Cyclobenzaprine for the treatment of myofascial pain in temporomandibular disorders
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess efficacy and safety of cyclobenzaprine in the treatment of myofascial pain in temporomandibular disorders.
To test the null hypotheses that there are no differences in outcomes between cyclobenzaprine versus physiotherapy or other active treatments for treating myofascial pain.
Background
Myofascial pain (MP) in the temporomandibular area is a painful condition characterized by pain in local areas in the jaw, temples, face, preauricular area, or inside the ear (Fricton 1989; Manfredini 2006; Okeson 1998; Okeson 2006; Solberg 1986; Travell 1952). Trigger points (TP) can produce a characteristic pattern of irradiated pain or autonomic symptoms when stimulated (Fricton 1989; Okeson 1998; Solberg 1986). The pain can occur at rest or during function, and may be accompanied by co‐contraction of the masticatory muscles, resulting in limitation of the mandibular opening (Dworkin 1992; Manfredini 2006; Okeson 2006). The prevalence of MP without opening limitation is between 31% and 76%, and in populations with MP with opening limitation prevalence is between 1% and 26%. Myofascial pain was initially described in 1952, although odontological and medical communities were very slow to understand its meaning (Travell 1952). There are many diagnostic systems for temporomandibular disorders (TMD) of which MP is a part. The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) was created to provide a classification criteria that is universally accepted and validated. A diagnosis of MP is given by the RDC/TMD when pain is reported by the subject in response to palpation of three or more sites of the masticatory muscles (De Lucena 2006; Dworkin 1992; Manfredini 2006). Studies of prevalence show different results between Americans, Europeans and Asian populations for MP. Myofascial pain shows an unusual distribution in the general population, with a predominance in females and an age of onset ranging between 20 and 40 years (List 1996; List 1999; Manfredini 2006; Yap 2003).
The etiology of MP is complex and it is difficult to be specific as to all etiological factors, however, some authors have described local and systemic factors that seem to be associated: trauma, stress, emotional tension, deep pain impulse, hypovitaminosis, infections, fatigue and patients who are physically inactive, and have a weak physical conditioning (Laskin 1969; Okeson 2006; Simons 2005).
Treatment options for MP include reassurance (patient education, self care and behaviour therapy), physiotherapy (ultrasound, megapulse, short wave laser, heat exercises, biofeedback), acupuncture, splint therapy, occlusal adjustment, dry needling, drug therapy and combined treatment (Al‐Ani 2005; Koh 2003; McMillan 1997; Shi 2003; Solberg 1986). Medicines used to treat MP include analgesics, non‐steroidal anti‐inflammatory drugs (NSAIDS), muscle relaxants and tricyclic antidepressants such as amitriptyline (Al‐Ani 2005; Koh 2003; Shi 2003).
Cyclobenzaprine, a muscle relaxant, is a centrally acting serotonin receptor antagonist that reduces muscle tone by the inhibition of serotonergic descending systems in the spinal cord (Kobayashi 1996). It suppress the muscle spasm without interfering with the muscle function (Lance 1972). Cyclobenzaprine is structurally related to amitriptyline. In fact, it was initially produced and tested in clinical trials for antidepressant activity at doses above those used presently for muscle relaxation. That similarity to amitriptyline has raised concern about side effects such as drowsiness, lethargy, sinus tachycardia, agitation, and both hypertension and hypotension, but a five‐year multicenter review of its toxicity shows that cyclobenzaprine does not appear to produce life threatening cardiovascular and neurological effects (Kobayashi 1996). Also the incidence of troublesome side effects are less than with amitriptyline in some trials (Lance 1964; Lance 1972). Cyclobenzaprine is used in the clinical management of MP in temporomandibular disorders to improve the quality of sleep and to reduce pain (Pertes 2005).
Objectives
To assess efficacy and safety of cyclobenzaprine in the treatment of myofascial pain in temporomandibular disorders.
To test the null hypotheses that there are no differences in outcomes between cyclobenzaprine versus physiotherapy or other active treatments for treating myofascial pain.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) and quasi‐randomised controlled trials (quasi‐RCTs) that fulfil the criteria outlined below will be included.
Types of participants
Patients of both sexes, aged over 18 years with clinical diagnosis of myofascial pain in temporomandibular disorders, regardless of race, social and economical status, profession or residential location.
We will exclude patients for whom cyclobenzaprine is contraindicated with conditions such as: heart problems, glaucoma, hyperthyroidism, and those who are pregnant or breastfeeding.
Types of interventions
Intervention group: cyclobenzaprine in any dose by any route.
Control group: placebo, no intervention, physiotherapy, or other control.
We will also consider studies that evaluated different doses of cyclobenzaprine.
Types of outcome measures
Primary outcomes:
intensity, frequency and duration of pain crises recorded using validated visual analogue scales (VAS) or categorical scales.
Secondary outcomes:
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quality of life measured by OHRQoL and SF‐ 36;
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adverse events, such as drowsiness, lethargy, sinus tachicardia, agitation, hypertension and hypotension.
Search methods for identification of studies
There will be no language restrictions. To identify trials we will search the Pain Palliative and Supportive Care Collaborative Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), PubMed (1966 to present), EMBASE (1980 to present), Literatura Latino‐Americana e do Caribe em Ciências da Saúde ‐ LILACS (1982 to present) and the Scientific Electronic Library Online ‐ Scielo (to present) to identify RCTs and quasi‐RCTs.
The search strategy will be composed of terms for myofascial pain and cyclobenzaprine. As we will search with both subject headings and free text words, we expect all studies of myofascial pain and cyclobenzaprine to be identified. The following exhaustive list of synonyms for myofascial pain and cyclobenzaprine will be used:
((Myofascial Pain Syndromes) OR (Myofascial Pain Syndrome) OR (Myofascial Trigger PointS) OR (Myofascial Trigger Point)) AND (cyclobenzaprine OR (cyclobenzaprine hydrochloride) OR Flexeril OR Lisseril OR Dibenzocycloheptenes OR Propylamines OR (Tricyclic Antidepressive Agents) OR (Central Muscle Relaxants) OR (Tranquilizing Agents) OR Miosan OR Mirtax OR Fexmid OR Flexeril OR Flexiban OR Flexitec OR Gen‐Cyclobenzaprine OR Masterelax OR Medarex OR Med Cyclobenzaprine OR Miosan OR Mirtax OR Nostaden OR Novo‐Cycloprine OR Amrix OR Apo‐Cyclobenzaprine OR Ciclamil OR Ratio‐Cyclobenzaprine OR Reflexan OR Relexil OR Riva‐Cycloprine OR Tensamox OR Tensiomax OR Tensodox OR Tonalgen OR Yuredol OR Yurelax)
Please see additional Table 1 for other bibliographic search strategies.
| PUBMED | EMBASE | LILACS | CENTRAL |
| #1 MYOFASCIAL PAIN SYNDROMES [MeSH] | 1. MYOFASCIAL PAIN SYNDROME [EMTREE term] | (Mh random allocation) OR (Mh double blind method) OR (Mh single blind method) AND NOT (Ct animal) AND NOT (Ct human and Ct animal) OR (Pt clinical trial) OR (Ex E05.318.760.535$) OR (Tw clin$) AND (Tw trial$) OR (Tw ensa$) OR (Tw estud$) OR (Tw experim$) OR (Tw investiga$) OR (Tw singl$) OR (Tw simple$) OR (Tw doubl$) OR (Tw doble$) OR (Tw duplo$) OR (Tw trebl$) OR (Tw trip$) AND (Tw blind$) OR (Tw cego$) OR (Tw ciego$) OR (Tw mask$) OR (Tw mascar$) OR (Mh placebos) OR (Tw placebo$) OR (Tw random$) OR (Tw randon$) OR (Tw casual$) OR (Tw acaso$) OR (Tw azar) OR (Tw aleator$) OR (Mh research design) AND NOT (Ct animal) AND NOT (Ct human and Ct animal) OR (Ct comparative study) OR (Ex E05.337$) OR (Mh follow‐up studies) OR (Mh prospective studies) OR (Tw control$) OR (Tw prospectiv$) OR (Tw volunt$) OR (Tw volunteer$) AND NOT ((Ct animal) AND NOT (Ct human and Ct animal)) | # Exp MYOFASCIAL PAIN SYNDROMES |
Reference lists of the included studies will be checked manually to identify any additional studies.
We will contact specialists in the field and authors of the included trials for unpublished data.
Data collection and analysis
Two review authors (FMGL and EJ) will independently screen the trials identified by the literature search, extract the data, assess trial quality and analyse the results. Other review authors will be consulted if there is any disagreement or need for quality assurance of the process. If consensus is not reached, data from the trials in question will not be included unless and until the authors of the trial concerned are able to resolve the contentious issues. The selection of the titles and the methodological quality of the RCTs and quasi‐RCTs will be assessed by two review authors (FMGL and RE) using the kappa test.
1. Quality assessment
The methodological quality of the included trials in this review will be measured using the Cochrane criteria described in The Cochrane Handbook (Higgins 2006), since scales and checklists are not a reliable method to assess the validity of a primary study (Jüni 1999).
1.1 Selection bias: was allocation concealment adequate?
Grade A: adequate allocation concealment (random)
Grade B: unclear, not described in the paper or by contacting authors
Grade C: inadequate allocation concealment
Grade D: not used
Any studies classified as D will be not included in this review.
1.2 Detection bias: was there a blinded assessment of outcomes?
Met: assessors unaware of the assigned treatment when collecting outcome measures;
Unclear: blinding of assessor not reported and could not be verified by contacting investigators;
Not met: assessors aware of the assigned treatment when collecting outcome measures.
1.3 Attrition bias: were withdrawals described?
Met: less than or equal to 20% for both groups;
Unclear: not reported in paper or by authors;
Not met: greater than or equal to 20% for both comparison groups.
2. Data extraction
Two review authors (FMGL and EJ) will extract data independently. Discrepancies in the results will be resolved by discussion. A standard form will initially be used to extract the following information: characteristics of the study (design, methods of randomisation); participants; interventions; outcomes (types of outcome measures, timing of outcomes pain scores ‐ VAS, total pain scale etc, adverse events). The form will be based on the recommendations made by the Pain, Palliative and Supportive Care Group and will be used as a first step in the process of data extraction.
3. Data analysis
For dichotomous data, relative risk (RR) will be used as the effect measure. For continuous data weighted mean difference (WMD) or standardized mean differences will be used as appropriate.
Intention‐to‐treat analysis will be carried out for dichotomous data. Participants who dropped out will be assumed to be non‐respondents (Unnebrink 2001).
3.1 Heterogeneity
Inconsistency among the pooled estimates will be quantified using the I2 statistic (Higgins 2003; Higgins 2006). We will use a fixed‐effect model in the absence of important heterogeneity and a random‐effects model if heterogeneity is found (DerSimonian 1986).
3.2 Subgroup analysis
Subgroup by type of intervention, dosage, follow‐up, age and sex is planned.
3.3 Sensitivity analysis
If there are an adequate number of studies, a sensitivity analysis will be performed to explore causes of heterogeneity and the robustness of the results. The following factors will be included in the sensitivity analysis, separating studies according to:
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quality of allocation concealment (adequate or unclear or inadequate);
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double‐blind method (adequate or unclear or inadequate or not performed);
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rates of withdrawal for each outcome;
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repeating the analysis excluding unpublished studies;
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different study design (parallel versus cross‐over).
3.4 Addressing publication bias
If a sufficient number of studies are available, we will assess publication bias by drawing a funnel plot (trial effect versus trial size). Funnel plots will be used in an exploratory data analysis to assess the potential for existence of small study bias. There are a number of explanations for the asymmetry of a funnel plot, including true heterogeneity of effect with respect to study size, poor methodological design of small studies (Sterne 2001) and publication bias. Thus, this tool may be misleading (Tang 2000; Thornton 2000) and we will not place undue emphasis on it.
| PUBMED | EMBASE | LILACS | CENTRAL |
| #1 MYOFASCIAL PAIN SYNDROMES [MeSH] | 1. MYOFASCIAL PAIN SYNDROME [EMTREE term] | (Mh random allocation) OR (Mh double blind method) OR (Mh single blind method) AND NOT (Ct animal) AND NOT (Ct human and Ct animal) OR (Pt clinical trial) OR (Ex E05.318.760.535$) OR (Tw clin$) AND (Tw trial$) OR (Tw ensa$) OR (Tw estud$) OR (Tw experim$) OR (Tw investiga$) OR (Tw singl$) OR (Tw simple$) OR (Tw doubl$) OR (Tw doble$) OR (Tw duplo$) OR (Tw trebl$) OR (Tw trip$) AND (Tw blind$) OR (Tw cego$) OR (Tw ciego$) OR (Tw mask$) OR (Tw mascar$) OR (Mh placebos) OR (Tw placebo$) OR (Tw random$) OR (Tw randon$) OR (Tw casual$) OR (Tw acaso$) OR (Tw azar) OR (Tw aleator$) OR (Mh research design) AND NOT (Ct animal) AND NOT (Ct human and Ct animal) OR (Ct comparative study) OR (Ex E05.337$) OR (Mh follow‐up studies) OR (Mh prospective studies) OR (Tw control$) OR (Tw prospectiv$) OR (Tw volunt$) OR (Tw volunteer$) AND NOT ((Ct animal) AND NOT (Ct human and Ct animal)) | # Exp MYOFASCIAL PAIN SYNDROMES |
