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Ethical Issues in Pain Research
There are numerous ethical considerations when conducting pain research with humans. In this chapter, we will briefly review the genesis and growth of research ethics as a field, often in response to historical examples of research misconduct. We then discuss ethical issues specific to the study of pain, including (1) how pain can affect an individual’s ability to act autonomously, (2) unique risks of study participation for patients with pain, (3) justice concerns regarding participant selection and distributing the benefits and burdens of research, (4) the ethics of inducing pain for research purposes, (5) controversies over the use of placebos, (6) issues specific to studying pain in children, and (7) burgeoning considerations in the study of genetic and epigenetic phenomena related to pain. We recognize that any one of these issues may warrant an entire chapter, and as a result, our effort is to summarize issues rather than address them exhaustively.
Brief Historical Overview
The field of research ethics with human participants was borne out of numerous instances of research misconduct and scandal that have marred the legacy of medicine and science. During the Nazi regime, harmful and deadly experiments were conducted on concentration camp inmates to determine the conditions (and limits) under which military personnel could survive, testing medications and treatments, and carrying out eugenic ideals. The Nuremberg Code was authored in 1947 by judges who presided over the trial of Nazi physicians, and this code laid the foundation for all subsequent research ethics declarations. It emphasized the protection of human research participants’ rights through informed consent and the right to withdraw from research, as well as the duty of the investigator to act in participants’ best interests. Other research scandals that have informed the field of research ethics include the intentional infection of disabled children with Hepatitis A at the Willowbrook Institute in the 1950s, the propagation and widespread distribution of an immortal cell line obtained without permission from Henrietta Lacks—a black woman dying of cervical cancer, and the United States Public Health Service’s “Tuskegee Study of Untreated Syphilis in the Negro Male,” a forty-year observation during which men were not told the truth about the study’s purpose, nor were they offered treatment when it became readily available.
In 1964, the World Medical Association developed the Declaration of Helsinki, which outlines proper conduct for physicians who perform research. It has been revised multiple times and remains a key resource guiding the ethical conduct of research worldwide. The 1975 revision defined the need for oversight by an institutional review board (IRB) to protect human subjects, paralleling a similar requirement instituted in 1974 by the Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in the United States.
That same commission authored the Belmont Report, published in 1979, which establishes respect for persons, beneficence, and justice as the ethical principles that must be considered and balanced in the research context. Respect for persons encompasses two “convictions”: that individuals should be allowed to act autonomously and that those with diminished autonomy are deserving of extra protection. Respect for persons underlies the requirement for informed consent in research participation. To act beneficently is to promote a person’s wellbeing. In research, this duty requires that investigators thoroughly assess the potential benefits and harms of their study and try to maximize benefits and minimize harms to participants. Justice, in the words of the Belmont Report, focuses on “who ought to receive the benefits of research and bear its burdens?” Ethically conducted research must have a process for participant selection that does not take advantage of vulnerable or captive populations, and the findings from publicly funded research must benefit everyone, not a privileged minority. Freedman writes that ethical research should also be scientifically valid (thereby producing reliable and generalizable data) and be of use to society.
The 2018 update to the United States Code of Federal Regulations governing human subjects research considers children, prisoners, individuals with impaired decision making capacity, and economically or educationally disadvantaged persons to be vulnerable populations. That is, these populations have constrained or limited autonomy and may be susceptible to coercion or undue influence. IRBs are obligated to scrutinize research involving these populations to ensure that the benefits of research participation are not outweighed by potential harms. When research involving children does not hold the prospect of direct benefit, it may still be approved if it is considered to present “minimal risk” or a “minor increase over minimal risk” of harm to the child. For a study to be deemed “minimal risk,” the probability and magnitude of harm or discomfort anticipated in the research “are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” This standard has been criticized because of its lack of specificity and potential for variable interpretation by individual IRBs; nonetheless, it remains the standard criterion employed to categorize research risks. ,
Ethical Issues Specific to Pain Research
The experience of having pain may compromise a participant’s ability to act autonomously and provide valid informed consent. Pain is noxious, and individuals’ judgment may be ill-affected by the immediate desire to make it stop. Included here is that pain may impair cognition, and the ability to reason beyond the immediate goal of relief. Especially patients for whom pain has been poorly controlled, there may be a tendency to overestimate the potential benefits of an experimental therapy resulting in a biased assessment of the harm to benefit ratio. Thus investigators have a heightened obligation to ensure that prospective participants can understand and reason with information pertinent to risks and benefits of study participation.
A crucial component of autonomous action is voluntariness; the potential research participant must be free to enroll in a study without experiencing overt or implicit coercion. The pain research context may threaten voluntariness in a few ways. For example, there is a risk that some individuals will feel compelled to enroll in a study that is presented by their healthcare provider to maintain the therapeutic relationship and be seen as a “good patient.” Also, incentives offered by the research program may overtly exert influence on potential research participants. Incentives are intended to attract participants and compensate them for the time, effort, and discomfort that research may entail. However, when an incentive is disproportionate to the study burdens and is so enticing that the participant feels there is really no choice to be made, this is termed “undue influence” and is considered unethical. On a more subtle level, improved access to healthcare services only while “on study” could serve to unduly influence some potential participants to enroll. This issue is especially problematic in developing economies.
Investigators must minimize harm to research participants. Investigational pain therapies pose risks of an altogether different type than that typically experienced in other pharmacologic trials. Analgesic trials for short-term acute or post-procedural pain involve very limited administration of the study drug. However, for chronic pain, participants may receive the study drug over several days to weeks. If that medication is superior to contemporary therapies, it may be difficult for the participant to revert back. This issue is highlighted even more when the study drug promotes physical dependence (as in the case of opioids). There is an obligation to ensure ongoing followup beyond the scope of the trial.
Last, investigators must consider if the participants they plan to enroll are representative of the population to whom they ultimately hope to provide benefit. Clinical trials are often relatively narrow in defining inclusion criteria, and biases based on age, language, and sociocultural factors are far too common. For example, vaso-occlusive episodes characteristic of sickle cell disease may be exceedingly painful and require potent analgesics for treatment. However, even fundamental research on analgesic medications (e.g. pharmacokinetic and pharmacodynamic studies) in this patient population was rare for many years. , The pediatric population has also been omitted from most analgesic trials, which will be discussed further below.
Ethics of Placebos
The long-standing method by which analgesics have been tested is by randomly assigning participants to receive the test drug or a placebo and then comparing mean pain scores (typically, a rating of pain intensity). The ethical concern is that those assigned to the control group are likely to experience pain until they receive rescue medications. This may be justified if there is true equipoise – that is, the researcher truly does not know if the test drug is superior to placebo. However, this is rarely the case with analgesics, and thus alternative study designs have been pursued.
Nagasako and Kalauokalani explicated these concerns drawing on lessons learned in psychiatry to make recommendations for the field of pain medicine. Whether the use of placebo controls may be judged as ethical depends partly on the state of existing treatment (i.e. if existing treatments have been rigorously studied and shown to be effective, then new drugs may be compared against existing treatment, not placebo). However, if the best available therapy has not been rigorously established or the treatment effects vary significantly across a population, then for some participants, treatment with placebo would be no better than treatment with the “best available” therapy.
Another consideration is whether the condition under study can allow for the potential harms of placebos. An individual exposed to a cold pressor stimulus (experimentally induced pain) would not experience significant harm if given a placebo. In contrast, a person who had undergone abdominal surgery could experience significant harm if given a sham epidural or a placebo instead of a parenteral analgesic.
It is also worth noting that placebo-controlled studies have merit. “Placebo concurrent control” is one of five study designs recommended in the United States federal regulations regarding controls in drug studies. Randomized, double-blind, placebo-controlled trials minimize bias (both on the part of the investigator and the participant), provide an internal standard against which efficacy of the study drug can be measured, and provide the cleanest conditions for distinguishing adverse drug effects from effects of underlying disease. Scientific validity can be considered an ethical principle, which lends support to the use of placebos. , Furthermore, one cannot ignore the profound clinical effects of a placebo. A review is well beyond the scope of this (see Chapter 17 ). However, any time one administers a drug, the clinical effect is the combined impact of the therapeutic effects of the drug and placebo, and often the latter is far greater than the former. The placebo effect is so strong that it remains intact, even when patients know they are receiving a placebo. , How could one measure this profound effect without including a placebo control?
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