Gabapentin (Neurontin) and Pregabalin (Lyrica)

Gabapentin (Neurontin) and Pregabalin (Lyrica) are anticonvulsant (i.e. anti-seizure) medications that have gained popularity among psychiatrists in the past decade. Gabapentin (Neurontin) was released in the United States in 1994 as add-on treatment for focal seizures. Initially, Gabapentin and Pregabalin were thought to enhance GABA neurotransmission in the brain, but this has not been definitively demonstrated. In fact, neither of these agents bind to GABA receptors at all and instead seem to affect calcium channels.

 

Gabapentin (Neurontin) and Pregabalin (Lyrica) target voltage-gated calcium channels (VGCCs) in the brain and spinal cord. They do this by binding to the α2δ subunit of these channels. The result is reduced calcium influx into neuronal axons during depolarization and thus reduced neurotransmitter release into the synaptic cleft.

 

In addition to focal seizures, Gabapentin (Neurontin) and Pregabalin (Lyrica) are approved for use in pain conditions and Pregabalin (Lyrica) was the first medication approved for fibromyalgia (Duloxetine was approved for this use later). To date, there are no randomized placebo controlled trials supporting either medication as an effective treatment for bipolar disorder or depression. That being said, case reports and anecdotal evidence does support their use in special circumstances.

 

There is accumulating data suggesting Gabapentin (Neurontin) and Pregabalin (Lyrica) may be most useful in anxiety disorders and neuropathic pain. In fact, double-blind studies and a few case reports suggest Gabapentin is an effective treatment for social anxiety disorder and panic disorder at dosages of 900-3,600mg/ day. Interestingly, Pregabalin at dosages of 150mg-600mg/day is as effective as benzodiazepines in the treatment of generalized anxiety disorder (GAD). At least five placebo-controlled trials (and maybe more) exist suggesting Pregabalin is at least as effective as alprazolam (xanax) and venlafaxine (effexor) and more effective than placebo in the treatment of GAD without the risk of serious dependence and abuse (Montgomery et al. 2006). While the FDA has not approved Pregabalin for GAD, the European Union did approve it for GAD in 2006. 

Gabapentin (Neurontin)

HALF-LIFE: 5-7 hours
PROTEIN BINDING: Minimal
METABOLISM: NONE (Excreted unchanged in urine)
STARTING DOSE: 100mg-300mg/day (divided doses)
TARGET DOSING RANGE: 300mg-3,600mg/day (divided doses)
BEST TIME TO DOSE: Nighttime due to sedation
HOW TO DOSE:
>>Start at 100mg at bedtime and increase by 100mg-300mg per day to 300mg TID.

>>Max Dose: 3,600mg/day

NOTABLE INTERACTIONS: Decreased absorption and bioavailability with antacids and Cimetidine 
NOTABLE SIDE EFFECTS: Dizziness, sedation, fatigue, weight gain, ataxia
PREGNANCY: More safety data is needed 
BREASTFEEDING: More safety data is needed 

FDA INDICATIONS:

  1. Partial Seizyrees
  2. Post herpetic Neuralgia
  3. Restless Leg Syndrome (Horizant)

 

ADDITIONAL INFORMATION

  • Serious but rare Drug reaction with eosinophilia and systemic symptoms (DRESS)
  • Used off label for anxiety disorders, alcohol withdrawal, benzodiazepine withdrawal, and cannabis dependence 

Pregabalin (Lyrica)

HALF-LIFE: 6 hours
PROTEIN BINDING: Minimal
METABOLISM: Minimal (Excreted unchanged in urine)
STARTING DOSE: 150mg/day (divided doses)
TARGET DOSING RANGE: 150mg-600mg/day
BEST TIME TO DOSE: Morning and/or Night
HOW TO DOSE:
>> Start at 75mg BID and increase slowly to max dose of 300mg BID

>> Use lower doses in patients with renal disease

NOTABLE INTERACTIONS: Reduced absorption with antacids; Additive sedative effects when used with other sedating medications 
NOTABLE SIDE EFFECTS: 

Peripheral Edema, Dizziness, Fatigue, Ataxia, Weight Gain

Serious, but rare, side effects include hypersensitivity skin reactions, angioedema, rhabdomyolysis

PREGNANCY:  More safety data needed
BREASTFEEDING: More safety data needed

FDA INDICATIONS:

  1. Diabetic Peripheral Neuropathy
  2. Neuropathic Pain
  3. Post-herpetic neuralgia
  4. Partial Seizures
  5. Fibromyalgia

 

ADDITIONAL INFORMATION

  • Pregabalin is structurally similar to Gabapentin but more potent with greater bioavailability
  • Schedule V controlled substance due to potential for abuse/dependence (abrupt withdrawal can cause insomnia, nausea, diarrhea, headache)
  • Off label uses include Generalized Anxiety Disorder, Alcohol withdrawal, Benzodiazepine withdrawal, cannabis use disorder, and restless leg syndrome

References

  1. Puzantian, T., & Carlat, D. J. (2016). Medication fact book: for psychiatric practice. Newburyport, MA: Carlat Publishing, LLC.
  2. J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill(pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
  3. Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  4. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  5. Stahl, S. M. (2014). Stahl’s essential psychopharmacology: Prescriber’s guide (5th ed.). New York, NY, US: Cambridge University Press.
  6. Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
  7. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.

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