Author(s): Diane Schretzman Mortimer, MD and Kerri Chung, DO
Originally published: October 22, 2013 Last updated: August 3, 2017
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1. OVERVIEW AND DESCRIPTION

I. Anticonvulsants for Pain Management

Pain is a significant public health problem. In addition to its effects on emotional well-being and overall function, pain has a considerable economic impact. Patients with pain have more emergency department and visits and longer rehabilitation stays. The presence of pain is associated with lost wages and productivity and is a burden to a person’s social support system. Pain’s national annual cost is estimated to be a staggering $560-$635 billion.1

Neuropathic pain (NP) is one particularly consequential type of pain. It can interfere with function and quality of life. Its prevalence in the general population is nearly 10 percent. NP can be primary or an associated symptom in other medical conditions. For example, NP is a common comorbidity with diabetes and trigeminal neuralgia. It also occurs regularly in cancer, central nervous system injury, and following injury to peripheral nerves.2

Neuropathic pain is a multifaceted problem. It can be intermittent or continuous. Its associated abnormal pain sensory perception can present in multiple ways. Allodynia is pain that occurs with otherwise innocuous tactile stimuli. Hyperalgesia is an exaggerated response to a painful stimuli. Paresthesias are the abnormal sensation of pins and needles. NP is thought to result from damage to or dysfunction of the peripheral nerve, dorsal root ganglion, or central nervous system pain pathway. NP has been linked to spontaneous activation or modification of the stimulus response properties of nociceptor afferent nerves.2

Treating NP is a clinical challenge. There tends to be variable response to conventional pharmacological treatment and, in some cases, NP can be intractable to treatment. Commonly used medications include non-steroidal anti-inflammatory agents, tricyclic antidepressants, and anticonvulsants.3

Anticonvulsants, or antiepileptic drugs (AEDs), have been found to be beneficial in multiple systematic reviews.  AEDs can be used as first, second, or third-line, or alternative agents.  AEDs’ mechanisms include suppressing spontaneous neuronal discharges, decreasing neuronal hyperexcitability, and facilitating pain inhibitory processes. By affecting specific ion channels, these drugs can influence synthesis, metabolism, or function of neurotransmitters or receptors which control channel opening and closing. Some AEDs have multiple mechanisms while others have actions that are not yet certain.3,4,5

2. RELEVANCE TO CLINICAL PRACTICE

II. AEDs can be classified according to mechanisms of action:

Sodium channel blockers: AEDs target the sodium channels and block their activation, stabilizing them in an inactive state.

  • Phenytoin and is a potent blocker of voltage-gated sodium channels, selectively dampening pathologic activation of sodium channels without interacting with normal sodium channel function. Side effects include dizziness, diplopia, nausea, ataxia, nystagmus, gingival hyperplasia, aplastic anemia, rash, Stevens Johnson syndrome (SJS) and blood dyscrasias. It is eliminated hepatically.5,6
  • Carbamazepine is also a potent blocker of voltage-gated sodium channels. Side effects, which can occur more often at higher serum concentrations, can include dizziness, diplopia, dizziness, ataxia, syndrome of inappropriate secretion of anti-diuretic hormone, rash and blood dyscrasias. It is eliminated hepatically.5,6
  • iii. Oxcarbazepine is an analogue of carbamazepine. It inhibits voltage-dependent sodium channels. Side effects include dizziness, diplopia, hyponatremia, nausea, blood dyscrasias, and SJS. It is eliminated hepatically.6
  • Lamotrigine blocks voltage-dependent sodium channels and also likely has other, less understood, mechanisms. Side effects include rash, SJS, dizziness, tremor, nauseas, headache, and blood dyscrasias. It is eliminated hepatically.6,7

Calcium channel blockers: The predominant mechanism of action is believed to be through decreased excessive accumulation of intracellular calcium, leading to reduced neurotransmitter release and attenuated postsynaptic excitability.

  • Levetiracetam’s exact mechanism unknown but it is believed to stabilize nerves with inhibition of calcium channel presynaptically, modulating neurotransmitter release. Side effects include agitation, dizziness, and hepatic failure. It is renally and hepatically eliminated.6

Gamma-aminobutyric acid (GABA) agonists: GABA receptors mediate chloride influx, leading to hyperpolarization of cell and inhibition of neural transmission. They GABA also modulates potassium channel function. AEDs may act to enhance chloride influx or decrease GABA metabolism.7

  • Gabapentin is a GABA analogue but it does not affect GABA receptor binding, uptake or degradation. Gabapentin likely binds to subunits of the calcium channel. This binding, and subsequent N-methyl-D-aspartate (NMDA) receptor depolarization on GABA inhibitory neurons, result in decreased release of glutamate, norepinephrine and substance P. Side effects include dizziness, fatigue, neutropenia, renal failure, pancreatitis, and hepatitis. It is eliminated renally.6,8,9
  • Pregabalin is a newer agent that binds strongly with alpha2-delta subunits of voltage- dependent calcium channels that are present in the dorsal horn of the spinal cord and brain. This inhibits neuronal excitability and modulates release of glutamate and noradrenaline. Side effects include dizziness, confusion, ataxia, and myoclonus. It is renally eliminated.6,10

Glutamate receptor blockers. Glutamate is the main excitatory neurotransmitter in the central nervous system. The glutamate receptor has five potential binding sites that facilitate the flow of both sodium and calcium ions into the cell, while potassium flows out, resulting in excitation.

  • Valproate blocks voltage-dependent sodium channels and enhances the release of GABA. It may also block calcium channels. Side effects include tremor, nausea, ataxia, rash, blood dyscrasias, pancreatitis, SJS, thrombocytopenia and hepatotoxicity. It is eliminated hepatically.6

 

Carbonic anhydrase inhibitors: increase the intracellular concentration of hydrogen ions and decrease the pH, causing potassium ions to shift to the extracellular compartment with resultant hyperpolarization, which increases the seizure threshold of the cells.

  • Topiramate has multiple mechanisms. It appears to block voltage-dependent sodium channels, block the NMDA-glutamate receptor and thus increase GABA and its inhibitory effect, and inhibit carbonic anhydrase. Side effects include memory cognitive impairment, dizziness, fatigue, tremor, anorexia, weight loss, paresthesias, nephrolithiasis, narrow-angle glaucoma, and metabolic acidosis. It is renally eliminated.6,11

Formal guidelines for using the assessment/treatment procedures(s):

Guidelines for recommending AEDs as treatment for NP have been synthesized from multiple randomized controlled trials. However, it is important to remember both that virtually all these uses are off-label and that additional research is ongoing.

When selecting an AED for NP, clinicians need to consider factors including desired effect, potential adverse events, patient age, other health problems, pharmacokinetic and pharmacodynamics issues. Clinicians need to keep in mind that, with some AEDs, patients require monitoring for potential transient and/or long-term laboratory abnormalities that can herald toxicity and physiological stress to organs. While research studies and clinical evidence guidelines and provide valuable information, appropriate clinical judgment is also instrumental.5 Treatments also vary by presumed origin of the pain.

  • Pain following traumatic spinal cord injury (SCI) pain, post-stroke pain (PSP) and in multiple sclerosis (MS): Pathophysiology can include spinal cord compression or ischemia, nerve root compression, or cauda equine syndrome. Central neuropathic pain mechanisms may include central desensitization, disinhibition, and astrocyte and microglia activation. Gabapentin and pregabalin have demonstrated efficacy and been recommended as first-line treatment.4 Lamotrigine may be considered in PSP or incomplete SCI with allodynia.3
  • Trigeminal neuralgia (TN): a classic example of pain due to vascular compression of a nerve. When the trigeminal nerve is compressed in the cerebellopontine angle, brief episodes of shooting electric-type pain result. Carbamazepine is the standard treatment. Oxcarbazepine and phenytoin can be tried as second-line agents.3
    III. Painful polyneuropathy (PPN) includes diabetic and HIV-associated neuropathy.

    • Diabetic peripheral neuropathy (DPN), which can affect more than 25 percent of adults with diabetes, is caused by metabolic dysfunction. Glycosylation end products inhibit axonal transport and sodium-potasium/ATPase. This leads to axonal degeneration. Gabapentin and pregabalin have been associated with a meaningful pain reduction in neuropathic pain due to DPN.10 In small trials, carbamazepine and levetiracetam have also been efficacious to some degree.3
    • Non-diabetic neuropathy, also called HIV-associated neuropathy, has been shown to respond to lamotrigine in some cases.3
  • Post-herpetic neuralgia (PHN), a common sequelae of zoster infection, often causes a painful persistent rash. Gabapentin and pregabalin are first-line treatments. They have established efficacy in relieving pain when compared with placebo.9,10
  • Cancer pain occurs in up to two-thirds of patients with cancer. NP, which accounts for much of this pain, likely occurs secondary to both direct invasion of nervous tissue and neurotoxic effects from chemotherapy or radiation. Treatments for various unique cancer pain syndromes are very targeted and specific.12
    • AEDs are generally used for refractory pain in cancer as an adjunct to opioid treatment. Carbazepine and oxcarbazepine are used for pain from cancers that invade the head and neck neurologic structures. Since this nerve damage is analogous to non-malignant atypical pain syndromes caused by trigeminal neuralgia, it tends to respond in the same manner. Gabapentin and pregabalin can be helpful for peripheral neuropathies.12
  • Migraine headache, one of the most common types of chronic pain and the seventh leading cause of disability, likely has at least some neuropathic component. Topiramate and valproic acid are first-line medications for migraine prophylaxis.11,13

Translation into practice: clinical pearls or potential performance improvements in practice:

Optimizing treatment: Most AEDs have more than one mechanism of action. Identification of ways to match key molecular targets in specific pain syndromes with therapeutic effects would be beneficial. Clinicians could apply that knowledge to optimize drug choice, dosing and duration of treatment. This knowledge would also allow clinicians to target treatments more effectively.

3. CUTTING EDGE/UNIQUE CONCEPTS/EMERGING ISSUES

I. Role of AEDs in the Effort to Decrease the Use of Opioids

AEDs can be an alternative to opiates. For example, AEDs can be effective for post-operative pain, where opiates are currently the mainstay. Gabapentin and pregabalin, which appear to have both analgesic and opioid-potentiating effects, have been shown to decrease pain and the need for opioids in patients recovering from knee and back surgery. 14, 15 An important downstream effect of decreasing the use of opioids could be the prevention of misuse or overdose.

II. Combination Therapy

Combination therapy of medications, such as opiates, AEDs, and antidepressants, are commonly prescribed for NP. The combination may provide greater analgesia that monotherapy with any of the included medications. For example, the combination of gabapentin with opioids is effective for some types of NP in cancer.8 In diabetic peripheral neuropathy, the sum effect of gabapentin plus nortriptyline can be more effective than either drug alone. Combination therapy may lead to reduction in dose, and side effects, of AEDs.4 Additional head-to-head-comparative trials assessing the clinical effectiveness, tolerability, and cost of combination treatments would be helpful. The combination of medications with non-pharmacological interventions like physical therapy also warrants additional study.

III. Non-AED Treatment of Neuropathic Pain

  1. Capsaicin: This topical agent capsaicin when given in high concentration (8% patch) can be used to treat postherpetic neuralgia, HIV neuropathy, and painful diabetic neuropathy. In small studies, it had moderate to substantial pain relief compared to placebo.16
  2. Transcutaneous electrical nerve stimulation (TENS): This treatment produces mild electrical currents to the body through electrode pads attached to the skin. TENS may reduce the intensity of pain. While it has demonstrated efficacy in the treatment of general and acute pain, its benefit in NP is not yet firmly established.17
  3. Spinal cord stimulators (SCS): These stimulate nerves in the spine with the goal of decreasing pain. They have been used extensively in patients with chronic pain, including NP and have demonstrated benefit in acute pain. Patients with SCS can have decreased pain medication use and can tolerate more activity.18
  4. Botulinum toxin (BoNT) injections are used for painful conditions like cervical dystonia, myofascial pain and spasticity. Ongoing research is evaluating the effectiveness for BoNT for neuropathic pain.19

4. GAPS IN KNOWLEDGE/EVIDENCE BASE

  • Matching AEDs with therapeutic targets: Early and aggressive intervention in treatment of neuropathic pain seems to afford the best chance of alleviating pain and avoiding complications like worsening pain, psychological problems, and disability. However, the best way to do that has not yet been conclusively determined. It is possible that research about molecular mechanisms and neural networks in neuropathic pain may lead to more effective treatments.
  • Improving research studies in this field: It is difficult to compare studies in the burgeoning field of pain research. Studies of NP tend to use outcome measures that are varying or of questionable clinical significance. This makes it difficult to compare studies and to apply results to clinical situations. The development of uniform and appropriate outcome metric, such as a validated numerical pain rating scale or quality of life measure, can enhance the strength and clinical utility of future studies.

REFERENCES

  1. Institute of Medicine Report from the Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research. The National Academies Press; 2011. Washington, D.C.
  2. Bouhassira D, Lanteri-Minet M, Attal N, Laurent B, Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain. 2008;136(3):380-387.
  3. Attal N, Cruccu G, Baron R, et al. European Federation of Neurological Societies guidelines on the pharmacological treatment of neuropathic pain, 2010 rev. Eur J Neurol. 2010;17(9):1113-1188.
  4. Bril V, England J, Franklin GM, et al. Evidence-based guidelines: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. PM&R. 2011;3(4):345-352, 352.e1-21.
  5. O’Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med. 2009;122(10 Suppl):S22-32.
  6. Yablon SA & Towne AR. Post-Traumatic seizures and epilepsy. In Zasler ND, Katz DI & Zafonte RD.(Eds.) Brain Injury Medicine: Principles and Practice (2nd Ed.) New York: Demos Medical Publishing; 2013.
  7. Wiffen PH, Derry S, Aldington D et al. Antiepileptic drugs for neuropathic pain and fibromyalgia: An overview of Cochrane reviews. Cochrane Database Sys Rev. 2013: 11: 1-26
  8. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin or their combinations for neuropathic pain. N Engl J Med. 2005;352:1324-1334.
  9. Rullan M, Bulilete O, Leiva A, et al. Efficacy of gabapentin for prevention of postherpetic neuralgia: Study protocol for a randomized controlled clinical trial. Trials. 2017: 18: 24-33.
  10. Moore A, Wiffen P, Kalso E. Antiepileptic drugs for neuropathic pain and fibromyalgia. JAMA. 2014;312(2):182-183.
  11. Silberstein S. Topiramate in migraine prevention: A 2016 perspective. Headache. 2017:1:165-177.
  12. Vadalouca A, Raptis E, Moka E, et al. Pharmacological treatment of neuropathic cancer pain: A comprehensive review of the current literature. Pain Pract. 2012;12(3):219-251.
  13. Mulleners W, Mccrory D, Linde M. Antiepileptics in migraine prophylaxis: An updated Cochrane review. Cephalalgia. 2015;35(1):51-62.
  14. Jiang HL, Huang S, Song J, Wang X, Cao ZS. Preoperative use of pregabalin for acute pain in spine surgery: A meta-analysis of randomized controlled clinical trials. Medicine. 2017;96(11):e6129.
  15. Peng C, Li C, Qu J, Wu D. Gabapentin can decrease acute pain and morphine consumption in spinal surgery patients: A meta-analysis of randomized clinical trials. Medicine. 2017; 96(15);e6463.
  16. Derry S, Rice ASC, Cole P, et al. Capsaicin applied to the skin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017: 1.
  17. Johnson MI, Mulvey MR, Bagnall A. Transcutaneous electrical nerve stimulation (TENS) for phantom pain and stump pain following amputation in adults. Cochrane Satabase Syst Rev. 2015:8.
  18. Ubbink DT, Vermeulen H. Spinal cord stimulation for patients with chronic critical leg ischemia who cannot have blood vessel surgery. Cochrane Database Syst Rev. 2013:2.
  19. Waseem Z, Boulias C, Gordon A, et al. Botulinum toxin injections as a treatment for low-back pain and sciatica. Cochrane Database Syst Rev. 2011: 1.

Original Version of the Topic

Eduardo Lopez, MD, Lauren Shaiova, MD. Anticonvulsants for Pain Management. 10/22/2013.

Author Disclosure

Diane Schretzman Mortimer, MD
Nothing to Disclose

Kerri Chung, DO
Nothing to Disclose