html xmlns=”http://www.w3.org/1999/xhtml”>
32 The ethics of research on pain and other symptoms for which effective treatments already exist
The Case
Dr. Smith is an anesthesia resident on the hospital “pain service,” who has been asked to consult on a patient who has been admitted for palliative care for terminal colon cancer. The patient has had breakthrough pain on maximal oral therapy. He feels nauseous and limits his oral intake. Subcutaneous (SQ) administration of morphine is initiated, and brings partial relief. The patient requests epidural analgesia. The attending on the pain service is conducting a placebo-controlled crossover research study evaluating the efficacy of administration of SQ recombinant human hyaluronidase to improve the absorption of SQ morphine in patients with terminal illness. Each study subject will receive morphine via a different method on each of 3 days: intravenous morphine, SQ morphine plus placebo, and SQ morphine plus hyaluronidase. As part of her role on the pain service, Dr. Smith is supposed to help recruit clinical research subjects, but she is bothered by the fact that this patient is terminally ill, is in considerable pain, and is requesting a specific therapy that is not on the research protocol. Is it ethical for her to try to recruit him for this study?
Research on the management of pain and other symptoms is crucial to provide better care for acute, postoperative, and chronic symptoms, as well as better symptom management at the end of life. However, participation in clinical research places subjects at risk of harm for the benefit of others. This tension is intrinsic to all clinical research, and underlies the need for protection of human subjects. A number of national and international regulatory documents aim to protect participants in research while also taking into account the interests of future patients by allowing research to be conducted1 All refer to similar basic principles, which have been synthesized thus: social value, scientific validity, fair subject selection, favorable risk/benefit ratio, independent review, informed consent, and respect for enrolled participants. All of the requirements are equally necessary, and each is relevant to research on the management of pain and other symptoms, which requires the same ethical protections as any other form of research with human subjects. Some aspects, however, do present difficulties more specific to the context of symptom management studies. These include difficulties related to scientific methodology, fair subject selection, obtaining a favorable risk/benefit ratio, and informed consent.
Scientific methodology
Although individual patients may benefit indirectly from research participation, the intention of research is to generate valid data to inform the care of future patients. The research may involve delaying pain relief in participants. The investigator is responsible for minimizing risks and avoiding unnecessary harm for the patients. He/she is also accountable for the scientific validity and clinical relevance of the experimental question. Methodological issues in the design of symptom management trials, the collection of adverse effects, and the reporting of data, have ethical importance. Failure to give proper attention to these issues can make the results of a trial difficult to interpret and prevent comparisons. This limits usefulness in clinical practice, causing research to fall short of its purported goal and fail to fulfill its commitments towards patients and society. Risks to human subjects must be justified in part by the social benefit of research. Therefore any risk, however small, in a study that cannot answer its research question is excessive.
Randomized, double-blind trials have become standard in acute as well as in chronic pain trials. The inclusion of patients with moderate to severe pain at baseline may be crucial for sensitivity, i.e., the ability to detect the analgesic effect of the tested drug. Primary outcomes are usually a difference in pain intensity and a measure of pain relief. Analgesic consumption after a surgical procedure has also been used as a surrogate endpoint because it can prove more convenient to measure. Data other than pain intensity and pain relief are also useful in characterizing patients’ responses. In acute pain trials onset and duration of analgesia, the time to rescue analgesia and the number of patients requiring a rescue dose at various time points all provide valuable information. Observation periods must be long enough to gather relevant data. As chronic pain impacts different aspects of the patient’s life, decreasing health-related quality of life, chronic pain trials must address issues considered important by patients, such as physical and emotional functioning, sleep, relations to family, and social activities. Whenever available, a standard set of outcome measures should be used to assess these dimensions. Studies should also assess what magnitude of change brings a meaningful difference for the patient, as opposed to finding a statistical difference only. Defining a “meaningful difference” is therefore necessary. Such an approach enables researchers to determine which patients benefit from treatment and to perform responder analyses.
Overall patient satisfaction depends on treatment efficacy in alleviating pain, and on treatment adverse effects. Single-dose studies do not adequately characterize drug toxicity because most side effects are dose dependent and will occur only after repeated dosing. Careful monitoring of adverse effects is warranted in all pain trials to assess the balance between risks and benefits in the specific clinical context. It also helps interpret the results in trials where analgesic consumption is an outcome, as sedation, confusion, or nausea may all lead to reduced opioid use without achievement of adequate pain relief. Whatever the method, the type, frequency, and severity of adverse events should be recorded for placebo and active treatment, and the causal relationship between adverse events and the study drug should be evaluated.
For results to be readily understandable, data must be reported in a way that relates to clinical practice. Data on pain intensity and pain relief do not have a normal distribution but are highly skewed, in acute pain as well as in chronic pain trials. Giving mean values does not reflect clinical reality as some patients may benefit considerably from the intervention, while others do not experience any improvement. Analysis of individual patient data has been proposed as a more relevant way of reporting results.2 In addition to absolute changes in pain intensity, percent change provides valuable information, and correlates with patient global satisfaction.3
Fair subject recruitment
Potential subjects should be selected based on the potential for generalizability of study results, and to maximize the risk/benefit ratio for enrolled subjects. They should not be recruited on the basis of misleading expectations, lesser ability to defend themselves, or because they are persons whose risk is somehow discounted.
The problem of misleading expectations
A major expectation of informed consent in clinical research is to help patients understand the difference between the goals of the research and those of medical care – the research goal is to acquire generalizable knowledge that will help improve the care of future patients, rather than providing the best care to individual patients. Chronic pain patients have often received treatments that did not satisfy them, and may welcome access to a novel treatment they believe will work better. This makes them particularly prone to “therapeutic misconception.” Their hope for personal benefit can also lead them to minimize or overlook inconveniences and risks. Most chronic pain trials involve fixed-schedule drug titration, prohibit or limit the use of other pain medication, and impose constraints on nonpharmacological and alternative treatments. Moreover, chronic pain patients often experience impaired physical, emotional and social functioning, all of which have been associated with the therapeutic misconception.4
Therapeutic misconception is also ethically problematic because it represents misplaced trust, which can endanger the physician–patient relationship.5 Participants may question the researcher’s competence and blame him if their expectations are not fulfilled. This risk may be especially high with patients suffering from chronic pain, as it is difficult to treat, with even the best treatments available providing only partial relief. Moreover, patients may experience the side effects of medication without benefiting from its therapeutic effect. Patients’ distrust towards physician investigators can extend and impact on their relationship with their own physician, thus possibly jeopardizing routine clinical care.
Is research at the end of life a special case?
The exclusion of terminally ill patients from research would not be easy to defend. Research is useful to improve therapies at the end of life and thus help the very people whom such a ban would attempt to protect. Terminally ill patients do enroll in studies, and research has shown that, when given hypothetical scenarios, a majority of palliative care patients want to participate in research6 with motives including the hope of personal benefit, altruism towards patients going through the same ordeals7 and the wish to maintain hope.8 Moreover, terminal disease does not by itself invalidate the capacity for informed consent. Were it so, we would not routinely respect the choices expressed by the terminally ill in their wills.
The conduct of research with terminally ill patients is, however, often described as requiring special care due to risks of coercion or exploitation. Coercion is best described as a credible and strong threat exerted by a person that limits the options in a negative way available to another person. Having limited options through no fault of anyone’s does not constitute coercion. Indeed, the possibility of enrolling in a clinical trial actually gives terminally ill patients an additional option.
Related posts:
Informed consent and the pediatric patient
The use of ethics consultation regarding consent and refusal
Revising the Uniform Anatomical Gift Act – the role of physicians in shaping legislation
Animal subjects research Part I: Do animals have rights?
Physician conscientious objection in anesthesiology practice
Opioid therapy in addicted patients: background and perspective from the US
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
