Home Repeated nociceptive stimulation for detecting drug effects
Article Publicly Available

Repeated nociceptive stimulation for detecting drug effects

  • Michele Curatolo
Published/Copyright: July 1, 2010
Download Article (PDF)
Become an author with De Gruyter Brill
Author Information Explore this Subject
Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 1 Issue 3

Early seminal studies have revealed that prolonged nociceptive stimulation induces hyperexcitability and prolonged firing of spinal cord nociceptive neurones, both phenomena persisting after cessation of the peripheral stimulus [1,2]. These observations provoked substantial changes in the understanding of pain pathophysiology. They demonstrated that activity of central pain pathways may persist in the absence of a peripheral nociceptive input, and neural pathways may undergo long-lasting sensitisation. These findings were mirrored by human studies showing that repeated peripheral stimulation at constant intensity evokes an increase in pain sensation during the stimulation train, so that the last stimuli are perceived as painful [3,4]. This phenomenon is known as temporal summation and is believed to reflect aspects of central sensitization induced by the peripheral nociceptive input.

Due to the widely recognised importance of processes of central sensitisation, the temporal summation model soon found application in human pain research. Clinical studies have found that the threshold to evoke temporal summation is lower in chronic pain patients, compared to pain-free subjects. This has been observed in a variety of pain conditions, such as complex regional pain syndrome [5], whiplash [6] and fibromyalgia [7]. The reduced temporal summation threshold suggests that sensitization processes can be induced in patients at low stimulation intensities. This is expected to promote exaggerated pain even when no major tissue damage is present.

The temporal summation model has also been used to assess drug efficacy. The main rationale for this application is the assumption that certain drugs have a particular action on the mechanisms underlying central sensitisation processes, which would make the temporal summation model suitable for detecting such drug effects. The paper by Enggaard et al. [8] in the present issue of this journal used amultimodal pain testing approach to investigate the analgesic effect of gabapentin in healthy volunteers. The investigators found a clear effect of gabapentin on temporal summation, a quantitatively lower influence of the drug on pain after single electrical stimulation, and no significant effect on pain ratings after the cold pressor test. Similar findings were obtained by a previous study, in which gabapentin acted on part of the experimental tests employed, including cutaneous temporal summation [9]. Perhaps the most striking case of selective drug action is ketamine, which affects the pain thresholds after repeated stimulation while being ineffective on pain after single nociceptive stimulation [10].

Despite the interesting perspectives offered by the use of the temporal summation model, limitations apply. Although the method has been shown to be sensitive to different drugs, most of the centrally acting analgesics affect also a variety of different types of experimental stimuli. Interestingly, the previous study by Arendt-Nielsen et al. [9] found an effect of gabapentin on temporal summation only after cutaneous electrical stimulation, whereas the drug was not better than placebo for attenuating temporal summation after intramuscular electrical stimulation. This effect cannot be attributed to lack of efficacy on muscle pain, since in the same study gabapentin significantly reduced pain ratings after intramuscular injection of hypertonic saline. Indeed, two recent reviews on the efficacy of analgesics in experimental pain models revealed a complex and somewhat confusing picture [11,12]. An additional limitation needs to be mentioned: temporal summation is a short-lasting phenomenon that reflects only a minimal part of the complex mechanisms of central neural plasticity. Caution is therefore required when findings obtained with this model are translated to pathophysiological mechanisms of sensitisation. While the temporal summation model is probably an important tool for detecting the efficacy of centrally acting analgesics, there is at present no way of avoiding a multimodal testing approach for pharmacological studies [13].

DOI of refers to article: 10.1016/j.sjpain.2010.04.001.

References

[1] Woolf CJ. Long term alterations in the excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat. Pain 1984;18:325–43.Search in Google Scholar

[2] Dickenson AH, Sullivan AF. Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology 1987;26:1235–8.Search in Google Scholar

[3] Price DD. Characteristics of second pain and flexion reflexes indicative of prolonged central summation. Exp Neurol 1972;37:371–87.Search in Google Scholar

[4] Arendt-Nielsen L, Brennum J, Sindrup S, Bak P. Electrophysiological and psychophysical quantification of central temporal summation of the human nociceptive system. Eur J Appl Physiol 1994;68:266–73.Search in Google Scholar

[5] Price DD, Long S, Huitt C. Sensory testing of pathophysiological mechanisms of pain in patients with reflex sympathetic dystrophy. Pain 1992;49:163–73.Search in Google Scholar

[6] Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Giani C, Zbinden AM, Radanov BP. Central hypersensitivity in chronic pain after whiplash injury. Clin J Pain 2001;17:306–15.Search in Google Scholar

[7] Price D, Staud R, Robinson M, Mauderli A, Cannon R, Vierck C. Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain 2002;99:49–59.Search in Google Scholar

[8] Enggaard TP, Mikkelsen SS, Zwisler ST, Klitgaard NA, Sindrup SH. The effects of gabapentin in human experimental pain models. Scand J Pain 2010;1:143–8.Search in Google Scholar

[9] Arendt-Nielsen L, Frokjaer JB, Staahl C, Graven-Nielsen T, Huggins JP, Smart TS, Drewes A. Effects of gabapentin on experimental somatic pain and temporal summation. Reg Anesth Pain Med 2007;32:382–8.Search in Google Scholar

[10] Arendt-Nielsen L, Petersen-Felix S, Fischer M, Bak P, Bjerring P, Zbinden AM. The effect of N-methyl-D-aspartate antagonist (ketamine) on single and repeated nociceptive stimuli: a placebo-controlled experimental human study. Anesth Analg 1995;81:63–8.Search in Google Scholar

[11] Staahl C, Olesen AE, Andresen T, Arendt-Nielsen L, Drewes AM. Assessing analgesic actions of opioids by experimental pain models in healthy volunteers—an updated review. Br J Clin Pharmacol 2009;68:149–68.Search in Google Scholar

[12] Staahl C, Olesen AE, Andresen T, Arendt-Nielsen L, Drewes AM. Assessing efficacy of nonopioid analgesics in experimental pain models in healthy volunteers: an updated review. Br J Clin Pharmacol 2009;68:322–41.Search in Google Scholar

[13] Arendt-Nielsen L, Curatolo M, Drewes A. Human experimental pain models in drug development: translational pain research. Curr Opin Investig Drugs 2007;8:41–53.Search in Google Scholar
Published Online: 2010-07-01
Published in Print: 2010-07-01

© 2010 Scandinavian Association for the Study of Pain

Articles in the same Issue

  1. Editorial comment
  2. Functional brain imaging of acute postoperative pain
  3. Clinical pain research
  4. Brain activation due to postoperative pain from the right hand measured with regional cerebral blood flow using positron emission tomography
  5. Editorial comment
  6. Long-term low-dose transdermal buprenorphine therapy for chronic noncancer pain
  7. Original experimental
  8. A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent opioids
  9. Editorial comment
  10. Repeated nociceptive stimulation for detecting drug effects
  11. Original experimental
  12. The effects of gabapentin in human experimental pain models
  13. Editorial comment
  14. Whether the weather influences pain: High prevalence of chronic pain in Iceland and Norway: Common genes? Or lack of sunshine and vitamin D?
  15. Observational studies
  16. A population based study of the prevalence of pain in Iceland
  17. Editorial comment
  18. Swedish nurses are prone to chronic shoulder and back pain because of miserable working conditions and poor leadership?
  19. Observational studies
  20. Predicting of pain, disability, and sick leave regarding a non-clinical sample among Swedish nurses
  21. Abstracts
  22. Trigeminal neuralgia or odontogenic pain
  23. Abstracts
  24. What’s wrong with animal models of pain?
  25. Abstracts
  26. Immunotherapy for neuroblastoma elicits a complement dependent whole body allodynia
  27. Abstracts
  28. Pain mechanisms in animal models of rheumatoid arthritis
  29. Abstracts
  30. Translating basic research to pharmacological treatment of neuropathic pain
  31. Abstracts
  32. Free Poster Presentations: Forearm heat pain does not inhibit electrically induced tibialis anterior muscle pain
  33. Abstracts
  34. Offset analgesia evoked by non-contact thermal stimulator
  35. Abstracts
  36. Inhibition of FAAH reverses spinal LTP
  37. Abstracts
  38. Hyperexcitable C-nociceptors in human paroxysmal pain
  39. Abstracts
  40. Pain sensitivity and experimentally induced sensitization in red haired women
  41. Abstracts
  42. How are opioids used in Norway? Persistent use, utilization of depot formulation and age profile in non-palliation patients
  43. Abstracts
  44. To which extent does incident and persistent use of weak opioids predict problematic opioid use?
  45. Abstracts
  46. Is transdermal buprenorphine for chronic non-malignant pain used long term without co-medication with other potentially addictive drugs?
  47. Abstracts
  48. Prostaglandin E2 production in synovial tissue and acute postoperative pain after knee arthroscopy
  49. Abstracts
  50. Girl presenting with oesophageal spasm pain after fundoplication
  51. Abstracts
  52. Epidemiology of persistent postoperative pain: Association of persistent pain and sensory abnormalities
  53. Abstracts
  54. Cost–benefit of a 13-week multidiciplinary rehabilitation course for chronic non-malignant pain patients
  55. Abstracts
  56. A novel and effective treatment modality for medically unexplained pain
  57. Abstracts
  58. Somatocognitive therapy in the management of chronic gynaecological pain. A review of current approach and historical background
  59. Abstract
  60. The Manual Intervention Trial (MINT)—The effect of various combinations of naprapathic manual therapy. The study protocol of a randomized controlled trial
  61. Abstracts
  62. The experience of chronic pain, loss and grief
  63. Abstracts
  64. Effect of buprenorphine and fentanyl in experimental induced superficial, deep and hyperalgesic pain
  65. Abstract
  66. Pretreatment with opioids enhances afferent induced long-term potentiation in the rat dorsal horn
  67. Abstracts
  68. Pigs in pain—Porcine behavioural responses towards mechanical nociceptive stimulation directed at the hind legs
  69. Abstracts
  70. A human experimental bone pain model
https://doi.org/10.1016/j.sjpain.2010.01.008

Articles in the same Issue

  1. Editorial comment
  2. Functional brain imaging of acute postoperative pain
  3. Clinical pain research
  4. Brain activation due to postoperative pain from the right hand measured with regional cerebral blood flow using positron emission tomography
  5. Editorial comment
  6. Long-term low-dose transdermal buprenorphine therapy for chronic noncancer pain
  7. Original experimental
  8. A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent opioids
  9. Editorial comment
  10. Repeated nociceptive stimulation for detecting drug effects
  11. Original experimental
  12. The effects of gabapentin in human experimental pain models
  13. Editorial comment
  14. Whether the weather influences pain: High prevalence of chronic pain in Iceland and Norway: Common genes? Or lack of sunshine and vitamin D?
  15. Observational studies
  16. A population based study of the prevalence of pain in Iceland
  17. Editorial comment
  18. Swedish nurses are prone to chronic shoulder and back pain because of miserable working conditions and poor leadership?
  19. Observational studies
  20. Predicting of pain, disability, and sick leave regarding a non-clinical sample among Swedish nurses
  21. Abstracts
  22. Trigeminal neuralgia or odontogenic pain
  23. Abstracts
  24. What’s wrong with animal models of pain?
  25. Abstracts
  26. Immunotherapy for neuroblastoma elicits a complement dependent whole body allodynia
  27. Abstracts
  28. Pain mechanisms in animal models of rheumatoid arthritis
  29. Abstracts
  30. Translating basic research to pharmacological treatment of neuropathic pain
  31. Abstracts
  32. Free Poster Presentations: Forearm heat pain does not inhibit electrically induced tibialis anterior muscle pain
  33. Abstracts
  34. Offset analgesia evoked by non-contact thermal stimulator
  35. Abstracts
  36. Inhibition of FAAH reverses spinal LTP
  37. Abstracts
  38. Hyperexcitable C-nociceptors in human paroxysmal pain
  39. Abstracts
  40. Pain sensitivity and experimentally induced sensitization in red haired women
  41. Abstracts
  42. How are opioids used in Norway? Persistent use, utilization of depot formulation and age profile in non-palliation patients
  43. Abstracts
  44. To which extent does incident and persistent use of weak opioids predict problematic opioid use?
  45. Abstracts
  46. Is transdermal buprenorphine for chronic non-malignant pain used long term without co-medication with other potentially addictive drugs?
  47. Abstracts
  48. Prostaglandin E2 production in synovial tissue and acute postoperative pain after knee arthroscopy
  49. Abstracts
  50. Girl presenting with oesophageal spasm pain after fundoplication
  51. Abstracts
  52. Epidemiology of persistent postoperative pain: Association of persistent pain and sensory abnormalities
  53. Abstracts
  54. Cost–benefit of a 13-week multidiciplinary rehabilitation course for chronic non-malignant pain patients
  55. Abstracts
  56. A novel and effective treatment modality for medically unexplained pain
  57. Abstracts
  58. Somatocognitive therapy in the management of chronic gynaecological pain. A review of current approach and historical background
  59. Abstract
  60. The Manual Intervention Trial (MINT)—The effect of various combinations of naprapathic manual therapy. The study protocol of a randomized controlled trial
  61. Abstracts
  62. The experience of chronic pain, loss and grief
  63. Abstracts
  64. Effect of buprenorphine and fentanyl in experimental induced superficial, deep and hyperalgesic pain
  65. Abstract
  66. Pretreatment with opioids enhances afferent induced long-term potentiation in the rat dorsal horn
  67. Abstracts
  68. Pigs in pain—Porcine behavioural responses towards mechanical nociceptive stimulation directed at the hind legs
  69. Abstracts
  70. A human experimental bone pain model
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 3.10.2025 from https://www.degruyterbrill.com/document/doi/10.1016/j.sjpain.2010.01.008/html?lang=en
Scroll to top button