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CME

Unraveling the Mechanisms and Clinical Consequences of Pain: Recent Discoveries and the Implications for Pain Management: A Case-Based Interactive Expert Forum

  • Authors: Tong Joo Gan, MBBS, FRCA, FFARCS; Clifford Woolf, MD, PhD; Timothy J. Brennan, MD, PhD; Henrik Kehlet, MD, PhD; Nagy A. Mekhail, MD, PhD
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Target Audience and Goal Statement

This activity has been designed to meet the educational needs of physicians and other healthcare providers, including pain specialists and orthopedic surgeons involved in the care of patients experiencing pain.

Optimal management of pain requires a lucid understanding of their pathophysiology. Recent research has defined many aspects of the underlying mechanisms that give rise to the inflammatory pain response, as well as the central and peripheral effects that promote sensitization and resultant pain. However, in spite of these achievements, numerous questions surrounding the etiology and pathophysiology of pain remain unresolved.

During this interactive forum, comprising leading investigators in the fields of anesthesia, surgery, and pain management, current and novel data regarding the mechanisms of pain and the consequences associated with insufficient treatment will be discussed. In addition, several case studies will be presented, and current therapeutic perspectives regarding complete patient management in these cases will be examined.

Upon completion of this activity, participants will be able to:

  1. Explain the pathophysiology behind inflammation and pain in the central nervous system and periphery
  2. Discuss recent discoveries surrounding the pathophysiology of pain
  3. List the multiple systemic effects associated with pain
  4. Discuss appropriate management strategies for patients in pain


Author(s)

  • Timothy J Brennan, MD, PhD

    Associate Professor, Departments of Anesthesia and Pharmacology, Roy J. and Lucile A. Carver School of Medicine, University of Iowa, Iowa City, Iowa

    Disclosures

    Disclosure: Grants/Research Support: Pharmacia Corporation, Pfizer Inc
    Consultant: Pharmacia Corporation, Pfizer Inc

  • Tong Joo (TJ) Gan, MBBS, FRCA, FFARCS

    Associate Professor of Anesthesiology, Duke University Medical Center, Durham, North Carolina

    Disclosures

    Disclosure: Grants/Research Support: Pharmacia Corporation, Pfizer Inc
    Consultant: Pharmacia Corporation, Pfizer Inc
    Speakers' Bureau: Pharmacia Corporation, Pfizer Inc

  • Henrik Kehlet, MD, PhD

    Professor of Surgery, University of Copenhagen School of Medicine; Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark

    Disclosures

    Disclosure: Consultant: Pharmacia Corporation, Pfizer Inc

  • Nagy A Mekhail, MD, PhD

    Chairman, Department of Pain Management, Cleveland Clinic Foundation, Cleveland, Ohio

    Disclosures

    Disclosure: Consultant: Pharmacia Corporation
    Speakers' Bureau: Pfizer Inc

  • Clifford Woolf, MD, PhD

    Director of Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital, Charleston, Massachusetts

    Disclosures

    Disclosure: Grants/Research Support: Pfizer Inc
    Consultant: Pharmacia Corporation, Pfizer Inc


Accreditation Statements

    For Physicians

  • This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). The Postgraduate Institute for Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

    The Postgraduate Institute for Medicine designates this educational activity for a maximum of 3.0 category 1 credits toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

    The American Medical Association has determined that non-US licensed physicians who participate in this CME activity are eligible for AMA PRA category 1 credit.

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For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]


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CME

Unraveling the Mechanisms and Clinical Consequences of Pain: Recent Discoveries and the Implications for Pain Management: A Case-Based Interactive Expert Forum: Etiology of Pain

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Etiology of Pain

Multiple Pains, Multiple Mechanisms Presented by Clifford Woolf, MD, PhD

What I'd like to do today is to discuss the implications of our increased understanding of the mechanisms that are responsible for the generation of pain in terms of diagnostic and therapeutic approaches to the clinical problem of pain. Pain has been an area where over the last 10 years, there's been extraordinary progress in understanding the neurobiology, and we are at a point now where this is beginning to have enormous implications for clinical pain.

  • For many years the clinical study of pain has been dominated by investigations looking at particular and different pain syndromes, trying to identify what syndromes are present in which patients. A feature of this has been to try and relate particular etiological or disease factors with those pain syndromes--for example, herpes zoster with postherpetic neuralgia, diabetes with diabetic neuropathy, elective surgery with surgical pain. The interface of this has been to look at the symptoms that the patient complains of and attempt to relate the cause--the disease--with the response--the pain experience. What's been missing in this analysis until now has been what I consider to be one of the most important features, which are the actual mechanisms that are responsible for the pain the patient experiences. We are now at a point where we have sufficient insight into those mechanisms to be able to understand how they generate different pains, but even more important, they have become thetarget for very particular forms of treatment.

  • slide

    Slide 1.

    Etiological Factors, Pain Mechanisms, Pain Symptoms, Pain Syndromes

    (Enlarge Slide)
  • One of the important issues that we've recognized is that pain is not a homogeneous experience. There are several rather distinct forms of pain, and I'm going to run through these and highlight the mechanisms that we think are particularly important for these. The reason for this is that when it comes to a rational rather than an empirical approach to pain management, it's important to know what pain your patient is complaining of.

  • slide

    Slide 2.

    Multiple Pains

    (Enlarge Slide)
  • We also need to recognize that there are multiple mechanisms that can operate to produce pain. This is an area of ongoing study, and the list I have is incomplete and almost certainly will change as our knowledge improves. But the challenge is to try and match the mechanisms with the pain syndromes.

  • slide

    Slide 3.

    Multiple Mechanisms

    (Enlarge Slide)

Types of Pain: Nociceptive, Inflammatory, Neuropathic

  • To begin with, let's look at nociceptive pain. This is the pain that we experience in our everyday lives in response to a noxious stimulus. This is a protective pain. It acts as an early warning system. It is an essential protective mechanism that prevents tissue damage by alerting the body to the presence of an intense, potentially damaging stimulus in the environment. In patients who lack the capacity to feel nociceptive pain, there is enormous damage. And in fact, in patients who have congenital analgesia, there are deformities of the tips of their fingers, of their lips and tongues, and indeed, their life expectancy is reduced. Apart from these rare patients, fortunately, the clinical implications of nociceptive pain really relate to procedural pain, such as vaccinations or minor surgery. Whenever a surgeon uses his or her scalpel to cut through skin, that will activate this nociceptive system and, indeed, that is one situation where we need to control nociceptive pain. But formost patients who have chronic diseases, it is important that while we control the pain, we do not eliminate this protective warning device, this adaptive form of pain.

  • slide

    Slide 4.

    Nociceptive Pain

    (Enlarge Slide)
  • The mechanisms that are responsible for generating nociceptive pain have been identified, and essentially comprise 4 major features. There is transduction, which is the way in which external noxious stimuli are converted from, for example, heat or intense mechanical stimulus into electrical activity in highly specialized nociceptive primary afferents, which then transfer that information from the periphery to the central nervous system. So the first step is transduction. The second is the conduction of the sensory inflow from the periphery to the central nervous system. The next step is the transfer of that information from the primary sensory neurons to central projection neurons, and this is the process of transmission. And finally, once the information is transferred to those parts of the brain that are responsible for our perception, the actual sensory experience occurs.

  • slide

    Slide 5.

    Nociceptive Pain

    (Enlarge Slide)
  • Inflammatory pain has a number of different manifestations. Obviously one of them is a situation where the early warning nociceptive pain has been overwhelmed--where instead of preventing tissue damage by a withdrawal response, severe trauma occurs. So posttraumatic pain includes tissue damage and an inflammatory response. And an elective form of trauma, obviously, is surgery, and postoperative pain represents an acute form of inflammatory pain. And then there are a number of conditions which are associated with ongoing inflammation, of which the arthritides in general, and rheumatoid arthritis in particular, represent ongoing inflammation associated with severe pain.

  • slide

    Slide 6.

    Inflammatory Pain

    (Enlarge Slide)
  • What are the mechanisms that are responsible for the generation of this pain will--as opposed to the nociceptive system, which is designed to respond only to intense tissue damaging stimuli. A feature of inflammatory pain is the development of hypersensitivity so that stimuli, which normally would not produce pain, which would normally be innocuous, begin to do so. And this is the result of the production by inflammatory cells of a broad range of inflammatory mediators--cytokines and chemokines--which can act on the high-threshold primary-sensory neurons and change their properties. And we recognize now that there are 3 major features underlying inflammatory pain: There is a change in the peripheral sensitivity of high-threshold nociceptors--this is peripheral sensitization; there is an alteration in the chemical makeup of the neurons in the nervous system, a change in their properties and function--we call this a phenotypic switch; and finally there is an increase in theexcitability or the responsiveness of neurons within the central nervous system, increasing the gain of the system if you like, and this represents central sensitization.

  • slide

    Slide 7.

    Inflammatory Pain--Cont.

    (Enlarge Slide)
  • Neuropathic pain is quite distinct from inflammatory pain. Here there is a lesion to or an alteration in the function of the nervous system itself, and some examples of this would be compression of the median nerve with carpal tunnel syndrome; pain associated with the aftereffects of acute herpes zoster, postherpetic neuralgia; damage to the spinal cord producing a central pain; as well as poststroke pain when it affects the thalamic sensory relay nuclei. I've indicated on the slide some of the mechanisms that we think underlie neuropathic pain. Some of them overlap with those that are responsible for inflammatory pain, but many of them are quite distinct. And this is important because these 2 pains are distinct and will require different approaches for their management.

  • slide

    Slide 8.

    Neuropathic Pain

    (Enlarge Slide)

Types of Pain: Functional, Migraine, Osteoarthritis

  • A more recent group of pains that we're beginning to realize is one that we can call functional pain. These are pains where there is no clear peripheral pathology, nor can we identify pathology in the nervous system itself. There is no obvious lesion to either the peripheral central nervous system and yet the patients have pain. Some examples of this are the myofascial syndromes, fibromyalgia, gastrointestinal hypersensitivity disorders such as irritable bowel syndrome, and noncardiac chest pain--and one of the commonest form of headache, tension-type headache. We do not, at the present, have a detailed knowledge of the mechanisms, but again, it appears as if some of the mechanisms that are present in inflammatory and neuropathic pain may operate to produce this altered sensitivity of the pain system. And these include central sensitization, the increase in excitability of the somatosensory pathways, as well as a reduction in some of the inhibitory mechanisms that are present inthe nervous system, as well as some systems that facilitate transmission. So this appears to be a disease of an alteration in the function of the central nervous system, the way it responds to normal inputs.

  • slide

    Slide 9.

    Functional Pain

    (Enlarge Slide)
  • The last class of pain that I wish to discuss is migraine, which has some features that resemble inflammatory pain, in the sense that there may be the release of inflammatory mediators within the cortex, which can act on meningeal sensory fibers. But there are some features that appear to be due to alterations in the function of the cortex itself. So it seems to be a very particular kind of pain, but again, there's increasing evidence that 2 predominant mechanisms operate: the change in sensitivity of sensory terminals innervating blood vessels in the meninges, as well as an alteration on the responsiveness of excitability of central pain relay, neurons, central sensitization.

  • slide

    Slide 10.

    Migraine

    (Enlarge Slide)
  • There are two other very common conditions that are worth mentioning, osteoarthritis and low back pain. And the reason for that is that it is not always clear in these patients whether they have inflammatory or neuropathic pain. And this is one of our problems, that our diagnostic tools to identity the mechanisms that operate to produce pain are not fully evolved. So some patients with osteoarthritis who have a flare clearly have an inflammatory component, but many patients have no evidence of ongoing inflammation at all in their joints and yet have severe pain, and we do not know whether that pain arises from changes in the periphery innovating the joint or within the central nervous system. And the same is true of low back pain. Some low back pain may be due to soft tissue damage to ligaments, muscles, joints and other may be due to changes, compression of dorsal roots, or to the peripheral nerves. And this is important because, again, the therapeutic approach needs to bedifferent because the mechanisms that may be responsible for these heterogeneous groups of patients may be different.

  • slide

    Slide 11.

    Osteoarthritis, Low Back Pain, Inflammatory Neuropathic

    (Enlarge Slide)

Mechanisms of Nociceptive Pain

  • So what we need to attempt to do is to move away from a disease-based diagnosis of pain to one that is mechanism-based. And the reason for that is not just because that gives us increased knowledge of how the pain is generated, but much more so because we're reaching a point now where the identification of mechanisms will help us make rational choices for effective therapy.

  • slide

    Slide 12.

    Mechanism-Based Diagnosis, Mechanism-Based Therapy

    (Enlarge Slide)
  • And I'd like to illustrate this now by looking at one particular mechanism that operates to produce pain, and that relates to the production of prostanoids. Prostanoids are produced by the liberation from membrane phospholipids of arachidonic acid and its conversion by a number of enzymes--of which cyclooxygenase is the most important--into a precursor, which is then converted by specific syntheses into final prostanoid products. And the most important, in terms of pain and inflammation, is prostaglandin E2 (PGE2). The discovery that nonsteroidal antiinflammatory drugs, the mechanism for their analgesic and antiinflammatory action is the result of the inhibition of the production of prostanoids was made by John Vane, and he got the Nobel Prize for this. More recently it's been well appreciated that there are 2 cyclooxygenase enzymes that contribute to the conversion of arachidonic acid to prostaglandin H2; one is a constitutive form ofcyclooxygenase, COX-1, and the other is one that tends, in most tissues, to be induced by inflammation, which is COX-2.

  • slide

    Slide 13.

    Membrane Phospholipids

    (Enlarge Slide)
  • What I'd like to do is to run through some of the major mechanisms that I've highlighted as I've gone through the different pain syndromes and to try and see the particular role that COX-2 may play in these different pain mechanisms. So to begin with, to look at nociceptive pain, the first phase of that transduction, the conversion of intense stimuli, whether they be chemical stimuli such as a reduced pH, which occurs in inflamed tissue, intense heat above 42 degrees C, or mechanical forces. We now appreciate that there are very specific transducer proteins that are expressed in these nociceptive neurons and which convert these particular noxious stimuli into currents across the membrane, depolarizing the membrane and activating the peripheral terminal. And this process does not involve prostanoids or the production of prostaglandins by cyclooxygenase, so this pain, or this process, would not be affected by COX-2 inhibitors or nonselective COX inhibitors.

  • slide

    Slide 14.

    Nociceptive Pain: Transduction

    (Enlarge Slide)
  • The next stage of nociceptive pain was the transfer of information from the periphery to the central nervous system and this is mediated by conduction of action potentials along the axons and this action potential conduction occurs by means of voltage-gated sodium channels. And we now appreciate that there are very specific sodium channels that are expressed in nociceptive neurons that are responsible for this. And this is the target, obviously, for local anesthetics producing regional or epidural anesthesia. The conduction process does not, like the transduction process, involve cyclooxygenase, so, again, this will not be affected by COX-2 inhibitors.

  • slide

    Slide 15.

    Nociceptive Pain: Conduction

    (Enlarge Slide)
  • The next stage of nociception is the transfer of information from the primary nociceptive neurons to dorsal horn neurons, to projection neurons that will transfer the input to the brain. And again, we have made enormous progress in understanding the synaptic transmission that is involved in this transfer, and this involves release of an excited dicarboxylic amino acid glutamate, as well as peptides such as substance P acting on particular receptors on the postsynaptic neuron. And this enables the rapid transfer of input about the intensity, duration, location of different peripheral stimuli. And again, this process does not involve prostaglandins, and therefore cyclooxygenase inhibitors will not affect this function. So basically, the major features that are responsible for nociceptive pain, the major mechanisms, are not affected by cyclooxygenase inhibitors.

  • slide

    Slide 16.

    Nociceptive Pain: Transmission

    (Enlarge Slide)

Mechanisms of Peripheral Sensitization/Inflammation

  • When we move to peripheral sensitization, which you may recall was an increase in the excitability of the peripheral terminal of nociceptors in response to inflammation, here the situation is very different. I mentioned before that the inducible form of cyclooxygenase, COX-2, is produced, it's transcribed, in inflamed tissue, and indicated here is a Northern blot showing the levels of messenger RNA for COX-2. In normal, noninflamed skin, there is no COX-2. It is undetectable. But some hours after peripheral inflammation there is a massive increase in COX-2 and this can act on arachidonic acid to begin the sequence of steps that lead to the production of prostaglandins. This is a cartoon indicating the peripheral terminal of a nociceptor. And what we have as a result of this induction of COX-2 is the production of prostaglandins, which act on very specific receptors, prostaglandin receptors known as EP receptors, and these EP receptors are G-protein coupled receptors that set intrain intracellular signal transaction cascades in the peripheral terminal. In particular, they activate two kinases, protein kinase A, which is a cyclic AMP-dependant kinase, and protein kinase C, which is a calcium-activated protein kinase. So these kinases are activated by prostaglandin acting on EP receptors, and these kinases then phosphorylate two main targets. They phosphorylate some of the transducing proteins that are responsive, for example, to heat stimuli, reducing their threshold of activation. And they also phosphorylate sodium channels that are expressed in the membrane so that the membrane becomes hyperexcitable. And this then is the cellular basis for peripheral sensitization, the increase in sensitivity of the peripheral terminal of nociceptors. And this will occur wherever tissue inflammation is present and indeed, is responsible for the reduction in pain threshold at the site of tissue damage.

  • slide

    Slide 17.

    Peripheral Sensitization

    (Enlarge Slide)
  • Still in the periphery, looking at the effect of injury to primary sensory neurons. One of the features of damage to a peripheral nerve is production of a neuroma, which the damaged end of the peripheral nerve. And the feature of the neuroma is that it begins to fire spontaneously in the absence of any peripheral stimuli. This is what we call ectopic stimuli, or ectopic activity. And we now realize that this abnormal pacemaker-like activity in the injured nerve fiber is the result of changes in the expression of sodium and potassium channels. And these begin to generate this hyperexcitable state where bursts of activity occur without any peripheral stimulus producing spontaneous lancinating pain. And this ectopic activity in neuropathic pain patients does not involve prostaglandins and will not be sensitive to cyclooxygenase inhibitors.

  • slide

    Slide 18.

    Ectopic Activity

    (Enlarge Slide)
  • One of the breakthroughs in our understanding of pain mechanisms has been the realization that in response to tissue damage and inflammation as well as damage to the nervous system, there are massive changes in the properties of the neurons that innervate inflamed tissues or that are damaged by nerve damage. And these changes include alterations in gene expression, and these changes in gene expression can profoundly alter the properties of these sensory fibers. It so happens one of the genes that is regulated in this way is cyclooxygenase. We had become accustomed to the fact that cyclooxygenase can be induced at the site of tissue damage and inflammation in inflamed tissue. It is a more recent discovery that the same enzyme is also expressed in neurons when they are inflamed or sometimes damaged.

  • slide

    Slide 19.

    Transcriptional Changes in the DRG

    (Enlarge Slide)

Mechanisms of Central Sensitization

  • The next mechanism I'd like to discuss is central sensitization, the increase in excitability of neurons within the central nervous system. And we now have begun to appreciate that this phenomenon, this altered excitability in sensory pathways, has 2 phases: an immediate phase, which is activity-dependant--it depends on activity in nociceptors to drive it and essentially results in an increase, a rather transient increase in the excitability of central neurons. So, indicated in this slide is a diagram of the major mechanisms that underlie this immediate phase of central sensitization, which is activation of nociceptors in response, for example, to an intense peripheral stimulus, release of transmitters, which act in postsynaptic receptors to activate intracellular kinases that are very similar to the ones I've discussed for peripheral sensitization. So there's activation of both PKC and PKA, and these can phosphorylate receptors and ion channels in the central neurons and againalter their kinetics and thresholds, increasing excitability within the central nervous system. I've also indicated here a section through the spinal cord of a noninflamed animal. And when we stain this animal, there is very little COX-2 in a normal spinal cord, so that there is in this acute phase of central sensitization, no major role, if any, for COX-2. However, there is constitutive expression of COX-1 in the spinal cord and it looks as if COX-1 may have a role in this acute phase of central sensitization.

  • slide

    Slide 20.

    Central Sensitization: Immediate

    (Enlarge Slide)
  • What happens, though, later is that if there is peripheral tissue damage and inflammation, this can induce very profound changes in COX-2 within the central nervous system. And this is illustrated here. On the right, there is a Northern blot showing the levels of COX-2 messenger RNA in the spinal cord. In noninflamed conditions, there is a low level, but some hours after a peripheral inflammation there is a massive, 20-fold increase in the amount of messenger RNA for COX-2 in the spinal cord. And this increase is associated not with any messenger RNA but results in COX-2 protein production, increase in COX-2 enzyme activity. And from essentially undetectable levels of prostaglandins in normal CSF, some hours after peripheral inflammation, there is a very large and high level of prostaglandin in the CSF, resulting from this increase in COX-2 within the spinal cord.

  • slide

    Slide 21.

    COX-2 Induction in the Spinal Cord After Peripheral Inflammation (20-25)

    (Enlarge Slide)
  • And this has led us to appreciate that central sensitization has a second, late phase, one that requires transcription of some genes, and in particular this involves COX-2. So the photomicrograph on the right shows immunostaining for COX-2 after peripheral inflammation, and now we see many neurons expressing COX-2. What we realize is that the COX-2 expressed within these dorsal horn neurons produces prostaglandins, and this has multiple activities. The prostaglandins can act on the central terminals--the presynaptic terminals of nociceptive sensory fibers--to increase transmitter release. They can also act postsynaptically on the dorsal-horn neurons producing a direct depolarization. And finally, it has been appreciated that prostaglandins can inhibit the action of glycine receptor, which is an inhibitory transmitter. And together, all of these actions, the central actions of prostaglandins, act to produce an increase in excitability of neurons. So we have peripheral changesincreasing the peripheral excitability of nociceptor terminals, which is peripheral sensitization driven by prostanoids. And we now appreciate that a similar, analogous change occurs within the central nervous system.

  • slide

    Slide 22.

    Central Sensitization: Late

    (Enlarge Slide)
  • What is surprising is that the COX-2 that is induced within the central nervous system in response to peripheral inflammation is very widespread. It is not restricted only to that part of the spinal cord that innovates the inflamed area, but in fact seems to be distributed up and down the entire spinal cord, plus in parts of the brain, such as the thalamus. And this raises the possibility that central production of prostaglandin in response to peripheral inflammation may have multiple actions.

  • slide

    Slide 23.

    COX-2 Is Widely Induced in the CNS by Peripheral Inflammation

    (Enlarge Slide)
  • And this model attempts to look at this. We have peripheral inflammation producing cytokines, which produce local induction of COX-2. And prostaglandins; and these can act on nociceptor terminals to produce peripheral sensitization. Some of these cytokines, though, can spread via the blood system to the central nervous system where they act to increase levels of interleukin 1, which then induces COX-2 within central neurons. The important feature of this model is that the input to the central nervous system is not carried along nerve fibers. It is not an activity-dependant form of signaling, but rather a humoral form. The signal is transmitted by the bloodstream, and that explains why the COX-2 induction is so widespread. Once the COX-2 is induced within the central nervous system, it acts to produce prostaglandins, which as I've indicated, can change the excitability of neurons and contribute to pain hypersensitivity. These central prostaglandins also produce fever when acting onneurons in the hypothalamus and there is a possibility that they may play a major role in alterations in mood, in sleep cycles, in appetite, and other higher functions. And these collectively have become known as the "sickness syndrome." And it is possible then that inhibiting prostaglandin production, both peripherally and centrally, can have multiple advantages in terms of minimizing the effect of tissue damage and inflammation on a variety of different outcomes. Recently a putative third form of cyclooxygenase, COX-3, has been identified which is claimed to be expressed in the central nervous system and may be the target for the action of acetaminophen. The discovery of the induction of COX-2 within the central nervous system has important clinical implications. COX-1 is constitutively expressed. There's a low level present in most tissues, including the central nervous system. There are low levels of constitutive COX-2, but some hours after peripheral inflammation, there's a verymassive induction of COX-2 within the central nervous system. And this forces us to appreciate what forms of therapy should we target at these two enzymes, COX-1 and COX-2 and when.

  • slide

    Slide 24.

    Model

    (Enlarge Slide)
  • So in this last, this final slide, what I've attempted to do is to indicate different situations. basal pain sensitivity in a normal individual with no peripheral tissue damage, where the nociceptor system will not be susceptible to COX inhibition. The same will be true during surgery, when the immediate phase of tissue damage before transcription of COX-2 has occurred, because it takes some hours, both in the periphery and in the central nervous system for COX-2 to be induced. However, once it is induced, there are multiple actions in the periphery and in the CNS, and we obviously appreciate that inhibiting COX-2 at this phase, in the postoperative phase, has benefit for the patient. What we need to evaluate is what is the optimal timing of doing this inhibition, before the COX-2 is induced, or at the time that it is induced. We also have very limited information on the duration of COX-2 induction after, for example, surgical trauma. It is very likely that COX-2 will remainelevated in the periphery and in the CNS for many days until full healing has occurred. And this raises the issue of the duration that we should attempt to inhibit COX-2 and whether this longer term treatment by inhibiting COX-2 postoperatively may prove beneficial in terms of the prevention of persistent and ongoing pain after elective surgery. Thank you.

  • slide

    Slide 25.

    COX-1, COX-2 Graph

    (Enlarge Slide)