Evidence for Drug Treatments
for Pain Related to
Temporomandibular Joint Disorders
S. M. Gordon DDS, MPH, PhD 1
A. Viswanath, BDS, MSD 1
R. A. Dionne DDS, PhD
1
University of Maryland, School of Dentistry, Baltimore, MD;
Correspondence to:
Dr. Sharon M. Gordon
University of Maryland School of Dentistry, Baltimore, MD
650 West Baltimore Street, Room 6255
Baltimore, MD 21201
Telephone: 410 706 1656
Fax: 410 706 0864
Email: [email protected]
WHAT MEDICATIONS HAVE BEEN PROVEN EFFECTIVE FOR MANAGING
CHRONIC OROFACIAL PAIN?
In spite of its prevalence and impact, there is no standard of care for treatment of
temporomandibular joint disorders (TMD) and no drugs have ever been approved by the FDA
for this indication. Most drug-based (called “pharmacologic”) treatments used are based on
results from studies of other types of chronic pain. The NIH proceedings of the Technology
Assessment Conference on Management of Temporomandibular Disorders (1997) reported that
the absence of clear guidelines for diagnosis and treatment has resulted in experimental use of
new and inadequately tested approaches which may neither help patients nor have serious health
consequences. This article provides a synthesis of the clinical evidence for non-invasive
pharmacologic management for TMD since the time of that NIH conference. It should be noted
that a variety of diagnostic approaches, classification schemes, and nomenclature are found in
the literature; so we used the specific diagnostic terms as used in each reference that specified a
diagnosis consistent with chronic facial pain or TMD. Papers were classified based on the
Agency for Health Research and Quality (AHRQ) system for classifying strength of evidence 1 .
All the evidence located is shown in Table 1 for further reading, and summarized next.
RESULTS
Aspirin-like or Non-steroidal anti-inflammatory drugs (NSAIDs), have traditionally been the
most commonly prescribed for pain in the orofacial region 2 . As shown in Table 1, there is the
highest level of evidence for effectiveness of diclofenac (like “Dolobid” or “Voltaren®”) and
naproxen (a long-lasting drug marketed as Naprosyn® or Aleve®. Ibuprofen, one of the most
often-used NSAIDs, has only been shown to be effective for chronic facial pain when combined
2
with other modalities, but not when used alone. Concerns of toxic effects on other body systems
(digestive, kidney, and cardiac) modifies the long-term use of NSAIDs 3 4 5 6 .This makes them of
limited utility for managing chronic pain and has lead to development of longer-lasting
formulations, such as naproxen. Studies of piroxicam—another long-lasting NSAID—have
shown mixed effectiveness for chronic facial pain. The selective cyclooxygenase (COX-2)
inhibitor celecoxib (“Celebrex”) was not better than placebo, and naproxen was better for TMD
pain 7 . Considering this evidence, NSAIDs may be most useful for short-term treatment of facial
pain episodes (such as following TMJ injury or surgery) or for pain flares.
Opioids (“narcotics”) are widely prescribed, but there are no published studies of their use for
TMD pain, except as injection into the joints, which did not decrease pain. Use of opioids has
been discouraged due to the limitations of long-term use for this drug class in that they may lead
to an increase in pain or “hypersensitivity” over time, and they can lead to dependence (meaning
increasingly higher doses are needed to produce the same effect), or even addiction. To
overcome these problems, a related drug called “tramadol”, is sometimes used for chronic pain
treatment, but there are no published studies of its use for TMD pain.
Evidence for the effectiveness of muscle relaxants and benzodiazepines (“Valium-like”
drugs) is overall favorable for reduction of TMD pain when compared to placebo; although
benzodiazepines have not been shown effective when used alone. Similar to the benzodiazepines,
other drugs used to reduce anxiety (“anxiolytics”) are also not effective in reducing TMD pain
unless combined with other treatment approaches, or when treating a co-existing anxiety
disorder.
3
Neuropathic pain drugs, such as gabapentin 8 have been shown to be effective for chronic facial
myalgia, but there is only one published study to date. The most studied and promising drugs for
TMD are of the antidepressant type, specifically tricyclic antidepressants. Even though there
are now newer types of antidepressants available, there are no publications in the literature for
TMD pain. The name of the drug class may be misleading, because they work for pain whether
or not depression is present. Because these drugs need to build up in the system before they work
for pain, many times side effects (mainly dry mouth and eyes, nausea, etc) cause patients to stop
using them before they achieve optimal pain relief 9 .
Disease modifying agents used for arthritis, such as infliximab (Remicade®), glucosamine
hydrochloride, collagen hydrolysat, and chondroitin sulfate have been shown to be effective in
reducing TMJ pain, when specifically due to joint disease. In a study comparing glucosamine to
ibuprofen for TMD pain in patients specifically with TMJ disease, glucosamine improved pain
and function better than ibuprofen and the effects were longer lasting 10 .
Topically-applied agents, such as “Theraflex-TMJ” may also be effective in reducing TMD
pain when compared to placebo. Topical diclofenac (an NSAID) is also effective, and was shown
to be equally effective to diclofenac taken as a pill. Capsaicin cream (often used for diabetic
neuropathic pain) was not effective in reducing TMD pain when compared to placebo and topical
diclofenac.
4
SUMMARY
As can be seen in the Table, some drugs have been studied specifically for TMD pain. Taken
together, there is evidence available to support some drugs for treatment of TMD. The use of
these should be applied judiciously and usually in combination with other approaches. The
pharmacologic management of TMD should be based on the same principles that apply to other
conditions: demonstrated effort, an acceptable side effect liability, and safety when given for
prolonged periods 2. In addition, a broad range of other conditions can co-exist with TMD and
these conditions need to be taken into account when considering treatment, as they may modify
the safety or effectiveness.
5
References
1
Levels of Evidence Description: (AHRQ, Agency for Healthcare Research and Quality,
http://www.ahrq.gov/clinic/epcsums/strengthsum.htm)
2
Dionne RA. Pharmacologic treatments for temporomandibular disorders. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 1997 Jan;83(1):134-42.
3
Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl
1999 56:18-24.
4
Laura Plantinga, ScM1,2, Vanessa Grubbs, MD1, Urmimala Sarkar, MD1,2, Chi-yuan Hsu, MD1, Elizabeth
Hedgeman, MS3, Bruce Robinson, MD4, Rajiv Saran, MD3, Linda Geiss, MS5, Nilka Ríos Burrows, MPH5, Mark
Eberhardt, PhD6, Neil Powe, MD1,2 For the CDC CKD Surveillance Team. Nonsteroidal Anti-Inflammatory Drug
Use Among Persons With Chronic Kidney Disease in the United States. Ann Fam Med. 2011;9:423-430.doi:
10.1370/afm.1302.
5
Warde, N. Pain: The cardiovascular risks of NSAID use: which NSAID is the safest of them all? Nat Rev
Rheumatol 7, 129 (March 2011) | doi:10.1038/nrrheum.2011.9.
6
Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? Ann Intern
Med 1994; 121:289-300.
7
Ta, LE and Dionne RA.Treatment of painful temporomandibular joints with a cyclooxygenase-2 inhibitor: a
randomized placebo-controlled comparison of celecoxib to naproxen. Pain 2004; 111:13-21.
8
Kimos P, Biggs C, Mah J, Heo G, Rashiq S, Thie NM, Major PW. Analgesic action of gabapentin on chronic pain
in the masticatory muscles: a randomized controlled trial. Pain 2007; 127(1-2):151-60.
9
Zitman FG, Linssen AC, Edelbroek PM, Stijnen T. Low dose amitryptiline in chronic pain: the gain is modest.
Pain 1990; 42:35-42.
10
Thie N, Prasad NG, Major PW. Evaluation of glucosamine sulfate compared to ibuprofen for the treatment of
temporomandibular joint osteoarthritis: a randomized double blind controlled 3 month clinical trial. J Rheumatology
2001; 28(6):1347-1355.
6
Table Summarizing the Evidence for Pharmacologic, Non-invasive Treatments for TMD
Drug Class
NSAIDs
Piroxicam and occlusal
appliance vs appliance and
placebo
Piroxicam vs placebo
Piroxicam vs
acetaminophen vs placebo
Diclofenac vs placebo
Ibubrofen alone vs
diazaepam alone vs
combination of diazepam
and ibuprofen vs placebo
Glucosamine vs ibuprofen
Celecoxib vs naproxen vs
placebo
Reference
Findings
Evidence Level
+/Van den Berghe LI, de Boever JA,
Schautteet H: Double-blind clinical
study of piroxicam as adjuvant in the
treatment of the pain and dysfunction of
the temporomandibular joints. The J
Craniomandib Practice, 1986; 4(4):352356
Gordon SM, Montgomery MT, Jones
DL: Comparative Efficacy of
Piroxicam vs Placebo for
Temporomandibular Pain. J Dent Res
1990; 69:218
Gordon SM, Montgomery MT, Jones
DL: Comparative Efficacy of
Piroxicam, Acetaminophen and Placebo
for Temporomandibular Pain. J Dent
Res 1991; 70:329
Ekberg EC, Kopp S, Akerman S.
Diclofenac sodium as an alternative
treatment of temporomandibular joint
pain. Acta Odontol Scand 1996;
54:154-159
Singer E, Dionne R. A controlled
evaluation of ibuprofen and diazepam
for chronic Orofacial muscle pain. J
Orofacial Pain 1997; 11(2):139-146
Piroxicam was not effective as an adjuvant in the
treatment for pain and dysfunction. All patients
had equal improvement with no worsening of pain.
Pain was significantly decreased in the diazepam
and diazepam plus ibuprofen groups but not for
the ibuprofen alone or placebo groups
I
Thie N, Prasad NG, Major PW.
Evaluation of glucosamine sulfate
compared to ibuprofen for the treatment
of temporomandibular joint
osteoarthritis: a randomized double
blind controlled 3 month clinical trial. J
Rheumatology 2001; 28(6):1347-1355
Ta, LE and Dionne RA.Treatment of
painful temporomandibular joints with
a cyclooxygenase-2 inhibitor: a
randomized placebo-controlled
comparison of celecoxib to naproxen.
Pain 2004; 111:13-21
Glucosamine and ibuprofen both reduce pain in
patients with TMJ degenerative joint disease, with
more effect for glucosamine than ibuprofen.
I
II-1a
Piroxicam decreased pain compared to placebo
I
Piroxicam decreased pain compared to
acetaminophen.
Pain reduced significantly in the diclofenac group
compared to the placebo group.
Naproxen was more effective than celecoxib and
placebo in pain reduction.
7
I
I
I
Diclofenac vs occlusal
appliance
Mejersjö C, Wenneberg B. Dichloro
sodium and occlusion splint therapy in
TMJ osteoarthritis: a randomized
controlled trial. J Oral Rehab 2008;
35:729-738
Diclofenac gave more rapid improvement than occlusal
appliance, but both treatments gave a significant
reduction of symptoms within 3 months which
remained at the one-year follow-up.
Muscle relaxants and
benzodiazepines
Clonazepam vs placebo
Diazepam vs placebo
Carisoprodol vs placebo
Orphenadrine citrate vs
placebo
Meprobamate vs placebo
Alprazolam vs occlusal
splint vs the two combined
Triazalam vs placebo
I
+/Harkins S, Linford J, Cohen J, Kramer
T, Cueva L. Administration of
clonazepam in the treatment of TMD
and associated myofascial pain; a
double blind pilot study. J
Craniomandib Disorders 1991;
5(3):179-86.
Jagger RG. Diazepam in the treatment
of temporomandibular dysfunction
syndrome. A double blind study. J Dent
1974; 2: 37-40
Gallardo F, Molgo J, Miyazaki C, Rossi
E. Carisprodol in the treatment of
myofacial pain dysfunction syndrome. J
Oral Surg 1975; 33: 655-660
Franks AS. Mandibular spasm: a
double blind study of a muscle relaxant
drug. Br J Clin Pract 1965; 19: 281-284
Greene CS, Laskin DM. Meprobomate
therepy for the myofacial paindysfunction (MPD) symdrome: a
double blind evaluation. JADA 1971;
82: 587-590
Nemcovsky CE, Gazit E, Serfati V,
Gross M. A comparative study of three
therapeutic modalities in a
temporomandibular disorder (TMD)
population. J Craniomandib Practice
1992; 10(2):148-155
DeNucci DJ, Sobriski C, Dionne RA.
Triazolam inproves sleep but fails to
alter pain in TMD patients. J Orofacial
Pain 1998;12(2):116-123
Clonazepam decreases pain compared to placebo.
I
Diazepam was significantly better than placebo for
pain and dysfunction.
I
Carisoprodol failed to show a significantly greater
effect than the placebo.
I
Orphenadrine citrate reduces muscle spasm
compared to placebo.
Meprobamate effectively relieved painful
symptoms compared to placebo.
I
No significant difference between the treatments
for pain. Alprazolam improved jaw movement but
not joint noises. The combined treatments were
not better than either alone.
Improvement in sleep, but not pain or muscle
hyperactivity with triazolam compared to placebo.
8
I
II-1a
I
Clonazepam vs
cyclobenzaprine vs placebo
all with self-care instruction
Ibubrofen alone vs
diazaepam alone vs
combination of diazepam
and ibuprofen vs placebo
Occlusal splint therapy and
NSAIDS with orphenadrine
citrate and benzodiazepines
Herman CR, Schiffman EL, Look JO.
The effectiveness of adding
pharmacological treatment with
clonazepam or cyclobenzaprine to
patient education and self care for the
treatment of jaw pain upon awakening:
a randomized clinical trial. J Orofacial
Pain 2002; 16:64-79
Singer E, Dionne R. A controlled
evaluation of ibuprofen and diazepam
for chronic Orofacial muscle pain. J
Orofacial Pain 1997; 11(2):139-146
Cyclobenzaprine decreased jaw pain upon
awakening compared to clonazepam or placebo,
when added to self-care instructions. Sleep quality
was unchanged.
Rizzatti-Barbosa CM, Noguiera MT, de
Andrade ED, Ambrosano GM, de
Barbosa JR. Thereputic response of
benzodiazepine orphenadrine citrate
and occlusal splint association in TMD
pain. Cranio 2003; 21(2):116-120
All the groups experienced pain relief. No
significant difference was observed among groups.
Pain was significantly decreased in the diazepam
and diazepam plus ibuprofen groups but not for
the ibuprofen alone or placebo groups.
Neuropathic pain
agents, including antidepressants
Sharav Y, Singer E, Schmidt E, Dionne
RA, Dubner R. The analgesic effect of
amitryptiline on chronic facial pain.
Pain 1987; 31:199-209
Amitriptyline vs. placebo
appliance
Rizzatti-Barbosa CM, Noguiera MT, de
Andrade ED, Ambrosano GM, de
Barbosa JR. Clinical evaluation of
amitryptiline for the control of chronic
pain caused by temporomandibular
joint disorders. Cranio 2003; 21(3):221225
McQuay HJ, Carroll D, Glynn CJ. Low
dose amitryptiline in the treatment of
chronic pain. Anesthesia 1992; 47:646652
Low dose amitriptyline
I
II-1a
+
Low or high dose
amitriptyline vs placebo
Amitriptyline vs placebo
I
Plesh O, Curtis D, Levine J, McCall
WD Jr. Amitriptyline treatment of
chronic pain in patients with
temporomandibular disorders. J Oral
Rehab 2000; 27(10):834-841
Low and high dose amitriptyline effective in
treatment of chronic orofacial pain compared to
placebo, independent of its effects on depression.
Aminitriptyline significantly reduced pain
compared to placebo.
Low dose amitriptyline was effective in the
treatment of chronic pain compared to placebo.
Significant reduction for low dose amitriptyline
for all pain scores for myofascial and joint pain
after 6 weeks and 1 year post-treatment.
9
I
I
I
II-1a
gabapentin vs placebo
Kimos P, Biggs C, Mah J, Heo G,
Rashiq S, Thie NM, Major PW.
Analgesic action of gabapentin on
chronic pain in the masticatory
muscles: a randomized controlled trial.
Pain 2007; 127(1-2):151-60.
Gabapentin reduced pain compared to placebo
I
Immune Modifying
Drugs
infliximab (Remicade) +/methotrexate
glucosamine hydrochloride
and chondroitin sulfate vs
placebo
Glucosamine vs ibuprofen
Collagen hydrolysat
+/Koop S, Alstergren P, Ernestam S,
Nordahl S, Morin P, Bratt J. Reduction
of temporomandibular joint pain after
treatment with a combination of
methotrexate and infliximab is
associated with changes in synovial
fluid and plasma cytokines in
rheumatoid arthritis. Cells Tissues
Organs 2005;180(1):22-30
Nguyen P, Mohamed SE, Gardiner D,
Salinas T. A randomized double blind
clinical trial of the effect of chondriotin
sulfate and glucosamine hydrochloride
on temporomandibular joint disorder: a
pilot study. J Craniomandi Practice
2001; 19(2):130-139
Systemic treatment with a combination of
infliximab and methotrexate reduces TMJ pain in
rheumatoid arthritis in association with an increase
in anti-inflammatory cytokines and receptors in
synovial fluid and plasma.
Thie N, Prasad NG, Major PW.
Evaluation of glucosamine sulfate
compared to ibuprofen for the treatment
of temporomandibular joint
osteoarthritis: a randomized double
blind controlled 3 month clinical trial. J
Rheumatology 2001; 28(6):1347-1355
Olson GB, Savage S, Olson J. The
effect of collagen hydrolysat on
symptoms of chronic fibromyalgia and
temporomandibular joint pain. J
Craniomandib Practice 2000;
18(2):135-141
Glucosamine and ibuprofen both reduced pain in
patients with TMJ degenerative joint disease, with
more effect for glucosamine than ibuprofen.
Glucosamine hydrochloride and chondroitin
sulfate demonstrated improvements in pain
measures.
Pain decreased significantly in the overall group in
patients with fibromyalgia and concurrent TMD.
Topically-applied
agents
Capsaicin cream vs placebo
cream
II-1b
I
I
II-1b
+/Winocur E, Gavish A, Halachmi M, Eli
I, Gazit E. Topical application of
capsaicin for the treatment of localized
pain in the temporomandibular joint
area. J Orofacial Pain 2000; 14:31-36
Capsaicin cream for localized pain in TMJ area
did not significantly relieve pain compared to
placebo.
10
I
Theraflex-TMJ vs. Placebo
Oral diclofenac sodium vs.
topical diclofenac
1
Lobo SL, Mehta N, Forgione AG,
Melis M, Al-Badawi E, Ceneviz C,
Zawawi KH. Use of theraflex-TMJ
topical cream for the treatment of
temporomandibular joint and muscle
pain. J Craniomandib Practice 2004;
22(2): 137-144
Di Rienzo Businco L, Di Rienzo
Businco A, D'Emilia M, Lauriello M,
Coen Tirelli G. Topical versus systemic
diclofenac in the treatment of temporomandibular joint dysfunction
symptoms. Acta Otorhinolaryngol Ital
2004; 24:279-283
Significant reduction in pain from baseline in
Theraflex group compared to placebo.
I
Topically applied diclofenac and oral diclofenac
equally effective in the treatment of TMD
symptoms.
I
Levels of Evidence Description: (AHRQ, Agency for Healthcare Research and Quality, http://www.ahrq.gov/clinic/epcsums/strengthsum.htm)
Level I = Randomized controlled trials
Level II-1a = Psuedo-randomized controlled trials
Level II-1b = RCT without randomization
Level II-2a = Prospective cohort study with concurrent controls
Level II-2b = Prospective cohort study with historic controls
Level II-3 = Retrospective case-control studies
Level III = Observational natural history studies
Level IV = Opinion based on clinical experience; descriptive studies, case reports, reports of expert committees
*Drug class omitted in the table where no published papers were available for review.
11