Accepted Article
Received Date : 20-Mar-2014 Revised Date : 13-Apr-2014 Accepted Date : 23-Apr-2014 Article type
: Review Article
PHARMACOTHERAPEUTIC AGENTS USED IN TEMPOROMANDIBULAR DISORDERS
Running title: Pharmacotherapeutics for TMD
Burcu BAL KUCUK DDS, PhDa, Selin TOLUNAY KAYA DDS, PhDa, Pelin KARAGOZ MOTRO DDS, PhDa, Koray ORAL DDS, PhDa
a
: Yeditepe University, Faculty of Dentistry, Department of Prosthodontics, Bagdat Caddesi 238- Goztepe/Istanbul /TURKEY 34728
Corresponding author: Dr. Burcu BAL KUCUK Yeditepe University, Faculty of Dentistry, Department of Prosthodontics, Bagdat Caddesi 238 Göztepe-Istanbul-Turkey Phone: 0090 216 3636044 Fax:
0090 216 3636211
E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/odi.12255 This article is protected by copyright. All rights reserved.
Accepted Article
Key words: analgesic, myorelaxant, pharmacotherapy, temporomandibular disorder
Abstract Depending on the source and character, pharmacotherapy is one of the most commonly used methods to treat temporomandibular disorders in addition to the use of appliances, physiotherapy, behavioral therapy and surgical interventions. To decide on the appropriate treatment approach for the treatment of temporomandibular disorders, pharmacotherapeutics should be understood in great detail. As for other pain treatments, pharmacotherapy can be used as a monotherapy or combined with other treatment options in temporomandibular disorders. The aim of the present review is to overview the primary analgesics and myorelaxants used in temporomandibular disorders.
Key words: Analgesic, myorelaxant, pharmacotherapy, temporomandibular disorder
Introduction Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage (IASP, 1979). In cases of acute or chronic pain, pain control should be planned appropriately depending on the source, development and course of pain and the systemic and psychological condition of the patient. As is the case with the treatment of any type of pain, pharmacotherapy can be used in TMD as a monotherapy or combined with other treatment options, such as physiotherapy, behavioral therapy, use of appliances and surgical interventions. The
This article is protected by copyright. All rights reserved.
Accepted Article
commonly used pharmacological agents for TMDs are analgesics (NSAIDs, opioids), myorelaxants, corticosteroids, anti-anxiety drugs, anti-convulsants and tricyclic antidepressants (Fricton, 2007). Evidence-based literature that clearly establishes the efficacy and safety of these drugs in the TMD population is limited at best (Cascos-Romero et al, 2009). All of the current regulations admissible for other drugs are also admissible for the pharmacotherapeutics used for TMD, including proven effectiveness, acceptable side effects and long-term safety (List et al, 2003; Dionne, 1997).
Studies that evaluate the pharmacological treatment of pain observed with temporomandibular disorders (TMD) are more often observational clinical studies rather than randomized controlled trials (Cascos-Romero et al, 2009; List et al, 2003; Dionne, 1997). The main drawback of these studies is that the origin of TMD from either the muscles or joint is not well defined. Additionally, in observational treatments in the absence of an appropriate control group (placebo group, comparison with another treatment, etc.), the variable quality of the pain and studies planned conveniently for the psychological condition of the subjects may lead to misinterpretation of the results (Cascos-Romero et al, 2009; List et al, 2003; List and Axelsson, 2010; Moody et al, 1982; Greene et al, 1983; Speculand et al, 1983; Murray and Peck, 2007; Antczak-Bouckoms, 1995). Commonly used pharmacotherapeutics in TMD are analgesics, myorelaxants, corticosteroids, anticonvulsant and antidepressants (Fricton, 2007). This article aims to discuss primary analgesics and myorelaxants that have been used in the treatment of TMDs.
This article is protected by copyright. All rights reserved.
Accepted Article
Analgesics: The main purpose of analgesic application is to reduce pain (Israel and Ward, 2003; Neidle et al, 1983; Phero, 1984). Analgesics can be divided into two groups: (1) Primary analgesics a. Non-narcotics - salicylates (aspirin and diflunisal) - para-aminophenol derivatives (acetaminophen) - nonsteroidal anti-inflammatory drugs (ibuprofen etc.) b. Narcotics - opioids (2) Secondary analgesics a. Antidepressants b. Anticonvulsants
Non-narcotic analgesics: The analgesic mode of action of the drugs in this group occurs through the inhibition of the cyclooxygenase enzyme (COX) and the inhibition of the synthesis of proinflammatory prostaglandin (Cashman, 1996; Gotzsche, 2000; Walker, 1995). Prostaglandin stimulates the production of the mucus that protects the stomach and ileum, and the inhibition of the synthesis of this mucus with NSAIDs causes the major
This article is protected by copyright. All rights reserved.
Accepted Article
complications of these drugs, which includes gastrointestinal disorders. With the parenteral application of NSAIDs, the results caused by this inhibition can be avoided. Most of the NSAIDs inhibit COX-1 and COX-2 together. The more selective NSAIDs (exp: COX-2 selective celecoxib) have very few side effects on the gastric mucosa but may have thrombotic effects, such as myocardial infarction and heart attack. NSAIDs prevent thrombotic events via the antiplatelet effect of thromboxane. The antiplatelet effect of aspirin is irreversible (10-14 days). As the bond is weak, after the cessation of the drug, the NSAIDs’ effect terminates in a short time period. NSAIDs should not be used with anticoagulant agents and antiplatelet drugs.
Ibuprofen is the only NSAID that disrupts the antiplatelet activity of aspirin (CatellaLawson et al, 2001; MacDonald and Wei, 2003). Cryer et al (2005) demonstrated that the thromboxane inhibition caused by aspirin is only reduced by 1% with the use of ibuprofen for 10 days. Patel and Goldberg (2004) showed that the incidence of myocardial infarction did not change in coronary patients using ibuprofen in combination with low dose aspirin for 10 years. The use of NSAIDs in patients with hypertension is not indicated as they alter kidney function.
Patients using selective serotonin reuptake inhibitors (SSRIs) and NSAIDs together have a high risk for gastrointestinal mucosal damage. Although this risk is high with the use of NSAIDs for a long period of time, for the patients with a history of previous mucosal damage, short term use should be considered with caution (Yuan et al, 2006; Pinto et al, 2009).
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Ceiling Effect’ Non-narcotic analgesics do not have an additive analgesic effect with increasing doses. This is called the ‘ceiling effect’. The ‘ceiling effect’ for aspirin and acetaminophen occurs with a dose of 1000 mg, whereas for ibuprofen, it occurs with 400 mg (Troullos et al, 1986; Laska et al, 1986). For most NSAIDs, the recommended safe doses are indicated in the packet inserts; however, the analgesic’s ‘ceiling effect’ is not stated. Therefore, low doses are sufficient for a non-inflammatory analgesic effect, but to raise the antiinflammatory effect, higher doses should be applied. There are limited studies that have evaluated the efficacy of NSAIDs used for the treatment of temporomandibular diseases. The application of NSAIDs and the use of splints in temporomandibular joint (TMJ) arthritis patients was evaluated, and it was concluded that the application of the NSAID diclofenac (three months, three times a day, 50 mg) reduced the pain more than 50% (Mejersjo and Wenneberg, 2008). Similar results were obtained for the splint group, but a limitation of the study was that no placebo group was included. In a short term randomized clinical study, it was shown that diclofenac did not have a significant effect when compared with placebo (Ekberg, 1998). In a double blind randomized study comparing the NSAID naproxen sodium (three weeks, two times a day, 500 mg) and placebo, it was shown that the TMJ pain was reduced by 50% (McNeill C, 1993). According to these studies, the use of NSAIDs for TMJ pain is supported. The pain-reducing effect of NSAIDs in TMD is thought to originate more from its antiinflammatory effect than its analgesic effect. Thus, long-term use is recommended to obtain an anti-inflammatory effect when pain relief is targeted. However, long-term use can cause the above-mentioned side effects (Ta and Dionne, 2004). As an alternative to systemically effective NSAIDs, topically applied NSAIDs have fewer adverse effects. In a randomized study, oral diclofenac (50 mg twice a day) was mixed
This article is protected by copyright. All rights reserved.
Accepted Article
with topical diclofenac lotion, including dimethyl sulfoxide. Although both were found to reduce the pain more than 50%, the lack of a placebo control group, the lack of a double blind study design and the selection of patients with an unknown pain source (TMJ or masticatory muscles) were limitations of the study. More standardized studies related to the effect of topical NSAIDs are needed.
Narcotic analgesics (Opioids) Narcotic drugs whose main therapeutic effects are analgesia and sedation have a structure similar to that of morphine. Their application in chronic temporomandibular disorders is limited (Fordyce, 1991). In a review, Eisenberg et al (2006) concluded that the effect of opioids in neuropathic pain is equivocal. In a study with patients diagnosed with TMJ arthritis, List et al (2001) evaluated the pain-reducing effect of morphine and saline injection on TMJ. It was concluded that morphine and saline injections reduced the majority of the pain in five days. The researchers attributed the difference in pain in both of the groups to the change in the synovial fluid dilution. Great attention should be paid when prescribing these drugs, as they may cause addiction when used for more than 10 days (Ready and Brody, 1979). The most common adverse effects of opioids are sedation, lethargy, constipation, abdominal cramps and diarrhea. If the pain is not under control and full analgesia is expected, the side effects may be ignored. The gradual increase in the drug dose may reduce the symptoms (Gutstein and Akil, 2006). When non-narcotic analgesics are combined with narcotic analgesics such as codeine, propoxyphene, oxycodone and meperidine, their anti-inflammatory effects increase (Ready and Brody, 1979). Opioids show most of their therapeutic and side effects by acting as opioid receptor agonists, and these receptors are activated with endogenous
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secretions called endorphins. Opioid receptors are generally located in the central nervous system (CNS); however, some have a peripheral localization (Stein, 1995). Unlike the ‘ceiling effect’ of non-narcotic analgesics, their effect increases substantially with increasing doses. In a study, Van Dyke et al (2004) reported that the combination of oxycodone and ibuprofen is more effective in reducing pain then using both drugs alone. Tramadol, which is a narcotic analgesic with central effects, inhibits norepinephrine and serotonin reuptake. With their tricyclic antidepressant-like activity, their use in the treatment of chronic pain is supported by evidence; however, they are ineffective in post-operative pain (Cicero et al, 1999). Considering their side effects, narcotic analgesics are a risky group of drugs. Studies about their use for TMD are limited. More randomized clinical studies regarding their effect on chronic orofacial pain are needed.
Myorelaxants Centrally originated muscle relaxation caused by the drugs in this group is obtained by the partial suppression of the tonic flow of the nerve impulses transmitted to voluntary muscles (Neidle et al, 1989; Phero, 1984; Stanko 1990). Drugs that are thought to reduce skeletal muscle tone are frequently used for patients with chronic orofacial pain to reduce and prevent increased masticatory muscle activity caused by temporomandibular disorders (McNeill, 1993). In the preliminary treatment of myofascial pain, NSAIDs can be used in combination with myorelaxants. In a study where ibuprofen (600 mg every 6 h) was used in combination with diazepam, the combination was found to be significantly more
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effective than placebo. However, none of the drugs were more effective than placebo when used alone (Singer and Dionne, 1997).
Another myorelaxant, cyclobenzaprine, was reported to be more effective than placebo in myofascial pain; however, the confidence of this study is controversial, as the number of patients involved in the study was not sufficient (Herman et al, 2002; Harkins et al, 1991). In four different studies, where the placebo was compared with meprobamate, orphenadrine citrate, clonazepam and diazepam for the treatment of TMD, all of the drugs were found to be more effective in reducing pain (Harkins et al, 1991; Jagger, 1974; Franks, 1965; Greene and Laskin,1971).
In chronic musculoskeletal pain, myorelaxants are not as effective as they are in acute musculoskeletal pain (McQuay et al, 1995); however, the application of myorelaxants in combination with antispastic drugs like benzodiazepines, baclofen and tizanidine in chronic dysfunctions has a greater effect on reducing pain (Van Tulder et al, 1997). Benzodiazepines (diazepam) are a group of drugs with more sedative properties, and similar or better muscle-relaxing effect with lower toxicity than other centrally acting myorelaxants such as methocarbamol, clorzoxazone (dos Santos, 1995). Additionally, diazepam can be used as a support for the treatment of post-operative trismus and temporomandibular disorder (dos Santos, 1995). Although there are many centrally effective myorelaxants, attention should be paid when using these drugs, as their effect in peripheral muscle tone is not deeply understood. As systemic effects of myorelaxants are common and their long-term use may affect the whole system, the application of physiotherapy or drugs with local effects should be favored.
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10. Ekberg E (1998). Treatment of temporomandibular disorders of arthrogeneous origin. Controlled double-blind studies of a non-steroidal anti-inflammatory drug and a stabilisation appliance. Swed Dent J 131: 1-57. 11. Fordyce WE (1991). On opioids and treatment targets. American Pain Society Bulletin 1: 1-31. 12. Franks AS (1965). Mandibular spasm: a double blind study of a muscle relaxant drug. Br J Clin Pract 19: 281-284. 13. Fricton J (2007). Myogenous temporomandibular disorders: diagnostic and management considerations. Dent Clin North Am 51: 61-83. 14. Greene CS, Laskin DM (1971). Meprobomate therepy for the myofacial paindysfunction (MPD) symdrome: a double blind evaluation. J Am Dent Assoc 82: 587590. 15. Greene CS, Oleson RE, Laskin DM (1983). Psychosocial factors in the etiology, progression, and treatment of MPD syndrome. J Am Dent Assoc 105: 443-448. 16. Gotzsche PC (2000). Non-steroidal anti-inflammatory drugs. BMJ 320: 1063-1070. 17. Gutstein HB, Akil H (2006). Opioid analgesics. In: Brunton LL, Lazo JS, & Parker KL, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill.
18. Harkins S, Linford J, Cohen J, et al (1991). Administration of clonazepam in the treatment of TMD and associated myofascial pain; a double blind pilot study. J Craniomandib Disorders 5: 179-186. 19. Herman CR, Schiffman EL, Look JO et al (2002). The effectiveness of adding
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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 16: 64-70. 20. International Association for the Study of Pain: Sub- committee on taxonomy of pain terms: A list with definitions and notes on usage (1979). Pain 6: 249-252. 21. Israel HA, Ward JD (2003). Oral and maxillofacial surgery in patients with chronic orofacial pain. J Oral Maxillofac Surg 61: 662-667. 22. Jagger RG (1974). Diazepam in the treatment of temporomandibular dysfunction syndrome. A double blind study. J Dent 2: 37-40. 23.
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MacDonald TM, Wei L (2003). Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 361: 573-574.
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30. Mejersjo C, Wenneberg B (2008). Diclofenac sodium and occlusal splint therapy in TMJ osteoarthritis: a randomized controlled trial. J Oral Rehabil 35: 729-738. 31. Moody PM, Kemper JT, Okeson JP, et al (1982). Recent life changes and myofascial pain syndromes. J Prosthet Dent 48: 328-330. 32. Murray GM, Peck CC (2007). Orofacial pain and jaw muscle activity: a new model. J Orofac Pain 21: 263-278. 33. Neidle EA, Kroeger DC, Yagiela JA (1989). Pharmacology and Therapeutics for Dentistry, ed 3. St. Louis, C.V. Mosby, chapters 13 to 22. 34.
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41. Stein CS (1995). The control of pain in periphera l tissue by opioids. N Engl J Med 332: 1685-1690. 42. Ta LE, Dionne RA (2004). Treatment of painful temporomandibular joints with a cyclooxygenase-2 inhibitor: a randomized placebo-controlled comparison of celecoxib to naproxen. Pain 111: 13-21. 43.
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45. Van Tulder MW, Koes BW, Bouter LM (1997). Conservative treatment of acute and chronic nonspecific low back pain: a systematic review of randomized controlled trials of the most common interventions. Spine 22: 2128-2156. 46. Walker JS (1995). NSAID: an update on their analgesic effects. Clin Exp Pharmacol Physiol 22: 855-860. 47.
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Received Date : 20-Mar-2014 Revised Date : 13-Apr-2014 Accepted Date : 23-Apr-2014 Article type
: Review Article
PHARMACOTHERAPEUTIC AGENTS USED IN TEMPOROMANDIBULAR DISORDERS
Running title: Pharmacotherapeutics for TMD
Burcu BAL KUCUK DDS, PhDa, Selin TOLUNAY KAYA DDS, PhDa, Pelin KARAGOZ MOTRO DDS, PhDa, Koray ORAL DDS, PhDa
a
: Yeditepe University, Faculty of Dentistry, Department of Prosthodontics, Bagdat Caddesi 238- Goztepe/Istanbul /TURKEY 34728
Corresponding author: Dr. Burcu BAL KUCUK Yeditepe University, Faculty of Dentistry, Department of Prosthodontics, Bagdat Caddesi 238 Göztepe-Istanbul-Turkey Phone: 0090 216 3636044 Fax:
0090 216 3636211
E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/odi.12255 This article is protected by copyright. All rights reserved.
Accepted Article
Key words: analgesic, myorelaxant, pharmacotherapy, temporomandibular disorder
Abstract Depending on the source and character, pharmacotherapy is one of the most commonly used methods to treat temporomandibular disorders in addition to the use of appliances, physiotherapy, behavioral therapy and surgical interventions. To decide on the appropriate treatment approach for the treatment of temporomandibular disorders, pharmacotherapeutics should be understood in great detail. As for other pain treatments, pharmacotherapy can be used as a monotherapy or combined with other treatment options in temporomandibular disorders. The aim of the present review is to overview the primary analgesics and myorelaxants used in temporomandibular disorders.
Key words: Analgesic, myorelaxant, pharmacotherapy, temporomandibular disorder
Introduction Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage (IASP, 1979). In cases of acute or chronic pain, pain control should be planned appropriately depending on the source, development and course of pain and the systemic and psychological condition of the patient. As is the case with the treatment of any type of pain, pharmacotherapy can be used in TMD as a monotherapy or combined with other treatment options, such as physiotherapy, behavioral therapy, use of appliances and surgical interventions. The
This article is protected by copyright. All rights reserved.
Accepted Article
commonly used pharmacological agents for TMDs are analgesics (NSAIDs, opioids), myorelaxants, corticosteroids, anti-anxiety drugs, anti-convulsants and tricyclic antidepressants (Fricton, 2007). Evidence-based literature that clearly establishes the efficacy and safety of these drugs in the TMD population is limited at best (Cascos-Romero et al, 2009). All of the current regulations admissible for other drugs are also admissible for the pharmacotherapeutics used for TMD, including proven effectiveness, acceptable side effects and long-term safety (List et al, 2003; Dionne, 1997).
Studies that evaluate the pharmacological treatment of pain observed with temporomandibular disorders (TMD) are more often observational clinical studies rather than randomized controlled trials (Cascos-Romero et al, 2009; List et al, 2003; Dionne, 1997). The main drawback of these studies is that the origin of TMD from either the muscles or joint is not well defined. Additionally, in observational treatments in the absence of an appropriate control group (placebo group, comparison with another treatment, etc.), the variable quality of the pain and studies planned conveniently for the psychological condition of the subjects may lead to misinterpretation of the results (Cascos-Romero et al, 2009; List et al, 2003; List and Axelsson, 2010; Moody et al, 1982; Greene et al, 1983; Speculand et al, 1983; Murray and Peck, 2007; Antczak-Bouckoms, 1995). Commonly used pharmacotherapeutics in TMD are analgesics, myorelaxants, corticosteroids, anticonvulsant and antidepressants (Fricton, 2007). This article aims to discuss primary analgesics and myorelaxants that have been used in the treatment of TMDs.
This article is protected by copyright. All rights reserved.
Accepted Article
Analgesics: The main purpose of analgesic application is to reduce pain (Israel and Ward, 2003; Neidle et al, 1983; Phero, 1984). Analgesics can be divided into two groups: (1) Primary analgesics a. Non-narcotics - salicylates (aspirin and diflunisal) - para-aminophenol derivatives (acetaminophen) - nonsteroidal anti-inflammatory drugs (ibuprofen etc.) b. Narcotics - opioids (2) Secondary analgesics a. Antidepressants b. Anticonvulsants
Non-narcotic analgesics: The analgesic mode of action of the drugs in this group occurs through the inhibition of the cyclooxygenase enzyme (COX) and the inhibition of the synthesis of proinflammatory prostaglandin (Cashman, 1996; Gotzsche, 2000; Walker, 1995). Prostaglandin stimulates the production of the mucus that protects the stomach and ileum, and the inhibition of the synthesis of this mucus with NSAIDs causes the major
This article is protected by copyright. All rights reserved.
Accepted Article
complications of these drugs, which includes gastrointestinal disorders. With the parenteral application of NSAIDs, the results caused by this inhibition can be avoided. Most of the NSAIDs inhibit COX-1 and COX-2 together. The more selective NSAIDs (exp: COX-2 selective celecoxib) have very few side effects on the gastric mucosa but may have thrombotic effects, such as myocardial infarction and heart attack. NSAIDs prevent thrombotic events via the antiplatelet effect of thromboxane. The antiplatelet effect of aspirin is irreversible (10-14 days). As the bond is weak, after the cessation of the drug, the NSAIDs’ effect terminates in a short time period. NSAIDs should not be used with anticoagulant agents and antiplatelet drugs.
Ibuprofen is the only NSAID that disrupts the antiplatelet activity of aspirin (CatellaLawson et al, 2001; MacDonald and Wei, 2003). Cryer et al (2005) demonstrated that the thromboxane inhibition caused by aspirin is only reduced by 1% with the use of ibuprofen for 10 days. Patel and Goldberg (2004) showed that the incidence of myocardial infarction did not change in coronary patients using ibuprofen in combination with low dose aspirin for 10 years. The use of NSAIDs in patients with hypertension is not indicated as they alter kidney function.
Patients using selective serotonin reuptake inhibitors (SSRIs) and NSAIDs together have a high risk for gastrointestinal mucosal damage. Although this risk is high with the use of NSAIDs for a long period of time, for the patients with a history of previous mucosal damage, short term use should be considered with caution (Yuan et al, 2006; Pinto et al, 2009).
This article is protected by copyright. All rights reserved.
Accepted Article
Ceiling Effect’ Non-narcotic analgesics do not have an additive analgesic effect with increasing doses. This is called the ‘ceiling effect’. The ‘ceiling effect’ for aspirin and acetaminophen occurs with a dose of 1000 mg, whereas for ibuprofen, it occurs with 400 mg (Troullos et al, 1986; Laska et al, 1986). For most NSAIDs, the recommended safe doses are indicated in the packet inserts; however, the analgesic’s ‘ceiling effect’ is not stated. Therefore, low doses are sufficient for a non-inflammatory analgesic effect, but to raise the antiinflammatory effect, higher doses should be applied. There are limited studies that have evaluated the efficacy of NSAIDs used for the treatment of temporomandibular diseases. The application of NSAIDs and the use of splints in temporomandibular joint (TMJ) arthritis patients was evaluated, and it was concluded that the application of the NSAID diclofenac (three months, three times a day, 50 mg) reduced the pain more than 50% (Mejersjo and Wenneberg, 2008). Similar results were obtained for the splint group, but a limitation of the study was that no placebo group was included. In a short term randomized clinical study, it was shown that diclofenac did not have a significant effect when compared with placebo (Ekberg, 1998). In a double blind randomized study comparing the NSAID naproxen sodium (three weeks, two times a day, 500 mg) and placebo, it was shown that the TMJ pain was reduced by 50% (McNeill C, 1993). According to these studies, the use of NSAIDs for TMJ pain is supported. The pain-reducing effect of NSAIDs in TMD is thought to originate more from its antiinflammatory effect than its analgesic effect. Thus, long-term use is recommended to obtain an anti-inflammatory effect when pain relief is targeted. However, long-term use can cause the above-mentioned side effects (Ta and Dionne, 2004). As an alternative to systemically effective NSAIDs, topically applied NSAIDs have fewer adverse effects. In a randomized study, oral diclofenac (50 mg twice a day) was mixed
This article is protected by copyright. All rights reserved.
Accepted Article
with topical diclofenac lotion, including dimethyl sulfoxide. Although both were found to reduce the pain more than 50%, the lack of a placebo control group, the lack of a double blind study design and the selection of patients with an unknown pain source (TMJ or masticatory muscles) were limitations of the study. More standardized studies related to the effect of topical NSAIDs are needed.
Narcotic analgesics (Opioids) Narcotic drugs whose main therapeutic effects are analgesia and sedation have a structure similar to that of morphine. Their application in chronic temporomandibular disorders is limited (Fordyce, 1991). In a review, Eisenberg et al (2006) concluded that the effect of opioids in neuropathic pain is equivocal. In a study with patients diagnosed with TMJ arthritis, List et al (2001) evaluated the pain-reducing effect of morphine and saline injection on TMJ. It was concluded that morphine and saline injections reduced the majority of the pain in five days. The researchers attributed the difference in pain in both of the groups to the change in the synovial fluid dilution. Great attention should be paid when prescribing these drugs, as they may cause addiction when used for more than 10 days (Ready and Brody, 1979). The most common adverse effects of opioids are sedation, lethargy, constipation, abdominal cramps and diarrhea. If the pain is not under control and full analgesia is expected, the side effects may be ignored. The gradual increase in the drug dose may reduce the symptoms (Gutstein and Akil, 2006). When non-narcotic analgesics are combined with narcotic analgesics such as codeine, propoxyphene, oxycodone and meperidine, their anti-inflammatory effects increase (Ready and Brody, 1979). Opioids show most of their therapeutic and side effects by acting as opioid receptor agonists, and these receptors are activated with endogenous
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secretions called endorphins. Opioid receptors are generally located in the central nervous system (CNS); however, some have a peripheral localization (Stein, 1995). Unlike the ‘ceiling effect’ of non-narcotic analgesics, their effect increases substantially with increasing doses. In a study, Van Dyke et al (2004) reported that the combination of oxycodone and ibuprofen is more effective in reducing pain then using both drugs alone. Tramadol, which is a narcotic analgesic with central effects, inhibits norepinephrine and serotonin reuptake. With their tricyclic antidepressant-like activity, their use in the treatment of chronic pain is supported by evidence; however, they are ineffective in post-operative pain (Cicero et al, 1999). Considering their side effects, narcotic analgesics are a risky group of drugs. Studies about their use for TMD are limited. More randomized clinical studies regarding their effect on chronic orofacial pain are needed.
Myorelaxants Centrally originated muscle relaxation caused by the drugs in this group is obtained by the partial suppression of the tonic flow of the nerve impulses transmitted to voluntary muscles (Neidle et al, 1989; Phero, 1984; Stanko 1990). Drugs that are thought to reduce skeletal muscle tone are frequently used for patients with chronic orofacial pain to reduce and prevent increased masticatory muscle activity caused by temporomandibular disorders (McNeill, 1993). In the preliminary treatment of myofascial pain, NSAIDs can be used in combination with myorelaxants. In a study where ibuprofen (600 mg every 6 h) was used in combination with diazepam, the combination was found to be significantly more
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effective than placebo. However, none of the drugs were more effective than placebo when used alone (Singer and Dionne, 1997).
Another myorelaxant, cyclobenzaprine, was reported to be more effective than placebo in myofascial pain; however, the confidence of this study is controversial, as the number of patients involved in the study was not sufficient (Herman et al, 2002; Harkins et al, 1991). In four different studies, where the placebo was compared with meprobamate, orphenadrine citrate, clonazepam and diazepam for the treatment of TMD, all of the drugs were found to be more effective in reducing pain (Harkins et al, 1991; Jagger, 1974; Franks, 1965; Greene and Laskin,1971).
In chronic musculoskeletal pain, myorelaxants are not as effective as they are in acute musculoskeletal pain (McQuay et al, 1995); however, the application of myorelaxants in combination with antispastic drugs like benzodiazepines, baclofen and tizanidine in chronic dysfunctions has a greater effect on reducing pain (Van Tulder et al, 1997). Benzodiazepines (diazepam) are a group of drugs with more sedative properties, and similar or better muscle-relaxing effect with lower toxicity than other centrally acting myorelaxants such as methocarbamol, clorzoxazone (dos Santos, 1995). Additionally, diazepam can be used as a support for the treatment of post-operative trismus and temporomandibular disorder (dos Santos, 1995). Although there are many centrally effective myorelaxants, attention should be paid when using these drugs, as their effect in peripheral muscle tone is not deeply understood. As systemic effects of myorelaxants are common and their long-term use may affect the whole system, the application of physiotherapy or drugs with local effects should be favored.
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