Temporomandibular joint disorder is defined by pain and/or loss of function of the temporomandibular joint and its associated muscles and structures. Treatments include noninvasive pharmacologic therapies, minimally invasive muscular and articular injections, and surgery. Conservative therapies include nonsteroidal anti-inflammatory drugs, muscle relaxants, benzodiazepines, antidepressants, and anticonvulsants. Minimally invasive injections include botulinum toxin, corticosteroids, platelet-rich plasma, hyaluronic acid, and prolotherapy with hypertonic glucose. With many pharmacologic treatment options and modalities available to the oral and maxillofacial surgeon, mild to moderate temporomandibular joint disorder can be managed safely and effectively to improve symptoms of pain and function of the temporomandibular joint.
Key points
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Drug therapy for the treatment of temporomandibular joint disorder is often prescribed as an adjunct for noninvasive or minimally invasive treatments.
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Nonsteroidal anti-inflammatory drugs (with proton pump inhibitors) and muscle relaxants are first-line therapies shown to improve symptoms of temporomandibular joint disorder.
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Oral benzodiazepines, tricyclic antidepressants, and anticonvulsants are alternative therapies that may be considered in resistant or refractory temporomandibular joint disorder, in consultation with the patient’s physician.
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Botox injections have shown to be safe and effective for treatment for myofascial temporomandibular joint disorder as intramuscular injections. Intra-articular injections have shown marked improvement in symptoms. Evidence suggests they share similar effectiveness.
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Prolotherapy with hypertonic glucose is effective for treating hypermobility and subluxation of the temporomandibular joint.
Introduction
Temporomandibular joint (TMJ) disorders refers to multietiological conditions defined by pain and/or loss of function of the TMJ, the muscles of mastication, and other associated structures. , When symptoms are limited to the muscles of mastication, the term myofascial pain dysfunction is often used. The goals of therapy for patients with temporomandibular joint disorder (TMD) focus on the reduction of pain and the improvement or restoration of function. The current thinking on the etiology of TMD places a greater emphasis on the biochemical processes involved within the joint and therefore emerging therapies focus on halting the disease process. Management strategies included noninvasive, minimally invasive, invasive, or surgical interventions and salvage modalities. Noninvasive modalities are oftentimes preferred as the first line of treatment. Drug therapy is often prescribed as an adjunct for noninvasive or minimally invasive treatments. Although most patients respond well to conservative measures, those who cannot find relief for their symptoms through noninvasive therapies can suffer from debilitating functional limitations and pain that can negatively affect their overall quality of life. Increasing severity of symptoms, impediments to daily activities, and failure of conservative measures may be an indication for more invasive treatments, including surgical intervention. This article aims to review some of the most commonly used pharmacologic agents available to oral and maxillofacial surgeons for the treatment of mild to moderate TMD ( Box 1 ).
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Medicine therapies (by mouth)
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Nonsteroidal anti-inflammatory drugs
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Opioids
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Corticosteroids
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Antidepressants
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Anticonvulsants
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Antiepileptics
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Muscle relaxants
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Sedatives, hypnotics
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Injections
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Intramuscular
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Botulinum toxin
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Intra-articular
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Corticosteroids
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Local anesthetics
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Hypertonic dextrose (prolotherapy)
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Platelet-rich plasma
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Hyaluronic acid
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Medicine therapies
Nonsteroidal Anti-Inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease inflammation in the TMJ and associated muscles of mastication to provide relief of pain, promoting its use as a first-line treatment for TMD. The primary mechanism of action of NSAIDs is through the inhibition of cyclo-oxygenase (COX) enzymes. COX-1 functions as a protective agent in the gastrointestinal (GI) tract. COX-2 is responsible for the synthesis of key biological mediators, such as prostaglandins (namely prostaglandin E 2 ) and leukotrienes from arachidonic acid, which are essential for the inflammation cascade. Inhibition of COX-2, and therefore prostaglandin E 2 , cause a decrease in the classical signs of inflammation, namely, redness, swelling, and pain. For anti-inflammatory effects in TMD, NSAIDs should be taken around the clock for at least 2 weeks, even in the absence of pain. Commonly prescribed NSAIDs for TMD include ibuprofen, naproxen, diclofenac, and piroxicam.
To study the efficacy of NSAIDs, investigators conducted a double-blind, placebo-controlled study comparing naproxen (nonselective, 500 mg twice a day), celecoxib (COX-2 selective, 500 mg twice a day), and placebo (twice a day) for 6 weeks. Naproxen was shown to significantly decrease symptoms of painful TMJ disc displacement at week 3 to week 6 on a visual analog scale (VAS) pain scale compared with celecoxib and placebo, although celecoxib also showed minor improvements in symptoms. Kurita Varoli and colleagues demonstrated that, in combination with an occlusal splint, NSAID (sodium diclofenac, 50 mg twice a day) was more effective than placebo (only occlusal splint), promoting significant pain relief after the third day, and the occlusal splint provided relief after the eighth day. These results indicate the additive effects of multiple treatment modalities to treat TMD.
NSAIDs are widely used and considered safe for prolonged use in healthy patients, up to 2 months in consultation with the patient’s primary care physician. The most common and serious adverse effect of NSAIDs is the risk for GI bleeding. Owing to its inhibitory effects on COX-1, NSAIDs can cause ulcers and bleeding of the GI tract and, therefore, they are contraindicated in patients with active GI disease, especially the elderly. In patients with a high GI risk, COX-2 selective (eg, celecoxib) or a nonselective NSAID with a proton pump inhibitor (eg, omeprazole) may offer protection from upper GI events. Other considerations with NSAIDs include cardiovascular disease, likely owing to the inhibition of COX-2 and its decreased prostaglandin I2 production, predisposing to endothelial injury. In patients with low GI risk and high cardiovascular risk, naproxen may be preferred owing to its lower cardiovascular risk. Furthermore, NSAIDs are metabolized by the renal system, causing alterations to renal blood flow, electrolyte balance, and platelet function. Consequentially, NSAIDs should be avoided in patients with kidney disease.
Muscle Relaxants
Muscle relaxants inhibit overactive muscles of mastication and associated muscles to decrease myofascial pain and decrease the load on the TMJ. These spasmolytics have shown to decrease skeletal muscle tone and are beneficial for patients with chronic orofacial pain associated with increased muscle activity and TMD. They act at the level of the cortex, brain, or spinal cord, causing inhibition of polysynaptic pathways at the central nervous system (CNS). Commonly prescribed medications in this class of drugs include cyclobenzaprine, baclofen, tizanidine, carisoprodol, and methocarbamol.
A recent meta-analysis concluded that cyclobenzaprine improved TMD muscle pain in the short term through its effects over local spasms and associated acute musculoskeletal pain. A review of 8 studies supports that cyclobenzaprine can significantly decrease pain intensity on a VAS pain scale from myofascial TMD versus placebo at 3-weeks follow-up. Further evidence is necessary to evaluate the effectiveness of prolonged use beyond 3 weeks and associated side effects of cyclobenzaprine.
The most prominent short-term side effect of centrally acting muscle relaxants is sedation, owing to its inhibitory effects against the CNS. Other potential side effects include malaise, tachycardia, dysrhythmia, and additive effects with other CNS depressants, such as alcohol, benzodiazepine, opioids, and barbiturates. Cyclobenzaprine has a similar structure to tricyclic antidepressants (TCAs) and, therefore, can cause additional side effects familiar with this class of drugs, such as xerostomia, owing to its anticholinergic activity. Furthermore, it is contraindicated for patients with congestive heart failure, arrhythmias, hyperthyroidism and may have serious adverse drug interactions with monoamine oxidase inhibitors and tramadol (increased risk of seizure).
To decrease its sedative side effects, cyclobenzaprine is commonly prescribed at lower doses (10 mg) when treating TMD and is started as 1 dose per day at bedtime. As mentioned, it can be prescribed for up to 3 weeks safely; long-term therapy should be managed in consultation with the patient’s physician. Follow-up is critical to reassess the patient’s tolerance to adverse effects.
Benzodiazepines
Benzodiazepines are used primarily as an anxiolytic medication, but have shown benefit to patients with acute muscle spasms and sleep disorders. Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid at its receptor, which mediates inhibitory synaptic transmission throughout the CNS. It does this by facilitating the opening of chloride channels, therefore causing hyperpolarization of the neurons in the CNS. As a treatment modality for myofascial TMD, benzodiazepines promote muscle relaxation, sedation, and induce sleep. , Benzodiazepines commonly prescribed include diazepam, lorazepam, and alprazolam.
The effectiveness of benzodiazepines for TMD has been well-supported, specifically longer acting formulations with anticonvulsant activity, such as diazepam. In 1 double-blind placebo-controlled study of patients with myofascial jaw pain, investigators compared diazepam (5 mg 4 times a day for 4 weeks), ibuprofen (600 mg 4 times a day for 4 weeks), diazepam and ibuprofen combined, and placebo. They demonstrate that diazepam has a significantly greater decrease in myofascial and TMD pain than placebo. Ibuprofen alone was less effective at pain relief than diazepam, but diazepam and ibuprofen combined proved better than ibuprofen alone. This finding may indicate that the use of benzodiazepines as a secondary therapy should the patient fail first-line NSAID therapy for TMD.
Benzodiazepines present adverse effects such as drowsiness, confusion, amnesia, and impaired coordination. Side effects are dose dependent and may prove useful to the clinician to titrate dosages. Psychomotor deficits, such as memory impairment, are magnified in the geriatric population, owing to decreased biotransformation, decreased clearance, and increased receptor sensitivity. As a CNS depressant, benzodiazepines should be avoided with other depressants, such as opioids, alcohol, or centrally acting muscle relaxants. Other contraindications include myasthenia gravis, acute narrow-angle glaucoma, or any medications of CYP 4503A4 substrates (eg, grapefruit juice, azole antifungals, erythromycin, calcium channel blockers). Another concern with benzodiazepines is the development of tolerance and physical dependence with prolonged use. Withdrawal symptoms include anxiety, agitation, restlessness, insomnia, and seizures. Clinicians can minimize the negative effects of physical and psychological dependence by limiting the course of therapy to no more than 4 weeks. In light of these adverse effects, benzodiazepines are not the first-line pharmaceutical treatment of choice for TMD, but are an alternative for refractory TMD symptoms.
Antidepressants
Antidepressants have been well-supported to show the effectiveness in the management of pain arising from TMD. The major classes of antidepressants are TCAs, selective serotonin reuptake inhibitors monoamine oxidase inhibitors, and dual selective norepinephrine and serotonin reuptake inhibitors. The mechanism of action of antidepressants for analgesia is not clear, but some investigators suggest that their action on the neuronal circuits that regulate emotion show improvements in pain symptoms, even in the absence of concomitant depression. Although selective serotonin reuptake inhibitors are shown to have improved side effects, TCAs and selective norepinephrine and serotonin reuptake inhibitors display superior pain relief compared with the others. Commonly prescribed TCAs and selective norepinephrine and serotonin reuptake inhibitors include amitriptyline, nortriptyline, duloxetine, and venlafaxine.
To study the analgesic efficacy for TMD, a double-blind study of chronic patients with TMD pain concluded that low-dose amitriptyline (25 mg once per day for 14 days) significantly improved VAS pain scores during treatment and up to 1 week after treatment compared with placebo. Although higher doses of amitriptyline are commonly prescribed to control depression, increased dosage of amitriptyline to 50 to 75 mg/d did not increase analgesic effects.
TCAs, such as amitriptyline, can produce unwanted anticholinergic side effects, including sedation, dizziness, blurred vision, constipation, and dry mouth. Exogenous epinephrine may cause adverse cardiovascular effects, and therefore dental anesthetics with epinephrine should be limited to 0.04 mg (2 carpules containing 1:100,000 epinephrine) per appointment for patients taking TCAs. Furthermore, TCAs are absolutely contraindicated in patient’s taking monoamine oxidase inhibitors owing to potential lethal serotonin syndrome causing confusion, fever, ataxia, myoclonus, and severe hypertension. Although antidepressants are effective and safe as therapy for TMD, it is recommended for prescribing clinicians to comanage antidepressants with the patient’s physician for long-term use and supervision of side effects. Last, antidepressants require strict follow-up to not only assess efficacy and side effects, but also patient compliance because it may take up to a few weeks before therapeutic effects are seen clinically. However, not all patients respond to TCAs or other antidepressants; alternatives, such as anticonvulsants (eg, gabapentin), may prove useful for these resistant patients.
Anticonvulsants
Anticonvulsant medications are frequently prescribed for neuropathic pain, including orofacial pain and TMD. Medications in this class commonly prescribed for TMD include gabapentin and pregabalin. As structurally similar medications, gabapentin and pregabalin act in the CNS by inhibiting specific voltage-gated calcium channels causing a decrease in the release of excitatory neurotransmitters, such as glutamate and substance P. The decrease in these excitatory neurotransmitters diminishes neuronal hyperexcitability and abnormal synchronization, promoting antiseizure activity, analgesia, and anxiolysis.
In a double-blind, 12-week randomized controlled clinical trial, investigators demonstrated that gabapentin showed significant pain decrease on a VAS pain score versus placebo for myogenous TMD. After the initial dose of 300 mg/d, patients’ dose was increased by 300 mg every 3 days until pain was controlled with no adverse effects, with a maximum dose of 4200 mg. There were significant decreases in spontaneous pain by week 8 (mean dose, 3315 mg/d) and in the number of tender sites by week 12 (mean dose, 3426 mg/d).
Notable side effects of gabapentin include dizziness and drowsiness. Other adverse effects are memory impairment, xerostomia, peripheral edema, and hypoventilation. Contraindications for gabapentin are patients with depression, myasthenia gravis, severe chronic kidney disease, and pulmonary disease. Although anticonvulsants are not a first-line treatment for TMD, they may be useful as adjuvant analgesics in patients who have a history of failed TMJ surgeries or patients with longstanding unremitting pain.
Opioids
Although there are recent and emerging studies on the efficacy of arthrocentesis and intra-articular injections of morphine to manage TMD, there is a gap in the literature supporting oral or subcutaneous opioids in the use of chronic orofacial pain. Nonetheless, opioids may be considered acceptable therapy in a small subset of patients who have persistent TMD pain after failure of relief of symptoms after surgery or implants. Common opioids prescribed for chronic pain include oral morphine, oxycodone, hydromorphone, and transdermal fentanyl patches.
Opioids can cause patients to have physical dependence and tolerance, along with other side effects, including sedation, dizziness, nausea, vomiting, constipation, and respiratory depression. Patients may exhibit drug-seeking behavior by reporting TMD pain. Clinicians should perform an assessment of patients’ previous drug use and past and current psychiatric status, often in consultation with a behavioral medicine specialist. Additionally, clinicians should establish treatment goals with patients, including realistic goals for pain and function, and consider how therapy will be discontinued if benefits do not outweigh the risks. Contraindications for opioids include patients taking other CNS depressants, such as spasmolytics, benzodiazepines, antidepressants, and antipsychotics, owing to the additive sedative effects.
With the lack of data on the efficacy of opiate analgesics and its adverse effects of dependence, tolerance, and others mentioned elsewhere in this article, nonopioid pharmacologic therapy should be considered, if not exhausted, before initiating opioid therapy ( Table 1 ). More information on prescribing opioids for chronic pain can be found in the 2016 guidelines from the Centers for Disease Control and Prevention.
