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From Medscape Neurology & Neurosurgery

Expert Interview

New Perspectives in Chronic Pain: An Expert Interview With G. Fine, MD

Posted 05/25/2006

Editor's Note:

The 25th Annual Scientific Meeting of the American Pain Society (APS) took

place from May 3 to 6 in San , Texas. During this meeting, new

information about the diagnosis, treatment, and management of acute pain,

chronic pain, and recurrent pain was presented. Marni Kelman, MSc, Medscape

Neurology & Neurosurgery Editorial Director, discussed results presented at

this year's meeting and their implications with G. Fine, MD, Professor

of Anesthesiology, University of Utah, Salt Lake City; Vice President,

Medical Affairs, National Hospice and Palliative Care Organization,

andria, Virginia.

Medscape: In your opinion, what were the most important research findings

presented at this meeting this year?

Dr. Fine: Well, unfortunately, I couldn't be everywhere and attend all of

the sessions that I would have liked to because it was a meeting that was

very full, both in depth and breadth of material. I did take note of several

presentations that I believe will positively influence the field,

contributing to my continued sense of optimism that we're going to get

better at understanding and managing chronic pain. One significant repeating

theme has to do with the ever-increasing recognition of pain as a disease

process in and of itself, not just simply as a warning sign that something

is wrong with the body, that is, merely a sensory detection system. Examples

include Staud and colleagues'[1] symposium entitled " Evaluation of

Fibromyalgia Pain: From Bench to Bedside, " Neugebauer and colleagues'[2]

symposium entitled " The Pain Within: Pain Modulation by the Amygdala, " and

Carlton and colleagues'[3] symposium entitled " Peripheral Sensitization and

Inflammation: Sensory Nerves are a Two-Way Street. " Chronic pain is a term

that has evolved to describe not only a malfunctioning peripheral and

central nervous system, but more generally a condition in which other

systems, such as the immune system and neuroendocrine regulatory systems,

are also disrupted. Also, there is more generalized spreading of dysfunction

throughout the nervous system, with disordered memory, sleep, and mood. So,

there is growing evidence that a systemic and multisystem impairment arises

from an initial trigger or injury to the nervous system that, for reasons

that are still unclear, then doesn't recover.

Several sessions and posters at the APS meeting confirm these findings and

substantiate the theory that chronic pain is a complex pathophysiologic

state. New science, especially from genetics research and functional imaging

studies of the brain, is adding immensely to our fund of knowledge in this

area and helps to explain the great interindividual variation that is

observed in the expression and experience of both acute and chronic pain.[4

5]

Another important topic discussed was the genetic underpinnings and

neurobiology of addiction disorders as they might pertain to and overlap

with people who are subject or prone to having chronic pain. It is

increasingly recognized that there is an important -- but still poorly

defined -- relationship between exposure to drug therapies that are very

important for pain control and previously undetermined predispositions to

addiction or chemical dependency. New tools that are being developed to aid

in risk assessment and management were discussed at the meeting.[6,7]

Medscape: I presume that these findings will have implications in terms of

selecting patients for therapy. Correct?

Dr. Fine: Right. I think that the hopeful outcome in all of this is that

over time we're going to get better at being able to predict which patients

will do best with what forms of therapy in order to be able to mitigate and

manage risks over the long term.

Current pharmacogenetic studies reveal tremendous interindividual

variability in opioid receptors and how flexible and changeable opioid

receptors are over time and with different types of stimuli. New data in

this field were presented by Gavril Pasternak,[8] from Memorial

Sloan-Kettering Cancer Center and Cornell Medical Center, New York, NY, at a

dinner symposium entitled " Update on Opioid Analgesics: Receptors, Research,

Regulations and Real Patients. "

It is important to add that there is increasing recognition that

experimental pain may be very different from naturally occurring persistent

pain states. This creates challenges both for drug development and for

generalizing clinical trials results that are not necessarily based on

long-term " naturalistic " chronic pain models.

Medscape: Results from a number of studies were presented on fentanyl

effervescent buccal tablets. Can you summarize the key results?

Dr. Fine: Breakthrough pain is one of the areas that I have been interested

in for the last 15-16 years with the development of specific

pharmacotherapeutics for this type of pain. There are a growing number of

novel therapeutic formulations that should be referred to, or categorized,

on the basis of their onset characteristics. For the last decade or so, the

term " immediate release " has been used to describe the typical forms of oral

opioids that have not been pharmaceutically formulated for controlled or

sustained release. These drugs typically take a half hour to 1 hour for

onset and peak effects to occur. The rapid-onset opioids provide meaningful

relief in minutes, mirroring the characteristic onset and duration patterns

of breakthrough pain.

From a purely pharmacologic perspective, the initial clinical trials with

fentanyl effervescent buccal tablets are very promising.[9,10] A clinical

abstract reporting the advancement of this technology was presented by

and colleagues;[11] they presented results from a randomized,

placebo-controlled study of fentanyl effervescent buccal tablets for relief

of breakthrough pain in opioid-tolerant patients with cancer.

Clearly, there is a benefit of these agents as described by patients in

these trials. I think now what we'll be waiting for, and we can't really say

a whole lot about it at this time, is to determine what will happen in the

real-world setting in which we'll learn whether these drugs are effective

over the long run and gain insight into the risk management side for this

and other novel, rapid-release agents. Risk management is certainly the

chief concern of regulatory agencies and, by necessity, physicians who are

prescribing these therapies. I also think that the companies producing the

drugs will want to ensure that an otherwise good drug does not become

problematic because of misuse or inappropriate prescribing.

Medscape: A poster describing the Goal Attainment Scale for chronic pain

that assesses the functional and emotional impact of pain and effects of

treatment was presented at the meeting. Can you summarize the findings and

the impact of this scale to both physicians and patients?

Dr. Fine: The development of validated instruments or tools to assess and

monitor pain treatment has been a challenge in this field. Refinements, such

as the Goal Attainment Scale,[12] will benefit practitioners and patients

alike. This tool is an outgrowth of the commonly used, and highly useful,

Brief Pain Inventory, but it is tailored to the specific features of the

individual patient's unique circumstances -- a real breakthrough, I believe.

In terms of more general insights into pain scales, certainly I have seen a

change in thinking compared with 10-15 years ago. The 2-dimensional scales

that look at pain intensity without either more specific contextually

related outcomes, such as mood, functional improvement, and so forth, have

very little meaning outside of a purely experimental domain. This concept is

being embraced by the FDA [uS Food and Drug Administration] as well in

looking at drug approval in that it's not good enough just to say, by way of

example, that a drug can reduce pain intensity from a 9 to a 6 on an 11

point Likert scale with statistical significance. What's important is the

outcome of that pain-intensity change from the patients' perspectives: Are

they improving on quality-of-life axes as well? The global improvement

scales attempt to look at the whole person. This is tough because we can

measure aspects of quality of life, but we still really can't get our arms

completely around what this might mean for different persons under differing

circumstances over time. Even when the patient says, " Yes, the quality of my

life has been improved " or " I have an increased sense of well-being, " what

does that mean? What does that translate into that's in fact discrete,

measurable, and reliable over time? In sum, I think that there's still a bit

of a challenge with pain assessment tools, but overall it's recognized that

these latter forms of instruments speak much more to the human experience

than simple pain-intensity scales.

Medscape: Along the same vein of these challenges, are there any unmet needs

or other challenges that you can think of that should be focused on in the

near future?

Dr. Fine: I still think that we have a ways to go toward understanding

underlying mechanisms of persistent pain and being able to prevent the onset

evolution, and associated morbidities that are associated with chronic pain

As we gain more insight into how complicated nociceptive processing is even

before it gets to the brain, no less the frontal cortex, hopefully we will

make progress in preventing this devastating human experience. I think that

the real challenges in the immediate future are in being able to be

selective, sensitive, and specific enough with pharmacology so that toxicity

doesn't end up becoming the limiting factor.

The optimist in me is always present, but this has to be tempered by realism

I think that the reality is that we're going to make small incremental

steps in reducing toxicity, but the availability of new compounds or new

developments that will greatly improve efficacy without toxicity won't be on

the horizon for several years to come. Currently, the basic science, the

bench research in this area, is extraordinarily exciting. It's going to

ultimately lead to better tools, but I think that it's going to be some time

before the translational science will move from the bench to the clinic. So,

for the immediate future, the challenge is to educate clinicians to use the

available tools most effectively, integrate them well into comprehensive

pain treatment plans, and improve public policy to recognize and value the

importance of pain treatment and pain-related research.

Medscape: Is there anything else that you would like to add?

Dr. Fine: Going back to the area of breakthrough pain, an area that is of

particular interest to me, a growing challenge is to understand and be able

to clinically make sense of the concept of breakthrough pain outside of its

original, but limited, application to cancer pain and patients with

relatively short life expectancy. How do we apply the principles and

concepts that have served patients with advanced cancer so well to patients

with non-life-threatening illness, but with significant pain impairment?

Also, how do we do it with potent, rapid-onset pharmacologic therapies in a

way that will optimize outcomes and not merely exchange one set of problems

for another? I think that we're still challenged by this problem largely due

to risk management concerns, especially in pharmacotherapy for persistent

pain disorders.

Medscape: Do you have any thoughts on how this might change over the next

couple of years?

Dr. Fine: Well, I think that the ongoing process of rethinking definitions

will help, so when one person says " breakthrough pain, " everybody else knows

what is actually meant. It's important that everybody doesn't have his or

her own concept of what these different categories of pain are; having

standardized definitions allows clinicians to structure therapy to the

problem. In a sense, this is just an extension of making a proper diagnosis.

Along these lines, there will likely be a continuing push to educate primary

care physicians about pain definitions, taxonomy, assessment, and diagnostic

categories so that they can then optimize therapies and outcomes. I think

that the necessity for ongoing investigations and education about the

appropriate indications for opioid therapy, both for continuous pain relief

and for breakthrough pain, and how to couple this with other

nonpharmacologic therapies to optimize outcomes is still an ongoing area of

great need.

Another fascinating and increasingly relevant pain-related topic that I'd

like to share with the readership is the rapidly developing area of

cannabinoid pharmacology. This was covered in a plenary session by Dr. J.

, entitled " Endocannabinoids and Other Lipid modulators of

Pain. " [13] The more that we learn, the more that we recognize that

endogenous cannabinoids are important to nociceptive processing and,

ultimately, pain perception and experience. The question is whether we will

be able to take advantage of this growing knowledge to be able to reduce

pain and pain-related suffering. Of course, this is so interesting because

it crosses over into our cultural, sociologic, and political world of what

constitutes " acceptable " therapies. Historically and ongoing in the United

States, the use of cannabis for medical indications has been rife with

contention and controversy. As we continue to develop more refined products,

many that are derived from strains of the cannabis plant, will we be able to

overcome those cultural, social, and regulatory concerns and be able to

focus on medical need? I think that that's going to be an issue that will

require some significant resolution soon.

One last area that I think is very interesting and important to stay abreast

of, due both to the clinical prevalence of the problem of medication-related

constipation and the likelihood of commercial products becoming imminently

available, is opioid-induced bowel dysfunction. This subject, including

on-the-horizon innovations, was thoroughly covered by during a

luncheon symposium entitled " Current Advances in the Management of

Opioid-Related GI Events. " [14] There are many active investigations looking

at best approaches to reducing the untoward effects of opioid therapy, with

those evaluating pharmacotherapeutic agents for opioid-induced bowel

dysfunction leading the charge, including alvimopan and methylnaltrexone.

What will be the implications in terms of cost vs benefits in acute care

settings, such as reduction of postoperative ileus and in the treatment of

chronic pain, where opioid therapy is indicated? I think that the advent of

these and similar agents will move us into a new era of clinical risk

reduction.

References

Staud R, Price DD, Stone AA, et al. Evaluation of fibromyalgia pain: from

bench to bedside. Program and abstracts of the 25th Annual Scientific

Meeting of the American Pain Society; May 3-6, 2006; San , Texas.

Neugebauer V, Mayer E, Zhizhong ZP, Gereau RW. The pain within: pain

modulation by the amygdala. Program and abstracts of the 25th Annual

Scientific Meeting of the American Pain Society; May 3-6, 2006; San ,

Texas.

Carlton SM, Willis WD, Jasmin LD. Peripheral sensitization and inflammation:

sensory nerves are a two-way street. Program and abstracts of the 25th

Annual Scientific Meeting of the American Pain Society; May 3-6, 2006; San

, Texas.

Mittal P, Kim H, Dionne R. Variations of catecholamine metabolism genes

induce inter-individual variation in pain perception in humans. Program and

abstracts of the 25th Annual Scientific Meeting of the American Pain Society

May 3-6, 2006; San , Texas. Poster 614.

Ayres K, Kim H, Dionne R. The effects of genetic variation in serotonin and

dopamine transporters on acute clinical pain in humans. Program and

abstracts of the 25th Annual Scientific Meeting of the American Pain Society

May 3-6, 2006; San , Texas. Poster 612.

S, Jamison R, Katz N, Budman S, Fernandez K, Benoit C. Development

and validation of a screener to predict opioid misuse among chronic pain

patients (SOAPP V.2). Program and abstracts of the 25th Annual Scientific

Meeting of the American Pain Society; May 3-6, 2006; San , Texas.

Poster 969.

Katz N, S, Jamison R, et al. Screening for opioid abuse risk in

chronic pain patients: the SOAPP dissemination study. Program and abstracts

of the 25th Annual Scientific Meeting of the American Pain Society; May 3-6,

2006; San , Texas. Poster 980.

Fine P, Pasternak G, McCormick C. Update on opioid analgesics: receptors,

research, regulations and real patients. Program and abstracts of the 25th

Annual Scientific Meeting of the American Pain Society; May 3-6, 2006; San

, Texas.

Darwish M, on P Jr, Tracewell W, Jiang J. Comparative bioavailability

of the novel fentanyl effervescent buccal tablet formulation: an open-label

crossover study. Program and abstracts of the 25th Annual Scientific Meeting

of the American Pain Society; May 3-6, 2006; San , Texas. Poster 730.

Segal T, Hale M, Jhangiani H, Nalamachu S, Niebler G. Patients' experience

with fentanyl effervescent buccal tablets: interim analysis of a long-term,

multicenter, open-label study in cancer-related breakthrough pain. Program

and abstracts of the 25th Annual Scientific Meeting of the American Pain

Society; May 3-6, 2006; San , Texas. Poster 732.

D, Portenoy R, Messina J, Tremmel L. A randomized, placebo-controlled

study of fentanyl effervescent buccal tablets for relief of breakthrough

pain in opioid-tolerant patients with cancer. Program and abstracts of the

25th Annual Scientific Meeting of the American Pain Society; May 3-6, 2006;

San , Texas. Poster 729.

Farrar J, Messina J, Niebler G. A new tool for assessing the functional and

emotional impact of pain and effects of treatment: the Goal Attainment Scale

Program and abstracts of the 25th Annual Scientific Meeting of the American

Pain Society; May 3-6, 2006; San , Texas. Poster 941.

M. Plenary session. Endocannabinoids and other lipid modulators of

pain. Program and abstracts of the 25th Annual Scientific Meeting of the

American Pain Society; May 3-6, 2006; San , Texas.

Panchal SJ, Pergolizzi J, J, Fine P. Current advances in the

management of opioid-related GI events. Program and abstracts of the 25th

Annual Scientific Meeting of the American Pain Society; May 3-6, 2006; San

, Texas.

Funding Information

Supported by an independent educational grant from Cephalon.

G. Fine, MD, Professor of Anesthesiology, University of Utah, Salt

Lake City; Vice President, Medical Affairs, National Hospice and Palliative

Care Organization, andria, Virginia

Disclosure: Marni Kelman, MSc, has disclosed no relevant financial

relationships.

Disclosure: G. Fine, MD, has disclosed that he is a stockholder and

consultant for VistaCare. Dr. Fine has also disclosed that he has served on

the advisory boards for Cephalon, Endo, and Lilly.

Medscape Neurology & Neurosurgery. 2006;8(1) ©2006 Medscape

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