Clinical Pharmacology of Dependence & Addiction

CLINICAL PHARMACOLOGY OF DEPENDENCE & ADDICTION

To date no single pharmacologic treatment (even in combination with behavioral interventions) efficiently eliminates addiction. This is not to say that addiction is irreversible. Pharmacologic interventions may in fact be useful at all stages of the disease. This is particularly true in the case of a massive overdose, in which reversal of drug action may be a life-saving measure. However, in this regard, FDA-approved antagonists are available only for opi-oids and benzodiazepines.

Pharmacologic interventions may also aim to alleviate the with-drawal syndrome, particularly after opioid exposure. On the assumption that withdrawal reflects at least in part a hyperactivity of central adrenergic systems, the α₂-adrenoceptor agonist cloni-dine (also used as a centrally active antihypertensive drug) has been used with some success to attenuate with-drawal. Today, most clinicians prefer to manage opioid withdrawal by very slowly tapering the administration of long-acting opioids.Another widely accepted treatment is substitution of a legally available agonist that acts at the same receptor as the abused drug. This approach has been approved for opioids and nicotine. For example, heroin addicts may receive methadone to replace heroin; smoking addicts may receive nicotine continuously via a transdermal patch system to replace smoking. In general, a rapid-acting sub-stance is replaced with one that acts or is absorbed more slowly. Substitution treatments are largely justified by the benefits of reducing associated health risks, the reduction of drug-associated crime, and better social integration. Although dependence per-sists, it may be possible, with the support of behavioral interven-tions, to motivate drug users to gradually reduce the dose and become abstinent.

The biggest challenge is the treatment of addiction itself. Several approaches have been proposed, but all remain experimen-tal. One approach is to pharmacologically reduce cravings. The μ-opioid receptor antagonist and partial agonistnaltrexoneisFDA-approved for this indication in opioid and alcohol addiction. Its effect is modest and may involve a modulation of endogenous opioid systems.

Clinical trials are currently being conducted with a number of drugs, including the high-affinity GABA _B-receptor agonist baclofen, and initial results have shown a significant reduction ofcraving. This effect may be mediated by the inhibition of the dopamine neurons of the VTA, which is possible at baclofen con-centrations obtained by oral administration because of its very high affinity for the GABA_B receptor.

Rimonabant is an inverse agonist of the CB₁receptor thatbehaves like an antagonist of cannabinoids. It was developed for smoking cessation and to facilitate weight loss. Because of fre-quent adverse effects—most notably severe depression carrying a substantial risk of suicide—this drug is no longer used clinically. It was initially used in conjunction with diet and exercise for patients with a body mass index above 30 kg/m² (27 kg/m² if associated risk factors, such as type 2 diabetes or dyslipidemia are present). Although a recent large-scale study confirmed that rimonabant is effective for smoking cessation and the prevention of weight gain in smokers who quit, this indication has never been approved. Although the cellular mechanism of rimonabant remains to be elucidated, data in rodents convincingly demon-strate that this compound can reduce self-administration in naive as well as drug-experienced animals.