For some patients undergoing particular surgeries, we've developed specific techniques to greatly improve postoperative pain management. This is a patient who's about to undergo a thoracotomy, an open thoracic procedure. This patient is having a thoracic epidural catheter placed for postoperative pain management. Epidural local anesthetic and opioid will be infused to provide segmental analgesia for several days after the patient's surgery. This, the quality of pain relief from thoracic epidural analgesia, is very good.

This is another example of a patient who has undergone elbow reconstruction and has an infused catheter placed along the brachial plexus for continuous local anesthetic infusion. After this elbow reconstruction, the patient is required to participate in rehabilitation, active and passive range of motion, and again, for this particular surgery, this analgesic technique is excellent.

However, most patients who undergo surgery typically receive parenteral opioid therapy. This graph shows pain measures over several days in a typical patient who has undergone an abdominal hysterectomy and receives patient-controlled analgesia for postoperative pain relief. Before surgery, there is very little pain so the VAS score is zero or very near zero. Immediately after surgery, the patient might complain of moderate pain at rest. This pain at rest diminishes over several days after surgery, so it is very nearly gone, in this example, around postoperative day 4.

Not only do patients complain of pain at rest, but pain with activities is a particular problem. Again, recording visual analog scale over days after surgery, in this patient who has undergone an abdominal hysterectomy. Very little pain prior to surgery; however, pain is severe during activities like coughing even with optimized parenteral-controlled analgesia with opioids. This persistent pain with cough is present throughout the postoperative period and in this case shown that moderate pain is still present even on postoperative day 8.

Not only do patients have pain at rest and pain with activities, patients also have mechanical hyperalgesia. In the upper right-hand corner of this slide, shows an example of patients who underwent an experimental incision in the forearm and were probed for pain sensitivity using a mechanical stimulus immediately adjacent to the incision. Before patients underwent incision, their pain threshold was quite high, in this case 250 mN. After the incision, however, the pain threshold dropped markedly and remained decreased, even 4 days after the experimental incision.

This mechanical stimulus has also been used in several studies to map a large area of mechanical hyperalgesia around a surgical incision. In this particular example, a mechanical stimulus was probed, away large distances from the incision, to map this blue area, this very large area surrounding the incision of tenderness. This has been shown for patients undergoing abdominal hysterectomy, colectomy, and nephrectomy.

Most studies in postoperative pain management have focused on pharmacologic treatments. One approach we've taken to advance acute pain management and perioperative pain management is to better understand the etiology of incisional pain.

In preclinical studies in experimental animals, we've made small incisions in the hind paw, an area accessible to sensory testing, with the hope that we can translate how an incision in the operating room may cause acute and persistent pain after surgery.

As I showed in my earlier slides, in the upper right-hand corner is a schematic of patients who have pain at rest after a simple abdominal hysterectomy. In our model, we've been able to quantify a guarding behavior, or a nonevoked behavior after our experimental incision. We've quantified this in a cumulative pain score. The horizontal line represents a median, with the box representing a 25^th and 75^th percentile and the vertical line a 10^th and 90^th percentile. Before our experimental incision, we note very little guarding behavior or pain-related behavior. However, like our patients, immediately after incision there is an increase in guarding behavior, which gradually diminishes within 3 to 4 days after the experimental incision. So very similar to patients undergoing surgery who complain of pain at rest, even when parenteral opioids are optimized, our experimental model also shows nonevoked or guarding behavior similar to that seen inpatients.

Again, in the upper right-hand corner, we showed that in patients that incisions and probing immediately adjacent to the incision produces a marked reduction in mechanical pain threshold, or mechanical hyperalgesia. Similarly, we have probed with the same mechanical stimuli adjacent to the incisions in our model. Withdrawal threshold is shown on the vertical axis and time after incision on the horizontal axis. Before undergoing incision, there is a very high withdrawal threshold, or a pain-related behavior. However, immediately after incision, the pain--the withdrawal threshold, or the pain-related behavior--decreases markedly and stays reduced for 3 to 4 days before gradually returning towards preincision values. Note that the qualitative and quantitative similarity between our experimental incision and the incision and mechanical hyperalgesia shown in patients.

I showed earlier after surgery, patients have large areas of mechanical hyperalgesia to probing with these punctate mechanical stimuli. Similarly, we made our experimental incision and probed large distances away from the incision, in this case 1 to 1.2 cm distal to the incision, and as you can see, again, looking at withdrawal threshold on the vertical axis and time after incision on the horizontal axis, we begin with a high withdrawal threshold prior to incision and have a decreased withdrawal threshold remote to the incision, as we see in patients undergoing surgery.

With that, we undertook further studies to try to better understand mechanisms for incisional pain. We began by recording nociceptor activity. We're looking at activation of nociceptors during our experimental incision. This is performed by dissecting very small, fine filaments from the axons of the nerves innervated by the area to undergo incision.

Recall that patients, as shown in the schematic in the upper right-hand corner of this slide, patients have pain at rest immediately after incision. And also our, in our experimental model, following recovery from anesthesia, guarding behavior or nonevoked pain behavior is present immediately after surgery. When we dissected these fine filaments, we note that they are very heterogeneous population. And in a large part, most of the nociceptors that we dissected and recorded their activity, and then made our experimental incision, which we know produces remarkable pain-related behavior, we can find very little nociceptor activation by the incision. This suggests that likely a unique population of nociceptors, which are perhaps difficult to identify or difficult to characterize, are activated and sensitized by the incision to produce ongoing pain immediately after surgery.

We also examined evidence for mechanical hyperalgesia in these nociceptors. Again, in the upper right hand corner, note that patients undergoing experimental incision have exquisite pain sensitivity or reduced pain threshold when probing immediately adjacent to the incision. We again dissected individual nociceptors and recorded their activity and subjected the receptive field of these nociceptors to mechanical stimuli. And in the upper part of this slide, we note that this nociceptor is sensitive to mechanical stimuli, in this case 50- and 100-mN mechanical stimulus. When we then took the same nociceptor and produced our typical incision--which produces immediate evidence of mechanical hyperalgesia and reduced withdrawal threshold in our experimental model--we again found little evidence for mechanical sensitization of these nociceptors. Subjecting this fine afferent or nociceptor to the same mechanical stimuli largely produced similar responses, again suggesting that a unique,perhaps difficult-to-identify, population of nociceptors likely mediates the enhanced response to mechanical stimuli in patients after surgery and in our model.

One unique feature we found when recording nociceptor activity and trying to find evidence for mechanical sensitization is as follows: We examined the area of the receptive field of individual nociceptors shown on the left side of this graph, of this slide, and designated "the sham incision." The small green area outlined is the receptive field of a nociceptor in an uninjured region. However, after our incision, which produces remarkable pain behavior after recovery from anesthesia, we see very large receptive fields, large mechanical receptive fields in these nociceptors, to very low threshold or very low mechanical forces.

This was a consistent observation in our recording of mechanical responsiveness of these nociceptors and might lead us to a hypothesis for mechanical hyperalgesia and mechanical sensitivity after incisions in our model, and after postoperative--and after surgery in patients. Again, in the upper right hand corner, a schematic of reduced mechanical pain threshold in patients undergoing incisions, and the normal nociceptor activity on the top graph, showing a small mechanical receptive field, and activation of the nociceptor by a mechanical stimulus. Perhaps after surgery these small mechanical receptive fields greatly expand, 4 to 5 times greater than in the normal nociceptor, allowing for many more nociceptors to now be activated by the incision and produce a greater barrage into the central nervous system following mechanical stimulation after surgery.

We further went on to dissect the mechanisms of postoperative pain by recording activity in the dorsal-horn neurons of anesthetized animals. And again, a subjecting receptive field of dorsal horn neurons to the same plantar incision, which produces remarkable pain behavior.

In the upper right-hand corner of this slide shows, reminds us, that patients undergoing surgery and in our model have immediate pain at rest, or nonevoked pain in our model after recovery from anesthesia. We've documented this as early as 15 to 30 minutes after recovery from the anesthetic. Dissecting the spinal cord into its individual components to look at central nervous system activation and central nervous system sensitization is shown in the lower part of this graph. We are recording activity from a dorsal-horn neuron prior to incision, which has very little activity. Few action potentials are evoked. However, during incision and for the next hour after incision, we see a remarkable activation by the incision and continued ongoing activity for 1 hour after the experimental incision, indicating that this pain at rest is likely transmitted well through the dorsal horn and into the central nervous system--indicating that this neuron likely contributes to pain at rest in ourmodel and a similar mechanism likely contributes to pain at rest in patients after surgery.

We went on to look for evidence of mechanical sensitization of these dorsal-horn neurons, which was very difficult to find when we recorded nociceptor activity. Again, evidence for a reduced mechanical pain threshold reminds us of our patients in the upper right hand corner. We recorded individual dorsal-horn neurons' components of central activation and central sensitization. We, in the upper graph, we recorded the mechanical activity in a normal hind paw prior to making our incision. And note that this neuron is a touch-responsive neuron. It responds to low-intensity mechanical stimuli and has increased responsiveness to greater-intensity mechanical stimuli. The gray area represents the forces which typically do not produce withdrawal in an unincised animal, but produce withdrawal following our incision. In the lower recording, we show an increased responsiveness to these same mechanical stimuli 1 hour after our experimental incision and much greater responses in the areaoutlined in the gray in the lower portion of this slide, indicating that this neuron, which is a touch-sensitive neuron, likely converts touch to pain by increasing responsiveness to its mechanical stimuli after our experimental incision. And this wide-dynamic-range-type neuron likely contributes to the reduced mechanical pain threshold in patients after surgery.

Normally, these dorsal-horn neurons have particular receptive fields, or areas that respond to mechanical stimuli, and elicit action potentials or activation of dorsal-horn neurons. It is well known from earlier work by Dr. Woolf and other colleagues that there are areas outside the typical receptive field of this dorsal-horn neuron that are also, may activate, the neuron but that the activation of this neuron is insufficient to evoke action potentials. In other words, there are regions outside the typical receptive field, which are subliminal, which are capable of activating this neuron, but the activation is typically inadequate to view in action potentials.

In this slide, we have a schematic on the left for this large area of hyperalgesia that is seen in patients who undergo surgery. On the top, again, mechanical stimuli traced around a surgical incision, in the red, shows a large area of sensitivity outlined in the blue, following surgery. Recall that in our model, in the lower portion of this slide on the left, we were able to show large areas well outside the incision, of mechanical sensitivity following the plantar incision. On the left is a model for this mechanism that produces a large area of mechanical hyperalgesia following surgery. Nociceptors are likely activated in the plantar incision. Again, these nociceptors are difficult to identify but likely activate and sensitize the dorsal-horn neuron, now shown in pink. This activation and sensitization of this dorsal-horn neuron now permits areas outside the incision which were previously subliminal, or unable to evoke a response, now are sufficient to produce action potentialsand evoke a response and produce these large areas of hyperalgesia seen in patients after surgery and in our model.

With this plasticity demonstrated in the central nervous system, we were interested in the concepts of preemptive analgesia and the fact that with our model, and with our studies in sensitization, we might be able to better understand a preemptive analgesia, a controversial topic in acute pain management. We participated in a review article that was published 3 years ago in the Journal of Pain, entitled "Preemptive Analgesia: Moving Beyond Conventional Strategies and Confusing Terminology," in which we outlined several negative studies as well as positive studies in preemptive analgesia and asked the participants in studies that are interested in plasticity and postoperative pain to further define precisely their protocols for preemptive analgesia so the field could move forward. We responded to the editorials for our article with a rebuttal entitled "Analgesic Treatment Before Incision, Compared with Treatment After Incision, Provides No Improvement in Postoperative PainRelief" to provide a forum for further studies in preemptive analgesia and acute pain management.

Henrik Kehlet and his group answered this question further in a meta-analysis that summarized many preemptive analgesia studies that examined preincision treatments versus treatment after incision. This is a summary from his article on incisional local anesthetics, with VAS on the vertical axis in patients given preoperative treatments compared with several studies that also used, measured VAS in postoperative treatments with local anesthetics. The line through the middle of this figure shows that most of the studies are equivalent and that pretreatment with local anesthetics was roughly equal to treatment after incision for pain in the early postoperative period.

We used our model to perhaps determine why there was no difference in pretreatment before incision and treatment after incision for local anesthetics. This again is a dorsal-horn neuron recording. This particular dorsal-horn neuron had very little activity prior to incision. But after the incision, shown on the left side of this recording, there was remarkable ongoing activity. This was caused by the plantar incision. Two hours after the incision, the ongoing activity remained and local anesthetic treatment within the area of the incision remarkably, or markedly, decreased this ongoing activity, so that 10 minutes after anesthetic treatment, the activity of the dorsal-horn neuron returned to its preincision level, suggesting that local anesthetic infiltration after incision reduces central neuron activation caused by the incision to its presurgery level.

Our model for central nervous system activation during surgery and after surgery is as follows: difficult-to-identify nociceptors, shown on the left, are activated and sensitized by surgery and activate and sensitize the dorsal horn. This allows subliminal inputs to now be effective, produce large areas of hyperalgesia and central sensitization. After local anesthetic was administered into the incision to reduce ongoing afferent input from the incision to the dorsal horn neuron, the state of the dorsal-horn reverts back to its pre incisional level, with normal activity. Subliminal inputs are now ineffective in activating this neuron, thereby decreasing these large areas of sensitivity.

We are interested in mediators of postoperative pain. In particular, what may be released or increased by the incision that may sensitize nociceptors and contribute to postoperative pain in patients and pain-related behaviors in our model. Two such mediators are shown on the right side of this slide. Recent studies indicate that administration of prostaglandin receptor antagonists, or EP receptor antagonists, directly into incisions in our model reduced pain-related behavior and mechanical hyperalgesia. We are also interested in mediators like nerve-growth factor, which we reported several years ago: That blockade of nerve-growth factor reduced pain-related behaviors in our model. Other factors which may contribute to sensitization in postoperative pain within wounds and primary afferent activation and sensitization, include mediators such as ATP, glucotrienes, serotonin, decreased pH or low pH, tumor necrosis factor, or bradykinin.

We are also interested in factors that may contribute to central nervous system activation and sensitization caused by our incision. Again, recent studies indicate that prostaglandin receptor antagonists, or EP receptor antagonists, administered intrathecally reduce mechanical withdrawal threshold in our model, suggesting that prostaglandin may contribute to the increased responsiveness to mechanical stimuli after our incision. Our research has emphasized the AMPA/Kainate receptor system as an important mediator of enhanced responses to mechanical stimuli in the dorsal-horn in our model.

Other pharmacologic--experimental pharmacologic treatments that indicate a contribution to particular receptors for increased responsiveness to mechanical stimuli in our model are as follows: alpha-2 adrenergic agonist administered intrathecally also decreased pain-related behavior in our model. Ziconotide has been used in patients to decrease postoperative pain and is also effective in our model, as are alpha-2 adrenergic agonists. Gabapentinoids are quite effective at reducing responsiveness to mechanical stimuli in our experimental model and also have analgesic properties in postoperative pain patients. These 3 studies indicate that our model may reliably predict novel analgesic treatments for acute pain management in patients.

I conclude that the study and application of new discoveries in pain mechanisms will markedly improve perioperative pain management in the future, with our long-term goal will be painless surgery in our patients. Thank you.