Crossing the Threshold

My route into pain research was the dovetailing of two interests; research with clinical relevance, and martial arts. As a psychology major at college, it’s true that I found questions like “How do we form thoughts?” or “How do we perceive the environment?” interesting, but considering the time and effort involved in research, I wanted the satisfaction of knowing that discoveries I made in the lab could benefit people directly. At the same time, I was also intensively training in martial arts, a discipline that puts a great deal of emphasis on controlling the mind in order to control the body – including pain. I no longer do martial arts (mind cannot always triumph over matter, and the damage done to my body over the years has led me to take up lower-impact hobbies...), but my fascination with the link between the brain, body and pain remains very much intact.

My primary research interest is now peripheral mechanisms of pain. The vast majority of chronic pain is driven by aberrant activity in primary afferent nerves. The peripheral nervous system seems to be the ideal target for drugs to control pain, with the added bonus of avoiding CNS side effects. I study several different clinical and animal models of pain, working closely with colleagues in the clinic on migraine, temporomandibular disorder, trigeminal neuralgia and visceral pain; such as irritable bowel syndrome and inflammatory bowel disease.

When I started my career, we knew that there was a class of sensory neuron – referred to as nociceptors – whose function is to respond to noxious or potentially tissue damaging stimuli. The theory was that since these neurons were primarily responsible for pain, the key to controlling pain would be to prevent those neurons from talking to the central nervous system. If only it were so simple. As Einstein said, “The more I learn, the more I realize how much I don’t know.” As it turns out, the molecules that mediate transduction of mechanical, thermal and chemical stimuli into neuronal impulses, the transmission of those impulses to the central nervous system, and the variety of nociceptors in which they function, are under the influence of a constellation of interacting biological, social and psychological factors.

The sheer complexity of the mechanisms involved is a major hurdle to translating research into the clinic. Say you make a big discovery – a new and critical molecule in the pathway, for example – at first, it looks like a great drug target, but in most cases, further study reveals that the molecule only responds to very specific stimuli, in specific circumstances and in specific individuals. Even if you found a molecule that was relevant in a broad spectrum of pain, there is another problem – the nervous system likes to recycle. A receptor involved in pain pathways is often involved in a wide range of other neurological functions, making them poor drug targets in terms of specificity and selectivity. So the target is abandoned and the search begins again.

Recently, I have observed that clinicians are beginning to lose patience with basic scientists. The track record of translation has been poor, and despite the researchers’ oft-repeated cry of “We have a new target, it’s going to work this time,” in reality, doctors are faced with treating most patients with the same decades-old drugs. There might be an extended-release formulation or a different delivery route, but where are the game changers? Where are the alternatives to opioids or NSAIDs?  To clinicians, research can feel like a lot of time and energy devoted to an increasingly in-depth understanding of the molecules involved, with no real benefit for patients in pain. Perhaps as a consequence, while therapies have changed little, clinical practice has undergone a paradigm shift. The goal that drew me into the field in the 1990s – providing relief for all pain patients – is being abandoned. The emerging focus is on helping people to live with their pain.

The temptation for basic scientists – seeing that clinicians have little time for research – may be to retreat further into their labs. Both sides risk becoming entrenched in their camps, with the clinicians becoming ever more convinced that basic research is a waste of time, and the basic scientists pursuing mechanisms in models that may have limited clinical relevance. That must not be allowed to happen, because without collaboration between scientists and clinicians our chances of bringing new therapies onto the market are dramatically reduced. Basic scientists need to keep talking to clinician–researchers. Not only because access to clinical populations helps us advance our research, but because they keep us focused on the issues that really matter.

My conversations with clinicians about the problems they face and the observations they make have a profound impact on my research. A clinical perspective helps us ask the right questions. For example, clinicians will tell you that the primary complaint of their patients with neuropathic pain is ongoing pain – pain that is present without any stimulation – and yet the vast majority of preclinical studies of neuropathic pain employ evoked pain behavior as the primary experimental endpoint. These endpoints are easier to study, but may not be as clinically relevant.

Everyone agrees that collaboration between clinicians who treat pain and researchers who seek to understand it is vital, but I have found that funders often “talk the talk” more than they “walk the walk” when it comes to translational science. In my experience, NIH grant applications that involve both preclinical and clinical aims are often considered overambitious by reviewers, who point to the heterogeneity of clinical populations. If we are to encourage largescale multidisciplinary work, we need more than the willingness from clinicians and researchers to cooperate – we also need support from funding mechanisms.

"The Pain Puzzle"        Roger Fillingim

"Growing Pains"    Suellen Walker

"The Mouse Trap"      Jeffrey Mogil