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Over-the-Counter Pain Relief Medication in Patients with Epilepsy

Considerations and Recommendations for Healthcare Providers

Patients with epilepsy who require daily pain relievers or analgesics may experience interactions with their antiseizure medications (ASMs), potentially increasing the risk of side effects or reducing the efficacy of either drug. It is crucial for healthcare providers to discuss these interactions with their patients, especially if the pain relievers are used for more than one week.

Mechanism of Action and Clinical Implications

 

Acetaminophen

Mechanism of Action:

Acetaminophen is an analgesic and antipyretic that acts centrally to inhibit the synthesis of prostaglandins in the brain, providing pain relief and reducing fever.

Clinical Implication:

Increased Metabolism: ASMs such as carbamazepine (Tegretol, Carbatrol), phenobarbital (Luminal), primidone (Mysoline), and phenytoin (Dilantin, Phenytek) can induce hepatic enzymes, leading to increased metabolism of acetaminophen. This may reduce its effectiveness and raise the risk of hepatotoxicity, particularly with high doses and regular use.1,2 

Lamotrigine Interaction: Acetaminophen doses of 2700 - 4000 mg daily for several days may reduce levels of lamotrigine (Lamictal). Patients with plasmas concentrations of lamotrigine at the lower end of the therapeutic range may be susceptible to a clinically relevant interaction with acetaminophen.3-5 


 

Aspirin

Mechanism of Action:

Aspirin irreversibly inhibits cyclo-oxygenase (COX) enzymes, reducing the production of prostaglandins and thromboxanes, thus providing analgesic, anti-inflammatory, and antipyretic effects.

Clinical Implication:

Valproic Acid Interaction: Daily doses above 325 mg can increase plasma levels of valproic acid, leading to enhanced pharmacological effects and increased risk of toxicity.6-9 

Topiramate, Zonisamide, and Acetazolamide: Concurrent use can elevate the risk of side effects from both aspirin and these ASMs, potentially causing increased CNS depression and metabolic acidosis.10,11 

 

Ibuprofen

Mechanism of Action:

Ibuprofen is an NSAID that inhibits COX enzymes, decreasing the synthesis of prostaglandins, thereby reducing pain and inflammation.

Clinical Implication:

Valproic Acid Levels: Ibuprofen may slightly lower valproic acid levels, potentially reducing its efficacy.12 Variable effects on valproate levels with other NSAIDs have been seen without consistency.

Phenytoin Levels: Ibuprofen can increase plasma levels of phenytoin, heightening the risk of phenytoin-related side effects such as ataxia and nystagmus.13

 

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Mechanism of Action:

NSAIDs inhibit COX enzymes, reducing inflammation, pain, and fever.

Clinical Implication:

Kidney Damage: All NSAIDs may exacerbate renal toxicity in patients taking everolimus (Afinitor), necessitating close monitoring of renal function.14

 

Topical Lidocaine

Mechanism of Action:

Lidocaine is a local anesthetic that blocks sodium channels, preventing the initiation and conduction of nerve impulses.

Clinical Implication:

CNS Toxicity: When used in large amounts, lidocaine can interact with ASMs such as phenytoin and phenobarbital, increasing the risk of CNS toxicity. It should be used sparingly in these patients.15

Expert Opinion and Recommendations for Healthcare Providers

In people who take some ASMs daily use of pain relievers over time may increase the risk of side effects. Analgesics can raise or lower the levels of some ASMs. Some ASMs may make analgesics less effective.

Pain Reliever

Considerations

Acetaminophen

Monitor liver function tests in patients taking high doses of acetaminophen.

Be cautious of reduced lamotrigine levels and adjust dosages as necessary.

Acetaminophen dosing should never exceed 4000 mg per day in adults.

Doses should not exceed 3000 mg daily in those 65 years and older, children, those with liver disease and significant alcohol use.
Acetaminophen can be found in multiple combination OTC products. Maximum daily dosing should consider all sources of acetaminophen.

Aspirin

Avoid high daily doses (>325 mg) in patients on valproic acid to prevent toxicity.

Monitor for increased side effects when used with topiramate, zonisamide, and acetazolamide.

Ibuprofen

Regularly monitor valproic acid levels to ensure therapeutic efficacy.

Monitor phenytoin levels to mitigate the risk of elevated levels and side effects.

NSAIDs

Closely monitor renal function in patients taking everolimus and NSAIDs.

Topical Lidocaine

Limit the use of lidocaine in patients taking phenytoin or phenobarbital to avoid potential CNS toxicity. Monitoring for CNS symptoms and adjusting dosages is recommended when these drugs are used together. Lidocaine strengths above 4% may cause seizures.

 

 

Resources & References

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1 Amar PJ, Schiff ER. Acetaminophen safety and hepatotoxicity--where do we go from here?. Expert Opin Drug Saf. 2007;6(4):341-355. doi:10.1517/14740338.6.4.341

2 Perucca E, Richens A. Paracetamol disposition in normal subjects and in patients treated with antiepileptic drugs. Br J Clin Pharmacol. 1979;7(2):201-206. doi:10.1111/j.1365-2125.1979.tb00922.x

3 Carnovale C, Mosini G, Gringeri M, et al. Interaction between paracetamol and lamotrigine: new insights from the FDA Adverse Event Reporting System (FAERS) database. Eur J Clin Pharmacol. 2019;75(9):1323-1325. doi:10.1007/s00228-019-02691-4

4 Depot M, Powell JR, Messenheimer JA Jr, Cloutier G, Dalton MJ. Kinetic effects of multiple oral doses of acetaminophen on a single oral dose of lamotrigine. Clin Pharmacol Ther. 1990;48(4):346-355. doi:10.1038/clpt.1990.162

5 Gastrup S, Stage TB, Fruekilde PB, Damkier P. Paracetamol decreases steady-state exposure to lamotrigine by induction of glucuronidation in healthy subjects. Br J Clin Pharmacol. 2016;81(4):735-741. doi:10.1111/bcp.12840

6 Abbott FS, Kassam J, Orr JM, Farrell K. The effect of aspirin on valproic acid metabolism. Clin Pharmacol Ther. 1986;40(1):94-100. doi:10.1038/clpt.1986.144

7 Goulden KJ, Dooley JM, Camfield PR, Fraser AD. Clinical valproate toxicity induced by acetylsalicylic acid. Neurology. 1987;37(8):1392-1394. doi:10.1212/wnl.37.8.1392

8 Ichikawa H, Amano T, Kawabata K, et al. Fatal hyperammonemia in a patient with systemic lupus erythematosus. Intern Med. 1998;37(8):700-703. doi:10.2169/internalmedicine.37.700

9 Orr JM, Abbott FS, Farrell K, Ferguson S, Sheppard I, Godolphin W. Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects. Clin Pharmacol Ther. 1982;31(5):642-649. doi:10.1038/clpt.1982.89

10 Cowan RA, Hartnell GG, Lowdell CP, Baird IM, Leak AM. Metabolic acidosis induced by carbonic anhydrase inhibitors and salicylates in patients with normal renal function. Br Med J (Clin Res Ed). 1984;289(6441):347-348. doi:10.1136/bmj.289.6441.347

11 Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs. Focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet. 1996;31(1):29-46. doi:10.2165/00003088-199631010-00003

12 Gao P, Wang J, Zhang L, et al. The impact of ibuprofen on valproic acid plasma concentration in pediatric patients. Xenobiotica. 2022;52(6):535-540. doi:10.1080/00498254.2022.2117109

13 Dasgupta A, Timmerman TG. In vitro displacement of phenytoin from protein binding by nonsteroidal antiinflammatory drugs tolmetin, ibuprofen, and naproxen in normal and uremic sera. Ther Drug Monit. 1996;18(1):97-99. doi:10.1097/00007691-199602000-00016

14 Sridharan K, Shah S. Use of non-steroidal anti-inflammatory drugs in renal transplant patients: A retrospective study. Int J Risk Saf Med. 2023;34(4):379-386. doi:10.3233/JRS-220065

15 Lardieri AB, Crew PE, McCulley L, Kim IE, Waldron P, Diak IL. Cases of benzocaine-associated methemoglobinemia identified in the FDA adverse event reporting system and the literature [published online January 2, 2019]. Ann Pharmacother. doi: 10.1177/1060028018823532. [PubMed 30600685]

 

This information was curated by the AES Treatments Committee to offer providers guidance on approved over-the-counter (OTC) drugs with an emphasis on their use by people with epilepsy. The information presented on this page is designed to be informational for a broad audience and is not medical advice. For personalized recommendations, speak to a pharmacist or healthcare provider.