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Science 24 Aug 2018:
Vol. 361, Issue 6404, pp. 761
DOI: 10.1126/science.aau6548
Antiaddiction drugs could help curtail the opioid epidemic, but they may pose risks of their own.
Drug addiction is a major global health issue, and the opioid crisis is a notable example of its catastrophic effects (1). In his News In Depth story “Chemists seek antiaddiction drugs to battle hijacked brain” (13 April, p. 139), R. F. Service discusses some promising ways to treat drug addiction, including vigabatrin and a more effective version of that drug named OV329. However, the optimistic tone of the article should be tempered by the potential side effects of these treatments.
The gamma-aminobutyric acid aminotransferase (GABA-AT) enzyme plays a key role in brain signaling by inactivating GABA (2). Currently, the only licensed drug that targets this enzyme is vigabatrin, an antiepileptic that is usually reserved for severe intractable seizures (2). OV329 is mechanistically similar to vigabatrin, but—as Service explains in the News story—it binds more tightly to GABA-AT.
Although more potent GABA-AT inhibitors may reduce the dopaminergic signaling that is responsible for reinforcing addiction, we should be aware of the possibility that these drugs may themselves cause physical and/or psychological dependence. Benzodiazepines and barbiturates, drugs that increase GABA signaling by acting directly on the GABA-A receptor, cause a physical dependence with prolonged use, and rapid withdrawal may lead to fatal seizures (3). It is reassuring that vigabatrin has not been reported to have such effects (4), but the side-effect profile of this drug is such that it is seldom prescribed to those without a diagnosis of epilepsy, making it difficult to identify whether seizures that occur on withdrawal are due to the withdrawal of the drug or the underlying disorder. Furthermore, as OV329 is considerably more potent than vigabatrin, the effects of its withdrawal may be comparatively more prominent.
It should be noted that benzodiazepines were not found to be addictive until almost two decades after their introduction (5). When considering the role of GABAergic pharmacotherapy for opioid addiction, we should be cautiously optimistic, but it would be prudent to remember that opioid withdrawal, while highly unpleasant, is not lethal, whereas rapid decreases in GABA signaling may be.