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A Translational Study of the Effects of Ketamine and Pregabalin on Temporal Summation of Experimental Pain
  1. Lars Arendt-Nielsen, DrMedSci, PhD*,
  2. Heikki Mansikka, MD, PhD,
  3. Camilla Staahl, PhD,
  4. Huw Rees, PhD,
  5. Keith Tan, PhD,
  6. Trevor S. Smart, MSc,
  7. Russell Monhemius, PhD,
  8. Rie Suzuki, PhD and
  9. Asbjørn M. Drewes, MD, PhD§
  1. From the *Center for Sensory-Motor Interactions, Department of Health Science and Technology, Aalborg University, Denmark;
  2. Grünenthal GmbH, Aachen, Germany;
  3. Pfizer Global Research and Development, Sandwich, United Kingdom; and
  4. §Department of Gastroenterology, Aalborg Hospital, Denmark.
  1. Address correspondence to: Lars Arendt-Nielsen, DrMedSci, PhD, Center for Sensory-Motor Interaction, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 7, D3, DK-9220 Aalborg E, Denmark (e-mail: LAN{at}hst.aau.dk).

Abstract

Background and Objectives: Central sensitization is often seen in chronic pain. A relevant and potent mechanism of central sensitization is the central integration of nociceptive impulses. Temporal summation in humans and the wind-up process in animals share common features of central integration. This preclinical and clinical translational study investigated the effect of ketamine and pregabalin on temporal summation (TS) and wind-up of wide dynamic range (WDR) neurons of nociceptive electrical stimuli in healthy volunteers and rats.

Methods: This 3-way crossover study included healthy male volunteers (n = 18) receiving 3 doses of 300 mg pregabalin (orally) over 2 days, ketamine (intravenous loading dose 0.5 mg/kg followed by 9 μg/kg per minute for 20 mins) on the first day, or placebo. The pain detection thresholds to repetitive electrical cutaneous and suprathreshold responses stimulation were assessed.

In male Sprague-Dawley rats (n = 30), WDR neuron recordings after electrical stimulation were obtained before and after 15 minutes of intravenous infusion pregabalin (0.127, 0.42, and 1.27 mg/kg per minute) and ketamine (0.006, 0.02, 0.06, and 0.2 mg/kg per minute).

Results: In the human study, ketamine compared with placebo significantly increased the TS pain detection threshold (P < 0.001) and significantly reduced suprathreshold pain responses (P < 0.001). In rats, the highest dose of ketamine significantly inhibited the wind-up response of the WDR neurons (P = 0.014). Pregabalin affected neither of the parameters in TS and WDR responses.

Conclusions: It was shown that TS shares common features with wind-up of WDR neurons and that pregabalin does not affect this component of central sensitization.

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Footnotes

  • This study was supported by an unrestricted grant was received from Pfizer Ltd (Sandwich Laboratories, Kent, UK).

  • Drs. Mansikka, Rees, and Tan; Mr. Smart; and Drs. Monhemius and Suzuki are employees at Pfizer (Dr. Mansikka now moved to Grünenthal).

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