This article aims to provide the practitioner with therapeutic options to treat a broad spectrum of acute and chronic orofacial pain syndromes. The focus will be nonsurgical that the oral health care physician can implement to treat this population of patients. The World Health Organization estimated that more than 1 in every 3 people suffers from acute or chronic pain. This article is primarily devoted to medication management once the diagnosis of neuropathic pain, a true trigeminal neuralgia, or a variant of trigeminal neuralgia often referred to as traumatic neuropathic pain or traumatic trigeminal neuralgia.
Key points
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Chronic orofacial pain is multifactorial in origin, affecting lives in negative, even debilitating ways. There are many powerful therapeutic options to treat a broad spectrum of both acute and chronic orofacial pain conditions.
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The oral health care clinician must be diligent when diagnosing clinical presentations as odontogenic and other dental conditions as a primary versus secondary cause of orofacial pain. A careful deciphering of signs and symptoms for an accurate diagnosis will set the foundation for specific treatment to improve long-term prognosis and resolution of most of the orofacial pain conditions.
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Orofacial pain can be the result of a diverse set of pain disorders. When general dentists and especially oral and maxillofacial surgeons consult, many Orofacial pain patients will require treatment for a neuropathic pain disorder. Once a definitive diagnosis has been established for the patient’s pain disorder, the primary approach of pain management is through astute pharmacotherapy and potentially invasive and noninvasive techniques.
Introduction
General dentists and especially oral and maxillofacial surgeons will oftentimes be asked to consult with patients who have had a history of ongoing acute and chronic facial and oral pain. Many of these patients will have had multiple root canal therapies, extractions, and other assorted treatments for possible temporomandibular joint (TMJ) disorder, before they visit surgeons’ offices. After repeated visits to multiple practitioners, they will ultimately be diagnosed with a neuropathic pain (NP) disorder. NP conditions are a definitive entity that must be well understood by oral and maxillofacial surgeons along with possible treatment approaches. This article is primarily devoted to medication management once the diagnosis of NP, a true trigeminal neuralgia (TN), or a variant of TN often referred to as traumatic neuropathic pain (TNP) or traumatic TN. A more in-depth discussion regarding the physiologic factors involved in the etiology of TNP is addressed in many other textbooks on the treatment of chronic orofacial pain (OFP) patients.
The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Pain has significant effects on the physiology, psychology, and sociology of the population. The World Health Organization (WHO) estimated that more than 1 in every 3 people suffers from acute or chronic pain. ,
OFP refers to pain associated within the head and neck regions, soft and hard tissues, as well as both extraorally and intraorally. Jeffrey P Okeson, an international authority on OFP, divides OFP into physical (axis 1) and psychological (axis 2) conditions. Chronic OFP includes such phenomena as atypical odontalgia, burning mouth syndrome (BMS), and idiopathic facial pain. These entities are often considered diagnoses of exclusion, thus definitive diagnosis and therapeutic solution is a challenge. Physical conditions include disorders of the TMJ and the local musculoskeletal structures (eg, masticatory muscles, tendons, cervical spine); intraoral dental and pulpal pain of somatic origin; NPs, which include episodic (eg, TN) and continuous (eg, peripheral and centralized mediated) characteristics; and neurovascular disorders/headaches (eg, migraine and temporal arteritis). In addition, OFP can often be a presenting symptom for systemic illnesses such as chronic pain seen in fibromyalgia, gastroesophageal reflux disease (GERD)/irritable bowel disease, posttraumatic stress disorder or other psychological disorders, myocardial ischemia and cancerous lesions locally or elsewhere in the body.
The oral health care clinician must be diligent when diagnosing clinical presentations as odontogenic and other dental conditions as a primary versus secondary cause of OFP. A careful deciphering of signs and symptoms for an accurate diagnosis will set the foundation for specific treatment to improve long-term prognosis and resolution of most of the OFP syndromes.
The aim of this chapter is to provide the practitioner with therapeutic options to treat a broad spectrum of both acute and chronic OFP syndromes. The focus will be nonsurgical (pharmacologic management) that the oral health care physician can implement to treat this population of patients.
Principles of pharmacologic treatment for NP
Chronic NP is multifactorial in origin, affecting lives in negative, even debilitating, ways that oftentimes require pharmacologic modality of treatment for management. The International Association for the Study of Pain (IASP) defines NP as pain caused by a lesion or disease of the somatosensory system. NP is therefore a clinical descriptor rather than the diagnosis, differentiated by positive or negative symptoms. Positive NPs would be separated among stimulus-dependent, stimulus-independent, or paresthesias. The trigger for such positive NP could be perioral touch or cold on patients with orofacial NP. Negative NPs are described as numbness, loss of reflexes, and weakness in the involved nerve area. On the face, orofacial NP typically follows the dermatome of the trigeminal nerve. There are 5 well-studied mechanisms contributing to NP conditions identified, including ectopic activity, peripheral sensitization, central sensitization, impaired inhibitory modulation, and activation of microglia. Duration of pain will indicate different disease processes. Episodic NP, characterized by shooting pains lasting seconds to minutes, is typical of TN or glossopharyngeal neuralgia. Whereas, continuous NP arises because of neural structures and can vary in intensity without resolution, as in atypical odontalgia or nerve injury-neuromas. Treatment modalities are directed at the different etiologies including trauma, infection, chemotherapy, surgery, neurotoxins, inflammation, and tumor infiltration.
Local anesthesia may be helpful in discerning between peripheral or central origin of NP. Only once a nonpharmacologic, noninvasive trial of treatment for NP has failed, should pharmacologic modalities be used. When a single pharmacologic agent has failed to provide adequate pain relief, oftentimes a multimodal approach is taken because of the risk of side effects when increasing dosage. Through numerous review articles, different pharmacologic treatment algorithms are available.
With numerous pharmacologic agents available, special attention should be directed to the origin of the NP—such as, peripheral neuropathy secondary to diabetes, postherpetic neuralgia (PHN), central neuropathy secondary to multiple sclerosis, NP status after spinal cord injury, HIV, chemotherapy-induced peripheral neuropathy, and so forth—which would help identify best pharmacologic agent with the highest potential for reducing NP. Although different neuromodulators have been shown to provide transient relief, there is a lack of understanding regarding long-term usage of these drugs.
Analgesic drugs are typically the primary choice for relief in patients suffering from NP. , Morphine, like the body’s endogenous endorphins, acts on the central nervous system (CNS) to modify pain signaling. Tricyclic antidepressants (TCAs) can act to increase catecholaminergic analogs that travel systemically to targets for relief by both acting as membrane stabilizers and trans-synaptic effects. , The salicylates can act as anti-inflammatory agents that inhibit cyclooxygenase pathways with inhibition of prostaglandins. Anticonvulsant medications can act as membrane stabilizers because they suppress hyperexcitability of the axonal membrane. It is important for the clinician to apply careful dosing because of the potential for side effects, allergic reactions, and risk of drug dependence. Pharmacotherapy options are broad and varied, based on a diversity of analgesics whose dosing and concentrations vary with the type of NP being treated.
Acute facial pain versus NP
Within OFP, it is important to differentiate acute facial pain from neuropathic pain.
Acute Facial Pain
Pain presenting acutely is often relatively easy to definitively diagnose and effectively manage. The underlying sources include odontogenic, periodontal oral mucosa, hard tissue, or a combination of multiple of these sources. Odontogenic pain is often short in duration and sharp, then progresses to a dull ache depending on whether there exists reversible or nonreversible pulpitis. Pain within the mucosa presents as raw (sore or tender), aching, and burning. Periodontal disease also presents as a continuous or intermittent ache.
Other etiologies include maxillary sinusitis and salivary gland disorders. Maxillary sinusitis may or may not have pain associated with etiologies such as oral antral communications and bacterial/viral disease. Salivary diseases are often due to obstruction of ducts with consequent infection. Pain pathways from the trigeminal system will not only innervate the site but refer to other areas of the head and neck. Imaging/ultrasound can aid in localization and evaluation for surgical intervention.
Neuropathic Pain
NP is defined as pain caused by a lesion or disease of the somatosensory nervous system. NP is diagnosed commonly with up to 25% to 35% presenting to facial pain centers across the United States and Europe. Etiologies of NP include trauma, infection, chemotherapy, surgery, neurotoxins, inflammation, and tumor infiltration. Studies have described NP as dysfunctional pain due to afferent stimulation that can be both spontaneous and stimulus-dependent. The trigger can be perioral stimuli and/or environmental like ambient cold and touch. NP commonly presents on the face along the dermatome of the trigeminal nerve. Further classification separates NP into episodic and continuous. Episodic is characterized by sudden electric-like, as well as shooting pains that can last over seconds to minutes. Continuous NP is pain originating in neural structures constant and varies in intensity without total remission. Episodic disorders include TN and glossopharyngeal neuralgia, whereas continuous pain disorders can arise because of injury of nerves in both the peripheral and CNS, that is, neuromas and atypical odontalgia.
An understanding of the pathophysiology of episodic and continuous NP provides the clinician with a strong rationale for choices of pharmacologic therapy. Box 1 lists the pharmacologic therapies broken into 3 main tiers that vary in the mechanism of action due to site of neurologic innervation, that is, synapses, membrane stabilizing agents, and receptor agonists/antagonists. Each agent can be administered either by topical application or systemically. All agents may be preceded by the use of local anesthesia to localize peripheral versus central origin. ,
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Synaptic cleft
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Benzodiazepines
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Clonidine
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Tricyclic antidepressants:
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Amitriptyline
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Nortriptyline
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Imipramine
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Serotonin reuptake inhibitors/Norepinephrine selective reuptake inhibitors:
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Venlafaxine
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Duloxetine
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Trazodone
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Milnacipran
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Membrane stabilizing drugs
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Anticonvulsants:
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Carbamazepine
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Oxcarbazepine
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Phenytoin
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Gabapentin
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Pregabalin
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Lamotrigine
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Valproic acid
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Topiramate
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Tiagabine
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Zonisamide
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Additional pharmacologic agents
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Opioids
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Local anesthetics
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Corticosteroids
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NSAIDs:
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Aspirin
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Acetaminophen
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Antifungal agents
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Antiviral
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BOTOX
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Antioxidants:
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Alpha lipoic acid
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Salivary stimulants:
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Pilocarpine
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Cevimeline
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Topical agents
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Lidocaine patches
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Proparacaine
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Streptomycin/Lidocaine
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Capsaicin
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Topical NSAIDs
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Antidepressants
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Anticonvulsants
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Botulinum toxins
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Trigeminal neuralgia
Trigeminal neuralgia (TN), or tic douloureux, is an uncommon syndrome characterized by chronic, recurrent attacks of intense, lancinating pain localized to the dermatome of the trigeminal nerve. The trigeminal nerve is the fifth cranial nerve (CN V) that provides both motor and sensory functions of the face distributed by the 3 main branches, the ophthalmic, maxillary, and mandibular nerves. One or multiple branches of the trigeminal nerve can be involved, with the maxillary nerve involved the most and the ophthalmic nerve the least. A focal vascular compression of the trigeminal nerve root close to its point of entry into the pons is the most common cause of TN. The International Headache Society (INS) divides TN into 2 categories. The typical type I TN (TN1) presents as a sporadic but severely burning facial pain with each episode lasting up to 2 minutes. The onset of pain may occur in clusters that persist for several hours at a time. In contrast to TN1, the atypical type II TN (TN2) presents as a constant stabbing pain with less severity. , Any type of stimuli such as eating, drinking, light touching, washing, talking, smiling, draughts of wind, and applying make-up can trigger TN. The cutaneous perception of temperature and light touch can be slightly impaired within the affected area.
The annual incidence of TN is reported as 4.3 per 100,000 population, with slight female predominance. The male-to-female prevalence ratios range from 1:1.5 to 1:1.7. The overall prevalence is 0.015%. Advanced age is a risk factor. The peak incidence is at 60 to 70 years of age, and is unusual before age 40 years. However, it can occur at any age, including rare cases in children. TN is predominantly unilateral, though rarely can be bilateral. No racial predilections are associated with the disease. Most cases are sporadic with rarely reported familial inheritance. ,
The main theory of pathophysiology of TN involves neurovascular compression of the nerve root at the prepontine cistern. Primary compression results from the direct compression of the nerve without a secondary cause, whereas secondary compression can be caused by meningiomas, vestibular schwannomas, aneurysms, arteriovenous malformations, or epidermoid cysts. Compression of the trigeminal nerve root may be mediated by the tumor itself, by an interposed blood vessel, or by distortion of the contents of the posterior fossa with displacement of the nerve root against a blood vessel or the skull base. ,
The NP caused by TN is also believed to be caused by nerve demyelination leading to ephaptic transmission of impulses, which may transfer from nearby light touch to pain fibers. Certain conditions such as multiple sclerosis can lead to a plaque of demyelination encompassing the root entry zone of the trigeminal nerve in the pons. Carcinomatous deposits within the nerve root and trigeminal amyloidomas can both contribute as infiltrative disorders of the trigeminal nerve. Nondemyelinating lesions such as infarct or angioma can also lead to TN. Although familial TN is rare, there is a reported association between Charcot-Marie-Tooth disease and TN.
The International Classification of Headache Disorders categorizes TN into classical, secondary, or idiopathic types. In classical TN, paroxysmal attacks of noncontinuous pain last from a fraction of a second to 2 minutes involving one or more divisions of the trigeminal nerve. The pain is caused by neurovascular compression without any other neurologic defects. Secondary TN is associated with continuous pain triggered by underlying pathologies such as arteriovenous malformation, certain brain tumors, or multiple sclerosis. Idiopathic TN is diagnosed when there are no other clear causes. MRI is the standard imaging study to evaluate any neurovascular compression, brain tumors, or AV malformations. ,
Painful post-traumatic trigeminal neuralgia
Painful post-traumatic trigeminal neuralgia (PTTN) is one variant of TN which occurs secondary to trauma, brought about by common dental procedures. It is described as a “moderate-to-severe continuous burning pain” and can have a significant impact on daily function and a significant psychological impact on the affected patient. The domain of the trigeminal nerve encompasses the face, eyes, tongue, nose, and therefore heavily impacts our social lives. The pain may be similar to a toothache and lead to dental treatments that are not necessary. In many cases, it is overwhelming and relentless for the patient. From all cases of TN about 40% may be classified as PTTN. It has been described under several names including “phantom tooth pain,” “atypical facial pain,” or “atypical odontalgia.” The term “painful post-traumatic trigeminal neuralgia” is the most recent description by the International Headache Society.
Pulp extirpation, apicoectomy, other routine endodontic procedures, and tooth extraction can all precede the finding of PTTN. During a tooth extraction, iatrogenic trauma can be imposed upon the inferior alveolar nerve, lingual nerve, and branches of the maxillary nerve. Various reasons regarding the etiology of PTTN are brought to attention in current literature. Some noted reasons are self-explanatory and include poor surgical protocol being used during tooth extraction, and poor technique when administering injection of local anesthetic. Other causative factors include a long preoperative pain duration, previous chronic pain issues, and a history of pain during other treatments.
Some observational studies of PTTN found a higher distribution in males (60.4%) compared to females (39.6%) and found a large incidence of PTTN related to extractions of the mandible (79.2%). The reason for this is likely due to mandibular molars being close to the inferior alveolar nerve, lingual nerve, and other branches of the mandibular nerve.
The nature of severity of symptoms a patient is encountering (pain, psychological issues) will define the approach taken toward management. Treatment (medical or surgical) is often dependent on the nature of injury, the patient’s symptomatic findings, and length of injury. There is known to be a limited time to optimize IAN injury resolution as a result of implants, endodontic procedures, or extraction. One report suggests that removal of implants that impose injury to the IAN within 30 hours may assist in neuropathy resolution. The current indicated therapies for acute neuropathy include corticosteroids and anti-inflammatory medications. For those patients suffering from chronic NP due to injury, possible treatment options include topical local anesthetic, anticonvulsants for stimulus or spontaneous pain, TCAs, or serotonin reuptake inhibitors for constant/elicited burning pain. Of all patients who suffer from PTTN, 15% are using long-term systemic medications and 18% of patients are using topical medications. Botulinum toxin injections are sometimes poorly tolerated and can pose a risk of facial palsy as a side effect of treatment.
Carbamazepine and oxcarbazepine
The first-line medications for long-term treatment of TN are the antiepileptic medications carbamazepine and oxcarbazepine. There is controversy regarding which of the 2 medications is more efficacious and better tolerated by patients; however, there is substantial evidence that there is substantial variability of responses by patients taking the medications. This suggests and indicates that if one medication is not effective, the other should be tried next. However, there is caution indicating that cross-reactivity may occur in instances where one of the medications causes an allergic reaction. These medications are typically titrated slowly to the optimal symptom-eliminating dose while patients are monitored for any side effects that may arise. Patients taking these medications are instructed to alter the dosage in variance with pain severity and side effects. It is possible for patients to experience either partial or complete remission of symptoms.
In cases where there is a poor patient response to carbamazepine or oxcarbazepine, many alternatives exist. Lamotrigine, gabapentin, botulinum toxin type A, pregabalin, or phenytoin are all recognized treatments that may be adjunctive or used as monotherapies. The use of botulinum toxin type A is the most recent addition to the medical treatment portion found in the European Academy of Neurology guidelines, although studies are still pending and treatment results have not been finalized. Local anesthetics, greater occipital nerve blocks, and topiramate are considered second-line options; however, the evidence is limited and trials are needed ( Table 1 ).
| Treatment | Starting Dose | Dose Range | Typical Daily Dose Needed | Frequency | Titration | Tapering | Comments, Side Effects |
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| Carbamazepine (First-line) | 200–400 mg | 200–1800 mg | 200–1800 mg | 2–4 times a day | Increase by 200 mg every third day | Decrease by 100 mg every 7–14 d | Laboratory work and ECG are mandatory before initiating treatment. A slow-release preparation is also available. If there is no efficacy from carbamazepine, treatment can be switched directly to the equipotent dose of oxcarbazepine (200 mg carbamazepine = 300 mg oxcarbazepine). There can be allergic cross-reactivity between carbamazepine, oxcarbazepine, and lamotrigine. Long-term treatment is associated with low bone mineral density. Consider vitamin D and calcium supplements. Carbamazepine decreases the plasma concentration of warfarin and oral contraceptives (and other drugs) and can cause hyponatremia. Measure sodium after 1 mo and then regularly. Consider decreasing the dose in patients with reduced liver function. Exert caution with drug combinations with other anticholinergic drugs, especially in older people or people with dementia, as there is a cumulative effect of central and peripheral side-effects when using multiple anticholinergic drugs. Do not combine with monoamine oxidase inhibitors. It is contraindicated in atrioventricular block (and other rarer conditions). Common side-effects include, but are not limited to, tiredness, dizziness, ataxia, nausea, and leukopenia. Carbamazepine can affect the ability to drive. |
| Oxcarbazepine (First-line) | 300–600 mg | 300–2700 mg | 300–2700 mg | 2–4 times a day | Increase by 300 mg every third day | Decrease by 150 mg every 7–14 d | Laboratory work and ECG are mandatory before initiating treatment. If there is no efficacy from oxcarbazepine, treatment can be switched directly to the equipotent dose of carbamazepine (200 mg carbamazepine = 300 mg oxcarbazepine). There can be allergic cross-reactivity between carbamazepine, oxcarbazepine, and lamotrigine. Long-term treatment is associated with low bone mineral density. Consider vitamin D and calcium supplements. Exert caution in cardiac insufficiency and conduction disorders. Oxcarbazepine might decrease the plasma concentration of oral contraceptives. Oxcarbazepine often causes hyponatremia. Measure sodium after 1 mo and then regularly. Decrease dose in patients with severe liver disease. Titrate slowly in patients with reduced kidney function. Exert caution at drug combinations with other anticholinergic drugs, especially in older people or people with dementia, as there is a cumulative effect of central and peripheral side effects when using multiple anticholinergic drugs. Common side effects include, but are not limited to, tiredness, dizziness, headache, double vision, ataxia, and nausea. Oxcarbazepine can affect the ability to drive. |
| Pregabalin (Second-line) | 150 mg | 150–600 mg | 150–600 mg | Twice a day | Increase by 150 mg every 7 d | Decrease by 150 mg every 7–14 d | Decreased dose recommended in patients with decreased kidney function. Exert caution advised in patients with cardiac insufficiency. Extreme caution when combined with opioids or other CNS depressants. Common side effects include headache, dizziness, and gastrointestinal symptoms. |
Nonsteroidal Anti-inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are best used orally for continuous NP conditions such as peripheral neuritis, atypical odontalgia, or PHN. Neuropathy due to inflammation mediated by the production of cytokines, such as due to implant placement in the case of orofacial NP, is described as peripheral neuritis. A commonly used delivery method is topically, like for peripheral trigeminal neuritis. Using topical drug delivery method can be effective locally, but also minimizes the possibility for undesired systemic adverse events. Topical NSAIDs have been shown effective in treating pain due to TMJ disorder without producing the typical gastric side effects seen with NSAIDs. Topical diclofenac (Voltaren Gel 1%) was shown equally as effective compared to 100 mg oral diclofenac.
Lyrica—Pregabalin
Pregabalin (Lyrica) is an anticonvulsant that inhibits the release of excitatory neurotransmitters like glutamate by combining with the α2δ subunit of the voltage-gated calcium channel, also used to relieve continuous NP. It is considered to be a first-line agent for the treatment of NP. , , The total daily dose recommended is 300 to 600 mg divided into two daily doses. The dosage should be titrated up over 1 to 2 weeks from 150 mg per day divided into 2 to 3 doses. Major adverse effects of pregabalin include sedation, dizziness, weight gain, edema, and blurred vision. , It may be prudent to track a patient’s weight, especially if they are diabetic. Owing to the dose-dependent sedation and dizziness effects, it is wise to start at lower doses and titrating up as needed. Renal insufficiency should also be taken into account when dosing, which can be made in relation to creatinine clearance. A combination therapy of duloxetine (SNRI) with pregabalin or gabapentin can be considered for second-line therapy of TN. Pregabalin has linear pharmacokinetics, making dosing easier than with gabapentin. Pregabalin and gabapentin are also effective in treating postherpetic TN pain and numbness, and diabetic neuropathy , ( Fig. 1 ; Table 2 ).
