth opening in diclofenac sodium group after treatment in TMD patients.

In this study, there was a significant reduction of pain in placebo and diazepam groups. The pain reduction between the groups was not statistically significant.

The preponderance of data does not support the superiority of any method for initial management of most TMD problems. Moreover, the superiority of such methods to placebo controls or no treatment controls remains undetermined as most individuals will experience improvement or relief of symptoms with conservative treatment, the vast majority of TMD patients should receive initial management using non-invasive and reversible therapies.

Conversely, the small sample size in the present study requires replication of these findings in a larger sample of patients, possibly using a crossover design to minimize the effects of confounding factors and to maximize assay sensitivity for detecting the difference between treatments.


   Conclusion Top


The placebo also gave near similar analgesic efficacy as the diazepam did. So the health professionals, active in pain management, should consider the role of placebo as one of the vital management strategies. Therefore, drugs in the management of temporomandibular disorders should be used judiciously to prevent the harmful side effects.

There was a significant reduction in the tenderness in all the muscles of mastication in both groups and the difference between two groups was minimal.

There was a significant improvement in the mouth opening in both groups. The improvement in the mouth opening was significantly better in the diazepam group when compared to the placebo.

The results of the present study reinforce the necessity for evaluating other putative therapies for TMD in careful controlled studies. More studies are needed to provide scientific validation for the use of a drug or other therapeutic modality for TMD.

In the present study, the sample size was small, so similar studies on a larger population are needed to further assess the efficacy of placebo to make patient's life easy and pain free.

 
   References Top

1.Hersh EV. Mechanism of pain. In: Peters RA, Sheldon GG, editors. Clinical management of temporomandibular disorders and orofacial pain. Carol Stream, Illinois: Quintessence publishing Co, Inc; 1995. p. 35-44.   Back to cited text no. 1
    
2.McNeill C. History and evolution of TMD concepts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:51-60.  Back to cited text no. 2
[PUBMED]  [FULLTEXT]  
3.Okeson JP. Causes of functional disturbances in the masticatory system, general consideration in the temporomandibular disorders, occlusal appliance therapy. In: Okeson JP, editor. Management of temporomandibular disorders. 5 th ed. St. Louis: Mosby; 2003. p. 49-189.  Back to cited text no. 3
    
4.Harkins S, Linford J, Cohen J, Kramer T, Cueva L. Administration of clonazepam in the treatment of TMD and associated myofascial pain: A double-blind pilot study. J Craniomandib Disord 1991;5:179-86.   Back to cited text no. 4
    
5.Singer E, Dionne R. Controlled evaluation of ibuprofen and diazepam for chronic orofacial muscle pain. J Orofac Pain 1997;11:139-46.  Back to cited text no. 5
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6.Truelove EL, Sommers EE, LeResche L, Dworkin SF, Von Korff M. Clinical diagnostic criteria for TMD: New classification permits multiple diagnosis. J Am Dent Assoc 1992;123:47-54.  Back to cited text no. 6
    
7.Dworkin SF, LeResche L. Research diagnostic criteria for temporo-mandibular disorders: Review, criteria, examinations and specification critique. J Craniomandib Disord 1992;6:302-50.   Back to cited text no. 7
    
8.Basmajian JV. Cyclobenzaprine hydrochloride effect on skeletal muscle spasm in the lumbar region and neck: Two double blind controlled clinical and laboratory studies. Arch Phys Med Rehabil 1978;59:58-63.  Back to cited text no. 8
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9.Herman CR, Schiffman EL, Look JO, Rindal DB. The effectiveness of adding pharmacologic treatment with clonazepam or cyclobenzaprine to patient education and self-care for the treatment of jaw pain upon awakening: A randomized clinical trial. J Orofac Pain 2002;16:64-70.  Back to cited text no. 9
    
10.Dionne RA. Pharmacologic treatments for temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:134-42.  Back to cited text no. 10
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11.Epstein JB. Understanding placebos in dentistry. J Am Dent Assoc 1984;109:71-4.  Back to cited text no. 11
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12.Ekberg EC, Kopp S, Akerman S. Diclofenac sodium as an alternative treatment of temporomandibular joint pain. Acta Odontol Scand 1996;54:154-9.  Back to cited text no. 12
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13.Greene CS, Laskin DM. Meprobamate therapy for the myofascial pain-dysfunction (MPD) syndrome: A double-blind evaluation. J Am Dent Assoc 1971;82:587-90.  Back to cited text no. 13
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14.Yuasa H, Kurita K, Treatment group on temporomandibular disorders. Randomized clinical trial of primary treatment for temporomandibular joint disc displacement without reduction and without osseous changes: A combination of NSAIDs and mouth opening exercises versus no treatment. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91:671-5.  Back to cited text no. 14
    
15.Management of temporomandibular disorders. National Institute of Health Technology Assessment Conference statement. J Am Dent Assoc 1996;127:1595-606.  Back to cited text no. 15
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Correspondence Address:
G V Pramod
Department of Oral Medicine and Radiology, Bapuji Dental College and Hospital, Davangere
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9290.87062

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