Contributor(s): Rachel Bloom
According to the most recent survey data in 2016, approximately 28.6 million Americans (10% of the population) report having used illicit drugs within the past month (National Survey on Drug Use and Health, 2016). Of those, 1.9 million report using cocaine regularly, and another 2.1 million have been diagnosed with an opioid use disorder (including heroin and prescription drugs). In total, 11.8 million people report misusing opiates, indicating that a significant number of Americans do not meet criteria to be considered consistent illicit drug users but are at heightened risk for developing addiction (National Institute on Drug Abuse, 2017). Many users of illicit drugs are vulnerable because of intersecting social identities and comorbid physical illnesses (Buchanan et al, 2002); injection drug use is a main cause of HIV in the U.S., a disease that carries with it enduring stigma despite medical advances (Abadie, Brown & Fisher, 2018). Illicit drug users are more likely to face economic challenges, social marginalization, and risk of arrest and incarceration (APHA, 2013). They are pushed to deal with these conditions in the face of cognitive challenges including intoxication and withdrawal symptoms (SAMHSA, 2018). Partially because of the chronic nature of substance abuse and the myriad of underlying psychological factors in addiction, there is a paucity of broadly-effective and empirically validated treatments for the disorder, despite many users’ desire to reduce or eliminate their substance use (Fisher, 2004). When informed consent procedures are followed in drug cessation studies, the extent to which participants understand the distinction between the goals of research and clinical care can be challenged by intoxication, withdrawal and the cognitive vulnerabilities associated with long-term substance use (Davidson et al, 2012; Fisher, 2004).
Driven by the economic costs of addiction and the human suffering it inflicts, there is a push within the field of drug cessation to develop treatment strategies and medications to address the unmet needs of illicit substance users. Randomized controlled trials (RCTs) are employed to measure both within-study treatment efficacy and real-world effectiveness of new approaches to drug cessation Different treatments present differential risks and potential benefits for research participants, and might range from treatment with opiate agonists like buprenorphine to antagonists such as naltrexone, to “treatment-as-usual” detoxification and counseling (Nunes et al, 2016). Under conditions in which there is no established treatment for a specific substance use addiction, a new medication can be compared to a placebo to assess its efficacy. Use of placebo is justified in these conditions when there is a state of genuine uncertainty on the part of the clinical investigator and the field regarding the comparative therapeutic merits of each arm in a trial, meeting requirements for clinical equipoise (Miller & Weijer, 2003).
Poor communication in RCT intake processes and an incomplete understanding of the research paradigm can lead to a therapeutic misconception. Appelbaum, Roth, and Lidz (1982) coined the term therapeutic misconception to describe two common but incorrect beliefs held by participants asked to participate in randomized clinical trials: (1) that their individualized needs will be taken into account when assigned to an experimental condition, and (2) that there is a high probability that they will benefit from research participation (Appelbaum, Lidz, & Grisso, 2004). These misconceptions may be due to poorly implemented informed consent, participant underestimation of risks, therapeutic optimism, or different cognitive “mind-sets” for planned actions (Horng & Grady, 2003; Jansen, 2014), and they may be compounded by therapeutic mistrust in underserved or marginalized populations (Fisher, Oransky, et al., 2009). Addiction RCTs may facilitate two kinds of therapeutic misconceptions among participants: one, that they believe they are receiving some kind of drug cessation treatment regardless of condition assignment, and two, that the experimental treatment will be effective in curbing their addiction.
In the video for this module, you will meet Marco, a cocaine user who expresses an interest in trying to get clean and stay sober. He comes to Dr. Alva at the recommendation of his social worker, believing that participation in her research would provide him with access to medication that could prove helpful in his endeavor. As you watch the module, be mindful of the specific therapeutic misconceptions Marco brings to his interview with Dr. Alva, both in terms of experimental condition and treatment efficacy. Ask yourself about the specific risks Marco could expect to face and the benefits he could potentially receive as a result of his participation. How might people with illicit drug substance use problems view these ethical considerations? To what extent might their accurate and inaccurate perceptions of research treatment efficacy be tied to their addiction, their economic status, their prior experience with healthcare providers, and external and internal stigma surrounding addiction?
This research was supported by a National Institute on Drug Abuse (NIDA) grant (R01 DA015649-01A2) to Fordham University, Principal Investigators, Celia B. Fisher, Ph.D. and Merrill Singer, Ph.D.
Reference: Oransky, M., Fisher, C. B., Mahadevan, M., & Singer, M. (2009). Barriers and opportunities for recruitment for non-intervention studies on HIV risk: Perspectives of street drug users. Substance Use & Misuse, 44, 1642–1659. PMID: 9938935.
Beyond protecting safety, researchers can look for opportunities to affect justice in treatment research by integrating insights from drug users themselves and the communities they belong to (Fisher, 2004; Fisher & Yuko, 2015). People who use drugs have been shown to have both the ability and willingness to grapple with complex dimensions of morality (Fisher, 2011). Marginalized communities have scripts and strategies through which they have learned to adapt to the past and current social climate, and this expertise should be acknowledged during the research process (Fisher, 1999). Their expertise in drug use can be called-upon for edification in research instead of being stigmatized; participants benefit from the ability to teach the research team something useful through their involvement.
Fisher et al (2008) presented this vignette to 100 self-described active or recent drug users (68% male, aged 22–70 years, mean age 43 years), with most participants self-identifying as either black (33%), Hispanic (37%), or non-Hispanic white (22%). The vast majority were unemployed (61%) and had no more than a high school education (79%). When applicable, the following discussion will draw on quotes from focus groups that were conducted with these participants following their viewing of the video presentation.
Despite the consensus in the field that therapeutic misconception is prevalent in RCTs, further analysis of RCTs involving illicit drug users has demonstrated that more salient issues exist around therapeutic misestimation and experimental mistrust, compared with therapeutic misconception. Fisher and colleagues found that drug users demonstrate good familiarity with RCTs and the uncertainties inherent in this research paradigm and are able to make informed decisions about their participation in research (Fisher et al, 2008). The therapeutic misconception that the experimental treatment will bring clinical benefit is not universally held by drug users. For example, upon viewing the video, one focus group member indicated that “we don’t know what the effects are when you use [the experimental drug]. It may affect you badly or it may help you. Who knows? Right now it’s just an experiment. The word says it all.” Another participant emphasized that in RCTs, “there aren’t any guarantees. You don’t know if it’s gonna work or not. It’s just a chance you’re taking.” When considering Marco’s request for clarification on the research, one participant observed that “I don’t think [Marco] was confused about what [Dr. Alva] was saying. He was confused whether he should participate in the experiment or not.” As for the randomized nature of assigning treatment conditions, one viewer emphasized that Marco “needs to hear it over and over to get it through his head that there’s no guarantee here. This is a trial. You may not end up with the medicine.” Another focus group participant observed that “what [Marco] wanted was to kick the habit or getting help in kicking the habit, so again that goes back to him maybe deciding not to go along with the study because it wasn’t guaranteed.”
At the same time, understanding of drug cessation RCTs can be hampered by experimental mistrust about the researchers’ motives and suspicion regarding the true goals of the study. Unlike the concept of therapeutic misconception, the extent to which distrust of health providers and investigators generate mistrust among marginalized populations with high levels of illicit substance use has been relatively unexamined in substance use research (Fisher, 2010). This mistrust can be driven by both past experience of clinical incompetence as well as knowledge of historical events involving willful experimentation and exploitation of vulnerable research subjects. Some focus group participants who viewed the video indicated that the researcher seemed “more interested in if their study gonna work” than Marco’s welfare, with one focus group member adding that researchers “need you to be a guinea pig, to take this stuff and see if it works for you.”
One misestimation driven by experimental mistrust arises around the double-blind nature of RCTs; while participants might be aware that they cannot know whether they are receiving the placebo or the experimental drug, they might be under the errant impression that the researchers actually do know the treatment condition they were assigned to, undermining trust in the research enterprise. “Doctors know everything and always have an answer for the questions,” according to one viewer, who attributed investigators’ blindness to treatment condition as a sign of incompetence. Another focus group member commented that “I think [Dr. Alva] has the responsibility to know” the treatments being administered to each participant and their comparative efficacy, while others believed she did have knowledge she refused to share, “as if she knew something and she did not want to say it to him.” Many participants assumed the “experimental” condition was also a placebo, with the discussion of two treatment arms considered a ruse. “I think that placebo is the thing. Because she never said nothing about the name of the real thing.” Another viewer assumed that “they give everybody the placebo for the first eight weeks just to see if they’ll come back,” while another observed that “the crazy part about that, everybody could be getting the placebo from the beginning.”
A related variant of a therapeutic misestimation that is common within drug cessation RCTs is that the research team is actually angling to study willpower, studying how users might phase off their drugs “naturally” and without introducing additional medication. Instead of seeing the experiment as testing a new potential medication, some focus group members watching the video assumed that “willpower” to stop their addictive behaviors around drugs was actually being researched. “What I’m getting [from] this video is that they are doing an experiment to find out about what kind of attitude people have in the program, if it works psychologically with the placebo or if it works with the real medicine. What I see is that this is a way of knowing if the person had a psychological will . . . a mental response, or if he had a true reaction.” This notion of studying willpower is a significant misperception to address, because the personal beliefs that participants hold around drug use and whether willpower plays an important role in cessation will influence how they weigh the potential benefits and risks of their participation in an RCT (Fisher et al, 2008; Nunes et al, 2016). One focus group member commented that the participant “could even get the placebo and psychologically [it would] help her get clean,” even though that is not the explicit or implicit focus of the research; this misestimation could lead some drug users to consent to participation under false pretenses.
Investigators have an ethical responsibility to minimize harm in research involving marginalized populations, (OHRP, 2018; S. Office of Human Subjects Research, 1979), especially those that are particularly vulnerable including people with HIV, prisoners, and youth under 18. Reducing the prevalence of therapeutic misconceptions and misestimations and resolving experimental mistrust should be a priority of drug cessation research teams. While overly-formalized safety procedures run the risk of increasing the therapeutic misconception if clinically-grounded safeguards are misinterpreted as a form of treatment, it is essential that they are implemented and that harm remediation procedures are securely in place before the study begins. For some focus group members, the uncertainty around treatment outcomes in RCTs were unacceptable given indeterminate side-effects and potential long-term consequences of experimental drugs, and one participant indicated that “at least with my cocaine I know what the effects are . . . why would I take a chance at hurting myself . . . [when]I know what the coke does to me.” Providing referrals for care and counseling outside of the study’s immediate provisions is thus advisable, and a participant’s involvement in treatment research should be stopped if and when they experience a relapse or if they suffer significant adverse reactions to either the experimental or control condition.
Striving for justice in treatment research is one step to take in mitigating experimental mistrust. Another approach is to ensure responsible recruitment procedures that safeguard the privacy of doubly-stigmatized populations, and developing interventions that specifically address the unmet needs of vulnerable populations who also use drugs. While placebo treatments generally involve detoxification, counseling, and administration of a placebo, this “treatment as usual” protocol only proves effective for approximately 30% of drug users (Nunes et al, 2016). Little is known about how to prospect for participants who might respond well to post-detox treatment that does not involve an active maintenance drug. These facets of drug cessation research merit further consideration in future studies.
Discussion Questions
1. In this study, Marco is given the opportunity to participate in a RCT involving a new medication and a sugar pill placebo. At one point, Marco objects to the idea that he wouldn’t be getting “real medicine” if he were assigned to the placebo condition. How do you imagine he might feel about the nature of the RCT if the control condition was a different medication that had shown preliminary efficacy? How would that shift our risk-benefit analysis of his participation in this research?
2. Marco seems to be wary of the prospect that he might get “hooked” on a maintenance drug in order to stay off cocaine, which turns out to not be the case given the particularities of this RCT. What are the risks drug users like Marco might incur from consenting to a long-term treatment plan? Do you consider those risks to be biological or social in nature?
3. What role do social and case workers play in addressing therapeutic misconception when recommending study participation to their clients? Do you think Dr. Alva did a sufficient job in addressing the information Marco had received prior to his appointment with her?
References
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Appelbaum, P. S., Lidz, W. L., & Grisso, T. (2004). Therapeutic misconception in clinical research: Frequency and risk factors. IRB: Ethics & Human Research, 26, 1–8.
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Research Ethics Teaching Modules 