A better understanding of the mechanisms of drug and alcohol dependence is helping to further development and use of pharmacotherapies against addictions
by Ann Thayer
Addictions, especially alcohol dependence, have been treated largely as behavioral disorders. Weaknesses in will, character, or faith were among the factors believed to contribute to an addicted person's dependence. Consequently, for decades, treatment has centered on psychological or behavioral therapy. Only recently, thanks to improved understanding of the neurologic and physiologic aspects of addiction, more medication-based treatments have emerged, along with a gradually expanding willingness to use them.
Pharmacotherapies for treating addictions have actually been around for decades, but only a few medications have been approved specifically for that purpose, and these have found limited use. Within the past few years, the number has nearly doubled as one or two new products each for smoking cessation, opioid abuse, and alcohol dependence have become available. Many researchers working in the field, as well as pharmaceutical companies developing and marketing the medications, believe this growth may herald a new phase in addiction pharmacotherapy.
"I believe we are in the midst of a paradigm shift in how alcohol dependence is perceived and then ultimately how it's treated," says Mark Willenbring, director of the Division of Treatment & Recovery Research at the National Institute on Alcohol Abuse & Alcoholism (NIAAA). "There is a much more medical approach emerging; treatment for alcohol dependence at this point is similar in some ways to where treatment for depression was about 30 years ago."
Behavioral therapies can be effective, he adds. "Most people don't get treatment, and the treatments we have are not as effective as they need to be," he says. "There are dual problems of expanding access and improving efficacy, and medications are really going to be a key component." The treatment community is grappling with the relatively recent recognition that addiction disorders are chronic, relapsing diseases stemming from genetics and environmental influences and that pharmacotherapies not only are available but can be effective.
NIAAA and the National Institute on Drug Abuse (NIDA) have been playing critical roles in increasing the neurobiological and neurochemical understanding of addiction disorders, as well as in running clinical studies to show where existing and new therapies offer promise. A resulting change, says Francis (Frank) Vocci, director of NIDA's Division of Pharmacotherapies & Medical Consequences of Drug Abuse, is that "pharmaceutical companies are starting to look at addiction as a viable indication, something worthy of evaluating in terms of developing medications."
Industry's involvement has been limited in the past by several factors, according to many people working in the field. These factors have included deficiencies in the ability to discover and effectively test new antiaddiction drugs, a scarcity of data-driven proof that drug therapies work, a small market size coupled with difficulties in reaching doctors and patients, and even cultural resistance, stigma, and other concerns around such products. The addiction pharmacotherapy market is currently worth only about $2 billion, reports the research firm Spectra Intelligence. The market is expected to grow to $2.9 billion by 2012, fueled by increased need, mounting health care and socioeconomic burdens in the hundreds of millions of dollars, and new products that will add sales and offer proof-of-principle.
About 9% of the U.S. population, or 22.3 million people aged 12 or older, were classified as having a substance dependence or abuse problem in 2005, according to the Substance Abuse & Mental Health Services Administration (SAMHSA), part of the U.S. Department of Health & Human Services. In its just-released survey-September is National Alcohol & Drug Addiction Recovery month-SAMHSA reports that in this group, 3.3 million used both alcohol and illicit drugs, 3.6 million used just drugs, and 15.4 million used just alcohol. But only 3.9 million people received any kind of treatment, most through self-help groups. Another 71.5 million people used tobacco products.
According to Spectra Intelligence's recent analysis, nearly 35 drug candidates are in the pipeline to treat alcohol, narcotic, and nicotine dependencies. The growing understanding of how addiction plays out is helping improve the design and testing of new and more efficacious medications. Not only are products that are more effective expected to emerge, but also, in a similar manner to how doctors treat other central nervous system (CNS) conditions, these products will provide more options for addressing complex addictive diseases in different patients.
Drugs of abuse are chemically diverse and thus have very different targets, mechanisms of action, and manifestations in the body. But addiction's common underpinning lies in how these molecules ultimately affect the brain's reward pathway, explains Eric J. Nestler in a review article (Nat. Neurosci. 2005, 8, 1445), prepared with support from NIDA. Nestler is chairman of the department of psychiatry and a member of the Center for Basic Neuroscience at the University of Texas Southwestern Medical Center in Dallas.
Addictive drugs reward their users, an outcome that encourages repeated use, and they produce unpleasant symptoms on withdrawal, Nestler says. Addiction also involves associating drug use with environmental cues and adaptive changes in the brain, believed to contribute to craving and relapse. Evidence suggests the common circuitry is in the brain's limbic system and, in very simple terms, ultimately involves either direct or indirect activation of dopaminergic pathways to increase dopamine levels.
"Because common mechanisms seem to contribute to at least some aspects of all drug addictions," Nestler writes, "it might be possible to develop treatments that would be effective for a wide range of addictive disorders." Drugs targeting the brain's dopamine, glutamate, corticotropin releasing factor (CRF), opioid, or cannabinoid systems might exert the desired effects. At the same time, he cautions that drugs should safely and effectively dampen common mechanisms of reward while not adversely affecting normal function.
Existing pharmacotherapies, he also points out, are specific for the target or receptor of the drug of abuse, and no treatment aimed at a common mechanism has yet been fully validated across a range of addictions. Meanwhile, along with identifying various molecular and cellular pathways, receptors, and neurotransmitters, scientists have found links between genes and the risk of dependence and other factors involved in addiction. Now they are trying to relate these genetic variations to behavioral phenotypes of addiction.
In turn, they are creating more predictive and robust animal models. And they are exploring targets and pharmacotherapeutic agents that run the gamut from agonists, partial agonists, antagonists, and modulators of appetitive systems in the brain to monoclonal antibodies and even vaccines (Eur. J. Pharmacol. 2005, 526, 101). The goal is to find pharmacotherapies that not only halt a drug's acute effect and prevent withdrawal but also block craving and other factors that cause relapse.
SMOKING CESSATION.
Nicotine replacement therapies (NRTs) have dominated pharmacological treatment for smoking. These are patches, gums, lozenges, nasal sprays, and inhalers for delivering controlled doses of the addictive drug itself. The Food & Drug Administration approved the first NRT gum for prescription use in 1984, followed by the first patch in 1991. In 1996, both the gum and patches became over-the-counter (OTC) products. According to NIDA, all NRT products are equally effective, working about 20% of the time.
Although NRTs ease withdrawal symptoms, they don't control neurotransmitter release or blunt the addictive effects of nicotine. An option is bupropion, a norepinephrine- and dopamine-reuptake inhibitor. GlaxoSmithKline (GSK) sells the off-patent drug as Wellbutrin for depression and, since 1997, as Zyban for smoking cessation. Nortriptyline, a tricyclic antidepressant and norepinephrine reuptake inhibitor, has been studied and is sometimes used for smoking cessation but isn't approved for this use.
In 2005, GSK had $611 million in sales of OTC smoking cessation products, primarily NRTs. Pfizer has been the other leading producer of NRTs, but these products are part of the consumer health business the company is selling to Johnson & Johnson. The total market for nicotine addiction therapies was about $1.5 billion in 2005, according to Spectra Intelligence, with sales of existing therapies expected to grow modestly.
The need for new therapies is tremendous, and the market potential is enormous. According to the World Health Organization, there are 1.3 billion smokers worldwide. Tobacco-related illnesses are the second leading cause of death among all people, accounting for about 5 million deaths per year. In the U.S. alone, about 60 million people smoke cigarettes. An estimated 70% say they want to quit, and 40% try each year. The Centers for Disease Control & Prevention lists smoking as the leading preventable cause of death.
The first new nonnicotine treatment to come along in a decade is varenicline, launched in August by Pfizer as the prescription drug Chantix. Its discovery and development took roughly one decade, says Martin R. Jefson, Pfizer's vice president for CNS discovery. The drug is a pharmacologically unique chemical entity that works through the same nicotinic receptor population used by the substance of abuse, he explains. But whereas nicotine is a full agonist, or activator, of the receptor, varenicline is only a partial agonist, which may be key to its ability to help patients quit and avoid relapse.
"There is good scientific evidence that nicotine targets nicotinic acetylcholine receptors located in a region of the brain thought to be very central to the process of reward and habituation," Jefson says. A specific abundant subtype called 42 is believed to mediate the reinforcing properties of nicotine. It does so by binding nicotine and then releasing dopamine; the pleasurable outcome of this event leaves a smoker wanting to do it again.
"We were looking for something that might offer the benefits of an antagonist, which would block the rewarding effects of nicotine taken in by relapse smoking, but also something that served as an activator or agonist of the receptor and provide some relief from the craving and withdrawal that comes with abrupt cessation," Jefson explains. A partial agonist does this by competing with nicotine itself for the receptor with comparable or even superior affinity and activating the receptor some but not nearly as much as the full agonist.
The discovery of varenicline involved screening, optimizing, and testing compounds inspired by the plant alkaloid (-)-cytisine (C&EN, June 6, 2005, page 36). Cytisine has been used to treat nicotine dependence in Eastern Europe for more than 40 years (Arch. Inter. Med. 2006, 166, 1553). "We were very gratified to see that varenicline worked in the clinical setting as we hoped it would based on the preclinical work," Jefson adds. It turns out, he explains, that varenicline is a very high-affinity, high-selectivity nicotinic receptor partial agonist specific for the 42 subtype.
Chantix was tested on a few thousand patients in a series of clinical trials. Results of several of these were published in the Journal of the American Medical Association (JAMA) in early July and in the Archives of Internal Medicine in August. In general, Chantix showed both short- and long-term effectiveness, being as much as four times as effective as placebo and twice as effective as Zyban. After one year without further treatment, about one in five patients who had received Chantix were not smoking.
Most smokers, even those using a therapy, don't manage to quit, and for those who do, the relapse rate is extremely high: Less than 10% stay abstinent for more than one year. Pfizer has developed a behavioral support plan, called GETQUIT, that it is offering at no charge with Chantix to increase the odds. The company anticipates initially offering the new drug through respiratory care specialists. A patient takes 1 mg twice daily for an initial period of 12 weeks and, if they succeed in quitting, for another 12 weeks to increase the likelihood of long-term abstinence.
Pharmaceutical industry analysts estimate that Chantix could boost the market for nicotine addiction therapies by $400 million to $500 million per year. "We saw an opportunity that was interesting scientifically and medically and where there was commercial opportunity for the right product," Jefson remarks. "Smoking's impact internationally on health is very dramatic, the prevalence is very high, and it's a very motivated patient population, which isn't the same across all substance abuse situations."
Response to the studies and to the drug's approval generally has been positive, with the events being called a step forward for smoking cessation therapy. Issues raised, nonetheless, were the side effects, generally nausea in as many as 30% of people; nontrivial dropout rates, which are reportedly typical in smoking cessation trials; and the generalizability to real-world patient situations, as is true of many clinical studies. In an accompanying JAMA editorial, University of Tennessee health scientists call varenicline a "definite promise, but no panacea" (J. Am. Med. Assoc. 2006, 296, 94).
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