Publications
APS Bulletin • Volume 16, Number 3, Fall 2006
Research Update
Norman Harden, MD, Department Editor
Practical Controlled Trials: Researching the Therapeutic Ritual and All Its Parts
David Rakel, MD
Editor’s note: The evolution of the clinical trial design has been stalled, at least in the pain field, since the successful gabapentin trials. Unexpectedly, the profit motive and subsequent FDA comfort level forced uniform adoption of that design and brought progress, unfortunately, to a screeching halt. The clinical designs used in pain research desperately need to begin evolving again; the field is ready. This interesting article reiterates the obvious complexity of human pain but calls for a much more serious attempt to embrace that complexity in diverse and unique outcomes. Furthermore, it calls for a reexamination of qualitative outcomes in pain research. Since the time of Renee Descartes and the “Cartesian split,” the reigning theory from the 16th century has been reductionism—if we can understand the parts, we can understand the whole. This has had a significant impact on our Western healthcare system and how we organize research. The church in Descartes’s day thought that the mind and the spirit were too sacred for science to try to define, substantially influencing the history of medicine, where the focus is still on the physical with little attention to the nonphysical. That is, science dissected the biological parts while the church claimed the mind and the spirit. This split prevented medical science from focusing on many mind-body and spiritual aspects of pain, most specifically the dynamic interaction between pain and suffering. This article explores how these nonphysical influences can be included in our research design.
We now realize that in order to understand complex symptoms such as pain, we need to look at all the possible influences. This requires evaluation of both the physical and nonphysical (e.g., physical and emotional influences on pain severity). We need to not only understand specific interventions (e.g., medications, epidural blocks) but also complex therapeutic modalities that require us to evaluate a system of care beyond its therapeutic tools. To use a music metaphor, we need to study not only the individual notes in the song but also the gestalt of the composition.
The randomized controlled trial (RCT) has been the main research tool since World War II. Developed to study the efficacy of pharmaceuticals and other acute interventions, it does a good job of isolating and evaluating factors to help us understand the intrinsic or specific value of a therapy. This model requires that we attempt to remove the nonspecific variables from the analysis with the use of a placebo or a control group. These nonspecific variables include things such as belief and expectancy. We have learned that these nonspecific influences can be very valuable and can sometimes have a larger effect than the intervention being studied (Hypericum Depression Trial Study Group, 2002; Kirsch, Moore, Scoboria, & Nicholls, 2002). Beecher (1955) reported evidence that placebo administration resulted in lower levels of pain. This was followed by data showing that postoperative pain was reduced through preoperative encouragement and patient instruction (Egbert, Battit, Welch, & Bartlett, 1964). An accumulation of the evidence to date has shown placebo analgesia to range from 10% to 75%. Combined data from 45 pain trials (2,833 participants) showed placebo (versus no treatment) to reduce pain by 25% (Hrobjartsson & Gotzsche, 2004). To evaluate the whole therapeutic intervention, we need to recognize that in the practical world of healthcare delivery no therapy is prescribed that does not include both specific and nonspecific variables ( Table 1).
Lessons from Researching Complementary and Alternative Medicine (CAM)
The RCT serves pharmaceutical research well but is limited in the study of complex effects of therapies that involve more than one isolated intervention. For example, acupuncture comes from a model of care that involves much more than needling. It involves taking a complete history, listening to the patient’s story, assessing pulse, and evaluating the tongue, for instance. This evaluation results in a series of interventions, such as nutritional recommendations, botanicals, and acupuncture, that are specific to the patient’s unique situation (Paterson & Dieppe, 2005). It is not unlike the ceremony or ritual in any medical encounter during which key nonspecific effects are used to enhance the results from a prescribed therapy, be it a drug or placement of an acupuncture needle. In the RCT the whole study design is based on removing these effects to understand the intrinsic value of the therapy being studied. Placebo is used to remove the impact of belief and expectancy on positive outcomes. The RCT removes the nonspecific variables that make up the “art of medicine.” An ideal study design, especially in pain research, would be one in which we try to capture and embrace data that include these positive influences (Table 2). The study of more complex interventions found in CAM has helped us better understand how we can expand our research design to include both specific and nonspecific influences to “stack the deck” in favor of improved symptoms and quality of life.
The Practical Controlled Trial (PCT)
Also known as the pragmatic controlled trial, the PCT is a clinical trial for which the hypothesis and study design are developed specifically to answer the questions faced by decision makers (Pincus & Stein, 1997). Its main focus is on practical outcomes that include whole systems of care. For instance, instead of evaluating a specific outcome to an acupuncture intervention (such as pain self-report), PCTs attempt to evaluate the whole ceremony in which the acupuncture is given. This would include both specific and nonspecific outcomes and effects. It addresses questions regarding risks, benefits, and costs of an intervention as they would occur in routine clinical practice (Roland & Torgerson, 1998). The PCT helps us change the focus from efficacy to effectiveness. It has four main ingredients (Tunis, Stryer, & Clancy, 2003):
- Clinically relevant interventions are selected for comparison (e.g., acupuncture and physical therapy).
- A diverse population of participants is studied.
- Participants are recruited from diverse practice settings.
- Data are collected on a broad range of health outcomes.
An example of a PCT would be a study that compares yoga, acupuncture, and pharmaceutical management for the treatment of low-back pain. The practical question would ask which clinical intervention results in the best composite outcome. As RCTs have evolved, they have included various measures that go beyond simply assessing pain and have included such diverse dimensions as experience of quality of life, physical functioning, affect, adverse events, cost, and well-being. The PCT would continue this pattern to diversify outcomes to best measure patients’ overall well-being. Participants would come from diverse settings, not too restricted by inclusion and exclusion criteria. Thus, the PCT allows for both specific and nonspecific effects. Participants might be given a choice to select the therapy that best matches their belief system, which in turn may enhance the benefits by empowering them to be active participants in the medical decision process. The PCT includes many of the things that are eliminated from the RCT. This allows us to more pragmatically assess how a therapeutic intervention, with all its potential healing influences, affects pain and quality of life. As the PCT grows in usage we will need to develop validated outcomes that help us measure these global effects more affectively.
A PCT for low-back pain evaluated three medical therapies head to head: chiropractic care, physical therapy, and a self-help educational booklet. The results from the 323 participants showed that chiropractic care and physical therapy increased patient satisfaction more than the educational booklet, but no significant difference between the three interventions was found in function or rates of pain recurrence (Cherkin, Deyo, Battie, Street, & Barlow, 1998). This type of analysis may have significant impact on costs and medical decision making. Handouts are much less expensive than chiropractic or physical therapy, but handouts obviously lack a key nonspecific effect (therapeutic touch) that may help explain the benefits seen in patient satisfaction with chiropractic and physical therapy.
Embracing the Nonspecific Effect of the Placebo
Throughout modern medical research, the placebo effect has been considered a nuisance and something to statistically eliminate so we can find the “true” value of the intervention studied. The complexity of how multiple influences (such as placebo) affect a symptom is honored when we include rather that negate all relevant effects in the PCT. In strict clinical terms, does it matter if an effect comes from a specific or a nonspecific influence? The PCT attmepts to answer the practical question—if the therapeutic process that includes a complex synergy of active ingredients, both physical and nonphysical, improves overall health and well-being, is there a need for further analysis? In other words, the RCT can help us understand more about how an intervention works; the PCT helps us learn more about if it works. It does not limit our understanding of one part of the therapy, but rather considers the whole therapy, which allows us to better appreciate its full potential.
If we look at RCTs of two therapies for low-back pain—spinal manual therapy (SMT) and nonsteroidal antiinflammatory drugs (NSAIDS)—we can understand how RCTs can teach us the importance of looking beyond the intrinsic value of an intervention (Figure 1). When an RCT was used to remove nonspecific effects to find the intrinsic value of NSAIDS, the NSAID was found to reduce pain by 20% compared to 17% with SMT. But when the whole therapy was evaluated (including placebo effects and regression to mean), the overall benefit for the NSAID was 55% compared to a 70% reduction with SMT (Curts, 2003). Why might SMT have more powerful nonspecific effects? Some might argue that it is because this therapy requires the laying on of hands. It also results in an audible crunch that tells the person something was done, which can increase empowerment and sense of control. In these trials, the PCT shows that the whole therapeutic process of SMT is better than handing a patient a prescription. Maybe if we hugged the patient after giving them the prescription, the NSAID would approach a 70% improvement!
Assessment of Suffering
In assessing therapeutic effects on pain, it is important that we include nonspecific effects in the study design (Figure 2), because it is often these influences that have the greatest effect on suffering. For example, in evaluating perceived pain from discography for low-back pain, the perceived stress and depression of the patient had the greatest effect on pain perception when compared to physical causes (Carragee & Alamin, 2001; Carragee et al., 2000). Pain and suffering is a good example of the physical and nonphysical interaction. Pain is a response we have to potentially damaging stimuli. Suffering is how we react to or perceive the pain. The more suffering we experience (nonphysical negative emotions), the more severe the pain report (Carragee, Alamin, Miller, & Carragee, 2005; Rubin, 2005). It is often those nonspecific influences that are assessed in the PCT that have a positive effect on suffering. Including relationship, expectancy, human connection, control, belief, touch, and other factors in our research designs will allow us to better understand how treating both pain and suffering will enhance the overall quality of care we provide.
Summary
The concepts and lessons we have learned from the RCT will continue to serve an important role in helping us understand the intrinsic value of a given therapy. As we evolve toward PCTs and analyzing nonspecific effects in our research design, we will allow the potential of the therapeutic ritual to be tested, a ritual that reaches beyond the reductionistic model towards recognizing the holistic effects on physical pain and nonphysical suffering. This research will give more credibility to the most rewarding aspect of our profession—the art of the healing encounter. n Special thanks to Debra B. Gordon, MS RN, clinical nurse specialist in pain management, University of Wisconsin Hospital and Clinics and fellow of the American Academy of Nursing, for her support and guidance in the preparation of this manuscript.
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David Rakel, MD, is assistant professor, department of family medicine, and medical director, UW integrative medicine program, University of Wisconsin School of Medicine and Public Health in Madison, WI.