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REVIEW ARTICLE
Year : 2020  |  Volume : 5  |  Issue : 2  |  Page : 53-56

Oxcarbazepine as a safe therapy for the management of trigeminal neuralgia (Trileptal®): Case series and review article


Department of Diagnostic Sciences and Oral Biology, College of Dentistry, King Khalid University, Abha, Kingdom of Saudi Arabia

Date of Submission14-Sep-2020
Date of Decision20-Oct-2020
Date of Acceptance24-Oct-2020
Date of Web Publication25-Feb-2021

Correspondence Address:
Dr. Khalil Ibrahim Assiri
Department of Diagnostic Sciences and Oral Biology, College of Dentistry, King Khalid University, Abha
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/KKUJHS.KKUJHS_11_20

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  Abstract 

Oxcarbazepine is an effective antiepileptic medication. It is typically used alone or in conjunction with other drugs to treat partial seizures and is believed to be the first line for the treatment of trigeminal neuralgia, which is a sharp pain attack lasting for seconds in orofacial territories and the distribution of the trigeminal nerve and its branches. Its therapeutic effectiveness is comparable to carbamazepine, but it has better pharmacokinetic properties, is better tolerated, and has a safe profile compared to carbamazepine drug-to-drug interactions and general side effects.

Keywords: Carbamazepine, oxcarbazepine, trigeminal neuralgia


How to cite this article:
Assiri KI. Oxcarbazepine as a safe therapy for the management of trigeminal neuralgia (Trileptal®): Case series and review article. King Khalid Univ J Health Sci 2020;5:53-6

How to cite this URL:
Assiri KI. Oxcarbazepine as a safe therapy for the management of trigeminal neuralgia (Trileptal®): Case series and review article. King Khalid Univ J Health Sci [serial online] 2020 [cited 2021 May 14];5:53-6. Available from: https://www.kkujhs.org/text.asp?2020/5/2/53/309603


  Introduction Top


Oxcarbazepine is an analog of carbamazepine, and its effectiveness is the same as carbamazepine in the management of epilepsy. It is often used in acute orofacial pain attacks lasting for seconds and in the distribution of the trigeminal nerve and its branches (ophthalmic, maxillary, and mandibular) termed trigeminal neuralgia (TN). Some physicians and clinicians prefer to use oxcarbazepine since it has fewer side effects compared to carbamazepine. They are having less impact on the hematological profile of the patient, oxacarbazepine merits over carbamazepine. About one-third of people who developed hypersensitivity to carbamazepine may develop sensitivity to oxcarbazepine.


  Case Scenario Top


Case 1

  • A 61-year-old female patient with a history of TN for several years
  • General examination: within a standard limit
  • Neurological examination: severe, sharp shooting pain from the right corner of the mouth extended to the lower right molar teeth area (pain usually stimulated by exposure to light touch)
  • Medical history: Diabetic patient
  • Brain magnetic resonance imaging: Normal
  • The patient started with oxcarbazepine (300 mg/day) then increased gradually to 600 mg/day. No significant side effects were noted, and the patient was relieved with pain.


Case 2

  • A 73-year-old male patient with a history of severe, sharp shooting pain in the distribution of the left V2 diagnosed clinically as TN
  • General examination: Within the standard limit
  • Neurological examination: Paroxysmal, sharp shooting pain from the left ala of the nose all around the distribution of left V2 (pain mostly activated by light touch)
  • Medical history: The hypertensive patient
  • Brain magnetic resonance imaging: Normal
  • The patient started with oxcarbazepine (300 mg/day) then increased gradually to 750 mg/day.


Patient exhibited no significant side effects with substantial relief for the pain.


  Discussion Top


Most TN cases result from microvascular compression at the trigeminal nerve root as it enters the brain stem. Small or large veins or arteries can cause this blood vessel compressing at the trigeminal nerve root entry zone. The most common artery that is responsible for this compression is the superior cerebellar artery. TN therapy modalities are pharmacological or surgical. Moreover, here we used oxcarbazepine as the first line of pharmacological management in TN cases, which has pain control property and a relatively safe profile compared to carbamazepine.

Tolerability and effectiveness of oxcarbazepine have been clinically tested in six patients (median age: 61 years) with TN cases that do not react well to carbamazepine therapy for 6 months. Tremendous clinical response to oxcarbazepine has been found in all patients with pain management. The potential benefits of the drug were evident quite early in all cases. An overall serum concentration level, in all patients, of 50–110 Imol/l of 10-OH-carbamazepine correlating to an adequate dose level of 1200–2400 mg (14 6-35-6 mg/kg body weight) oxcarbazepine was seen. There was a significant association between oxcarbazepine dose and serum oxcarbazepine (P < 0.05) and 10-OH-carbamazepine (P < 0.001) concentrations. Oxcarbazepine was well tolerable, and no apparent side effects were observed, except mild hyponatremia was seen with high doses (>28 and > 35 mg/kg/day) in two patients. In conclusion, oxcarbazepine has strong properties in the management of TN with no significant side effects and can also help manage refractory TN.[1]


  The Mechanism of Action Top


Oxcarbazepine and monohydroxy derivative of oxcarbazepines (MHD) mechanism of action are extensively similar to tegretol (carbamazepine), which are still unknown but appear that their mechanism of action is based on activity at the level of the subunit of voltage-gated sodium channels which are sensitive and leading to the establishment of an action potential, which was considered to be the first step to initiate pain mechanism in its way to high centers in the brain (neural membranes stabilization) and modulation of continual firing at neurons and then result in decrease propagation of synaptic impulses. It also works on potassium channels and increases its conduction and modulates calcium channels (high voltage), and the result of these actions give the anti-seizure effect of the drug.[2],[3],[4] At the level of the brain and interaction with brain neurotransmitters, there are no significant effects mentioned. However, some studies showed that using oxcarbazepine and its derivative of monohydroxy derivative (MHD) have minimal effects on cognition functions (attention, memory, etc.) of individuals using these medications.[5]

Studies on animals showed that Trileptal and its metabolite monohydroxy derivative (MHD) have high potency and very useful as anti-seizure drugs. These medications prevent seizures (of various types of seizures) in rodents and monkeys as well. Oxcarbazepine and its derivative of monohydroxy (MHD) have no attenuation in effect as other anticonvulsants after followed for several days post administration.[5]


  Pharmacokinetics Top


Absorption

Oxcarbazepine is quickly absorbed when it is administered orally. Hence, in the case of healthy fasting individuals, one study showed that the peak of concentrations in plasma, which is called Cmax, between 1.05 and 1.74 mg/L is arrived in about 2 h (Tmax) after giving of oxcarbazepine single dose 600 mg.[6],[7] On the other hand, the plasma concentration in area under the curve (AUC) is between 5.10 and 6.84 mg/L. The peak of attention in plasma (Cmax) of the monohydroxy derivative (MHD) is between 5.44 to 8.85 mg/L, which is achieved in duration between 4 and 6 h, and the AUC, which is the AUC, is around 16–32-fold higher than for the origin drug (oxcarbazepine). In this study, they found that the rate, extent, and efficacy of oxcarbazepine absorption did not affect food presence.[6]

Steady-state plasma concentrations of the monohydroxy derivative of Trileptal (MHD) are reached between 2 and 3 days of achieving a twice/day regimen. From this study, the linear relationship, which shows dose proportional to the dosage between 300 and 2400 mg/day, has explained the pharmacokinetics of oxcarbazepine.[6],[8]

Distribution

In distribution, the monohydroxy derivative (MHD) of oxcarbazepine is distributed between erythrocytes and plasma fairly which were found to be 3–5 higher than parallel saliva concentration at steady state of concentrations in plasma of monohydroxy derivative of (MHD) which indicated that monitoring of medication by saliva concentration is not accurate.[9] About one-third to one-half of MHD and two-third of oxcarbazepine are attached to the proteins in plasma.[10],[11] Since only a relatively small proportion of monohydroxy derivative of oxcarbazepine (MHD) can bind to protein, it is unlikely for this drug to compete with other antiepileptic medications in plasma protein binding.[12] The difference in the concentration of monohydroxy derivative of oxcarbazepine (MHD) between female plasma and her breast milk is around 0.5,[13] so the active fraction is excreted in breast milk.

Metabolism and elimination

After absorption of oxcarbazepine in the tract of the gastrointestinal system, oxcarbazepine rapidly goes under reduction reaction by one of the liver enzymes that are responsible for reduction, and some evidence in studies showed the formation of monohydroxy derivative of oxcarbazepine (MHD) by the metabolism in plasma.[14],[15] However, the metabolism of carbamazepine is entirely different from oxcarbazepine, which is by the oxidation reaction at the double bond by an enzyme called epoxidase and forms the epoxide form of carbamazepine. This transformation that occurs in carbamazepine, which is not like oxcarbazepine to MHD, needs liver enzymes (P450 isozymes), which migh initiate a chemical induction. The metabolism of carbamazepine is basically by autoinduction, which is not happening in treatment with oxcarbazepine. The 10-keto group of oxcarbazepine is reduced, which leads to the formation of an unsymmetrical carbon and finally to a chiral molecule. The monohydroxy derivative of oxcarbazepine (MHD) is structured in enantiomers pair way, with both the R and S enantiomers (structured in the percent of 20% to 80%, in respect) showing even potency in several laboratory studies animals of antiepileptic activity.[16] Since enantiomers have similar antiepileptic potency, most studies evaluating the effectiveness of oxcarbazepine have been nonstereospecific to oxcarbazepine (MHD) monohydroxy derived, despite these two compounds having distinct pharmacokinetic characteristics.[16] The kidney excretes most of the given dose of oxcarbazepine as an inactive substance of MHD in about (50%) and oxcarbazepine in about (10%) and monohydroxy derivative of oxcarbazepine (MHD) (27%). About 1% or less of the administered dose is excreted as oxcarbazepine without any change.[8],[17] A small amount (4%–7%) of monohydroxy derivative of oxcarbazepine (MHD) will be further metabolized to the dihydroxy derivative 10,11- dihydro-10,11-trans-dihydroxy carbamazepine that is inactive.[17] This latest reaction is the only one that needs inducible CYP isozymes, the same way as carbamazepine but with less extent induction.[18] Studies showed that in people with epilepsy who replaced Tegretol therapy with Trileptal, changed levels of lipids in serum associated with induction in the type of the CYP were back to normal.[2] The half-life of oxcarbazepine is 1–2.5 h, which explains its rapid transformation to monohydroxy derivative (MHD). Themonohydroxy derivative of oxcarbazepine (MHD) in healthy individual rates around 8–10 h.[8],[19] In healthy individuals, clearing of the monohydroxy product of oxcarbazepine (MHD) renally happens at a rate between 0.71 and 1.26 L/H.[16],[20]


  Pharmacodynamics and Side Effects Top


In general, the side effects of oxcarbazepine are almost similar to that of carbamazepine, although the severity and frequency of side effects have been shown to be less. It is giving the pharmacological effect by its active metabolite (monohydroxy derivative MHD).

Side effects and adverse reactions of oxcarbazepine: the most serious side effect of oxcarbazepine is hyponatremia (sodium level in serum < 135 mmol/L), so using of it forthe management of seizure, convulsions, and off-label use as in case of paroxysmal sharp shooting pain in the orofacial area (TN) should be monitored frequently through blood work to check the level of sodium in the body 2 weeks post administration and then at a monthly basis, especially first 3 months.[5]

Significant side effects related to hyponatremia are dependent on the chronicity of the case: Symptoms of acute hyponatremia (sodium level in serum <125 mmol/L) are vomiting, nausea, headache, seizures, and may be fatal, leading to death. Symptoms of chronic hyponatremia may include anorexia, cramps, personality changes, disturbance in gait, vomiting, and nausea.[21]


  Other Side Effects Top


  • Hematological disorders: Very rare, leading to thrombocytopenia and aplastic anemia
  • Endocrine effects: Rarely causes hypothyroidism
  • Nerves system effects: Somnolence, dizziness, headache, amnesia, tremor, and ataxia
  • Eye effects: Visual problem and diplopia
  • Ear effects: Vertigo
  • Cardiac and vascular effects: Arrhythmias and hypertension but very rare
  • Gastrointestinal effects: Nausea, vomiting, constipation, diarrhea, pain in the abdomen, and rarely Inflammation in the pancreas and increasing in some enzymes as amylase or/and lipase
  • Hepatic effects: Hepatitis
  • Skin and mucocutaneous effects: Acne, rash, alopecia, urticarial, and rarely Stevens–Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme
  • Connective tissue, bone, and muscle effects: Systemic lupus erythematosus but very rare
  • General side effects: Fatigue, asthenia, and loss of energy and strength.[5]


In patients with any renal problems or disease in which creatinine's clearance is low, we have to be careful with oxcarbazepine therapy and how to start the dose and titrate it up. Oxcarbazepine and its metabolite are classified as category D in pregnancy since it crosses the placenta and may lead to fetal malformations. Moreover, they are excreted in breast milk, so they should be avoided during breastfeeding.[5]


  Therapeutic Index Top


For example, in orofacial pain cases, TN typically begins at a dosage of 150 mg before sleep or 150 mg twice daily at two different periods depending on the patient's medical condition. In TN cases, the usual therapeutic dose is about 1500–1800 mg/day in multiple or divided doses. If we want to switch from carbamazepine to oxcarbazepine, about 1 and 1/2 times more oxcarbazepine will be needed to get the same therapeutic effect since oxcarbazepine has less potency than carbamazepine in about 50%. However, in old patients, the maintenance dose of oxcarbazepine is about 1.2 times that of carbamazepine.[22]

Oxcarbazepine is considered a narrow therapeutic range drug or narrow therapeutic index medication. The therapeutic window or index of any medication is the concentration range that gives efficacy without undesirable side effects and toxicity. Oxcarbazepine has a narrow therapeutic window, so doses should be titrated carefully, and close observation is always mandatory to accomplish its efficacy without severe toxicity.[23]


  Conclusion Top


Oxcarbazepine has almost similar effects as carbamazepine in the management of TN, and compared to it, it has a safer profile and does not need frequent hematological tests.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Zakrzewska JM, Patsalos PN. Oxcarbazepine: A new drug in the management of intractable trigeminal neuralgia. J Neurol Neurosurg Psychiatry 1989;52:472-6.  Back to cited text no. 1
    
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Calabresi P, Murtas M, Stefani A, Pisani A, Sancesario G, Mercuri N, et al. Action of GP 47779, the active metabolite of oxcarbazepine, on the corticostriatal system. I. Modulation of corticostriatal synaptic transmission. Epilepsia 1995;36:990-6.  Back to cited text no. 2
    
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Stefani A, Pisani A, De Murtas M, Mercuri NB, Marciani MG, Calabresi P. Action of GP 47779, the active metabolite of oxcarbazepine, on the corticostriatal system. II. Modulation of high-voltage-activated calcium currents. Epilepsia 1995;36:997-1002.  Back to cited text no. 4
    
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Äikiä M, Kälviäinen R, Sivenius J, Halonen T, Riekkinen P. Cognitive effects of oxcarbazepine and phenytoin monotherapy in newly diagnosed epilepsy: One year follow-up. Epilepsy Res 1992;11:199-203.  Back to cited text no. 5
    
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Degen PH, Flesch G, Cardot JM, Czendlik C, Dieterle W. The influence of food on the disposition of the antiepileptic oxcarbazepine and its major metabolites in healthy volunteers. Biopharm Drug Dispos 1994;15:519-26.  Back to cited text no. 6
    
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Flesch G. Overview of the clinical pharmacokinetics of oxcarbazepine. Clin Drug Investig 2004;24:185-203.  Back to cited text no. 8
    
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Cardot JM, Degen P, Flesch G, Menge P, Dieterle W. Comparison of plasma and saliva concentrations of the active monohydroxy metabolite of oxcarbazepine in patients at steady state. Biopharm Drug Dispos 1995;16:603-14.  Back to cited text no. 9
    
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Jung H, Noguez A, Mayet L, Fuentes I, González-Esquivel DF. The distribution of 10-hydroxy carbazepine in blood compartments. Biopharm Drug Dispos 1997;18:17-23.  Back to cited text no. 10
    
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Van Parys J, Meinardi H. Survey of 260 epileptic patients treated with oxcarbazepine (Trileptal®) on a named-patient basis. Epilepsy Res 1994;19:79-85.  Back to cited text no. 11
    
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Baruzzi A, Albani F, Riva R. Oxcarbazepine: Pharmacokinetic interactions and their clinical relevance. Epilepsia 1994;35 Suppl 3:S14-9.  Back to cited text no. 12
    
13.
Bar-Oz B, Nulman I, Koren G, Ito S. Anticonvulsants and breast feeding. Paediatric Drugs 2000;2:113-26.  Back to cited text no. 13
    
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Pienimäki P, Lampela E, Hakkola J, Arvela P, Raunio H, Vähäkangas K. Pharmacokinetics of oxcarbazepine and carbamazepine in human placenta. Epilepsia 1997;38:309-16.  Back to cited text no. 14
    
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Myllynen P, Pienimäki P, Raunio H, Vähäkangas K. Microsomal metabolism of carbamazepine and oxcarbazepine in liver and placenta. Hum Exp Toxicol 1998;17:668-76.  Back to cited text no. 15
    
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Volosov A, Xiaodong S, Perucca E, Yagen B, Sintov A, Bialer M. Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects. Clin Pharmacol Ther 1999;66:547-53.  Back to cited text no. 16
    
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21.
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22.
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Abstract
Introduction
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Discussion
The Mechanism of...
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Other Side Effects
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