Sponsored by
The National Institute of Dental and Craniofacial Research
The National Institutes of Health
Department of Health and Human Services
BACKGROUND
The National Institute of Dental and Craniofacial Research (NIDCR) of the
National Institutes of Health sponsors research and research training activities
in dental, oral and craniofacial disorders and diseases through its intramural
and extramural programs. Its research support portfolio includes a strong
component in orofacial and other aspects of pain, ranging from the genetic
analysis of nociceptor function to experimental therapeutics for acute and
chronic pain. The Institute has convened several expert panels in the
past year to help it identify long-range research opportunities in a number
of science areas central to its mission. As part of this initiative,
the Institute convened a Panel on Pain Research on May 13, 2003. This
is a summary report of the Panel’s deliberations and recommendations.
The Director of NIDCR opened the meeting by thanking the participants for
contributing to this important activity. He indicated that many of the
Panelists were aware of the history of NIDCR’s involvement in pain research,
both intramurally and as the leader in the trans-NIH Pain Consortium, which
was established in 1996. Recently, NIDCR has worked closely with the
NIH Director to revitalize the Consortium in 2003. This effort dovetails,
furthermore, with the road map initiatives being developed as trans-NIH programs
that identify scientific opportunities to serve as a framework for developing
NIH budgets for 2005 and beyond. The road map activity focuses on 3 general
themes, the building blocks of biology, multidisciplinary teams for the future,
and the reengineering of the clinical research enterprise. Pain research
certainly relates to all 3 themes and so the time is ripe to reassess the future
of pain research and to move it forward at the NIH and at NIDCR. The
Panel was asked to suggest how the Institute could best catalyze the opportunities
and its resources to accomplish this. Pain research is a good example
of an activity that no one Institute or Center can do on its own, and NIDCR
will be looking for leverage through partnerships to enhance this area of research
and take advantage of the resources of NIH.
NIDCR supports about 15% of the research related to pain at the NIH, but
has 1.4% of the NIH budget. About 85% of NIDCR’s funds go to the
extramural community and 10% to the intramural programs. Much of what
will be discussed today will apply to the external community, but we do have
a significant presence on campus in terms of pain research and it is clear
that the intramural program will take advantage of the opportunities that are
identified.
The Pain Consortium is being restarted and it could be a perfect example
of the type of program that transcends individual Institutes and Centers, both
extra and intramurally. In addition, NIDCR has issued a Request for Applications
(RFA) for a Center program and pain is one of the areas in which we are encouraging
applications.
STATE OF THE SCIENCE PRESENTATIONS
Some members of the Panel were asked to make presentations on the “state
of the science” in important aspects of pain research and to identify
emerging opportunities in those areas. Dr. Jeffrey Mogil presented an
overview of the use of genetic techniques in pain research. We have a
good idea now of the sub-cortical anatomy and neuro-chemistry associated with
pain transmission and pain modulation, and with recent advances in imaging
techniques, we are also improving our understanding of what is happening at
the cortical level as well. The trend in the last 20 years has been to
understand the phenotype and the genes coding for important proteins and their
interactions with each other. One type of approach is to define the molecular
building blocks (i.e., the proteins) of pain, and it turns out that it is easier
to do this by studying the genes rather than the proteins themselves. The
second approach is genetics as the study of variability and of inherited individual
differences.
There are two types of “pain genes” that can be considered. If
a protein is involved in pain, then the gene coding for that protein is a pain
gene. Some of these genes are poly-morphic and exist in different allelic
forms with some reasonable frequency in the population. These are the
ones responsible for individual differences. A number of options are
available to identify pain genes. The majority of studies involve picking
a gene and knocking it out and see what effects that has on the top-level behavioral
phenotype. Another approach is to start with the behavioral phenotype
and search for the genes (of the 35,000 present in the genome) that are responsible
for that phenotype. Two ways to do this are linkage mapping and gene
expression profiling.
A number of genes (approximately 45) have been identified in knockout mice
that are associated with altered sensitivity for thermal nociception alone. A
lot of these are potential new targets for drugs with better side-effect profiles
than the ones available now. But the problem is to determine which of
these genes are really critical, and we cannot make global concepts out of
such a list. We need to figure out which genes are “cause” versus “effect” and
if there are any “master” genes responsible for the differential
expression of other genes. We need to know which of these genes are involved
specifically in thermal nociception, but not in mechanical or chemical nociception
and which are involved in nociception across the board.
A technique that has been used in the Mogil lab is complex trait genetics
(linkage mapping). It is well known that humans exhibit great variability
in their sensitivity to pain. It is the case, apparently, that less than
15% of people receiving major peripheral nerve injuries go on to develop chronic
pain. Chronic pain after injury may be the classic example of gene-environment
interaction. So, figuring out if there really are susceptibility or propensity
genes for chronic pain might be a key to understanding whether there is a conversion
from a nociceptive to a neuropathic pathological state. There is a wide
range of heritability estimates for various pain-related traits, but there
are problems continuing to plague association and linkage studies in humans. The
solution is linkage disequilibrium mapping which combines the best features
of both, but is very expensive, though it will happen in the next few years
for some diseases.
In the meantime, we need to do genetic studies in animals and the question
is, is this okay? Now that the human and mouse genomes have been sequenced,
it has been found that only 2-3% of genes in each are species-specific. There
are analogs in each genome probably doing the same things. And so, mouse
pain genetics should actually work. We have investigated kappa-opioid
analgesia in the mouse and formed a linkage to a particular end of chromosome
8 in female (but not male) mice. We picked a candidate gene, the melancortin-1
receptor gene, and obtained and tested spontaneous mutants of this gene. We
looked at the human analog, which turns out to be the gene responsible for
red hair and found that female redheads had higher pentazocine analgesia than
all other groups, a finding directly predicted by the mouse data.
Despite the fact that we are using all these new molecular approaches, it
is important to remember that the entire exercise depends on the animal model
and that the power of the genotyping is only as strong as the accuracy of the
phenotyping. There has been good progress in pre-clinical pain models
and we have gone from acute models to chronic models, but most models are still
inadequate. The acute models may not be clinically relevant and the chronic
models, to a large extent, measures the wrong thing, (hypersensitivity to evoked
stimuli, both thermal and mechanical); there remain no models of chronic, spontaneous
neuropathic pain itself.
Some Panel members argued that measurements of spontaneous pain are available,
but others felt that the core issue is not being addressed by the usual measurements
done in animal models. The practicality of doing the right measurements
is just not there. Validation is what may be lacking. The same
issue regarding the validity of the measures occurs in the behavioral and psychological
study of pain because they are not believed by biologists as indices of what
is really going on. The future requires that the two universes (behavior
and biology) interact and interrogate each other. In a related dimension,
there is an easier association between animals and humans in inflammatory pain
models. However, there is a real dissociation in neuropathic pain models. In
addition, the profusion of models and lack of consensus has prevented the consolidation
of findings between models. There are incentives for the proliferation
of models, but if a mechanism is going to be translationally valid, it has
to be effective in more than one model. There has to be an instrument
that everyone accepts and uses to be able to do translational research and
to bridge the preclinical and the clinical sides.
Comments were also made about the role of the environment and its influence
on the genotype. The problem is that the genotype is quite finite but
the environment is infinite, and we may not be able to figure out what the
environmental factors are or what can be done about them. There is emerging
evidence that early experiences are important in how people respond to later
painful situations.
Dr. John Levine (UCSF) indicated that the peripheral nervous system is the
site of initiation of the pain in the vast majority of pain syndromes, and
that if you block its activity, you eliminate pain in the majority of patients
with acute or chronic pain. A great deal has been learned about the transduction
mechanisms in the primary afferent sensory neuron for pain (i.e., the nociceptor). Nociceptors
transmit information to the CNS but also release mediators at their peripheral
terminals, which can produce or enhance an inflammatory response. Although
nociceptors are a functionally heterogeneous group of sensory neurons, we can
extract RNA from individual cells and reconstruct the biochemical pathways
that are present in them and compare them with other cells to determine what
makes a nociceptor, as well as examine changes that occur in these biochemical
pathways under pathological conditions. While molecules in nociceptors
(i.e., acid-sensing ion channels, vanilloid receptors, etc.) were thought to
be unique to pain sensory neurons, they are now known to be part of much larger
families and not uniquely found in sensory neurons. Thus, it may well
be the interaction between these molecules what is unique to nociceptors. For
example, sustained stimulation of nociceptors produces pain sensation, which
increases with time, in contrast to other sensory modalities in which intensity
of the sensory experience decreases in the presence of sustained stimulation.
Clinical interest in the biology of the nociceptor focuses not so much on
the transduction processes (i.e., nociceptive pain) but on the alterations
in transduction that occur in the setting of inflammation or nerve injury. With
respect to inflammatory pain, the earliest models suggested that many of the
pain-producing mediators produce sensitization of the nociceptor and enhanced
transduction via a common biochemical mechanism, and the hope was that this
pathway could be targeted, providing a whole set of analgesic agents that would
work peripherally, never having to get into the central nervous system. It
is now clear that multiple pathways, signaling in parallel as well as with
cross talk between the pathways, contribute to pain associated with inflammation. The
number of ion channels involved in molding the function of the nociceptor has
now grown significantly and this needs to be addressed if progress is to be
made in terms of clinical relevance. There must be multiple mechanisms
in a very complex system and the ability to put this system together, including
identification of the molecular isozymes involved, is a major goal in pain
research.
There is a growing body of literature, both from animal experiments and clinical
studies, that there is a dramatic sexual dimorphism in pain and analgesic mechanisms,
at all levels of the neuraxis, including the primary afferent nociceptor. These
sex-related differences in nociceptor function are regulated by sex hormone
status, especially that of estrogen. This sexual dimorphism in pain mechanisms
needs to be understood in terms of the incidence and severity of, for example,
inflammatory diseases, most of which are more common and more severe in women.
While there has also been a “maturing” of our understanding of
the mechanisms underlying neuropathic pain, currently the most severe and intractable
pain syndromes requiring management of their symptoms, there is still a great
deal we do not understand in terms of how injury induces changes in nociceptor
function and whether injury induced by toxic (e.g., chemotherapy), traumatic
(e.g., CRPS-I/RSD), metabolic (e.g., diabetic) or infectious (e.g., AIDS) results
cause similar or different changes. Such information is critical to elucidating
novel therapies for the various neuropathic pain syndromes. The way that
the mechanisms responsible for neuropathic pain can be elucidated is to develop
clinically relevant models and to show a more direct correlation between several
levels of analysis, from behavior and physiology, to molecular and cell biology,
and genetics.
The complexity of the issues is certainly evident. In addition to a
large number of ion channels in individuals nociceptors, there are also multiple
isoforms of various enzyme systems and multimerization of these molecules well
as various splice variants. There are also issues of functional compartments
at the sub cellular level and elucidating them will help in understanding the
pathophysiological changes that occur in clinical pain syndromes. The
transition from acute to chronic pain involves plasticity at multiple levels,
from molecular plasticity to environmental plasticity and these need to be
understood if progress is to be made.
Being able to get from the bench to the bedside, and back again to validate
concepts more fully, is going to be real test of whether we are likely to be
successful in treating patients with intractable pain, or not. As far
as is known, the mechanisms underlying pain in the head and neck are the same
as elsewhere in the body and the ability to elucidate those mechanisms will
impact on multiple aspects of medicine and health care. Interdisciplinary
approaches and interdisciplinary-trained physician-scientists are needed to
allow us to cross the boundary between bench and bedside.
In the ensuing discussion, it was mentioned that the issues highlighted are
those of modern cell biology. The translational and clinical research
issues are also evident and more should be done about defining and characterizing
chronic pain. The definition of chronic pain as a function of time is
a convenience in the clinic. The implications of chronic pain start when
there are changes in the functioning of the person, independent of the progression
of the pathology. Both temporal and spatial dimensions are needed to
define chronic pain and it is important to recognize that chronic pain is a
state in which there has been reorganization (i.e., plasticity). Many
of the currently used animal models of chronic pain use a time frame (i.e.,
7 days) during which this plasticity may not yet have occurred.
The type of pain being discussed is pain as a disease itself. When
talking about cardiac pain (angina) a note of caution has to be indicated as
blocking it can eliminate the danger signals that it provides, as well as attenuate
input to the nervous system that can have negative consequences for the patient. The
issue of pain as a signal comes up in any disease and pain itself or its intensity
can be considered as an outcome. The issue of engaging other NIH Institutes
in pain research was discussed, and Dr. Tabak indicated NIDCR has to take the
lead in areas that are related to our core mission and to encourage others
through the Pain Consortium to address the many potential opportunities that
exist. The Pain Consortium uses resources housed within the participating
Institutes and Centers, but there is now a real opportunity to make it a powerful
engine of support through the road map initiatives of the NIH Director. The
Consortium can be used as the ideal road map initiative in terms of multi disciplinary
research, and of other road map guiding principles.
Dr. Michael Iadarola spoke about primary afferent neurons and their work
on vanilloid Type I receptors. Pain, or more accurately nociception,
can be broken down to 3 steps before it hits the brain: the genesis,
the transmission, and the processing in the spinal cord. The primary
afferent neuron connects the elements at both ends and is loaded with receptors
to modulate signal transduction and potential generation. Most aspects
related to individual variability in pain perception occur above the neck and
there is a large number of circuits that are activated, some dependent and
some independent of the intensity of pain. Below the neck there is a
lot of modularity and one of the modules is the vanilloid I receptors. These
are membrane receptors and have a six trans- membrane domain with a core loop
between domains 5 and 6. The receptor exists as a tetramer in the membrane
and can be phosphorylated by PKA and PKC dependent processes. A I EGFP
fusion protein of the vanilloid receptor was made and transfected into Cos-7
cells. The protein is expressed well and is highly localized in the endoplasmic
reticulum.
Exposure of these cells to Capsaicin or to Resnifertoxin (RTX) activates
calcium uptake. The latter drug also activates uptake in the axon, leading
to the idea that there is an axonal localization of VR1 and that this may contribute
to chronic pain. The VR1 in the ER can be activated independently and calcium
release and uptake is very important, particularly the calcium-induced calcium
release from the ER. The vanilloid receptor can desensitize under many
different conditions and release of VR1 through the plasma membrane has deleterious
effects on the cell. The calcium-induced calcium release preserves the
function of nerve endings in prolonged pain states and provides a controlled
source of intracellular calcium. Dehidroexphenylglycine blocks the desensitization. So,
this G-protein coupled receptor modulates the activity of an important depolarizing
ion channel in the pain-sensing cell. And there are a lot of activators
and sensitizers, including glutamate, bradykinin, NGF, protons and metabalites.
When RTX is added to both the ER and the mitochondria, the cell dies and
microinjection of the trigeminal ganglion produces a denervation on one side
of the face and removes pain-sensing cells in the ganglion. There is
also loss of other sensibilities (hyper-algesia and thermal sensations to some
extent). RTX could be given in the intrathecal CSF space. The concept
was further explored in a different model, dogs with advance osteosarcomas
or arthritis. They were injected intracisternally with RTX. The
animals improved significantly and were essentially pain-free after 9 months. Panel
members suggested that this needs to be approached with caution since neurolytic
injections have unintended effects due to spread and may affect motor function
(such as bowel and bladder functions). There were no problems observed
with the animals in this regard, and they retained their pinch sensation and
probably warm and cold sensations. This model introduces sub selective
neurolytic therapy. For terminal cancer patients celiac block has been
shown to be efficacious by rigorous meta analysis.
This offers an opportunity to try specialized procedure-based medicine, as
there is a great need for true tailor-made treatments in pain. The goal
of basic science is to find something interesting, while that of translational
research is to find something useful and practical. Translational research
is costly and one has to comply with FDA regulations to do a clinical toxicology
study. A question is how to handle the ethics of this type of study,
as placebo and traditional therapy do not resemble the intervention being used.
A mouse library can be created for the molecular labeling of pain circuits,
pain cells and pain molecules and study them in vivo. Subtypes of neurons
and their interactions can be studied and be very useful in future research. The
transcriptome in the dorsal ganglion suggests that there are 44,187 sequencing
reactions, a number ten-fold lower than those of the spleen and mammary glands.
Imaging should be done as well. An important question is where in the
brain, spinal cord or peripheral nervous system, is the physiological variability
found. This may be associated with different areas of the brain.
Additional discussion focused on the specificity of the findings and their
applicability to other species. For example, the rat VRI may be different
from the dog and human receptor. It would be useful to develop therapies
that worked equally well against dog and human enzymes, but unfortunately this
often turns out not to be the case. The work shown by Dr. Iadarola involves
the entire cell, or cell populations, rather than single molecules.
Dr. Kenneth Hargreaves spoke about the role of translational research. Orofacial
pain is the most common form of craniofacial pain in the U.S. and is reported
by 22% of the population or 39 million people. The major complaint is
toothache and chronic or persistent types of pain are actually less than half
as common. Surveys across the country indicate that 25-29% of respondents
are highly fearful of dental treatment and this contributes to the avoidance
of care. There is a parallel problem for clinicians in that with acute
pain there is an eight-fold increase in local anesthetic failure. Central
sensitization can play a role as well as changes (up regulation) of sodium
channels. The acute pain problem is relatively homogenous in different
populations and this facilitates research with less variance than those seen
in chronic pain conditions.
Management of this highly prevalent pain is not highly successful and poorly
managed acute pain is a risk factor for chronic pain. In terms of preclinical
research, it can be said that preclinical models are actually pretty good but
also have significant limitations. Animal research does not incorporate
the biopsychosocial and environmental interactions that represent major components
of the patient’s pain complaints and response to treatment. There
is a poor track record in terms of animal pharmacology. The NK receptor
antagonists work extremely well in animal models but are largely ineffective
in clinical trials. And there are issues in terms of SNPs and polymorphisms
(that do not translate between animal SNPs and human SNPs). There is,
therefore, a number of limitations that prevent routine translation between
preclinical research findings and what actually works in patients. In
transgenic animals, the expression levels of the target (e.g., receptor) can
alter signal pathways and display a pharmacological profile that is not seen
in the human tissue. Similarly, the expression level of receptors in
transfected cell lines can dramatically alter their coupling signals and proteins.
An important aspect refers to the demographics of pain. There are pain
conditions with clear age risk factors. One is trigeminal neuralgia. This
a unique craniofacial neuropathic pain that is not seen anywhere else in the
body. Another in post-hepatic neuralgia. The aging population in
the U.S. needs to be considered in the research agenda.
The approach in translational research may be to consider information from
preclinical studies and to incorporate mechanistic research into clinical trials. An
example is genetic research focusing on humans and performing heritability
studies. Patients who have congenital insensitivity to pain have almost
100% of their insensitivity due to polymorphisms in the TRK-A receptor. Other
conditions (sciatica, migraine, dysmenorrhea) range from 20 to 60% heritability. In
the dental field, the Minnesota twin study indicated that there was no evidence
of heritability in TMD-related pain. This suggests that not all pain
disorders are amenable to the genetic approach.
The other approach is to study polymorphisms. There are 2 hypothesis
in this type of study: One is that common forms of a disease result from
the most common polymorphisms in the gene; the second is the multiple rare
variant hypothesis that there are probably many polymorphisms that serve as
risk factors in a certain condition. The latter is probably more common
in pain research.
Another example of translational research are studies that focus on central
sensitization per se. They suggest that surgical pain may have a component
that results from central sensitization. This in turn suggests needed
changes in how clinician’s use drugs such as local anesthetics for managing
surgical pain. We have used a technique of microdyalisis in the surgical
wound. Preoperative administration of 125 mg of steroid significantly
reduced tissue levels of inflammatory mediators in humans experiencing surgical
pain. Another approach is to take surgical biopsies and evaluate under
in vitro conditions the pharmacology of peripheral nerve terminals. There
is a 2-3 fold elevation in substance P in the affected tissue and pretreatment
with receptor agonists blocks the release induced by capsaicin.
Another approach involves psychophysical or quantitative sensory testing.
This can give you some mechanistic information in people experiencing acute
facial pain and allows you to look at central sensitization or altered nociceptor
processing. Imaging studies can give information, but they are usually
done in small numbers of patients often involve correlational analysis and
are rarely replicated. Thus, caution must be employed in interpreting
the results of imaging studies.
General recommendations would include training to increase the pool of clinician
scientists trained in translational research. Tissue banks need to be
developed and additional support for “bridge” studies needs to
be stimulated.
The discussion centered on the need to do interventions first and, if they
work, to then do the mechanistic research. Many things are done where
we are not sure how they may work or, even more, that they really work. There
are successful trials statistically but with subgroups that do much better
than others. The question may be how to make the FDA happy to do the
intervention first and how do you justify it without substantiating evidence?
The Panel also discussed the issue of the availability of trained researchers
and the disincentives for research careers including accumulated student debt,
the regulatory burden, the administrative impact of grant awards, and the upfront
costs for enrolling patients in clinical research. The National Pain
Care Policy Act of 2003 was introduced in Congress on April 29, 2003, which
authorizes a White House Conference on Pain, establishes a National Center
for Pain and Palliative Care Research at the NIH, and speaks of 6 regional
centers for education and treatment.
Additional discussion was held about the demographics of pain in terms of
the age and gender, and of the similarity in both demographics and neurochemical
characteristics of some chronic pain syndromes and the major psychiatric disorders.
DISCUSSION AND RECOMMENDATIONS
The discussion following the presentations (summarized above) focused on
the following topics:
There is an array of pharmacological approaches and of behavioral interventions
available for the treatment of pain, but there are lots of people who are
not making use of these resources. Some of this is due to financial
barriers and some to lack of understanding. Behavioral and social scientists
are needed to bridge the gap. Current theraputics fail because they
are never implemented, because they are implemented ineffectively or because
they are ineffective. Issues of cultural background and beliefs about
pain have to be considered, as the country gets more diverse. Providers
in primary care settings have an unacceptably small understanding of pain
evaluation and what is available for its treatment.
If pain is a disease in its own right, perhaps there should be a pain institute
at the NIH. However, because it covers a broad spectrum of diseases
and organ systems, this would be in essence to create a second NIH and a
better approach may be a coordinating center or office.
The coverage of pain in the educational curriculum of medical and other
health professional schools is not adequate and practicing clinicians and
residents are not generally interested in pain management. NIH can
support changes in the educational system, perhaps through R25 awards (curriculum
development grants) to provide shared, multidisciplinary training modules
across the health professions. The culture of medical institutions
varies significantly across the country in terms of patient centricity.
RESEARCH OPPORTUNITIES
In terms of research questions, the Panelists highlighted the following:
We know quite a lot about the role of sodium channels in primary afferent
nociceptors, but more needs to be done in terms of the role of these and
other channels in the CNS.
Existing animal models can be utilized to look at the long-term consequences
of the injury or of chronic inflammation and neuroplasticity.
Pain research is already successful in terms of the identification of elements
within the pain “matrix” (genes, mediators, proteins). The
new opportunities lie in the translation to the every day use of therapeutic
combinations. A systems or integrated approach to the study of pain
is needed and the opportunity can be framed not so much in the discovery
of elements, but in trying to address gaps that may have clinical relevance. Perhaps,
mutual, cooperative funding with, for example, AHRQ to try to bridge the
interface of basic research and clinical care and to address issues of health
services research and cultural and other factors that may have a clinical
impact.
The field of pain research can draw upon existing evidence-based reports
(e.g., the Cochrane data base) that clearly indicate where the evidence is
good and where it is not. This can fill additional elements in the
matrix.
The diversity of assessment instruments and experimental design approaches
has resulted in waste, as it becomes impossible to aggregate studies and
their different output measurements and times. The treatment schedules
and diagnostic criteria used aren’t uniform in studies, for example,
of opioids. A benefit of evidence-based medicine is that it shows what
the gaps in knowledge are. There is a recent large-scale effort supported
by industry to standardize methods and assessment and outcome measures in
pain.
A good mechanistic understanding of the disease process resulting in pain
is needed. The answers in neurology are being propelled by genetics
(gene identification). It is important to identify all the molecules
that are involved in pain transduction using primary afferent neurons. Emphasis
should be placed in understanding what comes out of damaged or traumatized
tissues and how the nervous system responds. Imaging and other basic
investigative techniques should be used in humans as part of the translational
research agenda.
Targets of bench to bedside application and of bedside to bench impact
need to be identified. Both the chronic changes that occur in a setting
of persistent pain and the variability in pain perception and response to
therapy need to be clearly identified.
Translational models with an emphasis on comparative physiology and molecular
biology would be very valuable.
Although a great deal of progress has been made with the use of DNA microarrays,
we are still missing information about protein modification and protein-protein
interactions and how this leads to changes in function.
The issue of acute pain as a risk factor for chronic pain needs systematic
study to identify the medical, pharmacologic and behavioral strategies that
can minimize the expression of pain. Also, to elucidate how the brain
tracks and influences pain perception and behavior as a function of treatment
(the central processing of pain). Then the tailoring of drugs will
take on a different meaning. Pain should be assessed for intensity,
duration and, in clinical trials, for its impact on functionability and qualify
of life.
High quality epidemiology and defined diagnostic criteria is essential
for a company to develop therapies based on novel targets. The infrastructure
is not currently in place to even act on the known targets (e.g., sodium
channel, VRI, etc.) that exist. Beyond Cox-2 inhibitors, which are
essentially an improvement on a known mechanism, a novel mechanism-based
therapy has yet to be developed despite considerable progress in basic research. FDA
guidelines, which are fairly outdated and have not been substantially revised
to reflect progress in basics pain research, may represent a barrier to development
of novel therapies. The need for defining standard criteria in the
preclinical evaluation of pain was discussed. The risk is that too
rigid a standardization isn’t the best way to develop innovative scientific
ideas and pain research may need a degree of openness now as each form of
neuropathy may be a different disease that should be evaluated differently.
The elements of what are considered high quality clinical trials design
should not be suspended because one is trying to do a study of a mechanism;
however, one may have to go with small n’s for interventions that will
allow you to collect a certain amount of preliminary data to then move in
another direction.
Psychosocial treatments do help patients with disease-related pain. What
needs to be done is to elucidate the biological mechanisms that connect to
the psychosocial response. The opposite should also be investigated
to determine if there are important psychosocial effects that come late with
positive outcomes of drug or surgical therapies. Patient beliefs about
pain may be related to the phenomenon of chronification. This may also
be related to environmental plasticity.
When people talk about the disconnect between animal models and clinical
pain states, the focus is usually on the basic scientists and their failure
to come up with models that are appropriate representations of the clinical
state. Almost no one tries to go the other way and provide a good definition
and classification of clinical states. We do not know what animal models
are good surrogates for which clinical pain states. A related problem
is the failure of clinical trials (i.e., with NK1 receptor antagonists) and
the lack of information about the reason for what went wrong including, for
example, the possibility of species differences or the use of the wrong animal
model in the basic science phase, or the user of the wrong disease state
in the trial.
Genomics can be used for discovering new genes, but then work has to be
done on them with mice again one by one and this will take time. Genomics
is not going to absolve us from having to do a lot of slow arduous work,
for example, in animal models of clinical pain conditions. We still
need to do the phentoyping and the integrative biology.
Developing classification schemes for clinical states and for preclinical
models may be a difficult task at present because we are still in the earlier
stages of developing these important tools. But in genetic studies
of mice strains using up to 24 pain tests, it was possible to reduce them
to simplified categories in terms of variability in pain sensitivity. A
mechanistic classification of pain can be a great breakthrough but it may
be a long time before this approach can be done clinically to drive treatment. It
is not yet clear, however, how far one can generalize from animal genetic
studies to clinical pain conditions.
Focusing on translational research can have a major impact on the field. This
can be done in well-characterized acute and chronic pain models, where the
genetic and environmental influences on pain can begin to be sorted out. An
example of each type of model where it is relatively easy to have a clear
diagnosis can be selected to do mechanistic studies at the biological and
psychosocial levels. The same approach used in the Cell Signaling Research
Consortium can be used here and a national consortium focusing on these selected
models can be created. This can be followed by research on more diffuse
or generalized pain states. The general consensus of the Advisory Panel
was to give lower priority to the development of patient registries for chronic
orofacial pain conditions as likely not to be a cost-effective strategy at
present.
BARRIERS
The issue of bureaucratic barriers to translation of preclinical discoveries
into clinical care is not a trivial one. The time it takes to get a
protocol approved, let alone conducted, is itself enough to discourage people.
Barriers also exist in terms of the financial, administrative and bureaucratic
disincentives in clinical trials research and of societal attitudes (i.e.,
stigmatization of patients) and undervaluing pain as a symptom.
Patient-related barriers exist, particularly in minority groups, and they
need to be addressed or we will end up with pain management approaches that
work in one segment of the population but not across the diverse groups in
the U.S.
The issue of an adequate workforce in pain research was brought up. It
is a complex issue that includes a lack of interest in science careers, financial
disincentives, etc. and initiatives are needed to enhance the training of
new generations of researchers that address these barriers.
SPECIFIC APPROACHES
Revitalizing the trans-NIH Pain Consortium is absolutely critical and
resources are needed to increase the scope of the NIDCR’s intramural
program.
More support can be provided to GCRCs to have more staff and resources
to address these barriers and to become a better used venue for pain research. GCRCs
can enhance interactions between investigators and fields of science and
foster multidisciplinary collaborations. They could be a good place
where a major initiative in pain research could be developed and implemented.
New initiatives should be developed in the extramural program to support
innovative research activities and collaborations as the ones discussed at
this Panel. The visibility of the extramural program staff is very
important at national and international meetings.
Although money is being spent to train more physicians in science, a parallel
effort may be to provide basic scientists with the opportunity to understand
or at least observe clinical patients to get a good clinical perspective.
Given the excellent track record of NIDCR in pain research, this may be
an opportune moment to publicize and highlight the visibility of its programs,
to increase leverage and budgetary resources and to make people aware of
what has been done and will be done in the future.
National Institute of
Dental and Craniofacial Research
National Institutes of Health
Bethesda, MD 20892-2190
e-mail: nidcrinfo@mail.nih.gov
phone: 301/496-4261