Of Nature, Nurture, and National Comparisons: Where Might They Point Us?

Pain lies right at the heart of medicine – it is the most common reason for seeking medical care (1). Yet it is also enormously complex. For all that we now know about pain – what produces it, what worsens it, what eases it – there is still so much that continues to confound researchers, clinicians, and patients (2). Pain offers perhaps the quintessential demonstration of the impossibility of disentangling body from mind. Again and again research demonstrates the complicated, iterative looping processes involved in how the biological and the psychological shape one another, such that chronic pain can lead to psychological distress, while that distress can itself amplify pain, in just one rather simple example (3,4). Nor can we understand the interactions of mind and body in individual isolation, of course, for both are shaped in turn by the social environment in which they are enmeshed – what resources are available, what attitudes prevail, what relationships surround the individual are just a few of the consequential dimensions of the wider frame for how pain arises and for how it is understood and addressed (5). So, it seems clear that making real headway in improving pain management will require research into a dizzying array of factors, from genes and neurons and pharmacokinetics to exercise physiology and dietary habits, from mood and health beliefs and cultural values to clinical practice patterns and legal frameworks and national healthcare spending priorities, to name just a few of the pieces of this frustrating puzzle.

But we cannot, of course, study all of these things all at once. So even while we know that they are deeply entangled with one another, exerting mutual influence in many directions, we are driven to try to pick them apart, isolating one from the other in order to try to discern its individual effects on pain. Doing so all the while, of course, with an eye trained always toward intervention. For the whole point of trying to parse out what contributes to pain – by what mechanisms and to what degree – is the hope that understanding pain will allow us to change it, will help to loosen its punishing grip on patients’ lives. So researchers toil along multiple individual paths, constantly searching for a lever with which to shift things, something to help alter the intensity or frequency or activity- and joy-limiting dimensions of pain. Yet, we know, of course, that what is ultimately needed is not a lever but rather something that seems likely to look more like a Rube Goldberg sort of contraption, hooking together a complex conjunction of biologically-based tools and interconnected psychosocial mechanisms to accomplish what in the end seems like a relatively a straightforward goal. What is, in fact, the most fundamental goal of medicine writ large, to relieve pain. Though in this case the complexity seems not humorously gratuitous – in the spirit of so many of Rube Goldberg inventions – but simply, unavoidably, necessary.

So, how to proceed in the face of such entangled complexity? How to try, not just to manage or control for it, but to deliberately include and even start to account for it? The study by Kuppens et al. (6), comparing differences in illness perceptions between the populations of fibromyalgia patients in two adjacent countries, offers one intriguing – though in many ways still very preliminary – approach. On one level, bringing together patient populations from Belgium and the Netherlands for study simply – and usefully – responds to the relative dearth of cross-cultural comparative work in pain more generally, and fibromyalgia specifically. But this study design does more than just compare fibromyalgia patient experiences across national settings. The Kuppens et al. (6) study takes the existence of these two Dutch-speaking patient populations in two neighboring countries as an opportunity to control for some key elements of both biology and culture, while varying others. In this sense, we might imagine the study as a population-level version of the classic twin study design. Such designs have a terribly long history of scientific and popular fascination with twins and the opportunity they offer to leverage the reproductive phenomenon of twinning to explore the age-old nature vs. nurture question (7,8). Essentially, such studies seek to parse out the contribution of the biological and the social to human health and behavior, using the serendipitous variation of genetically identical twins raised separately, or of non-identical twins raised together, to name the two most classic twin design versions.

In so doing, the twin study design not only acknowledges but seeks to harness and explore precisely the kind of complex bio-psycho-social interactions that pose such thorny challenges in the treatment of pain. The basic, underlying logic of twin studies is that holding genes steady allows you to see the effects of different environments, or conversely, that holding the environment steady allows the contributing effects of genetic variation to stand out more clearly. In the Kuppens et al. (6) study, it is both a biological factor (fibromyalgia) and a cultural one (Dutch-speaking) that are “held steady” so to speak, across the two study populations. While what varies is the national setting and the wider sociocultural milieu that it implies. Yet, as with twin studies of individuals – where “environment” might entail everything from family relationships to diet to educational opportunities to local toxic exposures, to name just a few dimensions of the “nurture” side of the equation – there is an enormous amount of complexity enfolded within that category of national setting. Indeed, as the authors themselves point out, differences in everything from who typically diagnoses and cares for fibromyalgia patients (e.g. rheumatologists in Belgium vs. general practitioners in the Netherlands), to local media coverage of the condition, to the legal framework covering work absenteeism – among many other possible sources of variation one could suggest – could be contributing to the differences they report in negative illness perceptions between the two study populations.

There is clearly much still to dig into and further specify here both about all of the pertinent ways in which the sociocultural milieux of these two settings differ, and about how we might link that to distinctive ways patients interpret and experience their illness. At the same time, these authors also remind us that we cannot take entirely for granted that the “nature” side of the equation is quite so simple or “held steady” either – more data are needed on whether significant differences exist in the way fibromyalgia might be complicated in one population vs. the other by dimensions not captured in this study (such as medical co-morbidities, to name just one crucial possibility). Such has also been the case, it turns out, for the more classic versions of twin studies, where the notion of holding nature “fixed” (because monozygotic twins were understood as genetically identical) has also given way to considerable complexity as our understanding of genomics and epigenetics has grown in recent years (9). “Control,” it seems, is something of an illusion when it comes to managing the variation for which scientific research so doggedly strives to account.

Yet it is, nonetheless, an utterly useful illusion. For the comparison set up by the Kuppens et al. (6) study does allow us to identify some intriguing differences. For all of the variation and complexity that runs beyond our control, considering these two carefully-chosen populations alongside one another does reveal differences that seem worth thinking about and possibly pursuing with further study. A picture emerges from their data in which Belgian patients appear to harbor more negative illness perceptions overall, while Dutch patients reported more (relatively) positive illness perceptions. Specifically, Belgian patients reported higher frequency of some symptoms (headaches, nausea, etc.,), were more likely to attribute those symptoms to their fibromyalgia, and were more likely to anticipate negative consequences of their illness. While Dutch patients, in contrast, reported not only a better understanding of fibromyalgia, but a greater sense of control over it, as compared to their Belgian counterparts. Moreover – in what is perhaps their most intriguing finding – Kuppens et al.(6) argue that patterned differences could also be discerned between the two populations in how patients understood the causes of their disease. Interpreting the diverse list of possible causes as divisible into “external” attributed factors (e.g. infections, environmental issues, workload, meteorological changes, etc.) vs. “internal” attributed factors (e.g. genes, personality) allows us to see that Belgian patients were more likely to identify causes outside of themselves as important in their disease, whereas Dutch patients were more likely to look to internal causes.

Now, if we take – as the literature seems strongly to suggest – positive illness perceptions as more desirable in terms of patient outcomes, then it seems we should look to this comparative case for clues about what seems to foster them more among one patient population than the other. This is the all-important intervention question looming its head – what can this study tell us about how we might effect change in the suffering of fibromyalgia patients? And this study seems to point us toward a focus on internal causes over external ones as one of the key dimensions of the overall more positive picture among Dutch patients. Yet at the same time, the very study design itself points us toward external factors (national setting and all of the complex dimensions of the sociocultural milieu that it implies) as somehow important in fostering this orientation toward internally-attributed causes of disease. This raises intriguing questions about just what the target and goal of intervention might be if we were to follow this research further out: just what are the levers by which you can change illness perceptions? Indeed, this seems clearly to be the needed next-generation of illness perceptions research – not just identifying their effects, but figuring out how to actually shift them in deliberate directions (10). Extrapolating from the Kuppens et al. (6) study in terms of where this particular line of research might point us: do we aim to convince patients to think of their disease as most subject to internal causes by trying to shift the external factors that impinge upon them and shape their perceptions? And if so, is there a curious irony to taking advantage of the power of external factors to produce a sense of internal cause and control? Such an intervention might be beneficial while also, perhaps, having about it just a touch of the disingenuous.

Clearly, we are nowhere near being able to design an actual intervention based on just this study alone. Nor do I mean to suggest that if subsequent data bore out such an approach “a touch of the disingenuous” would necessarily rule out leveraging external factors to foster an internal sense of cause and control if, indeed, it proved helpful to patients. But in the endless parsing out of this variable and that variable that research requires of us, I do want to keep trying to think through the implications of our research for how we might act upon it, for the particular kinds of levers and Goldbergian contraptions toward which it might point us. And in the end, I cannot help but wonder whether there is perhaps a resonance here between the way a patient’s own sense of control (over disease) may be somewhat illusory and yet still beneficial, and the way that the research endeavor itself depends upon a sense of control (over complexity) that is, in its own way, illusory as well – and yet profoundly useful nonetheless.

Megan Crowley-Matoka, PhD

Departments of Medical Humanities and Bioethics

Medical Humanities and Bioethics Feinberg School of Medicine

Department of Anthropology

Northwestern University

E-mail: [email protected]