Medications for the Treatment of Addiction

Conceptual Approach for Understanding Current and Future Medications Development

As noted in What is Addiction?, an important goal of current neurobiological research is to understand the molecular, neuropharmacological, and neurocircuitry changes that mediate the transition from occasional, controlled drug use to the loss of behavioral control over drug seeking and drug taking that defines chronic addiction. The hypothesis elaborated here is that a combination of validated animal models of addiction, neurobiological targets derived from such models, and the translation to and from the clinical domain provide a framework for developing pharmacotherapeutics for addiction. The existing treatments for addiction that are applied to existing animal models and human laboratory models can provide an evolving Rosetta Stone to accelerate the translation of future novel targets to medications for the treatment of addiction (Box 9.1, Figure 9.1; for further reading, see Koob et al., 2009).

A key element of this approach is to prevent rigidity in the process such that animal models predict only what they have already created. Several points of the Rosetta Stone approach speak to this issue. First, as noted in Animal Models, no single animal or human laboratory model exists for all aspects of addiction. Instead, the models emulate different components of addiction, some of which are still evolving. Second, the process of validation is perceived as dynamic, with changes being discovered and implemented at both ends. New targets from neurobiology will feed forward through the system, and new medications will feed backward through the system, regardless of whether these medications are derived from the feed-forward process (e.g., naltrexone, acamprosate, varenicline), clinical experience (e.g., gabapentin), or serendipity. Third, using face validity of symptoms or components of the addiction cycle, new animal and human laboratory models are regularly coming online from basic research (for example, the animal model of compulsivity/drug seeking in the context of aversive consequences or the human model of imaging in the context of cue-induced imagery). Notably, to accomplish the iterative process described above, the procedures must be initiated to make the drug available for human administration. This requires a series of steps known as the four phases of clinical trials (Box 9.2). To initiate human studies for efficacy, Phase I trials must be completed. Human laboratory studies for proof-of-principle (or proof-of-concept) require an approved Investigational New Drug (IND) application from the US Food and Drug Administration (Box 9.3). Human laboratory studies are considered Phase IIa studies.

BOX 9.1

WHAT IS THE ROSETTA STONE?

The Rosetta Stone is an ancient Egyptian stone tablet inscribed with a decree issued at Memphis in 196 B.C. on behalf of King Ptolemy V. The tablet was found in 1799 near Rashîd in Egypt by a French soldier, Pierre-François Bouchard, a member of the French expedition to Egypt led by Napoleon. The decree is repeated in three scripts of three different languages: Ancient Egyptian hieroglyphs, Demotic script, and Ancient Greek. Thus, this tablet provided the key to the modern understanding of Egyptian hieroglyphs by translating the Greek. The British defeated the French in 1801, and the stone was delivered to the British Museum in 1802 where it can be observed today. For the present section, the argument is that the actions of medications that are known to be effective in treating alcoholism will be tested on animal models to validate the animal models or provide reverse translation, similar to how the Rosetta Stone provided a translation for hieroglyphics.

Figure 9.1 A critical aspect of the present hypothesis is the proposed dynamic feedback from the animal model and clinical components not only to provide converging evidence for identification of treatments for drug addiction likely to succeed in clinical trials, but also to facilitate further development of animal and human models. These data ultimately may provide a rational basis for combination therapies such that multiple components of the addiction cycle can be treated by a given pharmacological strategy. [Taken with permission from Koob GF, Lloyd GK, Mason BJ. Development of pharmacotherapies for drug addiction: a Rosetta Stone approach. Nature Reviews Drug Discovery, 2009, (8), 500–515.]

BOX 9.2

PHASES OF CLINICAL TRIALS

A clinical trial can be defined as “a prospective study comparing the effect and value of intervention(s) against a control in human beings” (Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials, Springer, New York, 2010). A prospective study means that subjects will be followed forward in time, although they may be followed from different starting points. Each subject is enrolled at their own starting date and followed for a specified duration of time. All clinical trials include intervention and control groups to which the intervention is compared. Often this is a placebo group. If the subjects are randomly assigned to groups and the investigators do not know which subjects received which treatment, then this is considered a randomized, double-blind, placebo-controlled trial. There are four phases of pharmaceutical clinical trials:

Phase I:

Largely pharmacological studies, examination of drug tolerance, metabolism, drug interactions, pharmacokinetics, and maximum tolerated dose.

Phase II:

Therapeutic efficacy studies, examination of different doses and measures of outcome.

Phase III:

Therapeutic confirmation studies, demonstration of clinical use and safety profile.

Phase IV:

Therapeutic use studies, examination of broad and special populations, and identification of uncommon adverse events.

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