Off-label use of gabapentin and pregabalin for anxiety

An excerpt from Understanding Medicines for Anxiety.

In addition to medicines with FDA indications for anxiety, such as benzodiazepines and some antidepressants, a number of drugs are frequently prescribed off-label. Among these are gabapentin and the related compound pregabalin, collectively known as gabapentinoids.  Their popularity is remarkable: gabapentin has been the tenth most commonly prescribed medicine in the U.S., and equally remarkable is that up to 95 percent of its prescriptions are for uses for which it does not carry an approved indication.  Similarly, in terms of sales, pregabalin is the fourth most commonly used drug among those typically found in primary care settings.  Although much of this prescribing is for pain, a significant amount appears to be related to anxiety.  In this article we will review this particular use, beginning with some background.

Gabapentin (Neurontin) and pregabalin (Lyrica) are anticonvulsants and nerve pain medicines which have structural similarities to the inhibitory neurotransmitter GABA. Gabapentin was developed in 1993 and has indications for shingles (‘postherpetic neuralgia’) and partial-onset seizures. It has had a growing popularity in off-label uses for fibromyalgia, pain from a variety of causes, migraine, cocaine withdrawal, anxiety, and insomnia. A related compound, gabapentin encarbil (Horizant), is approved for shingles and restless leg syndrome. Pregabalin was developed in 2004 and is approved for nerve pain from diabetes and spinal cord injuries, fibromyalgia, and adjunctive treatment of partial-onset seizures. Although prescribed off-label for anxiety in the U.S., it is approved for this purpose in the U.K., where it is sometimes called the ‘new Valium’.

Studies in animal models of anxiety have shown some benefit of gabapentin, but there are minimal systematic studies in humans. One showed benefits in social phobia, another showed no benefit in panic or agoraphobia in the overall group, although some individual patients were helped. There has been a report of improvement in anxiety and hot flashes in breast cancer patients. Some studies have reported improvement in pre-surgical anxiety. Overall, though, there are little systematic data on persons with generalized anxiety disorder (GAD). Most studies of pregabalin for GAD have shown some reduction in anxiety, though with one exception the duration of treatment was eight weeks or less. One study reported that treatment over a six-month period was more effective than placebo in preventing a return of symptoms. There are some data that it might be helpful as an augmenting medicine in persons who have not responded to antidepressants for generalized anxiety disorder.

Side effects: The most common side effects of gabapentin are somnolence (19%), dizziness (17%), and ataxia (13%). Uncommon but serious reactions are angioedema (swelling of the face or throat) and changes in blood cells with inflammatory reactions of organs including the liver, kidney, and heart (‘eosinophilia and systemic symptoms’). Pregabalin produces dizziness in about 30% and somnolence in 23%. It can cause weight gain, pooling of fluid in the extremities, and allergic reactions, including angioedema. Antiepileptic drugs as a class may increase the risk of suicidal ideation or actions, starting as early as one week of treatment and lasting at least as long as the 24 weeks which have been studied.

Dependence: Abruptly stopping high doses of gabapentin can produce anxiety, disturbed sleep, confusional states, disorientation, and agitation. This has usually been associated with persons misusing the drug, but milder forms of withdrawal disturbance have been seen after therapeutic doses. Pregabalin, if stopped abruptly, can cause transient sleep disturbance, anxiety, diarrhea, nausea, or seizures. Both drugs should be tapered slowly before stopping. Pregabalin was classified as a Schedule V controlled substance by the D.E.A. in 2005.  Both gabapentin and pregabalin are listed as controlled substances in the U.K. Gabapentin is currently not a federally scheduled drug in the U.S., but is classified as Schedule V by several states. It is under review by the U.S. Food and Drug Administration, based on some suggestions of abuse. There is growing recognition that it is used recreationally, and some illicit heroin preparations contain gabapentin as a way of increasing the euphoric experience. It is estimated that gabapentin is misused in 15-22 percent of persons who abuse opioids.

Overdose: Overdoses of gabapentin of up to 35 gm have been reported to produce drowsiness, dizziness, coordination difficulties, diarrhea, and lowered blood pressure, and have generally not been fatal when taken alone by healthy persons. In Kentucky, one of the states in which it is now a scheduled drug, it appeared in one-third of fatal overdoses, which included overdoses of combinations of substances. There is less experience in this regard with pregabalin. During development, an accidental overdose of 8,000 mg taken alone occurred without significant medical complications. Like gabapentin, it is sometimes used with opiates, with toxic or even lethal results. Similarly, when in combination with alcohol or nervous system depressants, there is the possibility of greater toxicity.

Choosing gabapentin and pregabalin: These drugs are widely used off-label as an alternative to benzodiazepines for anxiety disorders. The speed of their onset of action has not been clearly established, but many clinicians have the impression that it is often within a few days, much shorter than that for antidepressants. They are also used to augment anti-anxiety effects in persons who have not responded to the use of antidepressants. Among the difficulties, as is often the case with off-label use, is the absence of very much long-term data.

In summary, gabapentinoids became popular as a treatment for anxiety because they were thought to be safer than other available drugs such as benzodiazepines, with an initial perceived lack of abuse potential.  Systematic studies showing benefits for anxiety are relatively limited, and as we have gained experience with these compounds, there is increasing evidence of recreational use and dependence, and a growing recognition of their side effect profiles.

Wallace B. Mendelson is a psychiatrist and author of Understanding Antidepressants and Understanding Medicines for Anxiety.

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