Antiepileptic drugs, such as carbamazepine, are often used in the management of neuropathic pain. Neuropathic pain is pain caused by lesions in the somatosensory system. Neuropathic pain is part of a syndrome that can be based on various diseases, such as trigeminal neuralgia, postherpetic neuralgia, and diabetic polyneuropathy.

Carbamazepine is an old-generation antiepileptic drug that works to inhibit voltage-gated sodium ion channels in neuronal membranes. Carbamazepine can cause some side effects, for example, skin reactions, especially in patients with HLA-B * 1052 alleles, which increase the risk of Stevens-Johnson syndrome. Carbamazepine overdose can cause nystagmus, blurred vision, ataxia, and drowsiness. Hyponatremia can occur during the use of carbamazepine. Hyponatremia can interfere with seizure control. Other side effects are bradycardia and heart conduction blocks, vitamin D deficiency, osteomalacia, aplastic anemia, and agranulocytosis.

An understanding of the neuropathic pain mechanisms is very important in clinical assessment and treatment selection. Several theories related to the pathophysiology of neuropathic pain, namely:
1) Ectopic activity,
2) Peripheral sensitization,
3) central sensitization,
4) inhibitory modulation disorders, and
5) microglia activation.

Ectopic Activity
After a nerve injured, hyperexcitability occurs and causes potential ectopic action in the afferent nerve and its projections towards the central nervous system. That underlies the occurrence of pain, which is spontaneous, stimulus-independent, and has properties with certain time patterns such as paroxysmal, intermittent continuous, or continuous constant. This ectopic activity involves changes in ion channels such as sodium, potassium, and calcium channels that are voltage-gated, and hyperpolarization from other channels.

Peripheral Sensitization
Peripheral sensitization occurs in inflammatory pain. It appears as hyperexcitability and decreases the threshold of activation of afferent neurons. This mechanism often occurs in hyperalgesia and allodynia after nerve injury. Peripheral sensitization involves changes in the TrpV1 ion channel receptor potential (transient receptor potential cation channel subfamily V member 1).

Central Sensitization
Central sensitization is increasing excitability and synapse activity in the central nociceptive pathway, which is prolonged but reversible. This mechanism is triggered by changes in A-beta nerve fibers with increased levels of neuropeptides and increased excitatory activity through NMDA (N-methyl-D-aspartate) receptors.

Inhibitory modulation disorders
In some conditions with nerve injuries, there is an inhibitory of pain modulation. Changes that occur in the form of apoptosis from spinal interneurons that are GABAergic, which increases pain sensitivity after injury. The activation of microglia and non-neuron cells in the central nervous system also plays an important role in causing pain hypersensitivity, involves phosphorylation of protein kinases, increased chemokine receptors, and release of glia cytokines.

Scientific Evidence Regarding the Efficacy of Carbamazepine in the Management of Neuropathic Pain

Along with the development of antiepileptic drugs, research on the use of carbamazepine in the management of neuropathic pain is getting smaller. Existing research is research with a small sample size, short duration, and low evidence strength.

In a multicenter open-label clinical trial involving 452 participants with diabetic polyneuropathy, the result was found that carbamazepine can reduce pain intensity, improve quality of life, and show good tolerability. Only about 10 participants experienced symptoms of side effects. However, this study did not compare the efficacy of carbamazepine with other drugs.

For cases of central neuropathic pain, scientific data related to the efficacy of carbamazepine show mixed results and low quality of evidence. Therefore, its use is still not recommended.

Meanwhile, for trigeminal neuralgia, carbamazepine is still the first line according to the recommendations of the European Federation of Neurological Societies (EFNS) and the American Academy of Neurology (AAN). The recommended dosage of carbamazepine in trigeminal neuralgia is 200-1200 mg per day according to the clinical situation and patient response. In trigeminal neuralgia, focal demyelination occurs in the trigeminal nerve around nerve roots entering the pons. In that area, ectopic electricity spark is suspected. Mitochondria and other apparatus involved in the active pump process are concentrated in the Ranvier node region. Because demyelination occurs, the exit and entry of sodium ions occur more easily, and the axons do not have enough energy to make the membrane's action potential return to the resting potential. Then, the Axon becomes hyperexcitable both spontaneously or secondary to the stimulus. In these sodium ion channels, the role of carbamazepine as an inhibitory is effective in the management of trigeminal neuralgia.

A study by Di Stefano et al. in 100 patients with trigeminal neuralgia treated with carbamazepine and 100 treated with oxcarbazepine, showed that both have good efficacy in the majority of patients. However, it should be noted that side effects occur in 27% of patients taking carbamazepine and 18% using oxcarbazepine. These side effects cause the patient to stop treatment or reduce the dose until the effect of the drug becomes unsatisfactory.

A Cochrane review of the efficacy of carbamazepine in the management of chronic neuropathic pain and fibromyalgia involved 11 clinical trials with a total of 480 participants. The analyzed study involved patients who experienced neuropathic pain due to trigeminal neuralgia, diabetic neuropathy, and post-stroke pain. The results of the analysis show that carbamazepine can help some patients with neuropathic pain, but existing studies have not been adequate to determine which patients will benefit and which will not. The studies analyzed in this review have a duration that is too short, the quality of reporting is not good, and the outcomes are not significant enough to be applied clinically.

1. Jensen TS, Baron R, Haanpää M, Kalso E, Loeser JD, Rice AS, Treede RD. A new definition of neuropathic pain. Pain. 2011 Oct 1;152(10):2204-5.
2. Murnion BP. Neuropathic pain: current definition and review of drug treatment. Australian prescriber. 2018 Jun;41(3):60.
3. Vajda FJ, Eadie MJ. The clinical pharmacology of traditional antiepileptic drugs. Epileptic Disorders. 2014 Dec;16(4):395-408.
4. Mendlik MT, Uritsky TJ. Treatment of neuropathic pain. Current treatment options in neurology. 2015 Dec 1;17(12):50.
5. Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis and treatment. InMayo Clinic Proceedings 2015 Apr 1 (Vol. 90, No. 4, pp. 532-545). Elsevier.
6. Saeed T, Nasrullah M, Ghafoor A, Shahid R, Islam N, Khattak MU, Maheshwary N, Siddiqi A, Khan MA. Efficacy and tolerability of carbamazepine for the treatment of painful diabetic neuropathy in adults: a 12-week, open-label, multicenter study. International journal of general medicine. 2014;7:339.
7. Watson JC, Sandroni P. Central neuropathic pain syndromes. InMayo clinic proceedings 2016 Mar 1 (Vol. 91, No. 3, pp. 372-385). Elsevier.
8. Attal N, Cruccu G, Baron RA, Haanpää M, Hansson P, Jensen TS, Nurmikko T. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. European journal of neurology. 2010 Sep;17(9):1113-e88.
9. Cruccu G, Gronseth G, Alksne J, Argoff C, Brainin M, Burchiel K, Nurmikko T, Zakrzewska JM. AAN‐EFNS guidelines on trigeminal neuralgia management. European journal of neurology. 2008 Oct;15(10):1013-28.
10. Gronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel K, Nurmikko T, Zakrzewska JM. Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology. 2008 Oct 7;71(15):1183-90.
11. Cruccu G. Trigeminal neuralgia. CONTINUUM: Lifelong Learning in Neurology. 2017 Apr 1;23(2):396-420.
12. Di Stefano G, La Cesa S, Truini A, Cruccu G. Natural history and outcome of 200 outpatients with classical trigeminal neuralgia treated with carbamazepine or oxcarbazepine in a tertiary centre for neuropathic pain. The journal of headache and pain. 2014 Dec;15(1):34.
13. Wiffen PJ, Derry S, Moore RA, Kalso EA. Carbamazepine for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD005451. DOI: 10.1002/14651858.CD005451.pub3.