Day # 77: Gabapentin and Pregabalin

Welcome back to our current theme of anxiety disorders. We are continuing our conversation on the medications used in the treatment of anxiety disorders and other conditions. Today we will discuss gabapentin and pregabalin.

Today's content level: Intermediate

INTRODUCTION AND MECHANISM OF ACTION

•Gabapentin = Neurontin, Horizant

•Pregabalin = Lyrica

•These medications are technically classified as anti-epileptic drugs (AEDs) used for seizure disorders, but are also commonly used to treat neuropathic pain, anxiety disorders (second-line option), and other indications we will cover below.

•Gabapentin and pregabalin are structurally related and similar to GABA (the main inhibitory neurotransmitter in the central nervous system [CNS]). Given this structural similarity, it may surprise you that these medications do not appear to act on the GABA receptors as one might expect given their structure.

The major mechanisms of action include: 1

• Acts as a leucine analogue (amino acid) which allows transport across the blood brain barrier (BBB) via leucine transport.

• Binds to voltage-gated calcium channels in the CNS. It binds the channels in their inactive conformation and stabilizes the inactivated state. Consequently, both medications act to inhibit the release of various neurotransmitters, including glutamate.

Other properties: 2, 3

• Acts on the order of weeks, but relatively quick onset of action and response may be seen in the first week of treatment.

• Gabapentin and pregabalin are considered to have some potential for abuse, physiological dependence, and withdrawal but not on the same magnitude as discussed previously for benzodiazepines. Also, the current literature on this topic is limited and suggests that gabapentin/pregabalin is predominantly abused by patients with other substance use disorders, notably opioid use disorder. If you are discontinuing these meds then taper over at least a week due to risk of withdrawals.

• Pregabalin appears to have some distinct advantages over gabapentin which include rapid absorption, stable bioavailability, more potent anticonvulsant properties, and less side effects. It is, however, a newer medication and more expensive.

INDICATIONS

FDA approved indications:

• Epilepsy: Both gabapentin and pregabalin are approved for the treatment of partial seizures with or without secondary generalization (adjunctive).

• Post-herpetic neuralgia: Painful condition that affects the nerve fibers and skin that is a complication of infection with the varicella zoster virus (chicken pox / shingles). Both gabapentin and pregabalin are approved for the treatment of post-herpetic neuralgia.

• Neuropathic pain: Pregabalin is approved for the treatment of neuropathic pain associated with diabetes and spinal cord injury. Both medications, however, are commonly used to treat all types of neuropathic and chronic pain.

• Fibromyalgia: Poorly characterized disorder marked by widespread musculoskeletal pain that is accompanied by fatigue, sleep, memory, and mood issues. Pregabalin is FDA-approved and gabapentin is also frequently used. More on fibromyalgia in a later part of the curriculum.

Other off-label indications:

• Anxiety disorders: Gabapentin and pregabalin are used off-label as adjunctive or second-line treatment in anxiety disorders. Gabapentin has been shown to be effective in reducing symptoms of anxiety in social anxiety disorder and mixed results in panic disorder (significant improvement in more severely ill). It is also likely effective for other anxiety disorders such as GAD but is not well studied. Pregabalin is effective in reducing symptoms of anxiety, has approval for treatment of GAD in Europe, and also likely effective in other anxiety disorders. 4

• Alcohol use disorder: Gabapentin and pregabalin have been shown to have some efficacy in alcohol withdrawal and reducing drinking but evidence is limited.

• Adjunct in bipolar disorder?? Some anti-epileptic drugs (AEDs) have known mood stabilizing properties in the treatment of bipolar mania and depression (valproic acid, carbamazepine, lamotrigine, etc). It appears that the "gabapentinoids" do not share these same effects and there is little efficacy in bipolar disorder. It is hypothesized that it may have some efficacy by virtue of an anxiolytic effect and some authors have argued it may have use as prophylaxis although evidence is limited.

• Other uses: Mood lability/impulsivity in borderline personality disorder, migraines, Restless legs syndrome (RLS), insomnia, menopausal conditions (i.e., hot flashes), vertigo, and itching of the skin.

SIDE EFFECTS

Common side effects include:

• Sedation / Fatigue

• Dizziness / Ataxia

• GI -> nausea, dyspepsia, diarrhea, or constipation.

• Tremor / Nystagmus

• Blurry vision

• Peripheral edema

• Weight gain -> not common but also not unusual.

Serious side effects include:

• Like all AEDs, has black box warning for increased risk for suicidality. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

• Overdose: Relatively safe in overdose, as no fatalities have been reported. Overdose is characterized by sedation and ataxia.

CONCLUSION

Great work today. In our next post we will discuss "other" meds used in anxiety disorders to include hydroxyzine, alpha-2 agonists (clonidine, guanfacine), and beta-blockers (propranolol).

Resources for today's post include the Maudsley Prescribers Guide, Stahl's Essentials for Psychopharmacology, and Pocket Psychiatry.

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