Current Pain and Headache Reports (2019) 23: 37 https://doi.org/10.1007/s11916-019-0774-0 OTHER PAIN (A KAYE AND N VADIVELU, SECTION EDITORS) Membrane Stabilizer Medications in the Treatment of Chronic Neuropathic Pain: a Comprehensive Review Omar Viswanath1,2,3 & Ivan Urits4 & Mark R. Jones4 & Jacqueline M. Peck5 & Justin Kochanski6 & Morgan Hasegawa6 & Best Anyama7 & Alan D. Kaye7 Published online: 1 May 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review Neuropathic pain is often debilitating, severely limiting the daily lives of patients who are affected. Typically, neuropathic pain is difficult to manage and, as a result, leads to progression into a chronic condition that is, in many instances, refractory to medical management. Recent Findings Gabapentinoids, belonging to the calcium channel blocking class of drugs, have shown good efficacy in the management of chronic pain and are thus commonly utilized as first-line therapy. Various sodium channel blocking drugs, belonging to the categories of anticonvulsants and local anesthetics, have demonstrated varying degrees of efficacy in the in the treatment of neurogenic pain. Summary Though there is limited medical literature as to efficacy of any one drug, individualized multimodal therapy can provide significant analgesia to patients with chronic neuropathic pain. Keywords Neuropathic pain . Chronic pain . Ion Channel blockers . Anticonvulsants . Membrane stabilizers Introduction Neuropathic pain, which is a result of nervous system injury or lives of patients who are affected. Frequently, it is difficult to dysfunction, is often debilitating, severely limiting the daily manage and as a result leads to the progression of a chronic condition that is, in many instances, refractory to medical This article is part of the Topical Collection on Other Pain management. Common causes of neuropathic pain include lumbar radiculopathy, diabetic peripheral neuropathy, and * Omar Viswanath postherpetic neuralgia. While antidepressants and several an- [email protected] ticonvulsant medications are widely instituted as first-line therapy, there is a lack of consensus regarding next-line ther- 1 Valley Anesthesiology and Pain Consultants, Envision Physician apy in patients who continue to experience pain. In this re- Services, 645 E. Missouri Avenue, Suite 300, Phoenix, AZ 85012, view, an overview of membrane stabilizing medications is USA presented. These medications have been shown to be effective 2 Department of Anesthesiology, University of Arizona College of in the management of chronic neuropathic pain. Medicine-Phoenix, Phoenix, AZ, USA 3 Department of Anesthesiology, Creighton University School of Medicine, Omaha, NE, USA 4 Beth Israel Deaconess Medical Center, Department of Anesthesia, Sodium Channel Blocking Anticonvulsants Critical Care, and Pain Medicine, Harvard Medical School, Boston, MA, USA The sodium channel blocking class of drugs antiepileptic 5 Department of Anesthesiology, Mt. Sinai Medical Center of Florida, drugs has been proven useful in the treatment of neurogenic Miami Beach, FL, USA pain. Following insult to sensory neurons, there is well- 6 Creighton University School of Medicine – Phoenix Regional documented aberrant expression of sodium channels on pe- Campus, Phoenix, AZ, USA ripheral nerves. It is possible that the antinociceptive proper- 7 Department of Anesthesiology, Louisiana State University Health ties of these agents arise from countering this aberrancy [1]. Science Center, New Orleans, LA, USA Aside from sodium channels, each of the following agents has 37 Page 2 of 9 Curr Pain Headache Rep (2019) 23: 37 unique ranges of activity. Some block calcium channels while Carbamazepine others significantly modulate neurotransmitter levels. These additional, unique profiles may lend insight into best practice Carbamazepine (CBZ) is another antiepileptic compound with a use and limitations of each individual agent in the manage- wide range of molecular targets. The primary mechanism of ment of neuropathic pain [2]. analgesia is thought to be elicited through blockade of specific sodium channels found on peripheral neurons, restricting neuro- nal firing rates. It also inhibits calcium channels and Phenytoin NMDA/AMPA receptors, although only at concentrations signif- icantly higher than the therapeutic range [9]. CBZ has also been Phenytoin (PHT) is a compound derived from barbiturates. It shown to potentiate the analgesic effects of morphine, which is differs molecularly from barbiturates at the C5 position of the an effect consistent with many NMDA antagonizing agents [10]. hydantoin molecule, at which PHT contains two phenyl rings The primary use of CBZ is in the treatment of idiopathic rather than alkyl groups [3]. The mechanism of action has trigeminal neuralgia (ITN), for which it is the first line of treat- been historically understood as a sodium channel modulator, ment. The optimal starting dose is 100 mg PO bid, which should as it blocks virtually all subtypes of voltage-gated sodium be increased 100–200 every week to reach a target dosing of channels (NaV). Recently, PHT has also been shown to antag- 200–400 mg tid [11]. The maximum dose is 1200–1800 mg/ onize voltage-dependent L-type calcium channels and day, although adverse cognitive effects are observed at doses as GABA-A receptors, thus suggesting a more complex mecha- low as 800 mg and 1200 mg in females and males, respectively nism of reducing neuroexcitability and conductance [4]. [12, 13]. HLA genotyping must also be taken into consideration Phenytoin was the first non-sedative compound used to when dosing CBZ. Certain genotypes, such as the HLA-B*15:02 manage epilepsy. Its minimal hypnotic activity is thought to allele, which is common in individuals of Southeastern Asian be attributed to the previously mentioned chemical modifica- descent, are highly associated with life-threatening dermatologic tion. Many patients treated with PHT develop gingival hyper- complications including Stevens–Johnson syndrome and toxic plasia, and this finding sparked research that illustrated epidermal necrolysis [14]. Other adverse effects of CBZ include wound-healing properties and examined its efficacy in treating ataxia, fatigue, drowsiness, memory problems, and impaired diabetic foot ulcers [5]. Other adverse effects include dizzi- sleep, among others. Agranulocytosis is seen in some patients ness, nystagmus, ataxia, gingival hyperplasia, folate deficien- with chronic administration and is thought to be related to sup- cy, and polyneuropathy. As with many antiepileptic com- pression of colony-stimulating factor and impaired neurogenic pounds, drug-induced osteopathy is a potential adverse effect, inflammation [15, 16]. which is thought to be caused by the induction of cytochrome Although there are numerous adverse effects, CBZ appears to metabolism of vitamin D [6]. have a role in the management of neuropathic pain associated The efficacy of intravenous PHT in treating neuropathic with various conditions. Wiffen et al. established a slight efficacy pain was established in a double-blind randomized control of carbamazepine in treating PDN. Patients treated with 600– trial, showing significant pain relief at a dosage of 15 mg/kg 3600 mg/day CBZ reported higher percentages of pain benefit over a 2-h period. This pain relief significantly outlasted the when compared to the control group. While this finding was infusion period and plasma half-life of PHT, supporting future statistically significant, it was regarded as third tier due to small studies to examine the efficacy of topical creams. A series of study sizes and a wide range of doses [17]. A meta-analysis by case reports by Kopsky et al. showed that 10% topical PHT Liu et al. compared interventions for the treatment of neuropathic cream was an effective treatment in reducing neuropathic pain pain in Guillain-Barre syndrome, which included CBZ. A statis- in patients with chronic idiopathic axonal polyneuropathy tically significant reduction in pain scoring and need for rescue (CIAP) and painful diabetic neuropathy (PDN) [7]. In a analgesics was found by the third day of treatment when com- single-blind response study, Kopsky et al. established that pared with the placebo, although a separate randomized control 10% PHT cream, when compared to a placebo, provided sta- trial showed better outcomes associated with gabapentin treat- tistically significant relief in a cohort of 70 patients with neu- ment over CBZ [18]. While it is a mainstay in the treatment of ropathic pain. The mean daily application in this group was ITN, further research is needed to evaluate the use of CBZ in 2.3 g, and no PHT plasma levels were detected in any patient. treating other causes of neuropathic pain. Over 65% of patients achieved a pain reduction of at least 50%, with an average duration of action around 8 h. The mean Oxcarbazepine onset of action was around 15 min, which is significantly shorter than the days to weeks seen in other oral treatments Like CBZ, oxcarbazepine (OXC) is thought to exert its effect [8••]. These findings of significant pain reduction, long dura- through blockade of voltage gated sodium channels. Patel tion of relief, and short onset of action all support the use of et al. showed that OXC reduces spontaneous activity in the topical PHT as an effective treatment for neuropathic pain. ventral posterolateral thalamus in rats with spinal nerve Curr Pain Headache Rep (2019) 23: 37 Page 3 of 9 37 ligations.