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Endpoints in animal pain models

  • Andrew S.C. Rice
Published/Copyright: July 1, 2012
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Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 3 Issue 3

The acknowledged limited utility of animal models for the identification of disease mechanisms and drug targets, and in the pre-clinical prediction of clinical efficacy of new drugs is a current topic of discussion across most therapeutic areas, including pain. There are multiple reasons for this generic translational failure, but amongst the more feasible solutions are:

  • Improved replication of the lesion/disease underlying pain in animalmodels; in particular better matching with the conditions in which clinical trials are conducted

  • Development of a more clinically relevant portfolio of painrelated outcome measures, which better reflects the range of efficacy measures employed in clinical trials

  • Adoption of similar standards to clinical research for experimental bias reduction and transparency in reporting of experimental methods

The latter two aspects will be discussed in the lecture: Firstly, I will describe our work in developing pain-related behavioral outcomemeasures which are ethologically relevant to the rat:Wehave adapted from the fear/anxiety field pharmacologically sensitive outcomemeasures which reflect predator avoidance behaviors (e.g. avoidance of exposed areas in the open field paradigm). We have also validated an assay of burrowing behavior, which is known to be sensitive to rodent disease. These behaviors have been validated in a number of models of traumatic and non-traumatic neuropathic pain and also, as yet to a lesser extent, in inflammatory pain. They have been shown to be appropriately responsive to clinically effective drugs.

Secondly, it is clear that the clinical research standards for experimental bias reduction and transparent methodology reporting are not generally evident in pre-clinical research across most therapeutic areas, including pain. There is evidence that when bias reducing methods are not used, or at least not reported, in pre-clinical studies there is an overestimation of the efficacy of novel drugs. The considerable advances which have been made in this regard in the stroke field will be reviewed and the case for adopting their “Good Laboratory Practice” standards for mitigation of experimental bias in animal studies of pain will be argued. Furthermore, adoption of the recently published, CONSORT-equivalent, ARRIVE reporting format for animal studies will increase not only the readers ability to ascertain the methodological quality of studies, but also empower systematic reviews of the pre-clinical literature.

  1. Funding: Wellcome Trust (London Pain Consortium), Innovative Medicines Initiative – EUROPAIN (European Commission and selected EFPIA members) and Derek Butler Trust.

Recommended reading

[1] Rice ASC. Predicting analgesic efficacy from animal models of peripheral neuropathy and nerve injury: a critical view from the clinic. In: Mogil JS, editor. Pain 2010—an updated review: refresher course syllabus. Seattle: IASP Press; 2010. p. 415–426.Search in Google Scholar

[2] Andrews N, et al. Spontaneous burrowing behaviour in the rat is reduced by peripheral nerve injury or inflammation associated pain. European Journal of Pain 2012;16:485–95.Search in Google Scholar

[3] Hasnie FS, et al. Further characterization of a rat model of varicella zoster virus-associated pain: relationship between mechanical hypersensitivity and anxiety-related behavior, and the influence of analgesic drugs. Neuroscience 2007;144(4):1495–508.Search in Google Scholar

[4] Wallace VCJ, et al. Anxiety-like behaviour is attenuated by gabapentin, morphine and diazepam in a rodent model of HIV anti-retroviral-associated neuropathic pain. Neuroscience Letters 2008;448(1):153–6.Search in Google Scholar

[5] Wallace VCJ, et al. Characterisation of rodent models of HIV-gp120 and antiretroviral associated neuropathic pain. Brain 2007;130(10):2688–702.Search in Google Scholar

[6] Wallace VCJ, et al. Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy. Pain 2007;133(1–3):47–63.Search in Google Scholar

[7] Sena ES, et al. How can we improve the pre-clinical development of drugs for stroke? Trends in Neurosciences 2007;30(9):433–9.Search in Google Scholar

[8] Sena ES, et al. Publication bias in reports of animal stroke studies leads to major overstatement of efficacy. PLoS Biology 2010;8(3):e1000344.Search in Google Scholar

[9] Rice ASC, et al. Animal models and the prediction of efficacy in clinical trials of analgesic drugs: a critical appraisal and call for uniform reporting standards. Pain 2008;139(2):243–7.Search in Google Scholar

[10] Macleod MM, et al. Good laboratory practice. Preventing introduction of bias at the bench. Stroke 2009;40(3):e50–2.Search in Google Scholar

[11] Kilkenny C, et al. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biology 2010;8(6):e1000412.Search in Google Scholar
Published Online: 2012-07-01
Published in Print: 2012-07-01

© 2012 Scandinavian Association for the Study of Pain

Articles in the same Issue

  1. Editorial comment
  2. Spontaneous pain is reduced by conditioning pain modulation in peripheral neuropathy but not in fibromyalgia—Implications for different pain mechanisms
  3. Clinical pain research
  4. Differential pain modulation in patients with peripheral neuropathic pain and fibromyalgia
  5. Editorial comment
  6. Pulsed radiofrequency—Time for a clinical pause and more science
  7. Clinical pain research
  8. Pulsed radiofrequency in peripheral posttraumatic neuropathic pain: A double blind sham controlled randomized clinical trial
  9. Editorial comment
  10. Phantom pains and sensations – how does it feel? Only the patient really knows
  11. Clinical pain research
  12. Phantom phenomena – Their perceived qualities and consequences from the patient’s perspective
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  14. Impact of mental stressor on conditioned pain modulation
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  16. The effect of a mental stressor on conditioned pain modulation in healthy subjects
  17. Editorial comment
  18. Pharmacological modulation of chronic pain after whiplash injury
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  20. Whiplash Associated Disorders (WAD): Responses to pharmacological challenges and psychometric tests
  21. Editorial comment
  22. Why are autonomic responses to pressure pain different from those to heat pain and ischaemic pain?
  23. Original experimental
  24. Cardiovascular responses to and modulation of pressure pain sensitivity in normotensive, pain-free women
  25. Correspondence
  26. Piriformis muscle injection guided by sciatic nerve stimulation: Quick, simple, and safe technique
  27. Correspondence
  28. Musculus piriformis syndrome: Localization and injection therapy—Comment to letter from Mayo-Moldes M et al. [1]
  29. Abstracts
  30. The “pain matrix” reloaded
  31. Abstracts
  32. Endpoints in animal pain models
  33. Abstracts
  34. Evaluating pain-related behavior in spinal cord injury
  35. Abstracts
  36. The role of the amygdala in sensory and emotional-like pain behavior in neuropathic animals
  37. Abstracts
  38. Peripheral and central pain mechanisms—From animal models to clinical research
  39. Abstracts
  40. Human experimental models of central sensitization—Do they bridge the gap between animal models and clinical observations?
  41. Abstracts
  42. Assessment of central sensitization in the clinic. Is it possible?
  43. Abstracts
  44. Migraine neurobiology and treatment
  45. Abstracts
  46. Chronic headaches–Goals and obstacles
  47. Abstracts
  48. Trigeminal neuralgia and other cranial neuralgias
  49. Abstracts
  50. Temporomandibular disorders: Pathophysiology and diagnosis
  51. Abstracts
  52. HIV-associated painful polyneuropathy
  53. Abstracts
  54. Keynote: Neuronal and glial signalling in pain neuroplasticity
  55. Abstracts
  56. Neuropathic pain—From guidelines to clinical practice
  57. Abstracts
  58. Postoperative pain treatment. What’s the evidence—And how to use it?
  59. Abstracts
  60. NSAIDs in postoperative pain
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  62. How should we prevent persistent postoperative pain?
  63. Abstracts
  64. Opioids: Genetics and receptors
  65. Abstracts
  66. Chronic pain and sleep disorders
  67. Abstracts
  68. Population-based studies on chronic pain: The role of opioids
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  70. Living beyond pain: Acceptance and commitment therapy
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  72. Modality specific alterations of esophageal sensitivity caused by longstanding diabetes mellitus
  73. Abstracts
  74. Validation of a porcine behavioural model of UVB induced inflammatory pain
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  78. Pain sensitivity changes in chronic pain patients with and without spinal cord stimulation assessed by nociceptive withdrawal reflex thresholds and electrical pain thresholds
  79. Abstracts
  80. Acceptance and commitment therapy for fibromyalgia: A randomized controlled trial
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  82. Sortilins in neuropathic pain
  83. Abstracts
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  86. Pain prevalence in a university hospital in Iceland
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  88. The effect of tail-docking neonate piglets on ATF-3 and NR2B immunoreactivity in coccygeal dorsal root ganglia and spinal cord dorsal horn neurons: Preliminary data
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  90. Na+/K+-ATPase dependent regulation of astrocyte Ca2+ signalling: A novel mechanism for modulation of long-term pain?
  91. Abstracts
  92. Glutamate attenuates nitric oxide release from isolated trigeminal ganglion satellite glial cells
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  94. Acute behavioural responses to tail docking in piglets – Effects of increasing docking length?
  95. Abstracts
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  100. Time-course of analgesic effects of botulinum neurotoxin type A (BoNTA) on human experimental model of pain induced by injection of glutamate into temporalis muscle
  101. Abstracts
  102. The effect of nerve compression and capsaicin on contact heat evoked potentials (CHEPs) related to Aδ and C fibers
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  104. Effect of specific trapezius exercises vs. coordination training on corticomotor control of neck muscles
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  110. The variability in thermal threshold-assessments in post-thoracotomy pain syndrome
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  114. Neuroplastic alterations in brain responses to painful visceral stimulations reflects individual neuropathic symptoms in diabetes mellitus patients
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  116. Exercise and conditioned pain modulation have different effects on cuff pressure pain tolerance in humans
  117. Abstracts
  118. Hyperalgesia in human skin and deep-tissues inside and outside of a UVB irradiated area
  119. Abstracts
  120. Effect of experimental jaw muscle pain on bite force during mastication
  121. Abstracts
  122. Reflex threshold assessment methodology for evaluation of central sensitisation is vulnerable to EMG crosstalk
  123. Abstracts
  124. Cognitive modulation of experimental pain at spinal and cortical levels
  125. Abstracts
  126. Influence of emotionally loaded visual and gustatory stimuli on pain perception
  127. Abstracts
  128. Modulating pain with augmented reality
  129. Abstracts
  130. Offset analgesia: A reproducibility study
  131. Abstracts
  132. Visualization of painful process in peripheral tissue using positron emission tomography and [11C]-D-deprenyl
  133. Abstracts
  134. Mirror-image sensory dysfunction in the post-thoracotomy pain syndrome
  135. Abstracts
  136. Genetic variation in opioid receptor genes and sensitivity to experimental pain in male and female healthy volunteers
  137. Abstracts
  138. Mechanical sensitivity in migraine patients during attack, remission, and pain-free periods:A preliminary study
  139. Abstracts
  140. Multivariate pattern analysis of evoked brain potentials by temporal matching pursuit and support vector machine
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  142. Pain following stroke: A prospective study
  143. Abstracts
  144. Chronic thoracic pain in children after cardiac surgery
  145. Abstracts
  146. Chronic pain after breast augmentation is associated with both signs of peripheral nerve injury and central nervous mechanisms
  147. Abstracts
  148. Sensory phenotypes in patients with peripheral neuropathic pain evaluated with quantitative sensory testing
  149. Abstracts
  150. Is health related quality of life related to the pattern of chronic pain?
  151. Abstracts
  152. Comparison between ropivacaine local infiltration analgesia with ketorolac or placebo for total knee replacement surgery
  153. Abstracts
  154. Treatment with topical capsaicin: Experience from a pain clinic
  155. Abstracts
  156. Distribution of concussion related symptoms after whiplash injury in risk strata
  157. Abstracts
  158. HIV/AIDS in different cultures
  159. Abstracts
  160. Pain perception is altered in patients with medication-overuse headache but can improve after detoxification
  161. Abstracts
  162. Detoxification in a structured programme is effective for medication-overuse headache
https://doi.org/10.1016/j.sjpain.2012.05.003

Articles in the same Issue

  1. Editorial comment
  2. Spontaneous pain is reduced by conditioning pain modulation in peripheral neuropathy but not in fibromyalgia—Implications for different pain mechanisms
  3. Clinical pain research
  4. Differential pain modulation in patients with peripheral neuropathic pain and fibromyalgia
  5. Editorial comment
  6. Pulsed radiofrequency—Time for a clinical pause and more science
  7. Clinical pain research
  8. Pulsed radiofrequency in peripheral posttraumatic neuropathic pain: A double blind sham controlled randomized clinical trial
  9. Editorial comment
  10. Phantom pains and sensations – how does it feel? Only the patient really knows
  11. Clinical pain research
  12. Phantom phenomena – Their perceived qualities and consequences from the patient’s perspective
  13. Editorial comment
  14. Impact of mental stressor on conditioned pain modulation
  15. Original experimental
  16. The effect of a mental stressor on conditioned pain modulation in healthy subjects
  17. Editorial comment
  18. Pharmacological modulation of chronic pain after whiplash injury
  19. Clinical pain research
  20. Whiplash Associated Disorders (WAD): Responses to pharmacological challenges and psychometric tests
  21. Editorial comment
  22. Why are autonomic responses to pressure pain different from those to heat pain and ischaemic pain?
  23. Original experimental
  24. Cardiovascular responses to and modulation of pressure pain sensitivity in normotensive, pain-free women
  25. Correspondence
  26. Piriformis muscle injection guided by sciatic nerve stimulation: Quick, simple, and safe technique
  27. Correspondence
  28. Musculus piriformis syndrome: Localization and injection therapy—Comment to letter from Mayo-Moldes M et al. [1]
  29. Abstracts
  30. The “pain matrix” reloaded
  31. Abstracts
  32. Endpoints in animal pain models
  33. Abstracts
  34. Evaluating pain-related behavior in spinal cord injury
  35. Abstracts
  36. The role of the amygdala in sensory and emotional-like pain behavior in neuropathic animals
  37. Abstracts
  38. Peripheral and central pain mechanisms—From animal models to clinical research
  39. Abstracts
  40. Human experimental models of central sensitization—Do they bridge the gap between animal models and clinical observations?
  41. Abstracts
  42. Assessment of central sensitization in the clinic. Is it possible?
  43. Abstracts
  44. Migraine neurobiology and treatment
  45. Abstracts
  46. Chronic headaches–Goals and obstacles
  47. Abstracts
  48. Trigeminal neuralgia and other cranial neuralgias
  49. Abstracts
  50. Temporomandibular disorders: Pathophysiology and diagnosis
  51. Abstracts
  52. HIV-associated painful polyneuropathy
  53. Abstracts
  54. Keynote: Neuronal and glial signalling in pain neuroplasticity
  55. Abstracts
  56. Neuropathic pain—From guidelines to clinical practice
  57. Abstracts
  58. Postoperative pain treatment. What’s the evidence—And how to use it?
  59. Abstracts
  60. NSAIDs in postoperative pain
  61. Abstracts
  62. How should we prevent persistent postoperative pain?
  63. Abstracts
  64. Opioids: Genetics and receptors
  65. Abstracts
  66. Chronic pain and sleep disorders
  67. Abstracts
  68. Population-based studies on chronic pain: The role of opioids
  69. Abstracts
  70. Living beyond pain: Acceptance and commitment therapy
  71. Abstracts
  72. Modality specific alterations of esophageal sensitivity caused by longstanding diabetes mellitus
  73. Abstracts
  74. Validation of a porcine behavioural model of UVB induced inflammatory pain
  75. Abstracts
  76. Recovery after a lumbar disc herniation is dependent on a gender and OPRM1 Asn40Asp genotype interaction
  77. Abstracts
  78. Pain sensitivity changes in chronic pain patients with and without spinal cord stimulation assessed by nociceptive withdrawal reflex thresholds and electrical pain thresholds
  79. Abstracts
  80. Acceptance and commitment therapy for fibromyalgia: A randomized controlled trial
  81. Abstracts
  82. Sortilins in neuropathic pain
  83. Abstracts
  84. Systematic review of neuropathic component in persistent post-surgical pain
  85. Abstracts
  86. Pain prevalence in a university hospital in Iceland
  87. Abstracts
  88. The effect of tail-docking neonate piglets on ATF-3 and NR2B immunoreactivity in coccygeal dorsal root ganglia and spinal cord dorsal horn neurons: Preliminary data
  89. Abstracts
  90. Na+/K+-ATPase dependent regulation of astrocyte Ca2+ signalling: A novel mechanism for modulation of long-term pain?
  91. Abstracts
  92. Glutamate attenuates nitric oxide release from isolated trigeminal ganglion satellite glial cells
  93. Abstracts
  94. Acute behavioural responses to tail docking in piglets – Effects of increasing docking length?
  95. Abstracts
  96. Dose and administration-period play a key role in the effect of ceftriaxone on neuropathic pain in CCI-operated rats
  97. Abstracts
  98. Translational aspects of rectal evoked potentials: A comparative study in rats and humans
  99. Abstracts
  100. Time-course of analgesic effects of botulinum neurotoxin type A (BoNTA) on human experimental model of pain induced by injection of glutamate into temporalis muscle
  101. Abstracts
  102. The effect of nerve compression and capsaicin on contact heat evoked potentials (CHEPs) related to Aδ and C fibers
  103. Abstracts
  104. Effect of specific trapezius exercises vs. coordination training on corticomotor control of neck muscles
  105. Abstracts
  106. SNP in TNFα T308G is predictive for persistent postoperative pain following inguinal hernia surgery
  107. Abstracts
  108. Chronic pain in thoracotomy
  109. Abstracts
  110. The variability in thermal threshold-assessments in post-thoracotomy pain syndrome
  111. Abstracts
  112. Persistent pain, sensory disturbances and functional impairment after adjuvant chemotherapy for breast cancer
  113. Abstracts
  114. Neuroplastic alterations in brain responses to painful visceral stimulations reflects individual neuropathic symptoms in diabetes mellitus patients
  115. Abstracts
  116. Exercise and conditioned pain modulation have different effects on cuff pressure pain tolerance in humans
  117. Abstracts
  118. Hyperalgesia in human skin and deep-tissues inside and outside of a UVB irradiated area
  119. Abstracts
  120. Effect of experimental jaw muscle pain on bite force during mastication
  121. Abstracts
  122. Reflex threshold assessment methodology for evaluation of central sensitisation is vulnerable to EMG crosstalk
  123. Abstracts
  124. Cognitive modulation of experimental pain at spinal and cortical levels
  125. Abstracts
  126. Influence of emotionally loaded visual and gustatory stimuli on pain perception
  127. Abstracts
  128. Modulating pain with augmented reality
  129. Abstracts
  130. Offset analgesia: A reproducibility study
  131. Abstracts
  132. Visualization of painful process in peripheral tissue using positron emission tomography and [11C]-D-deprenyl
  133. Abstracts
  134. Mirror-image sensory dysfunction in the post-thoracotomy pain syndrome
  135. Abstracts
  136. Genetic variation in opioid receptor genes and sensitivity to experimental pain in male and female healthy volunteers
  137. Abstracts
  138. Mechanical sensitivity in migraine patients during attack, remission, and pain-free periods:A preliminary study
  139. Abstracts
  140. Multivariate pattern analysis of evoked brain potentials by temporal matching pursuit and support vector machine
  141. Abstracts
  142. Pain following stroke: A prospective study
  143. Abstracts
  144. Chronic thoracic pain in children after cardiac surgery
  145. Abstracts
  146. Chronic pain after breast augmentation is associated with both signs of peripheral nerve injury and central nervous mechanisms
  147. Abstracts
  148. Sensory phenotypes in patients with peripheral neuropathic pain evaluated with quantitative sensory testing
  149. Abstracts
  150. Is health related quality of life related to the pattern of chronic pain?
  151. Abstracts
  152. Comparison between ropivacaine local infiltration analgesia with ketorolac or placebo for total knee replacement surgery
  153. Abstracts
  154. Treatment with topical capsaicin: Experience from a pain clinic
  155. Abstracts
  156. Distribution of concussion related symptoms after whiplash injury in risk strata
  157. Abstracts
  158. HIV/AIDS in different cultures
  159. Abstracts
  160. Pain perception is altered in patients with medication-overuse headache but can improve after detoxification
  161. Abstracts
  162. Detoxification in a structured programme is effective for medication-overuse headache
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