Pharmacological research on addictions: a framework for ethical and policy considerations.
Abstract: Findings from neuroscience research hold promise for improved treatments for and prevention of substance use disorders (SUD), but ethical concerns about psychopharmacological research involving SUD may potentially undermine scientific progress. This article reviews the literature pertaining to seven ethical requirements that elucidate a coherent framework for evaluating the ethics of clinical SUD research protocols. Those requirements are social or scientific value, scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent, and respect for potential or enrolled subjects. An evidence-based analysis suggests that sound pharmacological research in SUD can safeguard the welfare of research participants while collecting valuable scientific data and benefiting society.

Keywords--ethics, policy, psychopharmacology, research, substance use disorders
Article Type: Report
Subject: Substance abuse (Care and treatment)
Substance abuse (Prevention)
Medical ethics (Evaluation)
Pharmacology, Experimental (Evaluation)
Pharmacology, Experimental (Ethical aspects)
Authors: Geppert, Cynthia
Bogenschutz, Michael P.
Pub Date: 03/01/2009
Publication: Name: Journal of Psychoactive Drugs Publisher: Haight-Ashbury Publications Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 Haight-Ashbury Publications ISSN: 0279-1072
Issue: Date: March, 2009 Source Volume: 41 Source Issue: 1
Topic: Event Code: 290 Public affairs Advertising Code: 91 Ethics
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 208534949
Full Text: Although psychopharmacological research on drugs of abuse and addiction has been conducted for nearly 50 years, most of the ethical conflicts in the early years of study centered on such psychosocial dilemmas as confidentiality, privacy, and criminalization of the ingestion of certain mood-altering drugs (Buchanan et al. 2002). Recent scientific discoveries in genetics, neurochemistry, and brain imaging have demonstrated that there is an important biological contribution to the development of substance use disorders (SUD). Additionally, neuroscience has provided evidence for cuing, context-driven consumption, and other behavioral phenomena associated with addiction (Goldstein & Volkow 2002; Miller & Goldsmith 2001; Volkow, Fowler & Wang 2003)

Gradually, a model of "addiction solely as a brain disease" has gained popularity, both supplementing and supplanting the traditional medical model and bringing with it expanded opportunities for research funding. According to Hall and colleagues, "Addiction as 'brain disease' has some of the appeal of the older 'disease models' of addiction with the added authority of the latest science. A 'disease' that can be 'seen' in the many-hued splendor of a PET scan carries more conviction that one justified by the possibly exculpatory self-reports of addicts who claim they are unable to control their drug use" (Hall, Carter & Morley 2003; Kleiman 2003; Wise 2000). The majority of researchers and opinion leaders in the field view SUD as having bases in not only neurobiology but also experience and environmental factors (Uhl 2003). Yet some contemporary interpretations of the brain disease model, such as the belief that biology determines addictive behavior to such an extent that individuals with SUDs are unable to make free choices (Charland 2002; Cohen 2002), could constrain the type of research that it is considered ethical to conduct.

Another constraint on research is that ethical decisions are often based on theoretical assumptions rather than scientific evidence. In a special issue of the Psychology of Addictive Behaviors dedicated to the empirical underpinning of the ethics of alcohol administration in research settings, Brandon and Lisman (2000) pointed out that many of the ethical concerns raised in both the professional literature and public media are not empirically grounded. More recently, Anderson and DuBois (2007) conducted a comprehensive literature review to determine to what extent substance abuse research has a body of evidence upon which to ground ethical best practices. They concluded:

Guidelines for safe and ethical experimental administration of substances of abuse have been formulated by both the National Institute on Alcohol Abuse and Alcoholism's (NIAAA) National Advisory Council on Alcohol Abuse and Alcoholism (2005) and the National Institute on Drug Abuse's (NIDA) National Advisory Council on Drug Abuse (2000), and several excellent reviews of the extant literature primarily related to alcohol administration have been published (Fischman & Johanson 1998; Dolinsky & Babor 1997). Yet questions remain regarding the extent to which these guidelines and reviews reflect evidence-based research.

Formulating empirically derived responses to the presuppositions underlying many of the proffered arguments against research with drugs of abuse is not purely an academic exercise. Many of the scientists, clinicians, ethicists and community members who serve on institutional review boards (IRBs) and other types of oversight committees reviewing proposals for SUD studies may unwittingly endorse these presuppositions. Investigators and clinicians involved in, or supportive of, research with drugs of abuse will need to understand and anticipate scholarly and popular objections to their work and be ready to offer scientifically rigorous and ethically sound defenses (Fischman & Johanson 1998; Gorelick, Pickens & Bonkovsky 1999)

To facilitate that process, this aticle seeks to delineate a seven-part framework to guide ethical development and evaluation of SUD research by investigators, IRB members, funding organizations and others, and to report on scientific studies relevant to evidence-based research ethics.

METHOD

Systematic Framework

To identify a comprehensive and systematic structure for considering the ethics of clinical research pertaining to substance use disorders, we selected the seven-part framework elucidated by bioethicists from the Department of Clinical Bioethics at the Warren G. Magnuson Clinical Center at the National Institutes of Health (Emanuel, Wendler & Grady 2000).

Drawing on the basic philosophies underlying the Nuremberg Code (Katz 1996), Declaration of Helsinki, (World Medical Association 1997) Belmont Report (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979) and other similar documents, Emanuel and colleagues (2000) formulated seven requirements for determining whether clinical research is ethical. Those seven requirements are:

(1) value--enhancements of health or knowledge must be derived from the research;

(2) scientific validity--the research must be methodologically rigorous;

(3) fair subject selection--scientific objectives, not vulnerability or privilege, must determine recruitment, the potential for and distribution of risks and benefits, which communities are selected as study sites, and the inclusion criteria for individual subjects;

(4) favorable risk-benefit ratio--within the context of standard clinical practice and the research protocol, risks must be minimized, potential benefits enhanced, and the potential benefits to individuals and knowledge gained for society must outweigh the risks;

(5) independent review--unaffiliated individuals must review the research and approve, amend, or terminate it;

(6) informed consent--individuals should be informed about the research and provide their voluntary consent; and

(7) respect for enrolled subjects--subjects should have their privacy protected, the opportunity to withdraw from studies, and their well-being monitored.

These seven requirements and ways they could be applied to SUD research were presented by Christine Grady, RN, Ph.D., then acting director of the Department of Bioethics at NIH's Clinical Center, during a seminar on "Bioethics Issues in Neuroscience on Drug Abuse" sponsored by the National Institute on Drug Abuse's Neuroscience Consortium (Walters & Grady 2000). Seminar participants agreed on these seven requirements, and this article includes suggestions for the ethical conduct of research pertinent to each criterion.

Review of the Literature

Theoretical articles and guidelines from the National Advisory Council on Alcohol Abuse and Alcoholism (2005) and the National Advisory Council on Drug Abuse (2000) were reviewed to identify ethical principles considered fundamental to conducting research involving the administration of ethyl alcohol or other drugs with abuse potential to human subjects. Broad subject headings were used to search the Medline database to find empirical studies that explore variables related to ethical issues in research with participants with substance use disorders.

RESULTS

Results of this review are formulated from several expert sources (Anderson & DuBois 2007; Emanuel, Wendler & Grady 2000; Gorelick, Pickens & Bonkovsky 1999; Roberts 1999) using an organizational framework of core requirements for ethical research as applied to substance use disorders, summarized in Table 1.

Social or Scientific Value

Substance use disorders are one of this nation's most pressing public health problems. There is both a scientific imperative to develop beneficial methods of preventing and treating SUD and an ethical mandate to alleviate the tremendous personal suffering of the drug user and the immense costs to society that are consequences of addictive disorders. According to the National Comorbidity Survey Replication, the 12-month prevalence of SUD was 3.8% (8.5 million) of the population aged 18 years of age and older, and the lifetime prevalence was 14.6% (32.6 million) (Kessler et al. 2005). Of 12-month cases, only about one fourth (26.4%) received any treatment from a mental health professional and only 38.1% received any form of assistance (Wang et al. 2005). The economic cost to society from alcohol use in the United States in 1998 was estimated at $184.6 billion (Harwood, Fountain & Livermore 1998), and the economic cost of drug abuse in 2002 was estimated at $280.9 billion (ONDCP 2004). These figures signify an enormous human and social cost in medical complications, premature morbidity, lost job productivity, dysfunctional families, criminal justice expenditures and numerous social services.

The social value of this research is closely linked to its scientific merit. The contributions of psychopharmacological research in SUD at the basic and clinical science levels are numerous and important. More research has been conducted with alcohol, but similar discoveries have been made in the pathophysiology and pharmacology of amphetamines, cocaine, and opioids, among other drugs. Table 2 lists some of the major discoveries in psychopharmacological research in SUD (Dolinsky & Babor 1997; Lindsey, Gatley & Volkow 2003; McCance-Katz, Kosten & Jatlow 1998; Zack & Poulos 2004).

Both the guidelines from the National Advisory Council on Alcohol Abuse and Alcoholism (2005) on the administration of alcohol to human subjects and those from the National Advisory Council on Drug Abuse (2000) on administration of drugs to human subjects recognize the importance of such research in addressing fundamental questions pertaining to the etiology, treatment and prevention of SUD, but both organizations also call for continuing attention to the fundamental ethical principles that govern such research.

Scientific Validity

Valuable research must be conducted in a methodologically rigorous manner. Certainly, research that uses biased samples, unsupported hypotheses, or flawed statistical evaluations, has insufficient power to detect differences, neglects critical endpoints, or could not realistically enroll sufficient subjects cannot generate valid scientific knowledge (Emanuel, Wendler & Grady 2000).

Fair Subject Selection

This criterion refers to justice in the selection and recruitment of participants. The Belmont Report, the cardinal statement of research ethics, established that those who are subjected to the risks of experimentation should also benefit from the research and that additional burdens of research should not be placed on those who already possess multiple vulnerabilities (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979). The National Advisory Council on Alcohol Abuse and Alcoholism (2005) warned that it is important to avoid using subjects merely because of their easy availability, low social or economic status or limited capacity to understand the nature of the research. These requirements are especially difficult to honor in SUD research given that many persons with substance use disorders also are economically disadvantaged, afflicted with medical and psychiatric comorbidities, or subject to the dictates of the judicial system. Conversely, justice is not served by depriving those members of the substance-using population who are capable of informed consent of the opportunity to participate in research that may be beneficial for themselves and society.

The current scientific consensus is that while animal and laboratory studies are necessary, they are not sufficient to investigate some aspects of drugs of abuse such as the cognitive and biobehavioral dimensions (Fischman & Johanson 1998) Kleber 1989). Pharmacological research, in particular, requires human subjects to investigate the pharmacokinetics and pharmacodynamics of study compounds as well as potential drug-drug interactions and adverse effects. Similarly, it may not be possible to understand mechanisms of abuse and dependence, craving, and other hallmarks of addiction without studying persons with SUD. Conducting research with a vulnerable population is more just if knowledge of, or ability to treat, this same vulnerability may potentially emerge from the research (Kleber 1989).

Compensation

The use of financial incentives to recruit individuals with SUD to participate in research raises ethical concerns (Fry et al. 2006) The National Advisory Council on Alcohol Abuse and Alcoholism (2005) stated that compensation should not be given at a level or in a form that could be considered to be coercive. It has been argued that many individuals with SUD cannot say no to money offered by researchers (Charland 2002).

Interestingly, the few empirical studies of the reasons persons with SUD participate in addictions research challenge the assumption that money is the only motivating factor. Fry and Dwyer (2001) interviewed 154 injecting drug users regarding their reasons for research participation. Forty-six percent mentioned economic gain; 38%, an expression of citizenship; 19%, altruism; 17%, personal satisfaction; 16%, drug use activism; and 5%, seeking information or assistance. Festinger and colleagues (2005) found no evidence that payment is coercive. They randomly assigned consenting drug abuse outpatients to receive payments of $10, $40, or $70 in either cash or a gift certificate for attending a six-month research follow-up assessment. Findings indicated that neither the amount nor type of the incentives had a significant effect on rates of new drug use or perceptions of coercion. Consistent with the contingency management literature, higher payments and cash payments were associated with increased follow-up rates.

There are several additional factors that can mitigate the potentially coercive quality of payments for research. Dispensing smaller payments at greater frequency has been advocated to reduce the effect of immediate reward on subjects' decisions. The use of non-cash payments such as vouchers for goods and services to compensate subjects has been proposed as a means of minimizing the risk that persons participating in addiction research would use cash incentives to obtain drugs (Fischman & Johanson 1998). Although these measures tacitly assume that persons with SUD, if given the chance, will use compensation for drugs of abuse, at least one study has shown this may not necessarily be the case. Forty-eight cocaine-dependent outpatients provided biweekly self-reports of how they used the cash money dispensed. Results indicated that money was used infrequently to acquire alcohol or other drugs but was used primarily for daily life activities such as purchasing food and gas or to pay debts and bills (Rothfleisch et al. 1999).

Recruitment of Prisoners

As in general psychopharmacological research, the recruitment of prisoners or those for whom research is the only treatment option or alternative to incarceration is ethically problematic. Yet substance use disorders have a high prevalence among those incarcerated in the criminal justice system, and research is urgently needed to inform rehabilitation and treatment programs in this population. A recent Bureau of Justice Statistics Special Report about prison and jail inmates noted that among inmates without a comorbid mental health problem, 55.6% in state prisons, 49.5% in federal prisons, and 53.2% in local jails were dependent on or abused alcohol or other drugs (James & Glaze 2006).

Prisoners who volunteered for research were actually used for much of the early work on drugs of abuse before implementation of more stringent human subjects protections (Kleber 1989). Now, the Code of Federal Regulations (45 CFR 46, subpart C) provides safeguards, acknowledging that because of their incarcerated status, prisoners may be under constraints that could affect their ability to make a truly voluntary decision whether or not to participate as subjects in research (DHHS 2005). Subpart C specifies that one member of the IRB for such protocols must be a prisoner or representative of prisoners, that risks must be commensurate with risks accepted by nonprisoner volunteers, that each prisoner must be clearly informed that participation will have no effect on parole, and that adequate provision is made for follow-up examinations or care. Research on conditions particularly affecting prisoners as a class, such as alcoholism or drug addiction, may proceed only after the Secretary of the Department of Health and Human Services (DHHS) through the Office of Human Research Protections has conducted extensive consultation with experts in medicine, ethics, and penology, and a published notice of an intent to approve the research has been published in the Federal Register.

Women

Research involving women with SUD who have children or who are pregnant is another ethically laden area in subject selection and recruitment. The National Advisory Council on Alcohol Abuse and Alcoholism (2005) recommends that a pregnancy test be done immediately prior to each alcohol administration in female research subjects and that women who are pregnant be excluded from participation. The rationale given is that research on alcohol and pregnancy has continued to identify new prenatal alcohol-associated adverse birth outcomes and to uncover cognitive and behavioral problems that may arise at alcohol exposure levels below those associated with the fetal alcohol syndrome (FAS). The National Advisory Council on Drug Abuse (2000) has stated that risk/benefit considerations virtually always would preclude administration of drugs to pregnant women as this may endanger the fetus. One exception would be in the treatment of pregnant, substance-dependent subjects. Investigators and IRBs are asked to adhere to the requirements in 45 CFR, Part 46, Subpart B, which discuss protections for pregnant women, human fetuses and neonates involved in research (DHHS 1991).

There have been several punitive judicial rulings and coercive policy approaches to SUD among pregnant women, including the prosecution of approximately 250 women in more than 30 states for substance use during pregnancy and the amendment of over 18 state child welfare laws to address the subject of a woman's drug use during pregnancy (DeVille & Kopelman 1998; Roberts & Dunn 2003). In some states, a pregnant woman's drug use triggers an evaluation of parenting ability, while in others it provides a basis for presuming neglect (Paltrow, Cohen & Carey 2000). No studies of the effect of potential prosecution on research participation could be located, but data regarding treatment seeking indicate that criminal justice considerations deter pregnant women from obtaining help. (National Advocates for Pregnant Women 2006; National Advocates for Pregnant Women 2004; National Coalition for Effective Drug Policies 2004).

A much more positive development in research with substance-abusing parents or pregnant women is NIDA's Perinatal-20 project. The project maintains the premise that for SUD research with these groups to be ethical, investigators must adhere to strict experimental standards while simultaneously offering appropriate clinical care. The project has examined ways in which these goals can be achieved through clear expectations of responsibilities for participants and clinical and research staff, sound experimental design, anticipation of possible problems in consent forms, and cognizance of the limitations of clinical services offered in the context of research (Howard & Beckwith 1996).

Favorable Risk-Benefit Ratio

The risk-benefit analysis is a central ethical dilemma in psychopharmacological research involving SUD (Brandon & Lisman 2000). Many of the risks associated with this research are analogous to those of any other pharmacologic research (e.g., adverse effects of medications, lack of efficacy of drug, use of placebo, relapse and its consequences, and loss of confidentiality). Both the National Advisory Council on Alcohol Abuse and Alcoholism (2005) and the National Advisory Council on Drug Abuse (2000) noted that any risk/benefit analysis should include consideration of the quality of the proposed research protocol, the value of the information to be gained, the degree and type of risk to subjects, the availability of alternative means of acquiring the same type of information, the research team's qualifications, and research site suitability.

Risk of abuse or relapse. In studies involving administration of potentially addicting substances, there is a unique set of risks, since these substances have the potential to initiate addiction or trigger relapse. Often, objections that research with drugs of abuse is inherently too high risk to be justified are based on understandings of the phenomena of addiction that have been insufficiently nuanced or contextualized, particularly when concerning drug-naive or treatment-seeking cohorts.

Although empirical data are limited and not always consistent, many guidelines caution against administering alcohol or drugs of abuse to persons who are alcohol or drug-naive, particularly if there is a family history of addiction or other risk factors (National Advisory Council on Drug Abuse). Ethical justification for research for such studies requires a compelling rationale that this vulnerable cohort's participation is necessary to answer an important scientific question and the existence of a strongly favorable risk/benefit assessment (National Advisory Council on Drug Abuse 2000). Potential participants must be advised that exposure to a drug of abuse could potentially trigger an underlying diathesis.

There is general agreement that studies with intoxicated or withdrawing subjects are considered the most ethically concerning due to subjects' diminished capacity (Uhl 2003). Similarly, the substantial risks involved in psychopharmacological research with addictions argue strongly against replicating findings that have already been demonstrated, such as the basic mechanisms of withdrawal (Goldman 2000).

Patients who are actively using drugs or without interest in treatment have generally been considered to experience only a small increase in risk over their daily use through experimental participation (National Advisory Council on Drug Abuse 2000; CPDD 1996). Assessments of the risk-benefit balance for enrolling subjects in various stages of recovery are somewhat incompatible. The National Advisory Council on Alcohol Abuse and Alcoholism (2005) stated that research studies involving individuals who are alcohol-dependent and who will be exposed to alcohol necessitate special attention. There should be a medical examination and screening to assure the absence of any medical or mental condition for which further alcohol exposure at the dose contemplated would be contraindicated. Additionally, there should be an assessment of current treatment-seeking status, duration of abstinence with the treatment regimen and risks entailed through exposure to alcohol, as well as an effort to encourage individuals not in therapy to enter treatment. Similar recommendations are contained in the guidelines of National Advisory Council on Drug Abuse (2000) for individuals who are dependent on drugs or who are frequent drug abusers.

For individuals already in treatment, the guidelines provide additional cautions. The Drug Abuse Advisory Council (National Advisory Council on Drug Abuse 2000) warned that any situation where drug administration could potentially interfere with the treatment process or motivation of patients to continue in care will almost certainly be contraindicated. Further participants should not be recruited simply for the convenience of the investigator.

For individuals involved in abstinence-oriented treatment for alcoholism, the National Advisory Council on Alcohol Abuse and Alcoholism (2005) recommends that the research team consider the potential for untoward effects on the treatment/recovery process and maintain treatment following conclusion of research participation for a sufficient period to ensure recovery. Research subjects with a short-term period of abstinence should be warned that administration of alcohol under experimental conditions might cause them to relapse to heavy drinking, and individuals who have achieved long-term abstinence should not be subjected to any risk of a return to drinking by administration of alcohol.

Empirical research. However, empirical research with both alcohol and other drugs challenges the guideline assumption that exposure to a substance of abuse necessarily exacerbates the course of a substance use disorder even with individuals involved in treatment (Modell, Glaser & Mountz 1993; Kranzler, Dolinsky & Kaplan 1990) For example, Modell and colleagues (1993) showed that even in recently abstinent chronic alcoholics, the experimental administration of alcohol did not result in relapse, urge to drink or significant behavioral problems. In reviewing clinical research that involves ethanol administration as part of the treatment, Dolinsky and Babor (1997) concluded that there is no compelling evidence that participation in ethanol administration research per se has adverse effects on alcoholic research subjects. Drobes and Anton (2000), looking at nontreatment-seeking alcoholics, found that no subjects reported increased drinking following study participation.

Although there is empiric evidence that the risk of negative outcome such as increased usage, switch to more deleterious and potent forms of administration, development of substance abuse or dependence, and relapse is less than theorized or anticipated, it remains incumbent upon researchers to minimize risks and maximize benefits to participants and society as a cardinal obligation of ethical research (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979).

During and after administration of the substance in an experimental setting, the welfare of the subject and public can be protected through providing transportation, keeping the subject in the setting until he or she is no longer exhibiting the effects of the substance, and requiring subjects to agree not to drive or operate machinery for some period (usually 24 hours) after a trial ends (Wood & Sher 2000).

Context. The College on Problems of Drug Dependence (1996) pointed out that the administration of drugs of abuse in the research setting is in actuality far safer than in a naturalistic setting, a fact that is seldom mentioned in risk/benefit analyses. In such uncontrolled settings, there is a high risk of morbidity and mortality from hepatitis C, HIV, and overdose. The purity and composition of street drugs is uncertain compared to the laboratory grade substances used in experiments, and generally smaller amounts of drugs for shorter periods of time are administered in the laboratory setting under medical supervision (Adler 1995).

Perhaps the least understood and most important ethical distinction between naturalistic and research use is that the environmental influence and psychological mindset which behavioral science has identified as essential for the development of addiction is far less operative in the laboratory. Too often, the social and psychological context is ignored when evaluating the risks of administering drugs of abuse. The classic study on this contextual effect is opioid use among Vietnam veterans. A study of 943 men leaving Vietnam in 1971 found that nearly half had tried narcotics and 20% were addicted to opioids. Before Vietnam, less than 1% had ever been addicted to opioids, and after return to the U.S. usage and addiction returned to pre-Vietnam levels (Robins, Helzer & Davis 1975). In a follow-up study of 374 Vietnam veterans who used heroin while in Vietnam, the researchers found most used it very occasionally or not at all after returning to the U.S. Predictors of those who used heroin after their return included having injected heroin in Vietnam or having used other drugs of abuse prior to going to Vietnam (Robins & Slobodyan 2003).

Participation benefits. The benefits of participation in research for persons with SUD are often neglected. The College on Problems of Drug Dependence (1996) pointed out that research subjects often receive free medical and psychological evaluation, and many research protocols include psychoeducation and referral for treatment that may motivate patients to change. A study of nontreatment residential drug abuse research with 233 subjects found a decrease on a range of psychopathologies between admission and discharge, indicating a positive effect of separation from the drug-using environment and placement in a structured setting (Montoya & Haertzen 1994). Studies that used a brief motivational interview actually resulted in reductions in substance use (Drobes & Anton 2000).

Independent Review

The need for ongoing independent review and outside expert consultation extends from the conceptualization of the proposal to publication of the data. According to federal regulation, IRBs bear the primary responsibility for reviewing protocols for ethical adequacy (Department of Health and Human Services 1991). Both the National Advisory Council for Alcohol Abuse and Alcoholism (2005) and the National Advisory Council on Drug Abuse (2000) place responsibility for the development and implementation of ethical research protocols first on the principal investigator and next with the IRB. Additionally, all HHS-conducted or funded research protocols involving human subjects must be reviewed by an IRB, with subsequent levels of review for all projects supported by the institutes and centers of the National Institutes of Health. However, because many IRBs lack experience and expertise in SUD research and because local knowledge and attitudes toward research with drugs of abuse vary widely, it is prudent for IRBs to obtain outside expert advice when considering such proposals (National Advisory Council on Alcohol Abuse and Alcoholism 2005; Fischman & Johanson 1998). Fry (2002) also saw addictions journals as playing a key role in raising the profile of human research ethics in addictions research.

Informed Consent

The capacity of persons with addictions to provide adequate and authentic informed consent is increasingly being debated (Charland 2002; Cohen 2002; Kleber 1989). A principle of Anglo-American law and ethics, informed consent requires the patient to exercise autonomy regarding medical decisions. Patients are free to accept or reject a treatment or research protocol, and physicians have the obligation to adequately explain the diagnosis and prognosis, nature of the proposed research or intervention, its risks and benefits, as well as alternatives.

In order to provide valid and authentic informed consent, a person must have adequate decisional capacity. Decisional capacity is a patient's ability to consent or refuse treatment or participation in research. Decisional capacity includes, at a minimum, the ability to understand information, deliberate about possible options, communicate a choice and appreciate the impact of that choice on one's life history and values (Beauchamp & Childress 2001). Many ethicists would also add that the choice to participate in research must be reasonably free of internal and external coercion, i.e., made in the context of voluntarism (Roberts 2002). Voluntarism has been defined as a principle that embodies respect for the person as a human being, as a self with a personal history and values, and as a moral agent with fundamental rights and privileges in society (Roberts 2002).

The National Bioethics Advisory Commission (NBAC) report, which was not adopted into federal law, includes the following statement regarding persons with SUD:

Neuroscientific research has documented cognitive and decision-making deficiencies with almost every substance of abuse--alcohol, marijuana, heroin, methadone, and stimulants--although their direct relevance to informed consent has not been investigated (Mintzer & Stitzer 2002; Simon et al. 2002; Solowij et al. 2002; Tamkin & Dolenz 1990). Problems with abstract reasoning, problem solving, perceptual motor functioning, verbal memory, and inhibitory mechanisms suggest persistent functional abnormalities perhaps with underlying neural network dysregulation in SUD that may compromise decision making (Block, Erwin & Ghoneim 2002). The behavioral phenomena of craving, compulsion, loss of control, and continued use of substances despite adverse consequences, which are the hallmarks of dependence in the DSM-IV-TR, may also impair decisional capacity and limit the ability to provide informed consent. However, almost no empirical work examining the influence of these research findings into the process of informed consent in research with persons with addictions has been conducted (Miller & Goldsmith 2001; APA 2000). The administration of drugs of abuse, even acutely, in challenge studies may result in further decrements in decisional capacity that affect the ability of patients with SUD to withdraw from the study.

The ramifications of such findings for informed consent, while still largely heuristic, are important to consider. Several decades of research with subjects who have serious mental illness have shown that their performance on decisional capacity assessments is not on par with that of normal controls or persons with medical illnesses (Appelbaum et al. 1999; Moser et al. 2002; Palmer et al. 2005) This work also demonstrates that education, repetition, and clinical interventions can ameliorate decisional capacity deficits, and that many more such patients than were originally presumed are capable of informed consent (Carpenter et al. 2000; Dunn et al. 2001; Kleinman et al. 1996; Wirshing et al. 1998).

A particularly salient finding with implications for the informed consent process is the tendency for persons with addiction to discount delayed but expected rewards for immediate unpredictable ones; this is termed "temporal discounting" (Ainslie 2003; Vuchinich & Simpson 1998). Persons with addiction may impulsively choose the immediate rewards of exposure to substances as part of research over future goals like abstinence (Bretteville-Jensen 1999). Persons with limited ability to obtain alcohol or other drugs or who have few other reinforcers, such as a job or family in their regular environment, may be less able to give fully voluntary consent. But even among substance-dependent individuals, choices are not predetermined or illogical, but rather dependent upon the constellation of rewards and negative consequences in any specific situation, and hence are not prima facie incompatible with informed consent (Tucker & Vuchinich 2000). Obtaining subjects' consent for research involving administration of drugs of abuse at a time removed from any actual exposure to the substances may offer additional protection to subjects, as may offering brief motivational interviewing, or access to treatment. Excluding patients who are extremely impoverished or who have limited health care options may also reduce vulnerability. Use of well-validated instruments such as the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) can enhance and standardize clinical determinations of capacity for consent (Appelbaum et al. 1999; Karlawish, Casarett & James 2002).

Some who argue against allowing current or former substance users to volunteer for research with drugs of abuse have contended that the compulsive drive to use substances of abuse makes it nearly impossible for participation to be truly voluntary, and recruitment of this population would hence be coercive (Jacob & Leonard 1991; Koocher 1991). Others have understood the data on presumptive cognitive and volitional deficiencies in SUD to mean that persons with addictions have impaired voluntarism regarding the research opportunity for drug administration. Charland (2002), for instance, argued that heroin addicts are incapable of refusing the offer of free prescription heroin because of their addiction, and that untreated heroin addicts given their drug of dependence in research trials are "vulnerable subjects" who cannot serve as experimental participants in such studies. One study of heroin prescription weakens Charland's thesis: when given the choice of entering a heroin maintenance program, only nine of 24 heroin addicts (38%) in the control group receiving conventional drug treatment (usually methadone maintenance) chose to enter the heroin maintenance program at follow up (Perneger et al. 1998). Cohen (2002: 74) even proposed a reversal of current research guidelines that recommend using nontreatment-seeking populations in comparison to those actively engaged in therapy:

While there is no empirical support for such a categorical disability, clearly much scientific work is needed to establish the capacity of persons with SUD to provide voluntary informed consent in research.

McCrady and Bux (1999) investigated the practices of federally-funded clinical investigators in obtaining informed consent from individuals who abuse alcohol and/or other drugs. Their findings provide grounds for both concern and confidence. Ninety-one researchers completed a 27-item survey on informed consent issues. Fifty-seven percent of investigators recruited participants who would be considered susceptible to coercion, such as prisoners, low-income individuals, minors, and the cognitively impaired. Two-thirds of researchers used objective assessments to evaluate decisional capacity and ability to give informed consent

Both the National Advisory Council on Alcohol Abuse and Alcoholism (2005) and the National Advisory Council on Drug Abuse (2000) noted that when there is a question of a potential subject's ability to give meaningful informed consent, an independent clinician, ethical consultant, or uninvolved third party with appropriate qualifications may be asked to evaluate this ability at the time that informed consent is obtained.

Respect for Potential and Enrolled Subjects

The study by McCrady and Bux (1999) also found that only half of investigators informed subjects of the limits to confidentiality, such as the need to report suicidality, homicidality or child abuse, despite encountering these events in research frequently. From the research participant's perspective, confidentiality protections may be the most important research ethics concern. With the exception of alcohol and tobacco, most drugs of abuse are illegal. Both researchers and participants may confront legal and criminal justice intrusions into research proceedings. Researchers must also assure participants that the privacy of their participation in studies of drugs of abuse will be maintained since their employment, insurance coverage and family relationships may be jeopardized if third parties learn they have a SUD. It is not just loss of livelihood or insurance coverage that may be at stake: there is considerable stigma associated with substance use in today's culture that may have a negative psychosocial impact on participants. Link and colleagues (1997) interviewed 84 men diagnosed with both SUD and mental disorders at their entry into treatment and then a year later when they were mostly free of alcohol and other drugs and less psychiatrically symptomatic. The men reported a "strong and enduring effect of stigma on well-being" which complicated their lives. These limitations and the impossibility of guaranteeing absolute confidentiality need to be clearly explained to potential subjects as part of the informed consent process (Fischman & Johanson 1998).

Confidentiality safeguards are essential to protect subjects participating in studies of drugs of abuse from social stigmatization and economic and legal consequences. Standard data protection strategies used in other aspects of human subjects research must be rigorously employed. Participant information should be stored in locked file cabinets. Some IRBs require the use of codes to separate the identity of subjects from the data collected, although this process is not universally required or recommended. Staff should receive privacy training and only a limited number of researchers should have access to data. Computer passwords and other electronic security measures must be employed. Findings should be published and presented in aggregate (Kleber 1989).

Recognizing the greater vulnerability of subjects in research with drugs of abuse, all branches of the National Institutes of Health are authorized to utilize certificates of confidentiality to protect the subject's identifiable information including health and legal data. A certificate of confidentiality authorizes but does not require investigators to withhold the identifying information of subjects in addiction research. Investigators connected with the project may not be compelled to provide the names or other identifying characteristics of the research subjects encompassed by the certificate in any federal, state, or local civil, criminal, administrative, legislative or other proceedings. The information is permanently protected once the certificate takes effect. Voluntary disclosure of information on the part of the subject or an authorized surrogate is not restricted. Researchers are authorized to withhold information even in cases where state laws mandate such disclosure, but the protections are not absolute. Authorized personnel from DHHS can request information for purposes of program evaluation or other quality assurance needs, and release of such information can be required by the Federal Food, Drug and Cosmetic Act or its implementing regulations (National Institute on Alcohol Abuse and Alcoholism 2004). Federal regulations, including 42 CFR Part 2, provide special protections for medical records containing sensitive information about SUD research and treatment. Investigators should familiarize themselves with these safeguards and their state, local, and institutional rules regarding confidentiality in SUD research.

DISCUSSION

The promise of SUD research has never been brighter (Koob 2000; Rawson et al. 2000). Scientists continue to refine behavioral therapies and are developing new pharmacological treatments for SUDs such as buprenorphine/naloxone for opioid addiction. Disulfiram, naltrexone, baclofen, tiagabine and modafinil have shown some efficacy for cocaine dependence (Vocci, Acri & Elkashef 2005) and naltrexone, acamprosate and combination therapy have demonstrated utility for alcohol dependence (Angelini & Brahmbhat 2007). Vaccines for cocaine, nicotine and other drugs of abuse are in development and a depot formulation of naltrexone was recently approved (Johnson 2008). These new medications not only bring new hope for treating SUD, but also raise unprecedented ethical dilemmas around privacy, stigmatization, and whether selection should be voluntary (Sofuoglu & Kosten 2006; Garbutt et al. 2005; Hall, Carter & Morley 2004; Cohen 1997). Future research in these and allied areas will need to pay particular attention to ensuring the long-term safety of vaccines and depot formulation, demonstration in randomized controlled trials of the drug's efficacy (Lobmaier et al. 2008) and adequacy of informed consent for what are novel treatments. In addition, research in this area will require safeguards against enforced participation particularly in a criminal justice context (Marlowe 2006), assurance of fair but not coercive incentives (Kantak 2003,) and the need to design protocols in which psychosocial aspects of treatment are also encompassed as with the COMBINE studies (Anton et al. 2006).

Ethicists, researchers and clinicians need to recognize that this vulnerability is part of a continuum of capacity for ethical participation in addiction research that must be assessed on a case-by-case basis. Education of both the public and political leaders regarding a balanced and nuanced view of the social and ethical implications of psychopharmacological and neurobiological research in addictions will be one of the most important shared responsibilities of all those working in the area of substance use disorders.

CONCLUSION

The empirically based studies of ethical issues involved in pharmacological research in addictions reviewed here represent a promising beginning for collaboration between researchers and ethicists. Rigorous and systematic attention to the scientific validity and value of research, just participant recruitment, informed consent, risk-benefit balance, respect for persons, and confidentiality protections will foster the progress of pharmacological research in addictions in consonance with protecting the rights and welfare of participants with substance use disorders and society as a whole.

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Cynthia Geppert, M.D., Ph.D., M.P.H. * & Michael P. Bogenschutz, M.D. **

([dagger]) The authors wish to express their gratitude to Ms. Arline Kaplan for her outstanding editing of this manuscript.

* Chief Consultation Psychiatry and Ethics, New Mexico Veterans Affairs Health Care System; Assistant Professor, Department of Psychiatry, University of New Mexico School of Medicine; Associate Director, Religious Studies Program, University of New Mexico, Albuquerque, NM.

** Vice Chair for Addiction Psychiatry and Professor of Psychiatry, Department of Psychiatry; Adjunct Professor, Department of Psychology, University of New Mexico School of Medicine, Albuquerque, NM.

Please address correspondence and reprint requests to Cynthia Geppert, M.D., Ph.D., M.P.H., University of New Mexico, Department of Psychiatry, MSC09-5030, 1 University of New Mexico, Albuquerque, New Mexico 87131. Phone: (505) 265-1711; email: ethicdoc@comcast.net
While the ethical issues in substance abuse research are numerous
   and well-documented, the evidentiary base for addressing these
   issues is inadequate.... If any one major theme emerged from the
   existing studies, it is that many well-intentioned, protectionist
   concerns--about recruitment incentives, consent comprehension, and
   drug administration studies--may be overstated. Policies based on
   such protectionist concerns may indeed hinder research without
   actually promoting the interests of participants.


Substance abuse disorders, for example, including use of
   alcohol and illegal drugs, result in states of intoxication and
   withdrawal that resemble delirium in their effects on attention,
   cognition, other mental functions, and, consequently, decision
   making. There also can be some decisional impairments associated
   with drug abuse and addiction outside the circumstances
   of intoxication and certain forms of withdrawal. However,
   it is important to emphasize that the diagnosis of substance
   abuse disorders does not imply that decision-making capacity
   is necessarily impaired (National Bioethics Advisory Commission
   1998).


As a result of this analysis, I will maintain that the nature and
   pathology of untreated substance dependence make the condition
   inherently incompatible with a rational, internally uncoerced,
   and informed consent on the part of those volunteering
   to receive addictive drugs in a non-therapeutic research setting,
   but that once addicts seek or undergo therapy this may
   no longer obtain.


TABLE 1

Criteria of Ethical Research in Substance Use Disorders

1) Social or scientific value

* Investigate a question of serious social and scientific interest.

* Do not duplicate prior research.

2) Scientific validity

* Ground protocol in previous animal, laboratory and human research.

3) Fair subject selection

* Avoid samples of convenience.

* Ensure subjects bearing risks can also obtain benefits.

* Provide reasonable but not excessive compensation.

4) Favorable risk-benefit ratio

* Choose the lowest-risk population that can answer the scientific
question.

* Match amount and type of drug of abuse to current consumption when
participants are given substances of abuse experimentally.

* Use recovered populations only cautiously and with added
protections when giving participants substances of abuse.

* Assure the physical and medical safety of participants and the
public.

5) Independent review

* Seek expert consultation.

* Provide consultation to IRBs lacking SUD expertise.

* Conduct publication reviews.

6) Informed consent

* Screen subjects for impairments in decisional capacity and
voluntarism.

* Provide ongoing monitoring of decisional capacity.

* Involve significant others of participants when appropriate.

7) Respect for potential and enrolled subjects

* Utilize certificates of confidentiality.

* Observe federal regulations regarding confidentiality of
participants' medical records.

TABLE 2

Scientific Value of Psychopharmacological Research on Alcohol and
Other Drugs with Abuse Potential

Determination of physiological and psychological effects of alcohol
and other drugs

Elucidation of the biological basis of drug-induced craving

Elucidation of mechanisms of pharmacological modification of
substance intake: fluoxetine, desipramine, naltrexone

Elucidation of basic mechanisms of dependence, tolerance and
withdrawal, through animal experimentation using substances of abuse

Discovery of lower sensitivity to alcohol in men with family history
of alcohol dependence

Development of opioid substitution therapy (methadone, levomethadyl
acetate [LAAM], buprenorphine)

Development of opioid antagonist treatment (naltrexone)

Development of pharmacologic treatments for alcohol dependence and
withdrawal (disulfiram, naltrexone, naltrexone for extended-release
injectable suspension, acamprosate)

Investigation of pharmacologic treatments for cocaine dependence
(disulfiram, naltrexone, baclofen, modafinil and tiagabine)

Neuroimaging identification of long-term drug-induced changes in
structure and function of the brain
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