Ethical Considerations in Research Using the Drug of Addiction as Treatment: What Can Researchers Learn from Heroin Prescription Studies?
Sylvia Baedorf Kassis, MPH
Clinical Research Manager, Center for Human Genetic Research and Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston, MA, USA
Alcohol and other drug (AOD) research is rife with ethical quandaries and controversy. Particularly polarizing have been studies investigating the use of the addictive agent as a treatment, such as recent research involving heroin (diacetylmorphine) maintenance therapy. Although not permitted in the US, pharmaceutical diacetylmorphine prescription is being studied in other countries, and many of the ethical considerations of those studies are relevant to any research covering sensitive topics and/or enrolling vulnerable populations. This article provides an overview of the ethical issues surrounding diacetylmorphine prescription research and methods to address those concerns that may be applicable to other AOD research.
Background
Research testing the agent of addiction as a potential treatment is not novel. Alcohol has been administered to subjects with alcohol dependence to treat withdrawal,1 and nicotine has been used as a therapeutic agent to decrease smoking.2 These studies have not generated enough controversy in the US to halt the research, however; alcohol and nicotine are legal drugs in the US, and, in general, accepted by society. Opioid agonist treatment is a related example. Although not exactly the agent of addiction, opioid agonists (methadone and buprenorphine) are among the most efficacious treatments for opioid (i.e., heroin and/or prescription-opioid) dependence. These agonists are also legal medications, which facilitates their study, although many people remain “against” these treatments.
Heroin addiction is highly stigmatized in the US. Although heroin was developed as a cough suppressant by Bayer Pharmaceuticals in the 1890s and was prescribed as a treatment for opioid dependence in the early 1900s, its use was restricted by the Harrison Narcotic Act in 1914, and by 1919, doctors risked prosecution for prescribing it to people with addiction.3 Nonetheless, diacetylmorphine has been used as a therapeutic agent on a limited basis in Britain since the early 1960s, and the first reported controlled clinical trial of diacetylmorphine prescription was conducted there.4
Over the last 20 years, governments and public-health authorities in Switzerland,5 the Netherlands,6 Germany,7 and Canada,8 to name a few, have supported the investigation of diacetylmorphine as a treatment for heroin dependence, due largely to an alarming increase in HIV transmission among people with injectable drug use9 and a desire to reduce drug-related crime.10 In the US, however, the overall attitude toward illicit drug use, and in particular, injection drug use, has blocked the study of diacetylmorphine as a potential treatment for heroin dependence.
Diacetylmorphine prescription, in and of itself, presents several ethical challenges. Even before considering a research study, debates over allocation of resources, reduction in use or consequences versus abstinence as treatment goals, addiction as a medical or social problem, and whether diacetylmorphine prescription unintentionally promotes heroin addiction, would need to be considered. These challenges will not be discussed here; rather, the ethical issues that have been raised in existing diacetylmorphine studies will be presented.
Considerations for Ethical Research
Consent
Informed consent is considered one of the fundamental tenets of ethical research.11,12 For consent to be valid, it must be voluntary, and the potential subject must be competent. Whether individuals addicted to heroin are capable of consenting to participate in research, especially studies that provide the drug of addiction as a potential treatment, is fiercely debated. Intoxication may impair capacity. A clinical determination can be made as to whether the potential subject is intoxicated. Most people using heroin will have tolerance and also have periods between drug administration when they are not intoxicated despite recent use.
But Charland9 argues that the compulsive need to seek and use heroin leaves potential subjects with impaired decisional capacity, rendering them incapable of giving valid consent. In contrast, Foddy and Savulescu13 reject the notion that people with addiction lack free will, arguing that heroin does not present an irresistible force but rather a strong appetitive desire that does not compromise consent. They further assert that a desire to engage in heroin use, a “harmful act,” should not be construed as evidence of irrational or compulsive thinking.13 The type of study may be relevant here—a study that dispenses carefully measured and regulated amounts of diacetylmorphine at a daily clinic visit may not be a study that a person with heroin addiction would find irresistible, whereas a supply for home use might be associated with impaired decisional capacity. In any case, both authors promote a better consent process—but what should that consist of?
If you determine that the population under investigation is not competent to provide consent, the study may still be able to proceed; however, additional safeguards would have to be incorporated. For example, Charland9 argued that substitute decision making in the form of a surrogate should be pursued. In cases where there is concern about obtaining valid consent but incompetence is unlikely to be an issue, a less stringent approach would be to include an impartial third party or research subject advocate in the process. An additional measure suggested by Foddy and Savalescu13 is to put sufficient time between the consent process and study participation to prevent craving for the drug or other influences (including the persuasion of researchers) from impacting consent.
Risk/Benefit Assessment
A thoughtful principal investigator carefully evaluates the potential risks and benefits of a research study, discussion of which should be included as part the consent process. Is the study of diacetylmorphine for heroin addiction considered minimal risk or greater than minimal risk?
Under US Federal Regulations,14 minimal risk means the probability and magnitude of harm anticipated in the research are not greater than those ordinarily encountered in daily life. The latter part of this definition may be open to interpretation depending on the population under study. What does the standard “ordinarily encountered in daily life” mean in a population engaged in behaviors associated with social stigma, infectious disease risk, and criminal activity that will most certainly be brought to light by research participation? Which is riskier—use of illicitly obtained heroin or use of prescribed diacetylmorphine under strict clinical supervision?
Orr and Wynia15 argue that researchers must be forthright about whether the primary goal of a study is to give subjects an opportunity to move toward recovery and avoid harms associated with addiction (health risks, financial costs, risk of arrest, etc.) or to reduce societal harms, such as crime. (A study of heroin prescription could be either.) In their view, the avoidance of therapeutic misconception—the belief that a study is for one’s benefit when this is not the case—requires the consent discussion to very clearly address study aims. Although altruistic participation is still possible in research addressing societal harms, the risks associated with a study are likely to be minimized if the primary goal is to benefit the subject.
Confidentiality Protections
Finally, risk discussion during the consent process will almost certainly include information about confidentiality. Since AOD research is likely to include the collection of sensitive personal information about substance use and illegal activities, there exists the real possibility of direct harm to participants if confidentiality is not protected.16 Such harms could include risks to employability, insurability, and/or reputation. As a result, US investigators are encouraged to seek a Certificate of Confidentiality17 to protect research data from compulsory disclosure, such as through a subpoena. Further, it is prudent to collect only the minimum information about subjects necessary to meet the scientific aims of the study.
Conclusion
There are certainly additional ethical issues to take into account when planning AOD research, particularly a study involving diacetylmorphine prescription (e.g., whether and how to provide financial compensation for participants, what to do after the trial ends, and what to do if results are positive). These have been discussed in relation to Canada’s North American Opiate Medication Initiative (NAOMI) trial8 but are beyond the scope of this article. Informed consent, as discussed above, is the paramount characteristic of ethical research, and whether or not heroin addiction renders individuals incompetent to consent must be carefully evaluated. Although diacetylmorphine prescription may not be studied in the US in the foreseeable future, awareness of the fundamental ethical issues inherent in such research may allow researchers to improve how well they incorporate protections into studies exploring similar topics.
References
1. Dissanaike S, Halldorsson A, Frezza EE, et al. An ethanol protocol to prevent alcohol withdrawal syndrome. J Am Coll Surg. 2006;203(2):186–191.
2. Moore D, Aveyard P, Connock M, et al. Effectiveness and safety of nicotine replacement therapy assisted reduction to stop smoking: systematic review and meta-analysis. i 2009;338:b1024.
3. Berridge V. Heroin prescription and history. N Engl J Med. 2009;361(8): 820–821.
4. Hartnoll R, Mitcheson M, Battersby A, et al. Evaluation of heroin maintenance in controlled trial. Arch Gen Psych. 1980;37(8):877–884.
5. Perneger TV, Giner F, del Rio M, et al. Randomised trial of heroin maintenance programme for addicts who fail in conventional drug treatments. BMJ. 1998;317(7150):13–18.
6. van den Brink W, Hendriks V, van Ree J. Medical co-prescription of heroin to chronic, treatment-resistant methadone patients in the Netherlands. J Drug Issues. 1999;29(3):587–608.
7. Haasen C, Verthein U, Degkwitz P, et al. Heroin assisted treatment for opioid dependence: a randomised, controlled trial. Br J Psychiatry. 2007;191:55–62.
8. Oviedo-Joekes E, Brissette S, Marsh DC, et al. Diacetylmorphine versus methadone for the treatment of opioid addiction. N Engl J Med. 2009;361(8):777–786.
9. Charland LC. Cynthia’s dilemma: consenting to heroin prescription. Am J Bioeth. 2002; 2(2):37–47.
10. Stimson SV, Metrebian N. Prescribing heroin: what is the evidence? Available at http://www.jrf.org.uk/publications/prescribing-heroin-what-evidence. Accessed on October 24, 2012.
11. Nuremburg Code. Available at http://www.nejm.org/doi/full/10.1056/NEJM199711133372006. Accessed on October 20, 2012.
12. Declaration of Helsinki. Available at http://www.who.int/bulletin/archives/79(4)373.pdf. Accessed on October 28, 2012.
13. Foddy B, Savulescu J. Addiction and autonomy: can addicted people consent to the prescription of their drug of addiction? Bioethics. 2006;20(1):1–15.
14. US Department of Health and Human Services: Code of Federal Regulations no. 45 CFR 46.102. Available at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.102. Accessed on October 22, 2012.
15. Orr AS, Wynia MK. Ethics and heroin prescription: no more fuzzy goals! Am J Bioeth. 2002;2(2):52–53.
16. Australian National Health and Medical Research Council: Ethical issues in research into alcohol and other drugs: an issues paper exploring the need for a guidance framework. Available at http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/ds12_ethical_issues_alcohol _drugs_120625.pdf. Accessed on October 21, 2012.
17. National Institutes of Health Office of Extramural Research: Certificates of Confidentiality Kiosk. Available at http://grants.nih.gov/grants/policy/coc. Accessed on October 21, 2012.