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Teaching affiliation: as above
The sequence of pathophysiological responses to repeated self-administration of addictive compounds is briefly described, as are prospects for development of drugs for addiction and some of those currently available. It is noted that the varying vulnerability of individuals to addictions creates ethical concerns regarding the application of drug abuse pharmacotherapies as they become more efficacious. It is noted further that relapse remains the most persistent challenge in the treatment of addictions.
Addiction comprises a multi-faceted cascade of neural processes and “neuroadaptations” that lead individuals to compulsively self-administer increasing amounts of addictive substances, despite not wanting to do so, deriving steadily declining pleasure from doing so and knowing with some certainty that doing so will cause deterioration not only of their own health, economic prospects and interpersonal relationships, but likely those of people to whom they are close. Compulsive repetition of certain activities such as gambling, videogaming, thrill seeking and working out also can acquire features of addiction. Furthermore, the nature of addiction is such that it doesn’t cease when an individual manages to regain a state of abstinence. To the contrary, it is a chronically relapsing condition that almost inevitably and irresistibly reoccurs, often after many hard won abstinent months. As regards the economic cost and profoundly negative effects of addiction on individuals, families and society, the National Institute on Drug Abuse reported the following in 2009:
Estimates of the total overall costs of substance abuse in the United States—including health- and crime-related costs as well as losses in productivity—exceed half a trillion dollars annually. This includes approximately $181 billion for illicit drugs, $168 billion for tobacco, and $185 billion for alcohol. Staggering as these numbers are, however, they do not fully describe the breadth of deleterious public health—and safety—implications, which include family disintegration, loss of employment, failure in school, domestic violence, child abuse, and other crimes. (NIDA InfoFacts: Understanding Drug Abuse and Addiction - http://www.drugabuse.gov/infofacts/understand.html).
Addiction thus presents unique and difficult challenges to researchers seeking to find ways to intervene therapeutically and literally thousands of excellent primary research and review papers have been published on the subject. In this short piece the author has attempted a summary that can in no way credit more than a negligible portion of the many superb research groups that have worked on these problems. Consequently, a number of excellent review papers have been cited in the hope that the interested reader will seek recourse to the many primary research papers cited therein. In addition, the author recommends recent special issues of Pharmacology and Therapeutics (Vol. 108, Issue 1, 2005), British Journal of Pharmacology (Vol. 154, Issue 2, 2008) and Philosophical Transactions of the Royal Society B Biological Sciences (Vol. 363, Issue 1507, 2008) that featured focused primary papers and reviews on addiction and addiction pharmacotherapy.
Addiction depends fundamentally on the shared capacity of addictive substances and activities to increase extracellular concentrations of dopamine mainly but far from exclusively in a brain structure called the nucleus accumbens1, either by blocking dopamine reuptake (as does, e.g., cocaine) or simulating the actions of naturally existing neurotransmitters that in turn elicit (or disinhibit) dopamine release (as does, e.g., heroin). The main perceptual correlates of the earliest stage of addiction, depending on the addictive substance, reflect a varying mix of frank pleasure (euphoria) and heightened sense of well-being. Perceived gratification encourages that behaviors that produced it be repeated. Consequent repetition of abnormally robust drug- or activity-stimulated dopamine release produces dysregulation and neuroadaptation in the dopamine-containing mesolimbic pathway, which in turn seeds a divergent cascade of additional compensatory neuroadaptations involving neuronal and glial receptors, transporters and exchangers, second messenger cascades, transcriptional regulators and somatodendritic structure in manifold glutamate-, gamma-aminobutyric acid (GABA)- and neuroactive peptide-containing pathways subject to dopaminergic modulation2–4. An early consequence of such neuroadaptations that reportedly can occur after even a single exposure to some drugs is a heightened behavioral sensitivity (sensitization) to subsequent drug exposures5 with a mental correlate comprising an intense sense of “wanting” (craving) linked to the drug and cues associated with it6. Craving portends more frequent drug use, which, in turn, results in the development of negatively valenced neuroadaptations such as “tolerance” (desensitization) that requires more drug be used to achieve a satisfactory “high” (i.e., level of euphoria). This is accompanied by down-regulation in the basal activity of the dopamine system, such that dysphoria and discontent are experienced when access to the drug or addictive activity is prevented7,8. Combined with this dampening of basal dopamine function, up-regulation of neurotransmitters and hormones representing the brain’s stress response systems contributes to what has been called the withdrawal/negative affect stage or, perhaps more impressively, the “dark side” of addiction9, comprising a basal condition of dissatisfaction, agitation, irritability and craving accompanied by a general feeling of sickness. Yet more neuroadaptations continue to develop, such that motor habits related to drug taking become particularly tenacious, likely because they have become stabilized by frequent, abnormally robust pulses of drug-induced dopamine release in the basal ganglia10. This habitual component of drug use combined with a desire to escape the profound discomfort that increasingly characterizes periods between bouts of drug taking and the growing difficulty to achieve a satisfactory “high”, leads individuals to take still more frequent doses of more drug, with the effect that cardiovascular, respiratory and digestive functions become impaired. Nutrition is neglected and serious illness or life-threatening events, such as drug overdose, ensue. Reversal of the process by abrupt abstinence, i.e., withdrawal, is accompanied by a transient and, depending upon the addictive substance or activity, variably severe syndrome comprising anxiety, nausea, insomnia, muscle pain and weakness, fevers and other flu-like symptoms. But, withdrawal is not the end of it. Long term abstinence after a sustained period of drug use is effectively opposed by the actions of enduring neuroadaptations that cause cues linked to circumstances in which drugs were previously used to be particularly potent in stimulating reinstatement of drug taking. Similarly, stress and even a single exposure to the previously used drug have been shown in experiments with animals to be very potent at producing relapse to intense drug seeking10. Propensity to relapse actually increases during a course of abstinence in a process called “incubation” and this also is a reflection of neuroadaptations11,12.
Difficult issues impede the development of effective pharmacotherapeutic approaches to the treatment of addictions. Insofar as the mesolimbic dopamine system is the common target of addictive compounds and activities, blockade of dopamine neurotransmission profoundly impairs normal reward capacity, thus producing listlessness and depression perhaps as devastating as an addiction. Were such drugs to be prescribed, patients would not take them in any event. In order to identify therapeutic targets that do not completely suppress the reward system, scientists have sought to understand the physiological, pharmacological, biochemical and molecular biological basis of individual neuroadaptations that characterize the several phases of addiction, such as behavioral sensitization13,14, multiple layers of tolerance15, derangements of neuronal and glial transmitter and receptor/transporter/exchanger homeostasis involving, e.g., glutamate16, GABA17 and neuroactive peptides18, up-regulation of the stress response9, drug-enhanced habit consolidation19 and the most insidious aspect of addiction – relapse11,20.
Whilst these kinds of studies collectively have opened up new vistas in our understanding of the neural processes and macromolecular mechanisms that underlie addiction, drugs largely have yet to emerge that effectively target any of these processes or mechanisms21. This is not to say, however, that numerous compounds with a potential to reduce drug intake and attenuate relapse have not been identified. To the contrary, many compounds show promise of therapeutic efficacy in treating addiction, based upon preclinical investigations22. Of these, quite a few have gone to clinical trial in dependent human subjects and some of these have exhibited slight to moderate clinical efficacy4,22,23. Among the more efficacious are those that subvert the principle that a drug high is dependent upon a rapid rate of entry into the brain circulation of a relatively high concentration of drug that produces a robust bump in accumbens extracellular dopamine concentration24. A drug with an action resembling that of the drug to which the subject is addicted, but which enters the brain more gradually due to slow pharmacokinetics or administration route, binds to receptors or transporters less avidly or acts as a “partial” agonist or antagonist tends to be less rewarding but usually not aversive and frequently attenuates craving for the more dangerous drug. Methadone programs and the nicotine patch, which for years have been used in the treatment of opiate addiction and smoking, respectively, are based on this rationale. Buprenorphine (a mu opiate receptor partial agonist) has been used in this way to treat heroin addiction, as has oral tetrahydocannabinol (THC) to withdraw patients from marijuana. Less promising results have been achieved with dopamine agonists and partial agonists in the treatment of psychostimulant addiction, although modafinil, a mild stimulant of uncertain mechanism of action, sufficiently offsets the want for cocaine and amphetamines as to be regarded moderately efficacious. Disulfiram (Antabuse), an acetaldehyde dehydrogenase inhibitor used in the treatment of alcoholism, reduces cocaine intake and craving, by a mechanism that appears at least in part to involve agonist replacement. Another modestly effective approach utilizes anticonvulsant, GABA-enhancing drugs, such as vigabatrin (GABA transaminase irreversible inhibitor), tiagabine (GABA re-uptake inhibitor) and topiramate (enhances GABA-activated chloride channels, inhibits kainate and AMPA glutamate receptors), which, by increasing the inhibitory tone on the dopamine system, reduce psychostimulant intake and propensity to relapse. Craving and relapse are also reported to be reduced by restoration of basal extracellular glutamate levels with drugs, such as n-acetylcysteine, that reverse cocaine-associated depression of cystine-glutamate exchange16. Immunization against drugs of abuse may become a quite effective approach if means can be found to lengthen the period during which subjects remain immunized. Ibogaine, an extract from the West Central African plant Tabernanthe iboga, is reportedly effective in reducing drug intake and craving, but due to pronounced psychoactive properties at higher doses and other dangerous side-effects is prohibited in most countries, including the United States. To date, no drug has received FDA approval for the treatment of psychostimulant addiction. GABA-enhancement and agonist replacement therapy do seem to modestly interrupt the cycle of addiction (conflicting reports exist), but both approaches are less than satisfactory because of poor subject compliance, whereas agonist replacement bears the additional yoke of being an exchange of one dependency for another. More importantly, both approaches inadequately address the critical issue of relapse. Naltrexone, a long-lasting antagonist of opiate receptors, was approved by the US Food and Drug Administration for the treatment of alcohol addiction and is currently promoted by numerous treatment centers as an aid to reducing craving and prolonging abstinence. Controlled clinical trials have produced results that both support and contest these claims and studies with the aim of determining how naltrexone may be utilized most effectively in conjunction with behavioral and psychological therapies are currently being done25.
Relapse, particularly of the variety induced by drug-associated cues, is a vexing problem in the sense that addicted individuals who may have thought that they had “kicked” their habit, seemingly inevitably fall prey to reinstated drug taking. Furthermore, most addicts enter into a cycle of repetitive withdrawal and relapse26, despite having learned in excruciating detail how irresistible is the progression and severe the consequences of reinstated drug-use. Consequently, finding a means to reliably prevent cue-induced relapse in the long term is a holy grail of drug abuse research that has fostered intense preclinical study in many laboratories11,20. As it turns out, such a large number of different experimental conditions and manipulations either elicit or, alternatively, prevent renewed drug seeking in animal models of reinstatement, that the prospect of defining the involved neural systems with any degree of specificity seems somewhat dimmed at present. This is not surprising given the daunting scope and nature of the problem. To wit, how does specificity develop such that drug craving is elicited by perceptual constructs associated with previous drug use and not others - even after years of abstinence? How is rational decision-making abrogated in favor of an obviously bad choice - renewed drug taking? A solution to the problem viewed this way begs consideration not only of the reward system, but rather of the whole of the sensory and perceptual apparatus, the systems that subserve decision-making and the motor outputs, i.e., much of the brain. A number of investigations using experimental animals27 and imaged humans28 have identified a collection of brain structures activated by cues associated with previous drug use and, perhaps not surprisingly, these include more or less the same structures activated by drug administration. Unanswered are the more difficult questions as to how only certain (drug associated) patterns of sensory stimulation produce this profile of activation and how producing the pattern subverts the decision making process in favor of the maladaptive choice. Approaches to answering these questions must at the core be neuroanatomical as much as pathophysiological because the central issue goes to the essence of how incoming sensory information in one pattern (associated with previous drug use) ignites the reward pathways and, hence, relapse, whilst that in a different pattern does not.
This having been said, one interesting approach to the problem of cue-induced relapse circumvents a need to discover the underlying mechanisms. It has been argued that memories are not static, but rather subject to “reconsolidation” such that, when elicited, they may be modified and upon yet later recall will re-emerge in the altered form. From this basis, the idea has emerged that recalled memories associated with previous drug use may be subject to pharmacological manipulation such as to diminish their potential to elicit future reinstatement of drug use29.
Challenges to a pharmacological approach to treating drug abuse are not only scientific in nature, but also ethical. Not everyone who takes drugs becomes profoundly addicted. Genetic disposition and the vagaries of psychosocial development influence how individuals respond to drug exposure and it turns out that many people are resistant to addiction. Nor are addictions necessarily as unrelentingly debilitating as mostly has been described herein, although it seems they always do come with a cost. Cigarette smokers may smoke heavily for decades with little adverse effect other than economic (i.e., the substantial cost of cigarettes), but on average they and people living with them, who may be non-smokers, suffer significantly increased risk to develop co-morbid health problems. Of the many people who partake in the “social” use of alcoholic beverages, which is pervasive in American culture, most do not develop alcohol dependency. However, blurry lines separate moderate from heavy drinking and the latter from frank addiction to alcohol. Substantial social fall-out accompanies moderate to heavy drinking in terms of health issues, joblessness, dysfunctional interpersonal relationships and ruinous child-rearing. The use of alcohol and addictive drugs by American children, adolescents and young adults is widespread and interacts dangerously with their on average immature psychosocial development. Furthermore, drug and alcohol use by the young carries additional risk of altered brain development, which now is known to be incomplete until near the end of the third decade of life. And, of course, a similar if not greater concern for the brains of the unborn is attached to the use of alcohol and addictive drugs by pregnant women (and girls). Consequently, one might argue that any level of use of addictive compounds within the culture is harmful, even discounting the severe effects on individuals of outright addiction, and it makes sense that constant effort should be exerted, perhaps through educational and religious institutions, the media, and family support services, to attempt to reduce the level of use of such substances. Difficult questions arise, however, if efficacious pharmacotherapeutic treatments for addiction are developed, and it seems that they will be, as to who among these groups of individuals ranging between non-addicted and variously addicted would be encouraged to seek such treatment or, possibly, be required to do so.
As regards severe addictions to alcohol, opiates and psychostimulants, protracted behavior modification, cognitive behavioral therapy, and, particularly, 12-step programs are presently the treatments that are most effective in the long term. Pharmacological compounds that dampen the activity of the brain systems underlying drug use and craving should offer a valuable complement to these “talking” therapies. Furthermore, the tremendous strides made in understanding the pathophysiological mechanisms that underlie addiction bespeak a promise of drugs to come that more specifically target critical mechanisms in the cascade of drug-induced neuroadaptations. All of this bodes auspiciously for the future of efficacious pharmacotherapies to be used in combination with expert counseling. The final and most persistent challenge in the treatment of drug addiction, however, is relapse, which, until its mechanisms are fully understood and countered, will continue renewing the cycle of addiction at points long after the aforementioned treatments were deemed successful and discontinued.