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Translational human pain research
European Journal of Pain Supplements 1 (2007) 38–40 www.EuropeanJournalPain.com
Translational human pain research Lars Arendt-Nielsen * Center for Sensory-Motor Interaction, Laboratory for Experimental Pain Research, Aalborg University, Aalborg, Denmark
Abstract Human experimental pain models require standardized stimulation and quantitative assessment of the evoked responses. This approach can be applied to healthy volunteers and pain patients before and after pharmacological interventions. Standardized stimuli of different modalities (mechanical, chemical, thermal, electrical) can be applied to skin, muscles and viscera for a differentiated and comprehensive assessment of various pain pathways and mechanisms. Using such a multi-modal, multi-tissue approach, new and existing analgesic drugs can be profiled. Human experimental pain models can bridge animal and clinical pain research and act as translational research providing new possibilities for designing successful clinical trials. Proof-of-concept studies provide cheap, fast and reliable information about dose-efficacy relationships and how pain from skin, muscles and viscera are inhibited. This is important knowledge to have prior to designing expensive clinical trials. © 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Pain assessment; Pain treatment; Drug screening; Translational research
1. Background It has always been the dream of pain researchers to have an objective measure of pain – this is not possible and will most likely never be possible. Pain is a multidimensional unpleasant sensory and emotional experience and cannot as such be represented or described by a single parameter or number. However, different possibilities in human experimental pain research exist to assess quantitatively various aspects of, and mechanisms involved in, the complex sensory experience of pain. Experimental pain research involves two separate topics: 1. Standardized activation of the nociceptive system 2. Measurements of the evoked responses The ultimate goal of modern pain assessment procedures is to obtain a better understanding of mechanisms involved in pain transduction, transmission, and perception
* Correspondence to: Lars Arendt-Nielsen, Center for Sensory-Motor Interaction, Laboratory for Experimental Pain Research, Aalborg University, Fredrik Bajersvej 7, D3, DK-9000 Aalborg, Denmark. E-mail address: [email protected]
under normal and pathophysiological conditions. Such a mechanism-based approach can provide better characterization, prevention and management of pain.
2. Experimental assessment of pain Experimental approaches can be applied in the laboratory for basic studies (e.g. central hyperexcitability or proof-of concept studies including screening of drug efficacy) but also in the clinic to characterize patients with sensory dysfunctions and/or pain (e.g. neurogenic pain). The primary advantages of experimental approaches to assess pain sensitivity under normal and pathological conditions are: • Experimental stimulus intensity, duration and modality are controlled and not varying over time. • Differentiated responses to different standardized stimulus modalities. • The responses can be assessed quantitatively and compared over time (e.g. profiling new/existing drug efficacy over time)
1754-3207/$32 © 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.
L. Arendt-Nielsen / European Journal of Pain Supplements 1 (2007) 38–40
• Pain sensitivity can be compared quantitatively between various normal/affected/treated regions. • Experimental models of pathological conditions (e.g. hyperalgesia) can be studied and the effects of drugs on such mechanisms quantified. For drug development and screening of new compounds, human experimental pain research can act as a translational bridge between animal and clinical research. Many of the mechanisms tested in animals can also be translated and evaluated in healthy volunteers, and may predict the efficacy of a given drug in specific patient populations. Such proofof-concept studies can speed op development programs within the industry and at the same time provide new fundamental knowledge for the scientists within academia. In recent years experimental pain research has developed significantly, and more advanced techniques have been developed for both induction and assessment of pain. Initially experimental pain research was based on cutaneous electrical stimulation and hence the area was discredited as e.g. morphine did not modulate a given electrical pain threshold. Today we know that the afferent fibers activated by a pinprick like cutaneous stimulus should not be dramatically modulated by morphine as this stimulus intensity activates A-nociceptive and A-tactile afferents. However, using a pain tolerance threshold to cutaneous electrical stimulation is sensitive to morphine as this stimulus intensity activates C-nociceptors (Brennum et al., 1994). The modern concept for experimental pain assessment is a multi-modality, multi-tissue approach where different pain modalities (thermal, mechanical, electrical, chemical) are applied to different tissues (skin, muscles and viscera) and the responses assessed by advanced psychophysical (thresholds, stimulus-response functions), electrophysiological (single nerve fibers, evoked potentials, EEG, nociceptive reflexes) or imaging techniques (fMRI, PET). Assessing pain has become a question of solving a multi-input, multioutput problem which provides the possibility to tease out which pain pathways and mechanisms are impaired or affected by investigational drugs (Arendt-Nielsen, 1997). It was suggested by Woolf et al. [1998] that pain diagnosis and therapy should be mechanism-based, and hence the pain assessment tools should be sufficiently sensitive and advanced to provide such mechanistic information. Translating clinical observations to mechanisms and visa versa is still not trivial but tools to assess quantitatively the different phenomena are mandatory e.g. tactile allodynia, cold hyperalgesia, wind-up like pain and after-sensation, muscle tenderness and referred muscle/visceral pain. In recent years it has become evident that the pain system is not a hardwired static system, but can undergo neuroplastic changes. This plasticity can be assessed in patients with e.g. neuropathy pain (where e.g. touch is experienced as pain). It can also be investigated in healthy volunteers if their central nervous system is changed experimentally.
39
An important area related to the pathophysiological changes in the pain system is experimentally induced hyperalgesia by topical application or intradermal injection of capsaicin (a hot substance in chili pepper). This procedure can be used to evaluate the effect of various drugs on peripheral (primary hyperalgesia) and central (secondary hyperalgesia) mechanisms. In the secondary area, allodynia to tactile stimulation can be generated, which is a manifestation of central neuroplasticity. Drugs inhibiting central summation, hyperalgesia, and allodynia are normally also alleviating neurogenic pain. In many cases a variety of single nociceptive stimuli are not adequate to evaluate the effect of a given drug. Recent studies have shown that central summation (spatial and temporal) plays an important role in nociception and is difficult to block by conventional drugs and procedures. In some studies, temporal summation has shown a significant facilitation in case of central hyperexcitability. Temporal summation is the human parallel to wind-up in animals, and human studies have shown that mainly NMDA-antagonists and tricyclic antidepressants block temporal summation. Human experimental pain research has been developed significantly and can today be applied in the laboratory as well as in the clinic for basic studies, for diagnosis and for assessing the efficacy of new analgesics.
3. Example The multi-modal, multi-tissue pain assessment approach provides the possibility to profile new drugs. A theoretical example (Fig. 1) is where a given drug (e.g. a kappa agonist) is evaluated by cutaneous, muscle and visceral stimulation. It is known that kappa-opioids have better effect on visceral pain as compared to somatic pain [Staahl et al., 2006]. The effect on skin, muscle and visceral pain is evaluated before and after drug evaluation and no, medium or strong analgesic effects can be detected depending on tissue and assessment parameter (mechanism).
Fig. 1. Effect on pain from different structures.
40
L. Arendt-Nielsen / European Journal of Pain Supplements 1 (2007) 38–40
4. Conclusion The concept of multi-modal, multi-tissue pain assessment has been developed to a stage where advanced drug screening in healthy volunteers and patients are possible (Staahl et al., 2006). The tools allow a mechanistic approach where (1) the effect of new investigational drugs can be monitored over time, (2) the efficacy can be benchmarked against other new/existing drugs and (3) the differentiated effect on specific pain mechanisms can be assessed quantitatively. This provides the possibility to profile drugs and translate animal findings into clinic. Such translational aspects can help designing clinical trials by being much better in selecting the right patient population: • Human experimental pain research bridges the gab between basic animal studies and clinical applications (translational approach) and provides the basis for proofof-concept studies of new compounds. • Experimental techniques can be used to study basic mechanisms in healthy volunteers or to characterise sensory dysfunction in patients. The experimental possibilities available for studying cutaneous, muscle and visceral pain are far from equal.
There is a need for more experimental and clinical studies on deep pain to provide new knowledge to this clinically relevant area. • It is recommended to combine various stimulus modalities and assessment techniques to get sufficient advanced and differentiated information about the human nociceptive system under normal and pathophysiological conditions.
References Arendt-Nielsen L. Induction and assessment of experimental pain from human skin, muscle and viscera. In: JensenTS, Turner JA, WiesenfeldHallin Z (eds.). Proceedings of the 8th World Congress on Pain, Vancouver, Canada, August 17–22: Progress in Pain Research and Management. Seattle: IASP Press 1997;8:393–425 Brennum J, Petersen KL, Horn A, Arendt-Nielsen L, Secher NH, Jensen TS. Quantitative sensory examination of epidural anesthesia and analgesia in man: combination of morphine and bupivacaine. Pain 1994;56:327–337. Staahl C, Christrup LL, Andersen SD, Arendt-Nielsen L, Drewes AM. A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model. Pain 2006;123:28–36. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R, Loeser JD, Payne R, Torebjork E. Towards a mechanismbased classification of pain? Pain 1998;77:227–229.
Translational human pain research Lars Arendt-Nielsen * Center for Sensory-Motor Interaction, Laboratory for Experimental Pain Research, Aalborg University, Aalborg, Denmark
Abstract Human experimental pain models require standardized stimulation and quantitative assessment of the evoked responses. This approach can be applied to healthy volunteers and pain patients before and after pharmacological interventions. Standardized stimuli of different modalities (mechanical, chemical, thermal, electrical) can be applied to skin, muscles and viscera for a differentiated and comprehensive assessment of various pain pathways and mechanisms. Using such a multi-modal, multi-tissue approach, new and existing analgesic drugs can be profiled. Human experimental pain models can bridge animal and clinical pain research and act as translational research providing new possibilities for designing successful clinical trials. Proof-of-concept studies provide cheap, fast and reliable information about dose-efficacy relationships and how pain from skin, muscles and viscera are inhibited. This is important knowledge to have prior to designing expensive clinical trials. © 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Pain assessment; Pain treatment; Drug screening; Translational research
1. Background It has always been the dream of pain researchers to have an objective measure of pain – this is not possible and will most likely never be possible. Pain is a multidimensional unpleasant sensory and emotional experience and cannot as such be represented or described by a single parameter or number. However, different possibilities in human experimental pain research exist to assess quantitatively various aspects of, and mechanisms involved in, the complex sensory experience of pain. Experimental pain research involves two separate topics: 1. Standardized activation of the nociceptive system 2. Measurements of the evoked responses The ultimate goal of modern pain assessment procedures is to obtain a better understanding of mechanisms involved in pain transduction, transmission, and perception
* Correspondence to: Lars Arendt-Nielsen, Center for Sensory-Motor Interaction, Laboratory for Experimental Pain Research, Aalborg University, Fredrik Bajersvej 7, D3, DK-9000 Aalborg, Denmark. E-mail address: [email protected]
under normal and pathophysiological conditions. Such a mechanism-based approach can provide better characterization, prevention and management of pain.
2. Experimental assessment of pain Experimental approaches can be applied in the laboratory for basic studies (e.g. central hyperexcitability or proof-of concept studies including screening of drug efficacy) but also in the clinic to characterize patients with sensory dysfunctions and/or pain (e.g. neurogenic pain). The primary advantages of experimental approaches to assess pain sensitivity under normal and pathological conditions are: • Experimental stimulus intensity, duration and modality are controlled and not varying over time. • Differentiated responses to different standardized stimulus modalities. • The responses can be assessed quantitatively and compared over time (e.g. profiling new/existing drug efficacy over time)
1754-3207/$32 © 2007 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.
L. Arendt-Nielsen / European Journal of Pain Supplements 1 (2007) 38–40
• Pain sensitivity can be compared quantitatively between various normal/affected/treated regions. • Experimental models of pathological conditions (e.g. hyperalgesia) can be studied and the effects of drugs on such mechanisms quantified. For drug development and screening of new compounds, human experimental pain research can act as a translational bridge between animal and clinical research. Many of the mechanisms tested in animals can also be translated and evaluated in healthy volunteers, and may predict the efficacy of a given drug in specific patient populations. Such proofof-concept studies can speed op development programs within the industry and at the same time provide new fundamental knowledge for the scientists within academia. In recent years experimental pain research has developed significantly, and more advanced techniques have been developed for both induction and assessment of pain. Initially experimental pain research was based on cutaneous electrical stimulation and hence the area was discredited as e.g. morphine did not modulate a given electrical pain threshold. Today we know that the afferent fibers activated by a pinprick like cutaneous stimulus should not be dramatically modulated by morphine as this stimulus intensity activates A-nociceptive and A-tactile afferents. However, using a pain tolerance threshold to cutaneous electrical stimulation is sensitive to morphine as this stimulus intensity activates C-nociceptors (Brennum et al., 1994). The modern concept for experimental pain assessment is a multi-modality, multi-tissue approach where different pain modalities (thermal, mechanical, electrical, chemical) are applied to different tissues (skin, muscles and viscera) and the responses assessed by advanced psychophysical (thresholds, stimulus-response functions), electrophysiological (single nerve fibers, evoked potentials, EEG, nociceptive reflexes) or imaging techniques (fMRI, PET). Assessing pain has become a question of solving a multi-input, multioutput problem which provides the possibility to tease out which pain pathways and mechanisms are impaired or affected by investigational drugs (Arendt-Nielsen, 1997). It was suggested by Woolf et al. [1998] that pain diagnosis and therapy should be mechanism-based, and hence the pain assessment tools should be sufficiently sensitive and advanced to provide such mechanistic information. Translating clinical observations to mechanisms and visa versa is still not trivial but tools to assess quantitatively the different phenomena are mandatory e.g. tactile allodynia, cold hyperalgesia, wind-up like pain and after-sensation, muscle tenderness and referred muscle/visceral pain. In recent years it has become evident that the pain system is not a hardwired static system, but can undergo neuroplastic changes. This plasticity can be assessed in patients with e.g. neuropathy pain (where e.g. touch is experienced as pain). It can also be investigated in healthy volunteers if their central nervous system is changed experimentally.
39
An important area related to the pathophysiological changes in the pain system is experimentally induced hyperalgesia by topical application or intradermal injection of capsaicin (a hot substance in chili pepper). This procedure can be used to evaluate the effect of various drugs on peripheral (primary hyperalgesia) and central (secondary hyperalgesia) mechanisms. In the secondary area, allodynia to tactile stimulation can be generated, which is a manifestation of central neuroplasticity. Drugs inhibiting central summation, hyperalgesia, and allodynia are normally also alleviating neurogenic pain. In many cases a variety of single nociceptive stimuli are not adequate to evaluate the effect of a given drug. Recent studies have shown that central summation (spatial and temporal) plays an important role in nociception and is difficult to block by conventional drugs and procedures. In some studies, temporal summation has shown a significant facilitation in case of central hyperexcitability. Temporal summation is the human parallel to wind-up in animals, and human studies have shown that mainly NMDA-antagonists and tricyclic antidepressants block temporal summation. Human experimental pain research has been developed significantly and can today be applied in the laboratory as well as in the clinic for basic studies, for diagnosis and for assessing the efficacy of new analgesics.
3. Example The multi-modal, multi-tissue pain assessment approach provides the possibility to profile new drugs. A theoretical example (Fig. 1) is where a given drug (e.g. a kappa agonist) is evaluated by cutaneous, muscle and visceral stimulation. It is known that kappa-opioids have better effect on visceral pain as compared to somatic pain [Staahl et al., 2006]. The effect on skin, muscle and visceral pain is evaluated before and after drug evaluation and no, medium or strong analgesic effects can be detected depending on tissue and assessment parameter (mechanism).
Fig. 1. Effect on pain from different structures.
40
L. Arendt-Nielsen / European Journal of Pain Supplements 1 (2007) 38–40
4. Conclusion The concept of multi-modal, multi-tissue pain assessment has been developed to a stage where advanced drug screening in healthy volunteers and patients are possible (Staahl et al., 2006). The tools allow a mechanistic approach where (1) the effect of new investigational drugs can be monitored over time, (2) the efficacy can be benchmarked against other new/existing drugs and (3) the differentiated effect on specific pain mechanisms can be assessed quantitatively. This provides the possibility to profile drugs and translate animal findings into clinic. Such translational aspects can help designing clinical trials by being much better in selecting the right patient population: • Human experimental pain research bridges the gab between basic animal studies and clinical applications (translational approach) and provides the basis for proofof-concept studies of new compounds. • Experimental techniques can be used to study basic mechanisms in healthy volunteers or to characterise sensory dysfunction in patients. The experimental possibilities available for studying cutaneous, muscle and visceral pain are far from equal.
There is a need for more experimental and clinical studies on deep pain to provide new knowledge to this clinically relevant area. • It is recommended to combine various stimulus modalities and assessment techniques to get sufficient advanced and differentiated information about the human nociceptive system under normal and pathophysiological conditions.
References Arendt-Nielsen L. Induction and assessment of experimental pain from human skin, muscle and viscera. In: JensenTS, Turner JA, WiesenfeldHallin Z (eds.). Proceedings of the 8th World Congress on Pain, Vancouver, Canada, August 17–22: Progress in Pain Research and Management. Seattle: IASP Press 1997;8:393–425 Brennum J, Petersen KL, Horn A, Arendt-Nielsen L, Secher NH, Jensen TS. Quantitative sensory examination of epidural anesthesia and analgesia in man: combination of morphine and bupivacaine. Pain 1994;56:327–337. Staahl C, Christrup LL, Andersen SD, Arendt-Nielsen L, Drewes AM. A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model. Pain 2006;123:28–36. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R, Loeser JD, Payne R, Torebjork E. Towards a mechanismbased classification of pain? Pain 1998;77:227–229.