Anticonvulsants

Overview and Description

Anticonvulsants for Pain Management

Pain is one of the most prevalent and significant public health concerns in the country. According to the CDC, the prevalence of chronic pain and high-impact chronic pain (chronic pain that limits participation in activities of daily living) in 2016 was estimated to be about 20.4% (50 million) and 8% (20 million) of the United States adult population, respectively.¹ Approximately 6.9-10% of the United States population experience neuropathic-type pain, which is a shooting or burning pain associated with nerve damage.² Pain has deleterious effects on emotional well-being and function of people, and it can have tremendous economic impacts when considering both high healthcare costs and lost productivity. In 2010, the annual cost of pain ($560-635 billion) exceeded that of heart disease ($309 billion), cancer ($243 billion), and diabetes ($188 billion) when also accounting for lost productivity and the burden to one’s social support system.³

When people present with pain, it is important to characterize their specific type of pain, as treatments vary significantly. Neuropathic pain is a sharp, prickling, or burning pain that is often precipitated by light touch or temperature changes in the setting of nerve damage. Neuropathic pain is commonly associated with other medical conditions that impair nerve conduction such as in diabetic neuropathy or trigeminal neuralgia. It also occurs in cancer, central nervous system disorders, peripheral nerve trauma, and critical illness.⁴ Furthermore, neuropathic pain is often associated with symptoms of allodynia, hyperalgesia, and paresthesia. Allodynia is pain that occurs with normally innocuous stimuli. Hyperalgesia is an exaggerated pain response to painful stimuli. Paresthesia is the abnormal sensation of pins and needles often in specific nerve distributions.⁵

The pathophysiology of neuropathic pain is complex, involving both central and peripheral neural pathways. Extensive research indicates that neural plasticity following nerve injury may cause aberrant signaling from the peripheral nervous system to the central nervous system, leading to signal remodeling and peripheral sensitization. These maladaptive neuro-modulatory changes include abnormal stimulation or decreased inhibitory activity, hyper-excitability in central and peripheral system neurons, ectopic firing of sodium and calcium channels, and neuronal membrane instability.^4-5 As a result, treatment of neuropathic pain is complex and there tends to be variable responses to conventional pharmacological treatment.

Given the pathophysiology of neuropathic pain, commonly used medications for treatment focus on sodium and calcium channel blockade and neuronal membrane stabilization. These medications are typically used for other indications, including but not limited to depression and seizures and include tricyclic antidepressants (TCAs), anticonvulsants, and local anesthetics.^6-8 Anticonvulsants or antiepileptic medications affect specific ion channels that target the synthesis, metabolism, or function of the neurotransmitters and receptors that govern channel opening and closure. However, some anticonvulsants have mechanisms of action that are less well understood but have demonstrated some efficacy. Overall, current literature suggests that the beneficial effects of anticonvulsants in neuropathic pain treatment is achieved through membrane stability, suppression of spontaneous neuronal discharges, decreased neuronal hyperexcitability, and inhibition of pain pathways. These effects help prevent maladaptive neuro-modulatory changes involved in neuropathic pain generation.^8-9

Several anticonvulsants including their mechanism of action, side effects, major clinical pearls, and indications are listed below, organized by their specific mechanism of action. The majority of the studies used to determine the efficacy of the following medications examined specific neuropathic conditions such as peripheral diabetic neuropathy or post-herpetic neuralgia. However, some conditions such as HIV-associated neuropathy or chemotherapy-induced neuropathy do not respond to all membrane-stabilizing agents. Although conditions associated with neuropathic pain often have similar presentations and pathophysiologic mechanisms, their response to treatments may differ.¹⁰ Overall, knowledge of an anticonvulsant’s mechanism of action can provide clinicians a rationale for prescribing specific agents, doses, and treatment durations given particular presentations of pain phenotypes.

Relevance to Clinical Practice

Calcium Channel Modulators: Calcium channel modulators work by decreasing calcium influx, which inhibits neuronal depolarization and neurotransmitter release from the presynaptic nerve terminals. This leads to attenuated post-synaptic excitability.¹⁰

Gabapentin:

• Mechanism of Action: Binds the alpha2delta subunit of L-type voltage gated calcium channels and decreases release of glutamate, norepinephrine, and substance P
• Side Effects: Dizziness, sedation, fatigue, somnolence, leg edema
• Major Clinical Pearls: Decrease dosing in patients with renal insufficiency
• Indications: Complex regional pain syndrome, diabetic neuropathy, post-herpetic neuralgia, lumbar stenosis and radiculopathy^10-12

Pregabalin:

• Mechanism of Action: Similar to Gabapentin, it binds the alpha2delta subunit of L-type voltage gated calcium channels, inhibiting release of neurotransmitters responsible for facilitating pain
• Side Effects: Dizziness, sedation
• Major Clinical Pearls: Decrease dosing in patients with renal insufficiency
• Indications: Post-herpetic neuralgia, diabetic neuropathy, spinal cord injury associated pain^10-12

Zonisamide:

• Mechanism of Action: Blocks T-type calcium channels and sodium channels, which increases the release of GABA
• Side Effects: Ataxia, decreased appetite, rash, renal calculi
• Major Clinical Pearls: Contraindicated in patients with sulfonamide allergies
• Indications: Post-stroke pain^10-12

Ziconotide:

• Mechanism of Action: Blocks calcium influx into N-type calcium channels in the dorsal horn laminae of the spinal cord, which prevents afferent conduction of nerve signals
• Side Effects: Dizziness, ataxia, confusion, headache
• Major Clinical Pearls: Administered via an intrathecal infusion pump
• Indications: Severe, chronic, and treatment-refractory pain in patients with or without cancer^10-12

Sodium Channel Blockers and Modulators: Anticonvulsants targeting voltage-gated sodium channels include phenytoin, lamotrigine, carbamazepine, oxcarbazepine, topiramate, and lacosamide. Slow binding of anticonvulsants prevents alterations in normal action potentials. Typically, these anticonvulsants are used for chronic pain.¹⁰

Phenytoin:

• Mechanism of Action: Blocks voltage-gated sodium channels, decreasing glutamate release
• Side Effects: Cognitive slowing, somnolence, ataxia, gingival hyperplasia, aplastic anemia, rash, Stevens Johnson syndrome (SJS) and blood dyscrasias
• Major Clinical Pearls: Activates the cytochrome P-450 enzyme system
• Indications: Diabetic neuropathy^10-12

Carbamazepine:

• Mechanism of Action: Potent antagonist of voltage-gated sodium channels
• Side Effects: Dizziness, diplopia, dizziness, ataxia, syndrome of inappropriate secretion of anti-diuretic hormone, rash and blood dyscrasias
• Major Clinical Pearls: Routine blood tests are recommended, given the increased risk for agranulocytosis and aplastic anemia
• Indications: Trigeminal neuralgia, diabetic neuralgia, post-stroke pain^10-12

Oxcarbazepine:

• Mechanism of Action: Antagonist of voltage-gated sodium channels
• Side Effects: Dizziness, somnolence, nausea, vomiting
• Major Clinical Pearls: Superior side effect profile compared to carbamazepine
• Indications: Trigeminal neuralgia, diabetic neuropathy^10-12

Lamotrigine:

• Mechanism of Action: Blocks sodium channels in actively firing nerves and prevents glutamate release
• Side Effects: Rash, SJS, dizziness, tremor, nauseas, headache, and blood dyscrasias
• Major Clinical Pearls: Similar to phenytoin and carbamazepine, can cause SJS
• Indications: Trigeminal neuralgia, lumbar radiculopathy, diabetic neuropathy, HIV-associated peripheral neuropathy^10-12

Topiramate:

• Mechanism of Action: Topiramate has multiple mechanisms including: 1) Blocks voltage-sensitive sodium channels, 2) increases GABA activity, 3) increases frequency of chloride ion channel opening, and 4) reduces activity of L-type calcium channels
• Side Effects: Weight loss, paresthesia, drowsiness, fatigue, cognitive symptoms
• Major Clinical Pearls: Inhibits carbonic anhydrase
• Indications: Diabetic neuropathy, post-herpetic neuralgia, intercostal neuralgia, complex regional pain syndrome^10-12

Lacosamide:

• Mechanism of Action: Enhances the slow inactivation of voltage-gated sodium channels without affecting fast inactivation
• Side Effects: Generally well-tolerated medication
• Major Clinical Pearls: Well-tolerated side effect profile
• Indications: Diabetic neuropathy^10-12

GABAergic Medications: GABA agonists bind to GABA receptors to augment chloride influx, which leads to hyperpolarization of the neuron and inhibition of neural transmission.¹⁰

Valproate:

• Mechanism of Action: Unclear mechanism of action but demonstrated to increase GABA
• Side Effects: GI upset, somnolence, dizziness
• Major Clinical Pearls: Has broad-spectrum use
• Indications: Migraine therapy^10-12

Benzodiazepines:

• Mechanism of Action: Increased GABA binding to the GABA-A receptor
• Side Effects: Drowsiness, ataxia, respiratory depression
• Major Clinical Pearls: Generally discouraged from use due to lack of efficacy
• Indications: Chronic facial pain, post-herpetic neuropathy^10-12

Local Anesthetics: Local anesthetics are used to rapidly block abnormal nerve conduction in the treatment of post-herpetic neuralgia, trigeminal neuralgia, radiculopathies, and peripheral neuropathies.¹⁰

Lidocaine:

• Mechanism of Action: Blocks action potential propagation by prolonging the inactivation phase of voltage-gated sodium channels
• Side Effects: Bradycardia, cardiac depression, dizziness, blurred vision, seizures
• Major Clinical Pearls: Avoid long-term, high-dose use
• Indications: Post-herpetic neuralgia, post-thoracotomy pain, intercostal neuralgia, meralgia paresthetica^10-12

Mexiletine:

• Mechanism of Action: Considered an oral analogue of lidocaine
• Side Effects: Somnolence, irritability, blurred vision, nausea, vomiting
• Major Clinical Pearls: Can readily convert IV Lidocaine to oral mexiletine
• Indications: Diabetic neuropathy, thalamic stroke pain, allodynia, spasticity^10-12

Miscellaneous Medications:

Magnesium:

• Mechanism of Action: Antagonizes NMDA receptors
• Side Effects: Lethargy, muscle flaccidity
• Major Clinical Pearls: Delivered intravenously
• Indications: No specific indications for neuropathic pain^10-12

Levetiracetam:

• Mechanism of Action: Unclear mechanism of action
• Side Effects: Dizziness, somnolence, headache
• Major Clinical Pearls: Predictable pharmacokinetic effects with dosing changes
• Indications: Multiple clinical trials have not demonstrated its efficacy yet in the treatment of neuropathic pain^10-12

Cutting Edge/ Unique Concepts/ Emerging Issues

Role of Anticonvulsants in Decreasing Opioid Use

Although opioids are the mainstay of managing acute post-operative pain, some anticonvulsants have been shown to help in adjunctive treatment. Gabapentin and pregabalin, which appear to have both analgesic and opioid-potentiating effects, have been demonstrated to decrease pain and need for opioids in patients recovering from knee and back surgery. As a result, increased use of anticonvulsants such as gabapentin and pregabalin could potentially decrease opioid use, thereby helping minimize opioid misuse or overdose.^13-14

Combination Therapy

Given the complex nature and pathophysiology of neuropathic pain, combination therapy involving multiple medications including opioids, anticonvulsants, and antidepressants are often prescribed. For instance, combining gabapentin and opioids have been effective in treating some types of cancer-related neuropathic pain. Additionally, in diabetic peripheral neuropathy, the summative effect of gabapentin and nortriptyline, a tricyclic antidepressant, can be more effective than either medication individually. Furthermore, anticonvulsants have long been recommended in combination with antidepressants, as in the treatment of post-herpetic neuralgia and fibromyalgia. Overall, combination therapy may lead to dose reduction and improved side effect profiles of anticonvulsants. Additional comparative trials assessing the clinical efficacy and cost of combination treatments is needed. Combining anticonvulsants with non-pharmacological interventions such as physical therapy also warrants further study.^15-18

Non-Anticonvulsant Treatments of Neuropathic Pain

• Capsaicin: Capsaicin is a topical agent that can be given in high concentrations (i.e. 8% patch) to treat postherpetic neuralgia, HIV neuropathy, and painful diabetic neuropathy. Capsaicin acts by diminishing substance P stores from nociceptors and by reducing the activity of nociceptor fibers within the skin.¹⁹
• Transcutaneous electrical nerve stimulation (TENS): TENS stimulates large diameter sensory A-beta fibers, which inhibits spinal cord signaling from nociceptive neurons as part of the Gate Control Theory of Pain. While TENS may reduce the intensity of general acute pain, its benefit in treating neuropathic pain has not been firmly established.^20-21
• Spinal cord stimulators (SCS)/Dorsal Root Ganglion Stimulators (DRG): SCS and DRG stimulators act on nerves in the spinal cord to decrease signaling from nociceptive pain fibers similarly to TENS. These stimulators have been used ubiquitously in patients with chronic pain, including neuropathic pain, with some evidence suggesting their utility in acute pain as well. Furthermore, SCS have been shown to reduce opioid use and increase activity tolerance.^22-23
• Botulinum toxin: Botulinum toxin has been used for several pain conditions including cervical dystonia, myofascial pain, and spasticity. However, research on its efficacy in treating neuropathic pain is ongoing. Research suggests that it produces muscle paralysis by blocking presynaptic acetylcholine release and by decreasing peripheral and central nerve sensitization.²⁴
• Ketamine: IV ketamine infusions have been used extensively to treat intractable neuropathic conditions. Ketamine blocks NMDA receptors, which is part of an excitatory glutamatergic pathway ubiquitously distributed throughout the brain and spinal cord that plays an integral role in pain signaling. Increased neuropathic pain relief is associated with higher dose of Ketamine, prolonged infusion, and co-administering adjunctive medications such as Midazolam or Clonidine.²⁵

Gaps in Knowledge/ Evidence Base

• Matching anticonvulsants with therapeutic targets: Treating neuropathic pain early and aggressively can help prevent complications of worsening pain, psychological problems, and disability. Currently, the best available evidence for treating neuropathic pain is with Pregabalin and Gabapentin for peripheral diabetic neuropathy or post-herpetic neuralgia. As mentioned previously, some conditions such as HIV-associated neuropathy or chemotherapy-induced neuropathy do not respond to all membrane-stabilizing agents effectively. Although conditions associated with neuropathic pain often have similar presentations and pathophysiologic mechanisms, they have variable responses to specific treatments. Research investigating specific molecular mechanisms and neural networks in neuropathic pain may hopefully 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 neuropathic pain tend to use outcome measures that are varying or of questionable clinical significance, making it difficult to apply results to specific clinical situations. The development of uniform and appropriate outcome metrics, such as a validated numerical pain rating scale or quality of life measure could enhance the strength and clinical utility of future studies.

References

1. Dahlhamer J, Lucas J, Zelaya, C, et al. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults — United States, 2016. MMWR Morb Mortal Wkly Rep 2018;67:1001–1006. DOI: http://dx.doi.org/10.15585/mmwr.mm6736a2
2. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain. 2012 Aug;13(8):715-24. doi: 10.1016/j.jpain.2012.03.009. Epub 2012 May 16. PMID: 22607834.
3. van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014 Apr;155(4):654-662. doi: 10.1016/j.pain.2013.11.013. Epub 2013 Nov 26. Erratum in: Pain. 2014 Sep;155(9):1907. PMID: 24291734.
4. Finnerup NB, Kuner R, Jensen TS. Neuropathic Pain: From Mechanisms to Treatment. Physiol Rev. 2021 Jan 1;101(1):259-301. doi: 10.1152/physrev.00045.2019. Epub 2020 Jun 25. PMID: 32584191.
5. Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol. 2014 Sep;13(9):924-35. doi: 10.1016/S1474-4422(14)70102-4. PMID: 25142459.
6. 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.
7. 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.
8. O’Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med. 2009;122(10 Suppl):S22-32.
9. Troels S Jensen. Anticonvulsants in neuropathic pain: rationale and clinical evidence. European Journal of Pain. Volume 6, Supplement A, 2002, Pages 61-68. ISSN 1090-3801. https://doi.org/10.1053/eujp.2001.0324.
10. Hurley, R., McGeeney, B. and Argoff, C., 2014. Membrane Stabilizers for the Treatment of Pain. In: Practical Management of Pain, 5th ed. Mosby, Inc., pp.543-551.
11. Peterson, S., Benzon, H. T., & Hurley, R. W. “Membrane Stabilizers.” Essentials of Pain Medicine, 4th ed., Elsevier, 2018, pp. 437–444.
12. Haroutountian, Simon, and Nana B. Finnerup. “Recommendations for Pharmacologic Therapy of Neuropathic Pain.” Essentials of Pain Medicine, 4th ed., Elsevier, 2018, pp. 445–456.
13. 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.
14. 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.
15. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin or their combinations for neuropathic pain. N Engl J Med. 2005;352:1324-1334.
16. 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.
17. 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.
18. Moore A, Wiffen P, Kalso E. Antiepileptic drugs for neuropathic pain and fibromyalgia. JAMA. 2014;312(2):182-183.
19. Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth. 2011;107(4):490-502. doi:10.1093/bja/aer260
20. Johnson M. Transcutaneous Electrical Nerve Stimulation: Mechanisms, Clinical Application and Evidence. Rev Pain. 2007;1(1):7-11. doi:10.1177/204946370700100103
21. 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.
22. 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.
23. Koetsier E, Franken G, Debets J, et al. Mechanism of dorsal root ganglion stimulation for pain relief in painful diabetic polyneuropathy is not dependent on GABA release in the dorsal horn of the spinal cord. CNS Neurosci Ther. 2020;26(1):136-143. doi:10.1111/cns.13192
24. 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.
25. Orhurhu V, Orhurhu MS, Bhatia A, Cohen SP. Ketamine Infusions for Chronic Pain: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Anesth Analg. 2019 Jul;129(1):241-254. doi: 10.1213/ANE.0000000000004185. PMID: 31082965.

Original Version of the Topic

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

Previous Revision(s) of the Topic

Diane Schretzman Mortimer, MD, Kerri Chung, DO. Anticonvulsants for Pain Management. 8/3/2017.

Author Disclosure

Steven R. Flanagan, MD
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Jason Kessler, MD
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Julia Tsinberg, MD
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Danni Lu, MD
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Richard Lau, MD
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