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3 Egyptian Dental Journal, 54, 1767:1774, July, 2008 EVALUATION OF GABA DeRIVATIVeS (BACLOFeN)

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EVALUATION OF GABA DeRIVATIVeS (BACLOFeN) AND ANTICHOLINeRgIC (ATROPINe) DRUg COMbINATION IN THe TReATMeNT OF MAXILLOFACIAL MUSCULOSKeLeTAL DISORDeRS. (OROMANDIbULAR DYSTONIA)
Atef A. Fouda*
ABSTRACT
them those that be related to the muscles. Myofascial pain dysfunction syndrome (MPDS) is one of A lot of problems may affect the face resulted in pain and sometimes dysfunction; among

the oldest facial painful muscular disorder that could be seen frequently by dental and maxillofacial specialists. Huge number of researches differentiate between facial pain types according to the source and nature of pain. Oromandibular dystonia is another muscular disease that may be

clinically misdiagnosed as myofascial pain dysfunction syndrome. Masticatory muscles disorders; specially (OMD); is one of the most challenging problems to treat. Anti-inflammatory, analgesics and muscle relaxants medications that act peripherally are generally not effective. In the current study patients received atropine ,concomitant with Baclofen; GABA derivatives and anticholinergic drugs preventing access of acetylcholine to its binding site on the receptor decreasing the muscular

rigidity. Results showed that all patients clinically improved after this combination therapy with reduced muscular abnormal activities in the affected muscles. Neither of patients got worse nor unimproved.

INTRODUCTION Myofascial Pain dysfunction syndrome (MPDS) is one of the most common muscular disorder seen in general dental practice. It is characterized by acute or chronic specific pain affecting a small number of muscles and involving single or multiple trigger points that are usually located in tight bands within the affected facial skeletal muscles. These trigger points are hypersensitive to pressure, producing a local twitch and referred pain (1) . Oromandibular dystonia (OMD) is a neuromuscular disorder characterized by tonic involuntary

muscle contractions producing repetitive jaw pain and dysfunction.(2,3) usually most patients with (OMD) belong to the idiopathic (primary) category. Haloperidol, thioridazine, calcium channel blockers, antihistamines, metoclopramide, amphetamine and organophosphorus compounds (OP) account for the majority of drug-induced cases of (OMD).(4) Amphetamine stimulates the release of nor-epinephrine from nerve terminals; while inhibition of acetyl-cholinesterase (AChE) is a very important toxic action of organophosphorus compounds (OP).(5)

* Associate professor of Oral and Maxillofacial surgery department, Faculty of Oral and Dental medicine, Cairo University, Egypt.

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Trauma involving the face or oral and dental structures, including routine dental procedures has been implicated of (OMD) or (MPDS), especially in predisposed people.(6,7) Psychological factors may also play a role in both (MPDS) and (OMD) disorders.(8) The involvement of masticatory muscles in (OMD) may be in the form of spasms of the muscles of mastication that may result in uncontrolled uncoordinated movements of the jaw specially during mastication. Many patients with previous disorder may complain of trismus, teeth clenching, grinding, bruxism, tension-type headache, dental wear, and or temporomandibular joint pain(9). A higher prevalence rate of bruxism has been reported in such disorders compared with normal controls.(10) Delayed treatment of bruxism can produce increased dental wear and also result in temporomandibular joint disk displacement and or degenerative arthritis that may complicate the condition. In order to prevent these complications, prompt early diagnosis as well as appropriate treatment is important.(11,12) Studies reported a relationship between severity of para-functions and pain in both the masticatory muscles and TMJ (13). Psychological conditions may lead to muscle tension due to para-functional teeth contact,(such as teeth grinding and clenching) which considered the main cause of jaw pain ( 14-17). In reverse manner patients with chronic pain may suffer severe psychological complications as a result of this chronic pain condition (14).High levels of muscle tension and para functional activity may have multiple biological consequences, including micro trauma to the joint and muscles, increased levels of pro-inflammatory cytokines in the joint, and sensitization of pain pathways.(15-20) The mechanisms associated with the development of musculoskeletal pain and disorders were

investigated and found that there is a relationships between prolonged muscle contraction, muscle imbalances, and pain. Psychological factors due to greater mental effort, more sadness and increased stresses were associated with more pain.(21,22) The neurotransmitters is altered in a variety of muscular disorders. Stimulation of the motoneuron for skeletal muscle results in the release of biogenic amines as Acetylcholine followed by contraction of the skeletal muscle fibers mediated by the catecholamines, dopamine and/or norepinephrine.(23) The role of psychosocial stresses, para functions in Oromandibular dystonia (OMD) have been examined in a number of studies and the results revealed that pain and stresses can increase masticatory muscle activity as para functions.(24-27) Studies that have used behavioral and psychological techniques specifically aimed at reducing para functions have reported success in reducing pain(28-30). In contrast, there is little evidence that tranquilizers that used in stresses can reduce muscular pain.(31) Masticatory muscles hyperactivity and para functions appears to have an important role in (OMD) disorders. The patho-physiology of masticatory muscle hyperactivity is proposed to be centrally mediated .Experimental evidence suggests a neurotransmitter imbalance in the basal ganglia, involving dopaminergic preponderance, or cholinergic and GABA-nergic function disturbance as the underlying cause .(32) Dystonic subjects showed bilateral abnormalities of perception of the tonic vibration reflex which were remote from the clinically affected site. These findings are discussed in relationship to the role of muscle spindle afferents block in dystonia.(2),(9) Masticatory muscle disorders specially (OMD) and (MPDS) are considered the most

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challenging problems to treat. Anti-inflammatory, analgesic and muscle relaxants medications that act peripherally are generally not effective, mild and transitory reduction in muscle spindle afferent activity achieved(33). Multiple lines of treatment; for example; injecting lidocaine and alcohol (muscle afferent block)(34), injecting botulinum toxin.(35-37) surgical resection of the coronoid process,were tried with variable results.(34) PATIeNTS AND MeTHODS 50 male Yemeni patients were clinically examined in the out patient clinic of Saudi German Hospital (Sanaa) complaining of facial muscle pain,muscle dysfunction , and spasm, diagnosed to have Oro-mandibular dystonia (OMD) . The patients were selected with history of symptoms (muscle dysfunction, pain, and abnormal muscular contractions) ranging from months up to 4 years without improvement after using different medications and splint therapy. The patients selected should be discontinued from medications at least 6 months ago. Patients with history of previous surgical manipulations or systemically ill were excluded. All patients received atropine injection 0.5 mg* as daily dose by intramuscular injection. The atropine injection was concomitant with oral medication of Baclofen**(central muscle relaxant) 50 mg per day for 15 days. After 15 days atropine injection stopped and gradual withdrawal of Baclofen medication is mandatory with dose decreased by increment of 10mg every 4 days interval. Results clinically evaluated; using visual analogue scale of pain scores, muscle palpation

and patient questionnaire about disappearance of dysfunction and abnormal muscular movements. Mean total improvement after 4 weeks was recorded. ReSULTS At the end of research period (~one month) the patients evaluated regarding pain, and muscular dysfunction. Regarding pain and headache; thirty seven patients (74 %) reported complete relief of pain within the first week after starting of treatment. Five patients (10%) reported 70 % reduction at the end of treatment. and three patients (6%) reported 30% reduction in pain after the first month. Three patients (6%) didnt improve at all regarding pain. Two patients (4%) previously didnt report pain in their chief complain.Most of patients (84%) reported significant pain reduction (above 50% reduction) at the end of follow up period. Regarding mouth opening; all patients included in the study had normal range of mouth opening except two patients (4%) with limited mouth opening that improved during the course of treatment markedly reaching the average measurements (more than 38 mm) at the end of the treatment period.(100 %). Regarding muscular dysfunction; (muscular rigidity and abnormal movements and deviation), twenty seven patients (54%) reported improvement above 90%, fourteen patients (28%) improved above 75%, four patients (8%) improved up to 60%, and the last five patients (10%) reported improvement less than 50% and these group of patients with reported bruxism and clenching before treatment.

*Atropine sulfate 0.5 mg ampules,product of chemical industries development (CID)-Giza, ARE. **Baclofen 10 mg tablets Misr company for pharma indust. Mataria Cairo Egypt.

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Patients that improved with score above 50% (90%) were able to eat properly and satisfied with results. While patients with score less than 50% (10%) suffered some difficulties to shew hard foods. Neither of patients selected getting worse during the treatment nor not improved at all. DISCUSSION All patients in the current research were selected to have Oro-mandibular dystonia; because it is more difficult to be treated than MPDS or any other facial muscles problems, however the principles of treatment could be same. Oromandibular dystonia (OMD) is a neuromusc cular disorder characterized by tonic or clonic inv voluntary spasms and contraction of the masticat tory muscles causing pain, headache, involuntary muscular movements with difficulties in masticat tion. It is differentiated from Myofascial pain-dysf function syndrome (MPDS); which is a stress-rel lated disorder that involves muscle hyperactivity with known trigger zone related to one of muscles of mastications. According to the concept of Scott (38) that the best line of treatment is to assess the biological disorder and use data in generating a treatment plan for patients with muscular disorders. Masticatory muscles hyperactivity appears to have an important role in temporomandibular disorders. A patho-physiological model for masticatory muscle hyperactivity is proposed that is centrally mediated, yet maintains support for present peripheral causes and therapies. In this hypothesis, masticatory muscle hyperactivity represents a mild extra-pyramidal disorder distantly related to orofacial dyskinesias. Previous experimental evidence suggests a neurotransmitter imbalance in the basal ganglia, involving dopaminergic or cholinergic and GABA-nergic function disturbance as the underlying cause. (39)

Respection of this concept suggests that the medications of use in the form of GABA derivatives (Baclofen) and anti-cholinergic (Atropine) drug combination in the treatment of patients in the current study will modify this disturbance and led to good results. Indeed, Sorting out how these drugs selectively affect one or more steps in the synthesis, packaging, or degradation of biogenic amines has been extremely useful in beginning to understand the molecular mechanisms underlying these disorders.(22) Stress conditions, some toxins or medications have the same action; stimulating the motoneuron of skeletal muscles results in the release of acetylcholine with subsequent contraction of the skeletal muscle fibers. Competitive blocking agents (GABA derivatives and anticholinergic drugs) lead to muscle paralysis by preventing access of acetylcholine to its binding site on the receptor decreasing the muscular rigidity.(40) So selection of atropine and Baclofen in the current study was based on this concept. Receptors that found in peripheral ganglia of skeletal muscles in which the transmitter is acetylcholine, catecholamines, dopamine and/or nor-epinephrine is blocked by Alphaadrenergic antagonists such as Atropine. Atropine selectively block the slow post-synaptic excitatory potential (PSEP) and diminish the efficiency of ganglionic transmission (central action). The current study is aimed to reducing muscle spindle afferent activity. The symptoms had been resistant to other therapies such as usual muscle relaxants(that act peripherally) or conservative dental treatment(in the form of spot grinding , oral splints or missing posterior teeth restoration. Surgical intervention for temporo-mandibular disorders was more frequent associated with worsening of dystonia. Furthermore, drugs that selectively block the slow electric potential, such as atropine, will

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diminish the efficiency of ganglionic transmission rather than eliminate it.(5) Resulted in proper balance between contraction and relaxation. Mouth opening not a common problem with OMD but may be associated mostly with MPDS. In my opinion which coincided with the report by Kreiner et al (41) that clinicians that use intra oral appliances to treat pain and dysfunction in patients with musculoskeletal disorders; actually that appliances can act as behavior-change devices, reminding patients to relax their masticatory muscles and to reduce para functional activity such as bruxism. In spite of the fact that splint therapy improves muscular and TMJ problems; researches that use Splint therapy alone couldnt improve the muscular rigidity but actually the patient get ride of bruxism and clenching that may be considered as co-factor in the treatment of patients with musculoskeletal disorders.(42) OMD Previously treated with administration of baclofen alone gave variable results, because this drug is a GABA-derivative and acts as a muscle relaxant. Clinical symptoms and dystonic pattern on the surface electromyography improved after the administration of baclofen and is considered one of useful medications that used for treatment of OMD.(32,38,39) A previous study evaluated patients with dystonia treated with muscle afferent block using intramuscular injection of lidocaine and ethanol in the affected muscle, the deviation abolished and difficulties in mastication was significantly improved. (37) Atropine led to faster relief of symptoms due to systemic anti-spasmodic action. Sometimes causes some drowsiness, but no other reported complications through the treatment course. Baclofen is one of GABA derivatives with central muscle relaxant effect that enhances the action of atropine, and the synergistic effect led

to faster improvement in muscle dysfunction and subsequently pain. In summary, our study of a select group of subjects (the majority of whom had associated movement disorders) has demonstrated that atropine administration can be a safe and effective treatment for severe muscular dysfunction. It is, however, an inexpensive treatment and should be considered as a therapeutic option only for those who have complicated or disabling bruxism and are refractory to other medical and dental therapy. How atropine abolishes severe muscular dysf function behavior. We speculate that masticatory muscles neuromusclar inhibition may disrupt the feedback loop from the trigeminal motor nucleus and inhibit the central bruxism or abnormal muscle movements generator. Alternatively, it also deactiv vate periodontal mechano-receptors during mastic cation, which have been thought to have a facilitat tory effect on jaw closure motoneurons. Previous study was resulted in with agreement of this conc (43) cept. The subjects had experienced their symptoms for months to years with muscular dysfunction that had failed to respond to various medical therapies and dental procedures, providing further evidence of its severity. Marked relief of teeth grinding and proper muscular functional movements during chewing are indications of patients improvement. We did not administer atropine and baclofen in higher doses in our preliminary research sample and further investigation of proper dosing of both medications may result in more clinical improvement . CONCLUSION Clinical Implications: Treatment that helps patients reduce para functions, excess masticatory muscle tension, could be effective in reducing muscular disorders pain. All patients showed

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clinical improvement after this combined therapy with reduced abnormal muscular activities in the affected muscles. Non of patients got worse with this combination treatment. The results of this study suggest that combination therapy of Atropine plus Baclofen administration is a safe and effective treatment for people with severe muscular dysfunction particularly those with associated movement disorders. This therapy is useful for the treatment of drug-resistant Oromandibular dystonia. REFERENCES
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