Pharmacologic Interventions in the Treatment of Temporomandibular Disorders, Atypical Facial , and . A Qualitative Systematic Review

Thomas List, DDS, Odont Dr Aims: To carry out a systematic review of the literature in order to Associate Professor assess the pain-relieving effect and safety of pharmacologic inter- Unit ventions in the treatment of chronic temporomandibular disorders Department of Stomatognathic (TMD), including rheumatoid arthritis (RA), as well as atypical Physiology facial pain (AFP), and burning mouth syndrome (BMS). Methods: Malmö University Malmö, Sweden Study selection was based on randomized clinical trials (RCTs). Inclusion criteria included studies on adult patients (≥ 18 years) Susanna Axelsson, DDS, Odont Dr with TMD, RA of the temporomandibular joint (TMJ), AFP, or Assistant Professor BMS and a pain duration of Ͼ 3 months. Data sources included The Swedish Council on Technology Medline, Cochrane Library, Embase, and PsychLitt. Results: Assessment in Health Care Eleven studies with a total of 368 patients met the inclusion crite- Stockholm, Sweden ria. Four trials were on TMD patients, 2 on AFP, 1 on BMS, 1 on RA of the TMJ, and 3 on mixed groups of patients with TMD and Göran Leijon, MD, PhD AFP. Of the latter, was effective in 1 study and ben- Assistant Professor zodiazepine in 2 studies; the effect in 1 of the benzodiazepine stud- Department of Neuroscience and ies was improved when ibuprofen was also given. One study Locomotion Division of showed that intra-articular injection with glucocorticoid relieved University Hospital the pain of RA of the TMJ. In 1 study, a combination of paraceta- Linköping, Sweden mol, codeine, and doxylamine was effective in reducing TMD pain. No effective pharmacologic treatment was found for BMS. Correspondence to: Only minor adverse effects were reported in the studies. Con- Dr Thomas List clusion: The common use of in TMD, AFP, and BMS is Orofacial Pain Unit not supported by scientific evidence. More large RCTs are needed Department of Stomatognathic to determine which pharmacologic interventions are effective in Physiology TMD, AFP, and BMS. J OROFAC PAIN 2003;17:301–310. Malmö University SE-214 21 Malmö Key words: orofacial pain, pharmacologic treatment, randomized Sweden Fax: +46 40 6658420 clinical trials, systematic review, temporomandibular E-mail: [email protected] disorders

ne national epidemiologic survey in the United States found that orofacial pain (other than tooth pain) has a Oprevalence of 10% in the adult population.1 Orofacial pain includes pain conditions that are associated with the hard and soft tissues of the head, face, and intraoral structures.2,3 Population-based studies have often not distinguished between dif- ferent types of orofacial pain conditions. However, the most com- mon subgroups of orofacial pain conditions are temporomandibu- lar disorders (TMD), mucosal pain such as burning mouth syndrome (BMS), and (AFP), including atypi- cal odontalgia.4,5 Temporomandibular disorder is defined as pain related to the masticatory muscles, the temporomandibular joints (TMJs), or both.6 Atypical facial pain and atypical odontalgia have been sug- gested to be of neuropathic origin.7 Burning mouth syndrome is

Journal of Orofacial Pain 301 List et al associated with pain and burning sensations on the Materials and Methods lips and in the oral cavity.8 These conditions are sometimes difficult to differ- Inclusion Criteria entiate since they often coexist in the same patient. Many features of TMD pain—pain intensity, fre- Randomized clinical trials on pharmacologic treat- quency of pain, and impact on daily activities— ment in adult patients (≥ 18 years) with chronic have been found to be similar to those of other pain pain because of TMD, RA of the TMJ, AFP, and conditions such as backache.9 And as in other BMS and with a pain duration of 3 months or chronic pain conditions, elevated scores more were included in the review. Reports were have been found for TMD, BMS, and AFP.8,10,11 included if they were randomized comparisons of Traditionally, clinical decisions have been based on pharmacologic drugs with other medications, knowledge gained through training, past experience, placebo, or no treatment. The diagnostic criteria practice traditions, and the opinions of recognized au- used were as follows: BMS was defined as oral thorities. This treatment approach has been ques- mucosal pain with no known dental or medical tioned, and a more scientific, evidence-based ap- cause for the symptoms; AFP was described as a proach has been recommended for managing TMD.12 deeply located throbbing or aching pain involving Evidence-based practice supports the translation of bony areas of the face (since there is no clear con- scientific evidence into clinical practice. In a system- sensus on the definition of AFP, articles were atic review of the TMD literature, it was found that accepted where the diagnosis AFP was reported); less than 5% of the articles were classified as ran- TMD was defined as a pain condition located in domized clinical trials (RCTs).13 Only a few system- the TMJ and/or the masticatory muscles. atic reviews in the epidemiology or management of orofacial pain and TMD have been published.4,5,13–18 Exclusion Criteria In the management of chronic orofacial pain, the use of pharmacologic interventions has been sug- Nonrandomized and experimental studies were gested both as the main mode and as a complement excluded from the review. to other treatment modes.19 Population-based stud- ies have shown that consumption of analgesics as Literature Search well as other drugs because of pain is common.20 Several textbooks and review articles have recom- Published articles on RCTs of pharmacologic mended the use of pharmacologic agents in the treatment of adult chronic pain patients with treatment of chronic orofacial pain.2,21,22 Today, TMD, RA of the TMJ, AFP, or BMS were sought there is no “gold standard” in the pharmacologic systematically. Searches were conducted in treatment of chronic orofacial pain. The positive Medline, the Cochrane Library, Embase (January effects of the drugs must be evaluated in relation to 1966 to October 2000), and PsychLitt (1974 to possible adverse and toxic effects and possible October 2000). The terms used were facial pain, dependency. An increasing number of harmful temporomandibular joint disorders, burning effects have been reported from, for example, non- mouth syndrome, randomized controlled trials, steroidal anti-inflammatory drugs (NSAIDs).23,24 meta-analysis, controlled clinical trials, random Since pharmacologic interventions are common— allocation, double-blind method, single-blind but efficacy and adverse events are unclear—a sys- method, placebos, , and chronic disease. tematic review seemed important. No restrictions were made on language or sample A systematic review is an overview of primary size. Reference lists of retrieved reports and review studies that contain a statement of objectives and a articles were hand searched. Unpublished reports, description of the materials and methods, and have letters, and abstracts were not considered. Authors been conducted according to explicit and repro- were not contacted for original data. ducible methodology. One of the advantages of a systematic review is that the conclusions are more Procedure reliable and accurate than in a narrative review.25 The objective of this study was to carry out a sys- Every report that could be described as an RCT tematic review of the literature in order to assess the was read independently by the 3 authors. Inter- pain-relieving effect and safety of pharmacologic observer reliability was not analyzed. All studies interventions in the treatment of chronic TMD, were judged independently and consensus was including rheumatoid arthritis (RA) of the TMJ, as achieved by discussion. The following data were well as AFP and BMS. extracted from each article: number of patients and

302 Volume 17, Number 4, 2003 List et al condition, design, pain duration, drug(s) tested, studies reported adverse effects, all of which were outcome measures, dose regimen, out- minor. In only 2 of 11 studies was the randomiza- come, withdrawals, adverse effects and dropouts, tion adequately described according to the proto- quality score, and authors’ conclusion. No attempt col.26 The median quality score was 4. Four trials was made to analyze pre- and postcrossover data. were conducted with TMD patients, 2 with AFP However, washout periods are clearly stated in patients, 1 with BMS patients, 1 with patients with Table 1. The reviewer’s opinion was based on the RA of the TMJ, and 3 with mixed groups of clinical relevance of the results. To assess the qual- patients with TMD and AFP (Table 1). ity of the study, the reviewers assessed each article The patients were referred to private clinics (n = by a 5-point quality scale.26 Reports that were 1) or orofacial pain clinics (n = 7), or patient refer- described as randomized (words such as randomly, ral was unclear (n = 3). random, and randomization were used) were given The pharmacologic interventions included 1 point. If the method of randomization was amitriptyline, clonazepam, cocaine, diazepam, appropriate (table of random numbers, computer- dothiepin, glycocorticoid, ibuprofen, a combina- generated), the report earned an additional point. tion of paracetamol and codeine plus doxylamine, Reports that were described as double-blind were salmon calcitonin, sodium hyaluronate, sumatrip- given 1 point. If the double-blinding was appropri- tan, trazadone, and triazolam. ate (identical placebo, active placebo, or dummy), an additional point was given. Publications that Analgesics and NSAIDs reported withdrawals and dropouts were given an additional point. An RCT could earn a maximum In TMD patients, 1 study found that mersyndol, of 5 points and a minimum of 1 point. an analgesic (450 mg paracetamol, 9.75 codeine, 5 The pain-relieving effect, the main measurement mg doxylamine ϫ 2) was significantly more effec- outcome, was estimated by comparing pain intensity tive than a placebo.27 It was difficult to determine measurements reported as visual analog scale (VAS) which pharmacologic ingredient of mersyndol was scores or verbal rating scale scores following phar- most effective. Another study of TMD found that macologic intervention compared with controls. ibuprofen (600 mg ϫ 4) was no better than diaze- Data showing any statistically significant difference pam or placebo. However, the combination of (P Ͻ .05) between drugs or compared with placebo, ibuprofen and diazepam was significantly more as reported in the original publication, were ex- effective than placebo.28 tracted. Quality scoring and reviewer’s opinion were achieved by consensus (vote-counting procedure).

Amitriptyline was significantly better than placebo in Results a study on TMD and AFP. Interestingly, no differ- ence was seen between low (10 to 30 mg) and higher Four databases were systematically searched for (50 to 150 mg) doses of amitriptyline.29 Another articles. A total of 89 articles were identified with study found dothiepin to be significantly more effec- the search strategy. Of these, 42 were reviewed in tive than placebo in a mixed group of TMD and full text. Besides one Spanish and one Italian arti- AFP patients.30 The results of the study are difficult cle, all were in the English language. In all, 26 ran- to interpret since large numbers of patients were domized studies were found, of which 11 were excluded and 50% of the patients were allocated to included in the study (Table 1). All 26 articles occlusal appliance therapy, with an unclear influence were found in Medline or the Cochrane Library. on the results. For BMS, trazadone was found to be Fifteen randomized studies were excluded because no more effective than the placebo.31 of a lack of data on pain duration or age, dual publication, or unclear diagnosis (Table 2). Benzodiazepines The median publication year was 1996 (1983 to 1999). The 11 studies that met the inclusion crite- In a study of TMD patients, clonazepam was ria had a total of 368 patients. Six of the studies found to be significantly more effective than had a crossover design (median size 25 patients, placebo.32 In another TMD study, triazolam was range 9 to 32) and in 5 comparisons with parallel compared to placebo.33 No pain reduction was groups were conducted (median size 39 patients, found but sleep improved significantly. Both stud- range 9 to 150). The follow-up period ranged from ies were on small patient groups, which makes it 1 hour to 1 year with a median of 4 weeks. Seven difficult to interpret the results.

Journal of Orofacial Pain 303 List et al ffect itive effect effect core: 4 points core: 4 points viewer opinion: not pain, not for clinical use of codeine, the anal- gesic effect probably related to paracetamol small sample size ative results, not con- clusive, small study d not Quality score: 4 points am Author: positive effect pontaneously Reviewer opinion: awals no reason given; Author: positive effect ovement, 1 dropped conclusive, small trial, out due to , 1 patient high dropout rate the pain; excluded patients werenot included in the statistical dropout rate, effect of analysis; drowziness, dry mouth, dizziness, drug-related withdrawals not stated biteguard unclear .001) 1 withdrawal due to no intention Author: positive effect .01) was resolved; relaxed feeling; Reviewer opinion: posi- .05) 57 patients excluded: 24 were Author: positive effect Ͻ Ͻ Ͻ P ) than place- significant increase in blood pres- Quality score: 3 points P P .01) com- no report of adverse effects Quality score: 2 points .05 Ͻ Ͻ P

P .05); 2 h: sensory, higher frequency of adverse Reviewer opinion: urning mouth syndrome. Ͻ ), left posterior TMJ group since pain was resolved, 7 Quality score: 3 points ), right TMJ (ns) had migraine, mild sedation

P .05) placebo not for clinical use .01), right TMJ and tempor- in the placebo dropped out due to Reviewer opinion: not .05 .05 Ͻ Ͻ Ͻ Ͻ

P P P P alis and masseter (ns); VAS no impr (patient): left TMJ, head and neck affective, total pain scores( events with sumatriptan than positive result at 2 h, placebo tablets every 4 h placebo mersyndol (8/30), placebo (4/30) tive results, low dose 10 mg/mL, glycocorticoid40 mg/mL, saline 9 mg/mL estimate: no difference between groups tive effect for glycocor- ticoid intra-articulary; cocaine 25% in, saline in effect on mood was observed reported nausea after lidocaine conclusive for chronic during palpation 1 mg daily and placebo VAS (patient): global pain levels in TMJ, ( Verbal pain scale Bedtime single dose dothiepin Pain relief: dothiepin ( head, neck questionnaire Dothiepin + biteguard, wk 1 ≥ 4-d placebo and discomfort increased to a maximum of pain reported at baseline Quality score: 4 points 1 single 15%, cocaine 25%, pain relief, mood pledgets (180 mg solution) cantly better ( 1-wk trial placebo global estimate 450 mg, codeine 9.75 compared with placebo, global participate, 1 dropout since pain Quality s single placebo affective, total 0.5 mL (6 mg), saline scores (ns), affective pain score pain symptoms were resolved; Quality s ϫ ϫ ϫ ϫ 4-wk trial placebo sodium hyaluronate pared with saline; global Reviewer opinion: posi- trial/Washout 3 d night 0.42 mg) and placebo 0.5 mg/night (mean fourth No withdrawals Reviewer opinion: neg- Crossover Sumatriptan,Crossover MPQ: sensory, Triazolam, Single dose sumatriptan4 parallel Pain intensity 1 h: sensory and total pain Bedtime single dose 0.125 mg 1 dropout with sumatriptan since No significant difference Author: pos Crossover 1 patient excluded because no Mersyndol, Author: no VAS pain intensity,2 parallel Mersyndol (paracetamol Clonazepam, VAS pain: mersyndol ( VAS (observer): pain3 parallel Bedtime single dose 0.25 mg, VAS (observer): left lateral TMJ Sodium hyaluronate, 5 dropouts in the clonazep VAS pain intensity, 2 intra-articular injections4 VAS pain intensity No withdrawals, Author: positive e 30-d trial masseter, temporalis by 0.25 mg to a maximum of ( Washout 3–6 wk washout No washout doxylamine 5 mg) and 2 estimate mersyndol ( treatment/ pain scores sc score ( 27 Pharmacologic Interventions in Chronic Temporomanibular Disorders, Atypical Facial Pain, and Burning Mouth Syndrome 36 33 32 37 34 30 DeNucci et al 20/TMD 2 20/TMD groups placebo intensity of TMJ, doses were increased weekly ( 41/RA of TMJ groups glycocorticoid, global assessment (0.7 mL) 2 weeks apart, glycocorticoid ( Kopp et al Table 1 Study/no. ofpatients/conditions duration Design/studyAl Balawi et al Drug(s) tested measures Outcome Dose regimen outcome results adverse effects Analgesic Conclusions Withdrawals/ 8/AFP 15050/ TMD43/AFP57/unclassified 9-wk trial groups dothiepin, placeboGerschman et al placebo + biteguard, Asberg Depression (0–4), Montgomery- mg/day; mean daily dose titration in the range 25–150 compared with placebo; no significant difference in tolerate dothiepin, 15 s unwilling to cooperate, 12 di eck personality Rating Scale, Eysen- 130 mg and placebo depression rating recovered, 6 had dental causes forAFP = atypical facial pain; TMJ temporomandibular joint; TMD disorder; RA rheumatoid arthritis; BMS b not conclusive, high MPQ = McGill Pain Questionnaire; VAS Visual Analog Scale. ns = no significance; in intranasal; sc subcutaneous. 30/TMD 2 Harkins et al 20/TMD 28 dose intranasal placebo lidocaine 4% in, cocaine 15% bo in reducing pain; no significant sure after 25% cocaine, 1 patient Re Marbach andWallenstein Crossover Lidocaine, cocaine VAS pain intensity, Single dose intranasal cotton Cocaine: 15% but not 25% signifi- 7 withdr Feinmann 19/AFP 2

304 Volume 17, Number 4, 2003 List et al oints 4 points ty score: 3 points eviewer opinion: nega- Author: no effect vs placebo, no long-term treatment because of risk of drug dependency high dropout rate, small sample size dropped out: poor ad- Author: positive effect one and 2 in placebo Author: no effect no information given; 3 Author: positive effect 5), insufficient pain relief mainly related to diaze- patients completed the entire .001) and drowsiness .05) were more common tive results, small study Ͻ Ͻ

P P ing salmon calcitonin and 14% in pla- few patients, high drop- cebo; most common adverse effect out rate, high frequency was nausea after salmon calcitonin of adverse effects ( in the trazadone group ( .01), patients dropped out due to poor Quality score: 4 points Ͻ

P .05), ibuprofen or spontaneous remission (2), and pam Ͻ

P .05). The analgesic adherence with protocol; no data Reviewer opinion: posi- Ͻ

P urning mouth syndrome. and nondepressed groups compared with placebo mg 4 tablets daily bo + ibuprofen ( given 3 times a week (100 IU/mL) fects were reported by 58% follow- conclusive, pilot study, 50 mg increasing to max and low-dose amitriptyline; amitrip- sion inventory Spielberg State-Trait (10 mg/d) increasing to maxAnxiety Inventory,Zung depression (20 mg/d)scale, depression + diazepam were not significant adjective checklist medical reasons (3); no data on Quality score: compared with placebo; no signi- adverse effects ficant difference in mood changes changes between the groups Reviewer opinion: posi- tive for combination of ibuprofen and diazepam 3-wk trial placebo global assessment placebo (1.0 mL) sc; placebo, seen in outcome measures 7-wk trial; reason for dropout was Quali 4-wk trial High dose: amitriptyline, MPQ, pain relief es- tyline and placebo. Low dose: cebo in VAS and MPQ ( ϫ ϫ washout 1 wk salmon calcitonin injections were severe adverse effect. Adverse ef- Reviewer opinion: not Crossover Salmon calcitonin, Digital pain scale, Salmon calcitonin (1.0 mL) andCrossover No significant difference was Low dose: amitriptyline; 9 of 3 VAS pain intensity, Bedtime single dose of amitrip- Amytriptyline was superior to pla- 1 dropout 4 parallel Diazepam, ibuprofen, VAS pain intensity, Ibuprofen 600 mg 4 tablets daily VAS and categoric scale, diazepam 10 patients groups placebo MPQ, global assess- increasing to 200 mg/d groups in VAS pain intensity, groups dropped out due to Quality score: 4 p 4-wk treatment placebo pain, pain relief scales diazepam 2.5 28 (continued) 35 31 29 9/AFP 2 Sharav et al 20 TMD washout 2 wk placebo timate, Hamilton de- 10 mg increasing to max 30 mg/d pain relief ( AFP = atypical facial pain; TMJ temporomandibular joint; TMD disorder; RA rheumatoid arthritis; BMS b MPQ = McGill Pain Questionnaire; VAS Visual Analog Scale. ns = no significance; in intranasal; sc subcutaneous. 37/BMS 8-wk trial ment, Beck’s depres- MPQ, or depression score adverse effects; dizziness R Table 1 Study/no. ofpatients/conditions duration Design/studySchwartz et al Drug(s) tested measures Outcome Dose regimen outcome results adverse effects Analgesic Conclusions Withdrawals/ 2/TMD + AFP5/AFP 1/unclassifiedSinger and Dionne pression inventory (mean 23.6 mg), high dose: effect did not differ between high- on adverse effects 150 mg/d (mean 129.4 mg) tive results tyline reduced pain in the depressed Tammiala-Salonenand Forssell 2 parallel Trazadone, VAS pain intensity, Bedtime single dose 100 mg/d No significant difference between 7 in trazad 32 3 49/TMD groups diazepam + ibuprofen, pain relief, categoric (total daily dose 2,400 mg), + ibuprofen was superior to place- herence (

Journal of Orofacial Pain 305 List et al

Table 2 Randomized Clinical Trials Excluded from the Study Study Drug(s) Reason for exclusion Bogetto et al55 Paroxetine, amitriptyline, Unclear if pain or depression was treated clordemetildiazepam, amisulpride Feinmann et al56 Dothiepin Dual publication (Feinmann30) Feinmann et al57 Dothiepin Dual publication (Feinmann30) Franks58 Orphenadrine No data on pain duration Gallardo et al59 Carisoprodol No data on pain duration, diagnosis unclear Greene and Laskin60 Meprobamate No data on pain duration or age range Harrison et al61 Sumatriptan Dual publication (al Balawi et al36) Lascelles62 Phenelzine, chlordiazeproxide No data on pain duration, diagnosis unclear hydrochloride Loldrup et al63 Clomipramine, mianserin Unclear if pain or depression was treated Rossi et al64 Prazepam No data on pain duration Sardella et al65 Benzydamine hydrochloride No data on pain duration Schwartz et al66 Carisoprodol No data on pain duration or age range Shin and Choi67 Indomethacin Pain duration and age range unclear Seltzer et al68 Dietary tryptophan Pain duration and age range unclear Stockstill et al69 L-tryptophan and dietary instruction No data on age range

Miscellaneous effects.39 A wide range of pharmacologic treat- ments has been used in an attempt to relieve orofa- Corticosteroids (glycocorticoid) injected intra- cial pain. Unfortunately, most of the trials on these articularly in patients with RA of the TMJ were treatments were not randomized and therefore not found to be significantly more effective than included in the study. Several RCTs were also saline.34 In the same study, sodium hyaluronate excluded from this review since data regarding did not differ significantly from either placebo or age, diagnosis, and pain duration were lacking. glycocorticoid. Salmon calcitonin administrated In this qualitative systematic review, no evi- subcutaneously was no better than placebo in a dence-based support was found for any specific small AFP study with a high dropout rate.35 In one pharmacologic treatment for TMD, AFP, or BMS. study on AFP patients, sumatriptan was found to Four studies were judged to be clinically relevant, be significantly superior to placebo.36 Finally, in a but sample sizes were low, and each pharmacologic single-dose study on a mixture of TMD and AFP intervention was only supported by 1 RCT. Strong patients, it was found that intranasal inhalation of scientific evidence is based upon at least 2 RCTs.40 cocaine was significantly better than placebo.37 More RCTs are needed to determine which phar- In 8 of the studies, the authors concluded that a macologic interventions are effective in these pain positive pharmacologic effect of the relevant drug conditions. All the investigated studies had small had occurred (Table 1). The reviewers judged the patient populations, and multicenter studies are positive effect of the treatment to be clinically rele- recommended to overcome this problem. vant in only 4 of the 8 studies. However, no par- In this review, an adult population was ana- ticular treatment could be considered to be effec- lyzed. Studies including children and adolescents tive since only one small study had been published were excluded since the results could be difficult to for each treatment. interpret. Doses would be different, and outcome measures would be affected by differing levels of maturity and cognitive abilities. Experimental Discussion studies were also excluded since their aim most often is a mechanism-based explanation and not Randomized controlled trials are considered to be an evaluation of clinical treatment. Abstracts and the most reliable way to estimate the effect of an letters were not considered since their data are intervention.38 In a randomized trial, each patient often insufficient for analysis in a systematic has an equal chance of receiving any of the inter- review. Strict diagnostic criteria were seldom pre- ventions. Randomization also reduces the possibil- sented in the studies, and many of the populations ity of bias from placebo responders. Inadequate seemed to represent a mixture of diagnostic randomization or inadequate concealment of ran- descriptions of TMD, AFP, and BMS. Since the domization has been found to increase treatment material was not homogeneous for diagnostic

306 Volume 17, Number 4, 2003 List et al groups and pharmacologic treatments and the effects has been reported in the use of NSAIDs and results were presented as group means, we decided Cox-2 inhibitors.23,24 However, none of the studies to conduct a qualitative systematic review instead in this review reported serious adverse effects. The of a meta-analysis. only indication for a short-term trial with anal- The most common designs in pharmacologic gesics is in patients with acute exacerbations and intervention studies on pain are the parallel group clinical signs of inflammation of the chronic pain and the crossover.41 In this review, 6 studies had a condition. Here, too, however, few RCTs have crossover design and 5 had a parallel group design. been published and the evidence is weak.46 A relative disadvantage with the parallel group There is evidence that antidepressants are effec- design is that more patients are needed (2.4 times) tive in several chronic pain conditions.47,48 In our for the results to be equivalent to those of a cross- review of a mixed population of TMD and AFP over design.42 Since the variability in patient patients, one study found that amitriptyline gave response to treatment is large, the size of the trial significant pain reduction compared with placebo. is essential to overcome random therapeutic Another study reported positive findings using effects.43 At least 40 patients in each group would dothiepin but was difficult to interpret because of be needed to detect differences between groups in the analysis of the data. In BMS patients, one postoperative pain.43 In the review, a median of 30 study found that trazodone did not have any participants per study was the average. This is a effect. Several studies have reported that depressive low trial size, especially considering that almost symptoms are common in TMD,11 AFP,10 and half of the studies had a parallel group design. BMS patients.8 In clinical trials where chronic pain None of the studies reported that the size of their and depression coexist, patients may obtain relief trial was based on a power calculation. It is possi- from both disorders.49 Today it is accepted that ble that the results in some of the studies would tricyclic antidepressives, eg, amitriptyline, exert an have been different if the number of patients had analgesic effect independent of the drug’s antide- been adequate. pressive effect.47,48 In this review, only minor A large variety of subjective and clinical assess- adverse effects were reported. The most common ment variables were used in the studies. The major adverse effects, such as dry mouth, constipation, reason for TMD, AFP, and BMS patients to seek blurred vision, and urinary retention, are related to professional help is chronic pain.4,5 The main out- the anticholinergic properties of the drugs. come measure in the studies was pain assessment. Chronic pain patients in the United States are 3 An acceptable reliability and validity has been to 4 times as likely to be using benzodiazepines as reported for categoric and VAS measures in pain.44 the general population, and they also continue Even with randomization, selection bias may treatment for longer periods than nonpatients.50 still be introduced if dropouts occur after alloca- Concerns have been raised regarding the adverse tion.45 In our review, several of the studies had a effects of benzodiazepines, such as sedation, cogni- high frequency of withdrawals and dropouts. An tive impairment, depression, and most of all, the adequate description of withdrawals and dropouts risk of abusing and becoming dependent on benzo- is important if an analysis of intention to treat is to diazepines.50 Benzodiazepines may, however, be be calculated. None of the studies were analyzed useful in the short-term treatment of , mus- according to intention to treat. cle spasm, and insomnia, which are frequently To evaluate the quality of studies, different scor- associated with acute pain and may occur during ing systems have been proposed.44 In the present acute exacerbation of chronic pain conditions.49 In systematic review, we used the scoring system by this review, one study found diazepam in combina- Jadad et al,26 which has been used in several stud- tion with ibuprofen to be significantly better than ies and found to be reliable.44 The median score placebo. The effect was mainly attributed to for the studies in this systematic review was 4, diazepam.28 Only minor adverse effects were which is comparable with the mean presented in reported in this study. similar reviews of pharmacologic interventions.44 Intra-articular corticosteroids are widely used in The analgesic drugs and NSAIDs used in this the management of arthritic conditions.51 In one review were ibuprofen and acetaminophen com- study it was found that corticosteroids injected bined with codeine. Here the results were conflict- into the TMJ produced significant improvement ing. The lack of clinical studies supporting the effi- compared with saline and sodium hyaluronate. No cacy and effectiveness of analgesics in the side effects were reported in this study.34 Case management of chronic orofacial pain becomes reports of adverse events following intra-articular more critical as increasing information on adverse injections have been published.52,53 Contradictory

Journal of Orofacial Pain 307 List et al to these findings are the results of a long-term Acknowledgments radiographic follow-up of intra-articular injections that found no negative effects on the TMJ.54 There This study was supported by the Public Dental Service of is little consensus in the literature on the appropri- Östergötland County Council, Östergötland, Sweden. ate technique of administration, and no clinical studies have compared various preparations for safety and effectiveness.51 References Due to considerable side effects, salmon calci- 1. Lipton JA, Ship JA, Larach-Robinson D. Estimated preva- tonin, cocaine, and subcutaneous sumatriptan can- lence and distribution of reported orofacial pain in the not be recommended for the clinical treatment of United States. J Am Dent Assoc 1993;124(10):115–121. chronic orofacial pain. 2. Okeson JP (ed). Orofacial Pain: Guidelines for Assess- One recent systematic review of the treatment of ment, Diagnosing and Management. Chicago: Quintes- BMS identified 6 trials.18 Only 1 of these studies sence, 1996. 31 3. McNeill C, Dubner R. What is pain and how do we clas- was evaluated in the present systematic review. sify orofacial pain? In: Lund JP, Lavigne GL, Dubner R, The other studies did not meet the inclusion crite- Sessle BJ (eds). Orofacial Pain. From Basic Science to ria or were excluded because of missing data. Clinical Management. Chicago: Quintessence, 2001: However, the authors’ conclusions in both reviews 183–192. were that there is little research evidence that pro- 4. Zarzewska JM, Hamlyn PJ. Facial pain. In: Crombie IK, Croft PR, Linton SL, LeResche L, Von Korff M (eds). vides a clear guidance for treatment of patients Epidemiology of Pain. Seattle: IASP Press, 1999:171–202. with BMS. Instead of focusing on different etio- 5. Drangsholt M, LeResche L. Epidemiology of temporo- logic factors, a better understanding of the neuro- mandibular pain. In: Crombie IK, Croft PR, Linton SL, physiologic mechanisms involved in the pain con- LeResche L, Von Korff M (eds). Epidemiology of Pain. ditions should improve assessment and treatment Seattle: IASP Press, 1999:203–233. 6. Dworkin SF, LeResche L. Research diagnostic criteria for of patients with orofacial pain. temporomandibular disorders: Review, criteria, examina- One of the major shortcomings of the studies in tions and specifications, critique. J Craniomandib Disord this systematic review was the low sample size. To 1992;6:301–355. overcome this problem in the future, large RCTs— 7. Woda A. Mechanisms of . In: Lund JP, preferably multicenter and cross-cultural investiga- Lavigne GL, Dubner R, Sessle BJ (eds). Orofacial Pain. From Basic Science to Clinical Management. Chicago: tions—are recommended to assess the efficacy of Quintessence, 2000:67–78. drugs and increase the generalizability of the 8. Ship JA, Grushka M, Lipton JA, Mott AE, Sessle BJ, results. Dionne RA. Burning mouth syndrome: An update. J Am The authors of this review judged 4 of the 11 Dent Assoc 1995;126:842–853. small studies to be positive and clinically relevant. 9. Von Korff M, Dworkin SF, LeResche L, Kruger A. An epi- demiologic comparison of pain complaints. Pain 1988;32: No clear indication was found that any drug is 173–183. superior to any other in the treatment of orofacial 10. Smith DP, Pilling LF, Pearson JS, Rushton JG, Goldstein pain, even though patients with TMD and AFP NP, Gibilisco JA. A psychiatric study of atypical facial tended to benefit more from medi- pain. Can Med Assoc J 1969;100:286–291. cation than BMS patients. Further research on 11. List T, Dworkin SF. Comparing TMD diagnoses and clini- cal findings at Swedish and US TMD centers using each drug is needed since a single small study is research diagnostic criteria for temporomandibular disor- not enough to provide evidence of effectiveness. ders. J Orofac Pain 1996;10:240–253. 12. Mohl ND. The anecdotal tradition and the need for evi- dence-based care for temporomandibular disorders. J Conclusions Orofac Pain 1999;13:227–231. 13. Antczak-Bouckoms AA. Epidemiology of research for tem- poromandibular disorders. J Orofac Pain 1995;9:226–234. The common use of analgesics in TMD, AFP, and 14. De Kanter RJ, Truin GJ, Burgersdijk RC, et al. Prevalence BMS is not supported by scientific evidence. More in the Dutch adult population and a meta-analysis of signs RCT studies (eg, of , antidepres- and symptoms of temporomandibular disorder. J Dent sants, analgesics, and nonsteroidal anti-inflamma- Res 1993;72:1509–1518. 15. Ernst E, White AR. Acupuncture as a treatment for tem- tory drugs) are needed to determine which phar- poromandibular joint dysfunction: A systematic review of macologic interventions are effective in these pain randomized trials. Arch Otolaryngol Head Neck Surg conditions. 1999;125:269–272. 16. Crider AB, Glaros AG. A meta-analysis of EMG biofeed- back treatment of temporomandibular disorders. J Orofac Pain 1999;13(1):29–37.

308 Volume 17, Number 4, 2003 List et al

17. Forssell H, Kalso E, Koskela P, Vehmanen R, Puukka P, 35. Schwartz G, Galonski M, Gordon A, Shandling M, Mock Alanen P. Occlusal treatments in temporomandibular dis- D, Tenenbaum HC. Effects of salmon calcitonin on orders: A qualitative systematic review of randomized patients with atypical (idiopathic) facial pain: A random- controlled trials. Pain 1999;83:549–560. ized controlled trial. J Orofac Pain 1996;10:306–315. 18. Zakrewska JM, Glenny AM, Forssell H. Intervention for 36. Al Balawi S, Tariq M, Feinmann C. A double-blind, treatment of burning mouth syndrome. In: Issue 1 ed. placebo-controlled, crossover study to evaluate the effi- Cochrane Library, Oxford: Update Software, 2002. cacy of subcutaneous sumatriptan in the treatment of 19. Denucci DJ, Dionne RA, Dubner R. Identifying a neurobi- atypical facial pain. Int J Neurosci 1996;86(3–4):301–309. ologic basis for drug therapy in TMDs. J Am Dent Assoc 37. Marbach JJ, Wallenstein SL. Analgesic, mood, and hemo- 1996;127:581–593. dynamic effects of intranasal cocaine and lidocaine in 20. Von Korff M, Galer BS, Stang P. Chronic use of symp- chronic facial pain of deafferentation and myofascial ori- tomatic medications. Pain 1995;62:179–186. gin. J Pain Symptom Manage 1988;3:73–79. 21. Truelove EL. The chemotherapeutic management of 38. McQuay HJ, Moore RA. Methods of therapeutical trials. chronic and persistent orofacial pain. Dent Clin North Am In: Wall PD, Melzack R (eds). Textbook of Pain, ed 4. 1994;38:669–688. Edinburgh: Churchill Livingstone, 1999:1125–1138. 22. Padilla M, Clark GT, Merrill RL. Topical medications for 39. Schultz KF, Chalmers I, Hayes RJ, Altman DG. Failure to orofacial neuropathic pain: A review. J Am Dent Assoc conceal treatment allocation schedules in trials influences 2000;131:184–195. estimates of treatment effects. Control Clin Trials 1994; 23. Silverstein FE, Faich G, Goldstein JL, et al. Gastro- 15:63–64. intestinal toxicity with celecoxib vs nonsteroidal anti- 40. Scottish Intercollegiate Guidelines Network (SIGN). Sign inflammatory drugs for osteoarthritis and rheumatoid 50: A guideline developer’s handbook. Available at: arthritis: The CLASS study: A randomized controlled trial. http:www.sign.ac.uk/guidelines/fulltext/50/index.html. Celecoxib Long-term Arthritis Safety Study. JAMA 41. Max MB, Laska EM. The design of analgesic trials. In: 2000;284:1247–1255. Max MB, Portenoy RK, Laska EM (eds). Advances in 24. Bombardier C, Laine L, Reicin A, et al. Comparison of Pain Research and Therapy. New York: Raven, 1991: upper gastrointestinal toxicity of rofecoxib and naproxen 55–95. in patients with rheumatoid arthritis. VIGOR Study 42. James KE, Forrest WH Jr, Rose RL. Crossover and non- Group. N Engl J Med 2000;343:1520–1528, 2 p follow- crossover designs in four-point parallel line analgesic ing 1528. assays. Clin Pharmacol Ther 1985;37:242–252. 25. Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers 43. Moore RA, Gavaghan D, Tramer MR, Collins SL, TC. A comparison of results of meta-analyses of random- McQuay HJ. Size is everything—Large amounts of infor- ized control trials and recommendations of clinical mation are needed to overcome random effects in estimat- experts. Treatments for myocardial . JAMA ing direction and magnitude of treatment effects. Pain 1992;268:240–248. 1998;78:209–216. 26. Jadad AR, Moore RA, Carroll D, et al. Assessing the qual- 44. McQuay HJ, Moore RA. An Evidence-Based Resource for ity of reports of randomized clinical trials: Is blinding nec- Pain Relief. Oxford: Oxford University Press, 1998. essary? Control Clin Trials 1996;17:1–12. 45. Sackett DL, Gent M. Controversy in counting and 27. Gerschman JA, Reade PD, Burrows GD. Evaluation of a attributing events in clinical trials. N Engl J Med 1979; proprietary analgesic/antihistamine in the management of 301:1410–1412. pain associated with temporomandibular joint pain dys- 46. Ekberg EC, Kopp S, Akerman S. Diclofenac sodium as an function syndrome. Aust Dent J 1984;29:300–304. alternative treatment of temporomandibular joint pain. 28. Singer E, Dionne R. A controlled evaluation of ibuprofen Acta Odontol Scand 1996;54:154–159. and diazepam for chronic orofacial muscle pain. J Orofac 47. McQuay HJ, Tramer M, Nye BA, Carroll D, Wiffen PJ, Pain 1997;11:139–146. Moore RA. A systematic review of antidepressants in neu- 29. Sharav Y, Singer E, Schmidt E, Dionne RA, Dubner R. ropathic pain. Pain 1996;68:217–227. The analgesic effect of amitriptyline on chronic facial 48. Sindrup SH, Jensen TS. Efficacy of pharmacologic treat- pain. Pain 1987;31:199–209. ments of neuropathic pain: An update and effect related to 30. Feinmann C. Psychogenic facial pain: Presentation and mechanism of drug action. Pain 1999;83:389–400. treatment. J Psychosom Res 1983;27:403–410. 49. Monks R, Merskey H. Psychotropic drugs. In: Wall PD, 31. Tammiala-Salonen T, Forssell H. Trazodone in burning Melzack R (eds). Textbook of Pain, ed 4. Edinburgh: mouth pain: A placebo-controlled, double-blind study. J Churchill Livingstone, 1999:1155–1186. Orofac Pain 1999;13:83–88. 50. King SA, Strain JJ. Benzodiazepines and chronic pain. Pain 32. Harkins S, Linford J, Cohen J, Kramer T, Cueva L. 1990;41:3–4. Administration of clonazepam in the treatment of TMD 51. Rozental TD, Sculco TP. Intra-articular corticosteroids: and associated myofascial pain: A double-blind pilot An updated overview. Am J Orthop 2000;29:18–23. study. J Craniomandib Disord 1991;5:179–186. 52. Acton CH. Steroid-induced anterior open bite. Case 33. DeNucci DJ, Sobiski C, Dionne RA. Triazolam improves report. Aust Dent J 1986;31:455–458. sleep but fails to alter pain in TMD patients. J Orofac 53. Aggarwal S, Kumar A. A cortisone-wrecked and bony Pain 1998;12:116–123. ankylosed temporomandibular joint. Plast Reconstr Surg 34. Kopp S, Akerman S, Nilner M. Short-term effects of intra- 1989;83:1084–1085. articular sodium hyaluronate, glucocorticoid, and saline 54. Wenneberg B, Kopp S, Grondahl HG. Long-term effect of injections on rheumatoid arthritis of the temporomandibu- intra-articular injections of a glucocorticosteroid into the lar joint. J Craniomandib Disord 1991;5:231–238. TMJ: A clinical and radiographic 8-year follow-up. J Craniomandib Disord 1991;5:11–18.

Journal of Orofacial Pain 309 List et al

55. Bogetto F, Revello RB, Ferro G, Maina G, Ravizza L. 64. Rossi E, Gallardo F, Weil MW. Prazepam as the initial Psychopharmacologic treatment of burning mouth syn- treatment of myofacial pain-dysfunction syndrome. IRCS drome (BMS). Minerva Psichiatr 1999;40:1–10. Med Sci 1983;7:637–638. 56. Feinmann C, Harris M. Psychogenic facial pain. Part 2: 65. Sardella A, Uglietti D, Demarosi F, Lodi G, Bez C, Management and prognosis. Br Dent J 1984;156:205–208. Carrassi A. Benzydamine hydrochloride oral rinses in man- 57. Feinmann C, Harris M, Cawley R. Psychogenic facial agement of burning mouth syndrome. A clinical trial. Oral pain: Presentation and treatment. Br Med J (Clin Res Ed) Surg Oral Med Oral Pathol Oral Radiol Endod 1999; 1984;288(6415):436–438. 88:683–686. 58. Franks AS. Mandibular spasm: A double-blind study of a 66. Schwartz L, Kutscher AH, Yavelow I, Cobin HP, Brod drug. Br J Clin Pract 1965;19:298–384. MS. Carisoprodol in the management of temporo- 59. Gallardo F, Molgo J, Miyazaki C, Rossi E. Carisoprodol mandibular joint pain and dysfunction: A preliminary in the treatment of myofascial pain-dysfunction syndrome. investigation. Ann NY Acad Sci 1960;86:245–249. J Oral Surg 1975;33:655–658. 67. Shin SM, Choi JK. Effect of indomethacin phonophoresis 60. Greene CS, Laskin DM. Meprobamate therapy for the on the relief of temporomandibular joint pain. Cranio myofascial pain-dysfunction (MPD) syndrome: A double- 1997;15:345–348. blind evaluation. J Am Dent Assoc 1971;82:587–590. 68. Seltzer S, Dewart D, Pollack RL, Jackson E. The effects of 61. Harrison SD, Balawi SA, Feinmann C, Harris M. Atypical dietary tryptophan on chronic maxillofacial pain and facial pain: A double-blind placebo-controlled crossover experimental pain tolerance. J Psychiatr Res 1982;17: pilot study of subcutaneous sumatriptan. Eur Neuropsy- 181–186. chopharmacol 1997;7:83–88. 69. Stockstill JW, McCall WD, Jr, Gross AJ, Piniewski B. The 62. Lascelles RG. Atypical facial pain and depression. Br J effect of L-tryptophan supplementation and dietary Psychiatry 1966;112:651–659. instruction on chronic myofascial pain. J Am Dent Assoc 63. Loldrup D, Langemark M, Hansen HJ, Olesen J, Bech P. 1989;118:457–460. Clomipramine and mianserin in chronic idiopathic pain syndrome. A placebo controlled study. Psychopharma- cology 1989;99:1–7.

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