Gabapentin and Pregabalin

Contents

Overview

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.

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)

Clinical Information

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 is 3,600mg/day

PREGNANCY: More safety data is needed 

BREASTFEEDING: More safety data is needed 

Side effects

Dizziness, sedation, fatigue, weight gain, ataxia, serious but rare drug reaction with eosinophilia and systemic symptoms (DRESS)

Drug Interactions

Decreased absorption and bioavailability with antacids and Cimetidine 

FDA Indications

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

Off Label Uses: Alcohol Withdrawal, Anxiety, Pain, Cannabis dependence

Mechanism(s) of Action

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.

Pregabalin (Lyrica)

Clinical Information

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

PREGNANCY:  More safety data needed

BREASTFEEDING: More safety data needed

Side Effects

Peripheral Edema, Dizziness, Fatigue, Ataxia, Weight Gain, hypersensitivity skin reactions (rare), angioedema (rare), rhabdomyolysis (rare)

Drug Interactions

Reduced absorption with antacids; Additive sedative effects when used with other sedating medications 

FDA Indications

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

Off Label Uses: Generalized Anxiety Disorder, Alcohol Cravings, Alcohol Withdrawal, Pain, Restless Leg Syndrome, Cannabis Use Disorder

Mechanism(s) of Action

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.

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)

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.