Anticonvulsants can help, but how?

Substance use disorders (SUD) are treated with a variety of pharmacological agents. For example, it is standard practice to see medications including clonidine, barbiturates, and benzodiazepines prescribed for acute withdrawal syndromes from alcohol, sedative-hypnotic medications, opioids, and nicotine.

For later, maintenance phases of SUD treatment, there are at present a limited number of labeled medications. For maintenance-phase, alcohol-abuse treatment, we see disulfiram (Antabuse), naltrexone (Depade, Nalorex, Opizone, Vivatrol, and others), plus acamprosate (Campral). For maintenance-phase opiate use disorder treatment, we see buprenorphine (Buprenex, Subutex, Transtec), methadone (Dolophine, Methadose, Metharose, and others) and the buprenorphine/naloxone (Suboxone) combination. Patients in the maintenance phase of SUD treatment may also be prescribed antidepressant, antianxiety, and/or antipsychotic medications that target coexisting mania, psychosis, anxiety, depression, or other psychological conditions.

More recently, anticonvulsant medications have assumed a greater role in the pharmacologic management of SUD maintenance-phase treatment. At one time, these agents were routinely prescribed for withdrawal states associated with a high risk of seizures, but more recently have been used to impact cognitive, behavioral, and symptomatic dimensions of SUDs.

Dr. Robert Post, Professor of Psychiatry at George Washington University School of Medicine, was a pioneer in the development of a role for anticonvulsants in treatment of bipolar disorder. He maintains that “some of the mechanisms that are pertinent to blocking seizure discharges in epilepsy may also be applicable to the broad uses of the anticonvulsants [in the treatment of] neuropsychiatric disorders, including SUDs.” Indeed, clinicians have employed anticonvulsants off-label to treat conditions ranging from anxiety disorders, substance abuse disorders, and migraines to eating disorders and obesity.

While the FDA has not approved any anticonvulsant for use in SUD treatment, many experts believe that they can play a role SUD treatment.

Dr. Jayesh Kamath, Assistant Professor of Psychiatry at the University of Connecticut Health Center, is one. “In my clinical experience and based on limited evidence, anticonvulsants, especially divalproex sodium (Depakote), have a significant role in [treating] patients with substance use [disorders].” He asserts that the impact of anticonvulsant medication therapy is “probably much more significant in bipolar patients with substance use comorbidities,” based on his belief that there are shared “pathophysiological mechanisms involving the GABA-ergic system.”

A recent scholarly review by a group of Italian psychiatrists led by Icro Maremmani noted that there are few studies of the role of anticonvulsants in SUD treatment.1 Of these, most are short-term in duration and therefore offer little insight into long-term effectiveness (e.g., relapses into agitation, impulsivity, and dissatisfaction). The authors believe that anticonvulsants are preferable to antipsychotics or antidepressants in dually diagnosed, substance-abusing patients with bipolar disorder. They argue that long-term use of antidepressants among such patients may contribute to “switches” into mania along with increased impulsivity and subsequent relapse into substance use. In addition, they argue that the long-term risks of antipsychotic medications outweigh those of anticonvulsants.

For providers considering the value of anticonvulsant medication therapy for “pure” SUDs (e.g., SUDs not associated with other clear psychiatric diagnoses), a handful of studies suggest effectiveness. According to Kamath, “Anticonvulsants have a larger application for [treatment of] alcohol and benzodiazepine use disorders than other substance use disorders.”

Some investigators, including Post, theorize that anticonvulsants may help in the treatment of some SUDs because they reduce cravings. “Most anticonvulsant medications have indirect effects on dopamine or glutamate. These are critical inputs to the nucleus accumbens [an area of the limbic system] that affects the brain's reward system.” Studies in alcohol, benzodiazepine, and cocaine dependent patients have borne out this thinking.

But if this is true, what is the mechanism of action through which anticonvulsant medications assert their effects? Post says: “I wonder about [their] mechanistic properties such as blockade of sodium channels and decreased release of glutamate, decreased calcium influx through the NMDA receptor, increases in potassium efflux, as well as a variety of aminergic effects and effects on gene expression.”

Spiegel and Radac recently described cases in which adding the anticonvulsants (valproic acid, levetiracetam or gabapentin) to benzodiazepines in patients experiencing alcohol withdrawal syndrome yielded better outcomes than seen with benzodiazepines alone.2 The authors also suggest that the long-term use of these anticonvulsant agents helped curtail craving in these patients.

There is at least some evidence to support the use of the anticonvulsants in substance-addicted/dependent patients (see table).1 Another review, originating in Greece, suggests that pregabalin (Lyrica) may be efficacious in SUD treatments for alcohol and benzodiazepine dependence.3

Table. Possible indications (X) for use of anticonvulsant medications in treatment of addicted/dependent patients1

Clinicians frequently struggle with two significant concerns when considering the possible use of anticonvulsant medication therapies for SUD treatment. First is the impact on liver function. Klamath says that “many of these patients have a history of Hepatitis C due to IV drug use or risky behaviors, or their livers are compromised from heavy alcohol use.” As a result, he says that “close monitoring of liver functions is critical in this population.”

A second concern is suicidality. A recent survey of prescription claims in a Danish population found an increased risk of suicide for patients who had recently initiated valproate or lamotrigine therapy.4 Of course, more work is indicated before causality can be inferred.

The role of anticonvulsant medications in the treatment of SUDs has resulted from a combination of psychopharmacologic tourism and therapeutic application of scientific constructs and principles. For this reason, prescriptions for off-label uses of anticonvulsants for SUD treatment should be managed only by skilled psychiatrists or addictionologists, and only then with careful monitoring of risks and benefits over time. There is, of course, a tremendous need for new and proven advances in the treatment of patients with SUDs. Here's hoping that some of our current anticonvulsant medications can help.

William M. Glazer, MD, is president of Glazer Medical Solutions ( https://www.glazmedsol.com) of Key West, Fla., and Menemsha, Mass. He is a clinician, researcher, lecturer, and consultant, and has been a member of faculty of the departments of psychiatry at the Yale and Harvard Schools of Medicine.

References

1. Maremmani I, Pacini M, Lamanna F. et al: Mood stabilizers in the treatment of substance use disorders. CNS Spectr 2010; 15:2, pp 95-109.
2. Speigel DR and Radac D:Alcohol withdrawal: When to choose an adjunctive anticonvulsant. Current Psychiatry 2010; 9:4, pp 27-39.
3. Oulis P, Konstantakopoulos G. Pregabalin in the treatment of alcohol and benzodiazepines dependence. CNS Neurosci Ther. 2010 Spring; 16 (1): 45-50.
4. Olesen JB, Hansen PR, Erdal J, et al. Antiepileptic drugs and risk of suicide: a nationwide study. Pharmacoepidemiol Drug Saf. 2010, Mar 16. [Epub ahead of print].

Behavioral Healthcare 2010 June;30(6):32-33