- Email: [email protected]
Reply to F. Cervero
262 Based on our animal data and limited human trials, we believe continuous infusions of intrathecal octreotide are safe. Randomized, double-blind trials using larger numbers of patients are necessary to further establish the efficacy and safety of intrathecal octreotide. Unfortunately, current availability of octreotide is limited and use of the commercially available formulation would exceed $20.000 annually.
References Leblanc, R., Gauthier. S., Gamin, M., Quirion, R.. Palmour, R. and Masson, H., Neurobehavioral effects on intrathecal somatostatinergic treatment in subhuman primates, Neurology, 38 (1988) 1887-1890. Penn. R.D., Paice, J.A. and Kroin, J.S., Octreotide: a potent new non-opiate analgesic for intrathecal infusion. Pain. 49 (1992) 13-19.
Richard D. Penn Judith A. Paice Jeffrey S. Kroin
This model, and many other current models of pain perception based on the ‘sensitization of the WDRs’, leave the brain stem, the thalamus, the limbic system, the cortex and all the other bits and pieces of the brain with very little to do. There is no room left for the higher centres (or lower centres in Price et al.‘s diagrams) in the processing of pain signals. That some people, including virtually all politicians, do not need a brain to go about their business is sadly evident. but isn’s it too much to expect that all pain is in the spinal cord’? We need to include supraspinal structures in our models of pain processing and we should stop peddling these ultra-specificity no tions by which if a spike occurs in a spinal cord cell (preferably a WDR) the perception of pain inevitably ensues. Max von Frey himself would have been very proud of these models. There must be a half way between Descartes’ well known representation of the spinal cord as just a transmission nerve and this exclusive role in pain perception given nowadays to spinal mechanisms. Incidentally. whatever happened to nociceptor-specific cells’? They do not even feature in Price et al.‘s model. But this, as they say, is another story.
References
PAIN 02180
Price, D.D.. Long, S. and Huitt. C., Sensory testing of pathophyxiological mechanisms of pain in patients with reflex sympathetic dystrophy, Pain, 49 (1992) 163-173.
Fernando
Cervero
Not all pain is in the spinal cord I am used to getting a certain amount of stick from the gurus of pain research for my having dared to suggest that the processing of nociceptive signals retains some specificity in its central organisation. So. imagine my surprise when I read the recent paper by Price et al. (1992) proposing an ultra-specificity model for the central processing of pain. Since none of the aforementioned gurus even raised an eyebrow at such temerity, here is this letter to redress the balance. The paper in question is a psychophysical study of pain sensation in patients suffering from reflex sympathetic dystrophy (RSD). I have no qualms about the study itself, barring a minor quibble about the use of the term ‘high threshold allodynia’. As allodynia is meant to imply that innocuous stimuli evoke pain; ‘high-threshold allodynia’ is at best ambiguous. But this is not the reason for my writing this letter so let’s get on with the real business. The problem is the model, or series of models, that Price et al. propose as possible mechanisms for the pain sensations observed in their patients. These models are all centred around a class of spinal cord neurone known as wide-dynamic-range cell (WDR) which, in the opinion of the authors, becomes a pain-cell extraordinaire. According to the model, if the peripheral input to WDR cells is dominated by nociceptor activity, as they suggest happens under normal circumstances, then you will feel normal pain. However, if the WDRs are activated by low-threshold mechanoreceptors, as they propose may happen in some cases of RSD, then you get lowthreshold allodynia. Furthermore, if the almighty WDRs are driven by enhanced activity in nociceptors then you will get high-threshold allodynia. The only role left to the rest of the CNS in this model is to follow blindly what these pain cells in the spinal cord dictate. The pain signal is processed and packaged by the WDRs and is then projected along a labelled line to the brain where all that is needed, I assume. is some kind of spike-perception convertor. Enigmatically, the WDR cells in Price et al.‘s diagrams project downwards (!) towards the brain.
PAIN 02181
Reply to F. Cervero Dr. Cervero has probably misunderstood and misrepresented the purpose of our explanatory models in our recent paper (Price et al., 1992, Fig. 2, page 171). The purpose of these models was simply to provide a general explanation of bofh peripheral and some central pathophysiological mechanisms that are likely to underlie some of the symptoms of reflex sympathetic dystrophy (RSD) and neuropathic pain encountered in our studies. The models focus on primary afferents and the spinal cord because the vast majority of current knowledge of pathophysiological mechanisms of neuropathic pain includes these two levels. One only has to peruse all of the issues of PAIN and other leading neuroscience journal issues published since 1988 (when the Bennett and Xie model was published) to see much of the evidence for this. That the spinal cord dorsal horn in general and wide-dynamicrange (WDR) sensory transmission neurons in particular have crucial roles in these pathophysiological mechanisms is supported by considerable evidence. To take just one of several examples from the literature, a recent paper by Palecek et al. (1992) shows that WDR neurons increase their spontaneous activity and become hyper-responsive to innocuous brushing after an experimental neuropathy is produced in the rat, a result consistent with A-beta allodynia in some patients. This is precisely the kind of result that would be expected. based on our model (no. II) in Fig. 2. Interestingly, nociceptivespecific and low-threshold neurons did not become nearly as pathologically altered as did the WDR neurons. Consistent with this
electrophysiological study, metabolic mapping of elevated neural activity in Bennett and Xie’s (1988) model shows that the largest increase in activity occurs in laminae V-VI, a region of highest concentration of WDR neurons (Mao et al. 1992a). That these abnormal spinal mechanisms are critical for the expression of abnormal pain-related behaviors is also supported by considerable evidence, for example the observations that pain-related symptoms can be almost completely reversed by intrathecal administration of small doses of NMDA antagonists and gangliosides (Mao et al. 1992b,c; Yamamoto and Yaksh 1992). Does all of this mean that “The only role left to the rest of the CNS in this model is to follow blindly what these pain-cells in the spinal cord dictate”? That is certainly not a position that we take or would attempt to defend. However, until we understand much of the neural transformations that take place between primary afferents and the next order of neurons in the spinal grey matter under both normal and pathophysiological circumstances, we cannot adequately evaluate pathophysiological mechanisms that are intrinsic to higher centers. It is entirely possible that the abnormal neural activities and responses that have already been recorded at higher levels (Guilbaud et al. 1990) are to a major extent passive reflections of abnormal responses that occur at spinal levels. But even if this is not the case, we still need to understand much of the primary afferent and spinal cord pathophysiology before we can begin to make comprehensible interpretations of the roles of specific brain structures in pathophysiological pain. This is no doubt a major reason why so many spinal cord papers have been published on Bennett and Xie’s model. Thus, the reason that specific brain structures are missing from our models is that we refuse to provide explanations for which there are no data. Moreover, filling these voids of ignorance with hypothetical constructs, such as ‘pattern generating mechanism’ and ‘central intensity monitor’ is not an exercise that we find compelling. However, the most disturbing aspect of Cervero’s comments is his misrepresentation of the authors’ current views on both normal and pathophysiological pain mechanisms. We have neuer stated or implied in any of our publications or diagrams that ‘if a spike occurs in a spinal cord cell (preferably a WDR) the perception of pain inevitably ensues’. For that matter, we know of no one who would assert or imply such an idea. Our current ideas about the roles of various types of spinal cord, brain stem, and cortical nociceptive neurons (including nociceptiur-specific neurons) in pain mechanisms are quite different than what is implied by Cervero and have been presented in detail (Price 1988). As to the question about nociceptive-specific cells, they are actually represented in all 3 models in Fig. 2 by the small interneurons receiving exclusive input from nociceptive afferents. Nociceptive-specific stalked cells in layer II that relay input to sensory transmission neurons serve as one example (Price et al. 1979). As for our WDR neurons projecting downward, that is appropriate considering that our rats face us directly (while we are standing) during most of our experiments!
References Bennett. G.J. and Xie, Y.-X., A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, Pain, 33 (1988) 87-107. Guilbaud, G., Benoist, J.M., Jazat, F. and Gautron, M. Neuronal responsiveness in the ventrobasal thalamic complex of rats with an experimental peripheral mononeuropathy, J. Neurophysiol., 64 (1990) 1537-1554. Mao, J., Price, D.D., Coghill, R.C., Mayer, D.J. and Hayes, R.L., Spatial patterns of spinal cord metabolic activity in a rat model of painful peripheral mononeuropathy, Pain, 50 (1992) 89-100.
Mao, J., Price, D.O., Hayes, R.L. and Mayer, D.J., MK 801, an NMDA antagonist and periperal nerve block synergistically reduce painful symptoms in a rat model of mononeuropathy, Brain Res., 576 (1992b) 254-262. Mao, J., Price, D.D., Hayes, R.L., Lu, J. and Mayer, D.J., Intrathecal GM1 ganglioside and local nerve anesthesia reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy, Brain Res., 584 (1992) 28-35. Palecek, J., Paleckova, V., Dougherty, P.M., Carlton, SM. and Willis, W.D., Responses of spinothalamic tract cells to mechanical and thermal stimulation of skin in rats with experimental peripheral neuropathy, J. Neurophysiol., 67 (1992) 1562-1573. Price, D.D., Psychological and Neural Mechanisms of Pain, Raven Press, New York 1988. Price, D.D., Hayashi, H., Dubner, R. and Ruda, M.A., Functional relationships between neurons of laminae I, II and III of the primate dorsal horn, J. Neurophysiol., 42 (1979) 1590-1608. Price, D.D., Long, S. and Huitt, C., Sensory testing of pathophysiological mechanisms of pain in patients with reflex sympathetic dystrophy, Pain, 49 (1992) 163-173. Yamamoto, T. and Yaksh, T.L., Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve: Excitatory amino acid antagonists, Pain, 49 (1992) 121-128.
Donald D. Price Pain
Management
Medical
College
Richmond,
Center
of Virginia
VA 23298,
USA
PAIN 02189
Comments on PAIN, 49 (1992) 293-300 We read with interest the article by Dr. S.L. Du Pen et al. entitled “Chronic epidural bupivacaine - opioid infusion in intractable cancer pain”. His results confirm our own positive experience with compounding morphine and bupivacaine for epidural treatment cancer pain. Like other pain centers we initially treated patients with intermittent epidural morphine. Although in many patients pain relief was better than with oral morphine, patients with intermittent nociceptive pain and neuropathic pain often failed to respond adequately to this treatment (Portenoy et al. 1990; Arner and Meyerson 1991; Samuelsson and Hedner 1991). Combining morphine with bupivaCaine did not become feasible until infusion devices became available on a large scale, since intermittent administration of bupivacaine often results in motor paralysis and hemodynamic instability (Hogan et al. 1991). Encouraged by good results achieved in the field of postoperative pain, we started compounding morphine and bupivacaine in 1989, initially doing so only after epidural morphine alone had failed. We quickly, however, adopted a policy of combining the 2 drugs in all patients from the outset of epidural treatment and have treated over 150 patients in thi! way. There is evidence that the 2 drugs potentiate one another (Akerman et al. 1988) and that the development of tolerance for morphine is delayed by combining the 2 drugs. Moreover, we feel that the quality of analgesia can be improved in all patients because of the morphine-sparing effect of bupivacaine. In this way morphine side effects can be avoided. Our drug regimen differs somewhat from that described by Du Pen et al. who use low concentrations of bupivacaine at flow rates of 5 ml/h. Although we too initially start at low concentrations of
References Leblanc, R., Gauthier. S., Gamin, M., Quirion, R.. Palmour, R. and Masson, H., Neurobehavioral effects on intrathecal somatostatinergic treatment in subhuman primates, Neurology, 38 (1988) 1887-1890. Penn. R.D., Paice, J.A. and Kroin, J.S., Octreotide: a potent new non-opiate analgesic for intrathecal infusion. Pain. 49 (1992) 13-19.
Richard D. Penn Judith A. Paice Jeffrey S. Kroin
This model, and many other current models of pain perception based on the ‘sensitization of the WDRs’, leave the brain stem, the thalamus, the limbic system, the cortex and all the other bits and pieces of the brain with very little to do. There is no room left for the higher centres (or lower centres in Price et al.‘s diagrams) in the processing of pain signals. That some people, including virtually all politicians, do not need a brain to go about their business is sadly evident. but isn’s it too much to expect that all pain is in the spinal cord’? We need to include supraspinal structures in our models of pain processing and we should stop peddling these ultra-specificity no tions by which if a spike occurs in a spinal cord cell (preferably a WDR) the perception of pain inevitably ensues. Max von Frey himself would have been very proud of these models. There must be a half way between Descartes’ well known representation of the spinal cord as just a transmission nerve and this exclusive role in pain perception given nowadays to spinal mechanisms. Incidentally. whatever happened to nociceptor-specific cells’? They do not even feature in Price et al.‘s model. But this, as they say, is another story.
References
PAIN 02180
Price, D.D.. Long, S. and Huitt. C., Sensory testing of pathophyxiological mechanisms of pain in patients with reflex sympathetic dystrophy, Pain, 49 (1992) 163-173.
Fernando
Cervero
Not all pain is in the spinal cord I am used to getting a certain amount of stick from the gurus of pain research for my having dared to suggest that the processing of nociceptive signals retains some specificity in its central organisation. So. imagine my surprise when I read the recent paper by Price et al. (1992) proposing an ultra-specificity model for the central processing of pain. Since none of the aforementioned gurus even raised an eyebrow at such temerity, here is this letter to redress the balance. The paper in question is a psychophysical study of pain sensation in patients suffering from reflex sympathetic dystrophy (RSD). I have no qualms about the study itself, barring a minor quibble about the use of the term ‘high threshold allodynia’. As allodynia is meant to imply that innocuous stimuli evoke pain; ‘high-threshold allodynia’ is at best ambiguous. But this is not the reason for my writing this letter so let’s get on with the real business. The problem is the model, or series of models, that Price et al. propose as possible mechanisms for the pain sensations observed in their patients. These models are all centred around a class of spinal cord neurone known as wide-dynamic-range cell (WDR) which, in the opinion of the authors, becomes a pain-cell extraordinaire. According to the model, if the peripheral input to WDR cells is dominated by nociceptor activity, as they suggest happens under normal circumstances, then you will feel normal pain. However, if the WDRs are activated by low-threshold mechanoreceptors, as they propose may happen in some cases of RSD, then you get lowthreshold allodynia. Furthermore, if the almighty WDRs are driven by enhanced activity in nociceptors then you will get high-threshold allodynia. The only role left to the rest of the CNS in this model is to follow blindly what these pain cells in the spinal cord dictate. The pain signal is processed and packaged by the WDRs and is then projected along a labelled line to the brain where all that is needed, I assume. is some kind of spike-perception convertor. Enigmatically, the WDR cells in Price et al.‘s diagrams project downwards (!) towards the brain.
PAIN 02181
Reply to F. Cervero Dr. Cervero has probably misunderstood and misrepresented the purpose of our explanatory models in our recent paper (Price et al., 1992, Fig. 2, page 171). The purpose of these models was simply to provide a general explanation of bofh peripheral and some central pathophysiological mechanisms that are likely to underlie some of the symptoms of reflex sympathetic dystrophy (RSD) and neuropathic pain encountered in our studies. The models focus on primary afferents and the spinal cord because the vast majority of current knowledge of pathophysiological mechanisms of neuropathic pain includes these two levels. One only has to peruse all of the issues of PAIN and other leading neuroscience journal issues published since 1988 (when the Bennett and Xie model was published) to see much of the evidence for this. That the spinal cord dorsal horn in general and wide-dynamicrange (WDR) sensory transmission neurons in particular have crucial roles in these pathophysiological mechanisms is supported by considerable evidence. To take just one of several examples from the literature, a recent paper by Palecek et al. (1992) shows that WDR neurons increase their spontaneous activity and become hyper-responsive to innocuous brushing after an experimental neuropathy is produced in the rat, a result consistent with A-beta allodynia in some patients. This is precisely the kind of result that would be expected. based on our model (no. II) in Fig. 2. Interestingly, nociceptivespecific and low-threshold neurons did not become nearly as pathologically altered as did the WDR neurons. Consistent with this
electrophysiological study, metabolic mapping of elevated neural activity in Bennett and Xie’s (1988) model shows that the largest increase in activity occurs in laminae V-VI, a region of highest concentration of WDR neurons (Mao et al. 1992a). That these abnormal spinal mechanisms are critical for the expression of abnormal pain-related behaviors is also supported by considerable evidence, for example the observations that pain-related symptoms can be almost completely reversed by intrathecal administration of small doses of NMDA antagonists and gangliosides (Mao et al. 1992b,c; Yamamoto and Yaksh 1992). Does all of this mean that “The only role left to the rest of the CNS in this model is to follow blindly what these pain-cells in the spinal cord dictate”? That is certainly not a position that we take or would attempt to defend. However, until we understand much of the neural transformations that take place between primary afferents and the next order of neurons in the spinal grey matter under both normal and pathophysiological circumstances, we cannot adequately evaluate pathophysiological mechanisms that are intrinsic to higher centers. It is entirely possible that the abnormal neural activities and responses that have already been recorded at higher levels (Guilbaud et al. 1990) are to a major extent passive reflections of abnormal responses that occur at spinal levels. But even if this is not the case, we still need to understand much of the primary afferent and spinal cord pathophysiology before we can begin to make comprehensible interpretations of the roles of specific brain structures in pathophysiological pain. This is no doubt a major reason why so many spinal cord papers have been published on Bennett and Xie’s model. Thus, the reason that specific brain structures are missing from our models is that we refuse to provide explanations for which there are no data. Moreover, filling these voids of ignorance with hypothetical constructs, such as ‘pattern generating mechanism’ and ‘central intensity monitor’ is not an exercise that we find compelling. However, the most disturbing aspect of Cervero’s comments is his misrepresentation of the authors’ current views on both normal and pathophysiological pain mechanisms. We have neuer stated or implied in any of our publications or diagrams that ‘if a spike occurs in a spinal cord cell (preferably a WDR) the perception of pain inevitably ensues’. For that matter, we know of no one who would assert or imply such an idea. Our current ideas about the roles of various types of spinal cord, brain stem, and cortical nociceptive neurons (including nociceptiur-specific neurons) in pain mechanisms are quite different than what is implied by Cervero and have been presented in detail (Price 1988). As to the question about nociceptive-specific cells, they are actually represented in all 3 models in Fig. 2 by the small interneurons receiving exclusive input from nociceptive afferents. Nociceptive-specific stalked cells in layer II that relay input to sensory transmission neurons serve as one example (Price et al. 1979). As for our WDR neurons projecting downward, that is appropriate considering that our rats face us directly (while we are standing) during most of our experiments!
References Bennett. G.J. and Xie, Y.-X., A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, Pain, 33 (1988) 87-107. Guilbaud, G., Benoist, J.M., Jazat, F. and Gautron, M. Neuronal responsiveness in the ventrobasal thalamic complex of rats with an experimental peripheral mononeuropathy, J. Neurophysiol., 64 (1990) 1537-1554. Mao, J., Price, D.D., Coghill, R.C., Mayer, D.J. and Hayes, R.L., Spatial patterns of spinal cord metabolic activity in a rat model of painful peripheral mononeuropathy, Pain, 50 (1992) 89-100.
Mao, J., Price, D.O., Hayes, R.L. and Mayer, D.J., MK 801, an NMDA antagonist and periperal nerve block synergistically reduce painful symptoms in a rat model of mononeuropathy, Brain Res., 576 (1992b) 254-262. Mao, J., Price, D.D., Hayes, R.L., Lu, J. and Mayer, D.J., Intrathecal GM1 ganglioside and local nerve anesthesia reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy, Brain Res., 584 (1992) 28-35. Palecek, J., Paleckova, V., Dougherty, P.M., Carlton, SM. and Willis, W.D., Responses of spinothalamic tract cells to mechanical and thermal stimulation of skin in rats with experimental peripheral neuropathy, J. Neurophysiol., 67 (1992) 1562-1573. Price, D.D., Psychological and Neural Mechanisms of Pain, Raven Press, New York 1988. Price, D.D., Hayashi, H., Dubner, R. and Ruda, M.A., Functional relationships between neurons of laminae I, II and III of the primate dorsal horn, J. Neurophysiol., 42 (1979) 1590-1608. Price, D.D., Long, S. and Huitt, C., Sensory testing of pathophysiological mechanisms of pain in patients with reflex sympathetic dystrophy, Pain, 49 (1992) 163-173. Yamamoto, T. and Yaksh, T.L., Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve: Excitatory amino acid antagonists, Pain, 49 (1992) 121-128.
Donald D. Price Pain
Management
Medical
College
Richmond,
Center
of Virginia
VA 23298,
USA
PAIN 02189
Comments on PAIN, 49 (1992) 293-300 We read with interest the article by Dr. S.L. Du Pen et al. entitled “Chronic epidural bupivacaine - opioid infusion in intractable cancer pain”. His results confirm our own positive experience with compounding morphine and bupivacaine for epidural treatment cancer pain. Like other pain centers we initially treated patients with intermittent epidural morphine. Although in many patients pain relief was better than with oral morphine, patients with intermittent nociceptive pain and neuropathic pain often failed to respond adequately to this treatment (Portenoy et al. 1990; Arner and Meyerson 1991; Samuelsson and Hedner 1991). Combining morphine with bupivaCaine did not become feasible until infusion devices became available on a large scale, since intermittent administration of bupivacaine often results in motor paralysis and hemodynamic instability (Hogan et al. 1991). Encouraged by good results achieved in the field of postoperative pain, we started compounding morphine and bupivacaine in 1989, initially doing so only after epidural morphine alone had failed. We quickly, however, adopted a policy of combining the 2 drugs in all patients from the outset of epidural treatment and have treated over 150 patients in thi! way. There is evidence that the 2 drugs potentiate one another (Akerman et al. 1988) and that the development of tolerance for morphine is delayed by combining the 2 drugs. Moreover, we feel that the quality of analgesia can be improved in all patients because of the morphine-sparing effect of bupivacaine. In this way morphine side effects can be avoided. Our drug regimen differs somewhat from that described by Du Pen et al. who use low concentrations of bupivacaine at flow rates of 5 ml/h. Although we too initially start at low concentrations of