Which medication is safer and less neurotoxic for long-term pro re nata (PRN) use for anxiety, Diphenhydramine or Gabapentin?

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Last updated: March 27, 2025View editorial policy

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From the Research

Gabapentin is generally considered safer and less neurotoxic than diphenhydramine for long-term PRN use in treating anxiety.

Key Considerations

  • Gabapentin, typically started at 100-300mg doses taken as needed up to three times daily (maximum 3600mg/day), works by modulating calcium channels and GABA neurotransmission without significant cognitive impairment when used appropriately 1.
  • Diphenhydramine, while effective short-term at 25-50mg doses, has anticholinergic properties that can cause significant cognitive side effects including memory problems and confusion, particularly concerning with regular use in older adults.
  • Long-term diphenhydramine use has been associated with increased dementia risk, while gabapentin generally maintains a better cognitive safety profile over extended periods 2.

Important Safety Information

  • Gabapentin requires careful dosing adjustments for kidney impairment and can cause sedation, dizziness, and potential physical dependence with prolonged use.
  • Neither medication should be abruptly discontinued after extended use, and both should be initiated under medical supervision with regular follow-up to monitor effectiveness and side effects.
  • The most recent and highest quality study 3 suggests that cognitive behavioral therapy (CBT) may be effective for discontinuing benzodiazepines, which could be considered as an alternative or adjunct to gabapentin or diphenhydramine for anxiety management.

Clinical Recommendations

  • Consider gabapentin as a safer alternative to diphenhydramine for long-term PRN use in treating anxiety, due to its more favorable cognitive safety profile.
  • Monitor patients closely for potential side effects and adjust dosing as needed to minimize risks.
  • Regular follow-up and medical supervision are crucial to ensure safe and effective use of these medications.

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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