Anticonvulsant agents used for neuropathic pain including trigeminal neuralgia
6.1 Four Common Orofacial Neuropathic Pains
When you begin to consider using anticonvulsant medications in pain management, the presumptive pain diagnosis should be neuropathic in origin. In general anticonvulsants are not good analgesics but they will decrease hyperactive neuronal activity.1 This means that if you are treating nociceptive pain secondary to inflammation, infection, or recent physical injury, analgesic medications are logical. However, when a nerve has undergone neuropathic conversion and is firing spontaneously or firing with minimal input because it is sensitized, this would logically indicate the need for anticonvulsants. The specific mechanism underlying the various neuronal changes that occur with neuropathic pain conversion is discussed in Chapter 17. To make sure the distinction between nociceptive pain and neuropathic pain is understood, this chapter starts with a review of the four common neuropathic pain disorders that affect the trigeminal system. These disorders can largely can be divided into one of the following four categories: (1) neuralgias (e.g., trigeminal and other cranial neuralgias), (2) neuritis (e.g., localized nerve trauma, nerve inflammation, immune-mediated neuritis, or cancer-related perineural invasion2–6), (3) neuroma (post-nerve-branch transection), or (4) neuropathy (e.g., traumatic neuropathy, postherpetic neuralgia,7–11 diabetic neuropathy,12,13 neuropathy induced by acquired immunodeficiency syndrome [AIDS],14 and idiopathic chronic trigeminal neuropathy15–19). These neuropathic disorders are listed in Table 6.1. The second part of this chapter discusses the various anticonvulsant drugs available for use in the management of neuropathic trigeminal pain. This chapter does not cover the nonpharmacologic treatment methods used in management of neuropathic pain.
|Condition||Pain features||Causes or mechanisms|
||Along distribution of affected nerve
Electric-like, stabbing, sharp
Lasting a few seconds to minutes
|Vascular compression and abrasion of the nerve root that results in demyelination of nerve fibers leading to ectopic nerve activity|
|Neuritis (peripheral nerve)||Continuous, unremitting, and burning||Localized nerve trauma
Cancer-related perineural invasion
Release of inflammatory mediators and cytokines
|Neuroma||Electric-like, stabbing, sharp; triggered by physical contact or movement||Nerve transection|
|Postherpetic neuralgia||Burning, recurrent, and persistent||Nerve damage induced by herpes zoster infection|
|Diabetic neuropathy||Continuous burning, tingling pain, paresthesia||Metabolic and vascular abnormalities resulting in nerve damage|
|Neuropathy induced by AIDS||Variable||HIV-induced nerve damage|
|Idiopathic chronic trigeminal neuropathy||Continuous burning, aching, or both||Most likely peripheral and/or central sensitization|
|Chronic trigeminal neuropathy sympathetically maintained||Continuous burning, aching, or both||Nociceptor sensitization to catecholamines (e.g., norepinephrine)|
AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus.
6.1.A Trigeminal Neuralgia and Other Cranial Neuralgias
When literally translated, the word neuralgia simply means “nerve pain,” but is also has a narrower medical meaning. The word neuralgia implies you are dealing with a pain that is sharp, brief, and electric-like or stabbing in character, usually unilateral and severe, and it stays within the distribution of the involved nerve branch or branches. When the pain is continuous, or burning, multidivisional, or just does not fit the preceding description, we would describe the pain (if neuropathic in nature) as a neuropathy, not as neuralgia.
The most common neuralgia in the orofacial region is trigeminal neuralgia (also known as tic douloureux).
The International Headache Society defines trigeminal neuralgia as a painful unilateral affliction of the face, characterized by brief electric-shock-like pain limited to the distribution of one or more divisions of the trigeminal nerve. Pain is commonly evoked by trivial stimuli, including washing, shaving, smoking, talking, and brushing the teeth, but may also occur spontaneously.20 The pain is abrupt in onset and termination and it usually last 15–20 seconds. It commonly afflicts a single division of the trigeminal nerve. In the vast majority of trigeminal neuralgia cases, it affects either the maxillary division or the mandibular division, with the ophthalmic division affected in less than 20% of cases. The unique feature of trigeminal neuralgia is that the pain can be triggered by a light innocuous touch of a perioral or intraoral site. After the pain attack subsides there is usually a pain-free period between attacks where the same innocuous stimulation does not trigger pain.
This condition is seen far more often in individuals in their fifth or higher decade. The likely link between aging and trigeminal neuralgia is that the intracranial artery closest to the trigeminal nerve root becomes stiff and elongated in the elderly and these arteries can produce an intracranial vascular compression or abrasion of the fifth nerve root as it exits from the brain stem. The other known causes of are neural damage due to multiple sclerosis.21,22 Multiple sclerosis associated trigeminal neuralgia is reported in 2–4% of patients.23–25 Because multiple sclerosis develops in much younger patients and their neuralgia is more frequently bilateral, any young trigeminal neuralgia patient (less than 50 years old) or any with bilateral pain should be tested for this disease. Finally, neural compression due to an intracranial tumor is also a possibility (e.g., cerebello–pontine angle tumors such as acoustic tumors, meningiomas, cholesteatomas, schwannomas, and neurofibromas) and is found in 2% of patients who present with typical trigeminal neuralgia.26 Occasionally oral and pharyngeal cancer can invade into the trigeminal nerve. Often this type of pain gives rise to sensory changes and constant pain, in other words, trigeminal neuropathy.27
The major limitation in diagnosing trigeminal neuralgia is that imaging of the nerve via magnetic resonance imaging (MRI) or computed tomographic (CT) scans is not yet reliable since usually the vascular abrasion cannot be easily seen, given the resolution of current imaging methods. Nevertheless, in 2008, the American Academy of Neurology in conjunction with the European Federation of Neurological Societies (EFNS) published a guideline on the diagnosis and treatment of trigeminal neuralgia (TN).28 The guideline recommends that physicians consider sending all patients with trigeminal neuralgia for MRI or trigeminal reflex testing, since up to 15% of patients have an underlying structural cause such as a tumor.29
The EFNS guideline recommends carbamazepine as first-line treatment, with oxcarbazepine as a possible alternative, and it goes on to suggest that surgery be considered for any medication-refractory case. See Sections 6.2.A and 6.2.B for details about the proper use of these medications.
Other Cranial Neuralgias
There are other cranial nerve (CN) neuralgias, which produce similar pains to trigeminal neuralgia.
For example, geniculate neuralgia (also know as nervus intermedius of CN VII) is a brief severe ear and preauricular pain triggered by ear canal touch, swallowing, or talking.30,31 Glossopharyngeal neuralgia (CN IX) is a brief severe pain in the tonsillar, tongue-base, oropharyngeal region.32 Vagal neuralgia, which is usually associated with glossopharyngeal neuralgia, presents with similar symptomatology but it might also present with vocal cord dysfunction, such as hoarseness.33,34 Superior laryngeal neuralgia (CN X) is a brief severe pain in the laryngeal, thyroid region and is triggered by swallowing, yawning, or talking.35,36
The etiology for these other facial-region neuralgias are not firmly established, but the same causes of trigeminal neuralgia should be suspected, namely, vascular compression, central nervous system (CNS) tumor, and multiple sclerosis
As with trigeminal neuralgia, MRI imaging is the primary diagnostic procedure, followed by a trial of an anticonvulsant to see if the neuralgia is suppressed effectively or not.
While these neuralgias are rare and can produce pain that is identical to that of trigeminal neuralgia, they only differ by the location of the pain.
6.1.B Trigeminal Neuritis
As this term implies, there is inflammation of a nerve and here we discuss four aspects of this condition: mononeuritis, which usually implies local pathology; polyneuritis, which implies more generalized pathology; the transformation of an acute neuritis to a long-lasting neuropathy disorder; and the special case of cancer-induced neuritis.
The term mononeuritis is used when an individual nerve or nerve trunk is inflamed.
The symptoms of neuritis are pain and dysesthesia (tingling) or numbness. Moreover, it is known that neuritis leads to hypersensitivity.37 These symptoms are continuous.
For the mononeuritis disorders, the first cause that should be suspected is trauma (e.g., fracture, intraneural injection, third-molar extraction, orthognathic surgical manipulations, implant-induced compression), then infection (bacterial or viral) or inflammation of the nerve. The three most common infections to affect the trigeminal nerves are dental abscess, sinus infection, and herpes zoster (shingles).
There are no specific imaging procedures that can detect inflammation of a peripheral nerve. Fortunately, mononeuritis pains have an acute onset and the cause is usually obvious based on the examination and history. Those caused by neural compression are also easy to figure out if the source is exogenous (i.e., dental implant). However, when neural abrasion comes from osseous growth or other slowly progressive external pressure (i.e., overlying tendons and blood vessels) the symptoms are slow to develop and more difficult to figure out.
Suppression of the inflammatory reaction is logical and using methylprednisolone is commonplace if an acute neuritis is present. See Chapter 12 for detailed instructions on the proper use of systemic methylprednisolone.
Polyneuritis Involving the Trigeminal Nerve
A neural inflammation that involves two or more nerve trunks in separate areas is called a polyneuritis. The most common polyneuropathy that affects the trigeminal nerve primarily is trigeminal sensory neuropathy (TSN), which is a multifactorial inflammatory disorder of the trigeminal nerve causing sensory dysfunction (numbness, pain). TNS patients usually present with symptoms such as unilateral or bilateral sensory loss of one or more divisions of the trigeminal nerve. The numbness can be either painful or nonpainful. Because of the association with mixed and undifferentiated connective tissue disease (see Etiology) there may also be complaints of Raynaud’s phenomenon, polyjoint arthritis, and sometimes muscle weakness. Diabetic neuropathy is also a common known cause of neuropathy and can produce both an acute (usually reversible) nerve inflammation as well as chronic (irreversible) neuropathic changes in the trigeminal nerve. Often the symptoms of diabetic-induced neuritis first occur in the fingers and toes (numbness, tingling, weakness). There are multiple immune-related neuritic conditions that induce these symptoms, although the location of the symptoms is varied.
Trigeminal sensory neuropathy is a condition that has been associated with Sjögren’s syndrome, undifferentiated and mixed connective tissue disease, and scleroderma, which are all considered to be connective tissue disorders.38–44 The source of the underlying neural dysfunction is thought to be autoimmune because of this association.45 Unfortunately, the symptoms of facial pain and numbness can and do occur before a clear serologically confirmed clinical diagnosis of one of these connective tissue diseases, by several years and with all sensory deficits; vigilance for cancer-induced neural dysfunction must be maintained. Other causes of polyneuritis include diabetes or a generalized autoimmune disease such as Guillain–Barré syndrome; chronic inflammatory demyelinating polyneuropathy and neuropathies associated with vasculitis; and monoclonal gammopathies. Viral-induced polyneuritis is caused by human immunodeficiency virus (HIV); Cytomegalovirus; Poliovirus; hepatitis B or C infections, causing vasculitic neuropathy. Bacteria-induced polyneuritis includes leprosy, diphtheria, Lyme disease, and trypanosomiasis. Nutritional-imbalance polyneuropathies are caused by deficiency of vitamins B12, B1 (thiamine), B6 (pyridoxine), and E. Renal failure polyneuropathy can cause degeneration of peripheral nerve axons as a result of accumulated toxins. Toxin-induced polyneuropathy is caused by alcohol and other toxins (megadoses of vitamin B6, lead, arsenic, mercury, thalium, organic solvents, and insecticides). Medication-induced neuritis and neuropathies include those caused by vincristine and cisplatinum in cancer; nitrofurantoin, which is used in pyelonephritis; amiodarone in cardiac arrhythmias; dideoxycytidine (ddC) and dideoxyinosine (ddI) in AIDS; and dapsone, used to treat leprosy.
Since polyneuropathies have multiple causes many diagnostic procedures are appropriate, depending on the suspected underlying disease; generally polyneuropathies are outside the diagnostic scope of an orofacial pain specialist and referral to a neurologist or infectious disease specialist is appropriate.
Again, depending on the underlying disease that is causing the polyneuropathy, the treatment will vary and is beyond the scope of this chapter. Of course, the neuropathic pain symptoms can be suppressed using anticonvulsants, beginning with gabapentin and moving toward carbamazepine as needed.
Neuritis Conversion to Neuralgia
As mentioned, nerve inflammations cause neuritis (acute pain); although in most cases the neuritis pain will fade as the inflammation resolves, sometimes acute neuritis can convert to chronic neuralgia. One example is postherpetic neuralgia (PHN).
Postherpetic neuralgia is a continuous cutaneous itching, burning pain in the involved nerve division. The conversion into neuropathy also occurs with HIV neuritis and diabetic neuritis.
Postherpetic neuralgia is largely diagnosed by history and clinical examination since there are no physical visible signs with neuralgia.
The treatment of PHN involves topical anesthetics as the primary treatment. The anesthetic is usually applied using patches that allow for transdermal transfer of the anesthetic agents (usually lidocaine) into the painful skin. See Section 6.2.K for details about the proper use of lidocaine.
Cancer-Induced Trigeminal Pain
Cancer-induced trigeminal pain is listed in the neuritis category because, when a cancer invades a nerve, this process causes either acute compression or injury to the nerve.
If a cancer invades a nerve sheath or root this will also induce pain that mimics the previously mentioned disorders (neuritis, neuralgia, neuropathy).
The most common cancers associated with trigeminal nerve are posterior tongue–lateral pharyngeal cancer, causing pain in the lingual nerve, and cancer of the nasopharynx invading the infratemporal region and affecting the trigeminal nerve as it exits the foramen ovale.
The primary diagnostic procedure needed with cancer-induced neurogenous pain is to confirm that the neoplastic tissue is indeed invading the affected nerve, using MRI to identify the shape, extent, and location of the neoplastic mass and its proximity to the nerve.
If the cancer is inoperable, then pain management with opioids is appropriate. See Chapters 4 and 13 for discussions about opioid medication use in cancer patients. If the cancer is operable, obviously, surgical removal is indicated.
6.1.C Trigeminal Neuroma
While there are neuromas that are neoplastic in origin, in this section we are considering only those that occur in peripheral nerves secondary to injury.
As discussed earlier, neural injury can produce an acute neuritis, but sometimes neuritis can result from transection of the nerve, resulting in numbness in the area being supplied by the nerve. Often this results in a degeneration of the nerve and subsequent numbness. If a larger axonal branch of a nerve is transected, then nerve sprouts may form a true neuroma at the proximal nerve stump. A neuroma is a bundle or ball of nerve fibers that may develop after damage to the peripheral nerve such as lacerations, crushing, cuts, or even stretching the nerve. Clinically it can appear as a slowly growing, whitish nodule that sometimes can be palpable; it represents an attempt at nerve reparation. The symptoms include hypersensitivity to light touch and spontaneously active pain. Furthermore, there might be tenderness on percussion, or pressure of the surrounding tissues.46 The most common locations in the jaw are the lingual nerve, inferior alveolar nerve, and auriculotemporal nerve.
Peripheral nerve transections and neuroma growth at the severed trunk are sequelae of trauma, often surgical.
If an inadvertent surgical transection did occur, the probable site of the neuroma is probably known, in which case a small amount of local anesthetic delivered in and around the neuroma will stop the pain. This is more or less diagnostic of the neuroma.
Some neuromas are not highly active and can be treated with mild anticonvulsants (gabapentin or pregabalin), while others are highly active with continuous spontaneous neuronal activity. These can be treated with cryoprobes (freezing injections) in an attempt to desensitize the neuroma.47
6.1.D Trigeminal Neuropathy
As mentioned previously, when neurogenic pain is continuous or burning and does not have a clinically or radiograpically evident pathologic basis in the ganglion or CNS, this pain is potentially a neuropathy. According to the International Association for the Study of Pain, neuropathic pain is, by definition, “pain initiated or caused by a primary lesion or dysfunction in the nervous system.”48 The pain is often described as aching and burning, varying in intensity from moderate to severe. Additionally, it can present with associated symptoms such as sensory loss, weakness, and dysesthesia. We have dedicated an entire chapter to chronic trigeminal neuropathy (see Chapter 17) so our discussion here is limited.
Trigeminal neuropathy usually produces a continuous pain sensation in the dental, alveolar, gingival–mucosal, or cutaneous tissues. This pain is localized to the distribution of the involved trigeminal nerve branch. Such pains have been described as atypical odontalgia, if pain is focused in the tooth–alveolar area. When the pain persists after the tooth is extracted it is described as a phantom tooth pain.
Often the injury or tissue insult that produces this neuropathic problem cannot be clearly identified. For example, the previously described neuritis disorders due to acute injury or inflammation can convert into neuropathic disease due to irreversible changes in the nerve (called peripheral and central sensitization). These sensitization changes are usually divided by the extent of the alteration into the following:
1 Peripheral sensitization Initially the pain is completely blockable with a local anesthetic and is more focal in character;
2 Central sensitization Long-term nociceptive neuron potentiation and sensitization, which does not respond fully to anesthetic blocks, is less localized, often crossing divisions and midline.
3 Complex–sympathetic sensitization The afferent nerves express receptors that respond to sympathetic nerve neurotransmitters (e.g., norepinephrine), causing pain, are stress driven.
This is largely a diagnosis of exclusion, so local dental and periodontal pathology must be ruled out. See Chapter 17 for a thorough discussion of orofacial neuropathic disease diagnosis.
Most commonly we use topical anesthetics and mild anticonvulsant medications to suppress the spontaneous activity in the damaged nerve. See Chapter 17 for more details on treatment.
6.2 Anticonvulsant Drug Therapy
The majority of the 12 anticonvulsant agents reviewed next (carbamazepine, oxcarbazepine, lamotrigine, levetiracetam, zonisamide, phenytoin, gabapentin, pregabalin, baclofen, valproic acid, topiramate, and lidocaine) are approved for control of epileptic seizures. Among these, only carbamazepine is approved for trigeminal neuralgia, but the others are used off-label for suppression of neuropathic pain as well. Anticonvulsants are not categorized with an FDA narcotic schedule classification but are dangerous nonetheless. If the neuropathic pain symptoms are severe, suppression of neuronal activity is best achieved with an anticonvulsant medication. Unfortunately anticonvulsant-type medications do not suppress just the painful nerve but they suppress all nerves, which means the medications have some serious side effects. While no patient wants pain, some also cannot tolerate the side effects, so all prescribing doctors will have to titrate the medication upward to balance the side effects with the pain relief. There are only few randomized controlled trials that have been conducted and in this section these various anticonvulsant medications are discussed.
This discussion must begin with a January 2008 FDA advisory letter to healthcare professionals that, based on placebo-controlled studies, the use of anticonvulsant drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.22%).49 The increased risk of suicidal behavior and suicidal ideation was observed as early as 1 week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the 11 drugs analyzed, which included carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. The relative risk of suicidality was higher in patients with epilepsy compared with patients who were given one of the drugs in the class for psychiatric or other conditions. They suggested that healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression. More details about the individual anticonvulsant agents used in neuropathic pain management are discussed in the following subsections.
Description, Mechanism of Action, and Primary Indications
The chemical structure of carbamazepine is related to the tricyclic antidepressant medications and to phenytoin. Carbamazepine acts by altering or slowing the opening and closing cycles of voltage-gated sodium ions across cell membranes. It does this by stabilizing the inactivated state of a sodium channel, which means that it takes longer for a sodium channel to close or reactivate after being opened. Carbamazepine has been used for trigeminal neuralgia, glossopharyngeal neuralgia, and other lancinating pain syndromes since the early 1960s and is approved by the FDA for treatment of these diseases.50
The starting dose for carbamazepine is 200 mg twice a day and the patient is then titrated upward to the effective dose range, 600–1200 mg/day.
Side Effects and Adverse Drug Reactions
Carbamazepine is metabolized by the liver cytochrome P450 enzyme 3A4 and it also induces the several cytochrome P450 enzyme systems. As a result it is known as a self-inducing drug. This means that its ability to induce or stimulate the liver enzymes that metabolize it to work faster, and the initial therapeutic dose where pain relief is found will stop working after a few weeks of continuous use. This is because essentially the drug level in the blood drops as it is metabolized much faster so the dose must be increased. For these reasons, it is necessary to conduct serologic assessment of the patient’s liver function and hematologic status and to see if the drug is in the suggested therapeutic range with regular blood tests. Carbamazepine does have a high risk of adverse reactions because its therapeutic dose is close to its toxic dose, and it produces a toxic epoxide metabolite that can cause liver damage and anemia quickly.51 In addition, this drug produces a 10% incidence of rashes and has a negative effect on bone density. The most common side effects are drowsiness, diplopia, and unsteadiness although aplastic anemia, reversible leukopenia and thrombocytopenia, are also a concern. In 2007, the FDA issued a warning newsletter to healthcare professionals specifically about carbamazepine and its increased risk for development of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Asian individuals who carry the HLA-B*1502 allele.52 This risk is now listed on the product labeling. They described two rare but life-threatening cases of an adverse dermatological reaction associated with the use of the anticonvulsant drug carbamazepine. Traditionally, the likelihood of developing CBZ-associated SJS/TEN has been considered very low.53,54 Recent reports, however, indicate that certain Asian populations may be at increased risk (10 times higher than Caucasians) for developing these conditions.55–59 The specific Asian populations that carry the HLA-B*1502 allele are Han Chinese, Filipino (Ivatan), Indonesians, Malaysians, Taiwanese (Minnan), Thai, and certain Asian Indians (Khandesh Pawra). There appears to be a lower incidence in allele frequency in Japanese individuals. The at-risk group is over 1 million individuals since 4–5% of individuals residing in the United States have identified themselves as Asian and up to 10% of Asian Americans will be positive for the HLA-B*1502 allele.60 Finally this drug has a D rating for pregnancy risk and does cross into breast milk.
Efficacy for Trigeminal Neuralgia
With regards to efficacy for trigeminal neuralgia, there are at least three well-designed double-blinded, placebo-controlled crossover studies that have examined carbamazepine. Combined they included a total of 151 patients61–63 with a good initial effect in approximately 70%. Based on the data from these three studies, a meta-analysis calculated the NNT (number-needed-to-treat) for effective pain control was 2.6 (defined as a >50% pain relief compared with placebo).64 This same article also calculated the NNH (defined as the number-needed-to-harm or where the adverse effects were in excess of those seen with placebo) to be about 3.4. In 2007 a review of the literature examine multiple randomized controlled trials (RCT) on pharmacologic management of trigeminal neuralgia.65 The evidence presented in this review suggests that carbamazepine is still the first-line drug for medical management. The authors of this review suggested that carbamazepine should be changed to oxcarbazepine if there is poor efficacy or unacceptable side effects. Combination of carbamazepine with lamotrigine or baclofen is the second-line treatment when monotherapy fails, but the evidence for this polypharmacy is scant. The authors also suggested that a neurosurgical treatment should be considered when a patient has poor efficacy and tolerability of drug treatment and no remission periods. There have been several small studies which have looked at the efficacy of other drugs (tizanidine, baclofen, pimozide, tocainade, and oxcarbazepine) for the treatment of trigeminal neuralgia but none have been proven superior to carbamazepine.66–69 Unfortunately, there are almost no data on the long-term efficacy of carbamazepine in managing trigeminal neuralgia. Only one case-series report even attempted to examine this issue and it reported that there was a loss of effect or problems with tolerability in one-half of patients over a 10-year period.70 There is the possibility that in some cases this loss of effect can be compensated to a degree by adding a second anticonvulsant (e.g., lamotrigine).
Efficacy for Other Neuropathic Pain Disorders
When dealing with other neuropathic pain disorders (e.g., diabetic neuralgia and postherpetic neuralgia, chronic trigeminal neuropathy) carbamazepine is not considered a first-line choice because of the high potential for adverse reactions and the complications to therapy that frequent blood tests produce. Nevertheless, carbamazepine has been suggested as a second-line anticonvulsant for neuropathic pain when the patient has not responded to gabapentin.71 The dosage of carbamazepine for neuropathic pain is usually lower than that used for trigeminal neuralgia (≤400 mg twice a day). In painful diabetic neuropathy, carbamazepine has an NNT of 2.3.72 In 2008 there was a report that examined the effects of carbamazepine and amitriptyline on tetrodotoxin-resistant (TTX-R) Na+ channels in immature rat trigeminal ganglion neurons.73 This study found that both carbamazepine and amitriptyline were able to inhibite TTX-R sodium channels in a dose-dependent manner. Interestingly they actually found that amitriptyline was a more potent inhibitor. The authors concluded that both drugs would be useful for the treatment of trigeminal nerve injury-induced continuous neuropathic pain disorders. In 2003 an experimental neuropathic pain study examined the comparative activity of the anticonvulsants oxcarbazepine, carbamazepine, lamotrigine, and gabapentin.74 With their rat model of partial sciatic nerve ligation they were able to show that neither oxcarbazepine nor carbamazepine reduced mechanical hyperalgesia or tactile allodynia. Conversely, with the same model in the guinea pig, both of these drugs produced up to 90% reversal of mechanical hyperalgesia. Lamotrigine was found to be effective against mechanical hyperlagesia in both species although it showed greater efficacy and potency in the guinea pig. Lamotrigine also produced slight inhibition of tactile allodynia in the rat only at the highest dose tested. Gabapentin also produced significant dose-related reversal of tactile allodynia in the rat. However, gabapentin was poorly active against mechanical hyperalgesia in either the rat or guinea pig following a single oral administration, but with repeated administration it produced up to 70% and 90% reversal in rat and guinea pig, respectively.
Description, Mechanism of Action, and Primary Indications
Oxcarbazepine is structurally related to carbamazepine and has many of the therapeutic properties of carbamazepine, while potentially avoiding its many toxicities. Oxcarbazepine acts by blocking voltage-gated Na+ channels and it modulates voltage-activated Ca++ currents. This drug is not FDA approved for trigeminal neuralgia and is used off-label for this disease, but there are published reports that have shown efficacy in trigeminal neuralgia (see the subsection “Efficacy for trigeminal neuralgia”).
Oxcarbazepine is typically started at 300 mg twice a day with a escalation plan of an additional 300 mg/day every 3 days up to a maximum of 1800–2400 mg/day. The half-life of this drug is 9 hours (metabolite) so that twice-a-day dosing is optimal.
Side Effects and Adverse Drug Reactions
Unlike carbamazepine, which is the active drug in its ingested form, oxcarbazepine is a prodrug or nonactive drug and its metabolite is the active agent. The substantial advantage of oxcarbazepine over carbamazepine is that it is not a strong inducer of the cytochrome enzymes so once the effective dose is established it is more stable. One known side effect is hyponatremia, and measurement of serum sodium levels should be considered during maintenance treatment, but drinking milk daily can prevent this complication.75 The incidence of rash is 4%, and drug–drug interactions are few.76 While the choice to institute therapeutic drug monitoring is based on the frailty of the patient, it is not mandatory to use blood monitoring with this drug. In 2007 a case report />