Dose response of tramadol and its combination with paracetamol in UVB induced hyperalgesia

Eur J Pain. 2012 Apr;16(4):562-73. doi: 10.1016/j.ejpain.2011.08.007.


Combining tramadol with paracetamol is an established analgesic treatment strategy. However, dosing and differential effects on peripheral and central hyperalgesia are still to be determined. After Ethics Committee approval, 32 volunteers have been included in this 2 phased, double blinded, placebo controlled, cross-over study. A defined small skin area was irradiated with a UVB source inducing hyperalgesia. Twenty-four hours after irradiation, heat pain-, cold pain threshold (HPPT, CPPT), mechanical pain sensitivity to pin prick (MPS) in the area of pin prick hyperalgesia (AsH) and MPS in the sunburn were determined. In phase I, measurements have been repeated 30 min after receiving cumulative 0.3, 0.6 and 1 mg/kg of intravenous (i.v.) tramadol or active placebo. Only at 1 mg/kg tramadol and solely for MPS in the sunburn a reduction to placebo could be demonstrated (p = 0.024). Accordingly in phase II, the trial has been repeated using 1 mg/kg tramadol and paracetamol or placebo in a cumulative i.v. dose of 330, 660 and 990 mg. Now the addition of 330 mg paracetamol to tramadol reduced thermal hyperalgesia by 1.15 °C (CI 0.55; 1.76). This effect, however, did not increase with higher doses. Tramadol showed week anti-hyperalgesia reducing CPPT, MPS and AsH compared to baseline measurements (p < 0.05). Paracetamol also reduced secondary hyperalgesia, but no combination effect with tramadol could be shown. We conclude, in inflammatory hyperalgesia tramadol alone exerts only weak anti-hyperalgesia. Even adding a small dose paracetamol enhances thermal anti-hyperalgesia.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / administration & dosage
  • Acetaminophen / therapeutic use*
  • Adult
  • Analgesics, Non-Narcotic / administration & dosage
  • Analgesics, Non-Narcotic / therapeutic use*
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / therapeutic use*
  • Cold Temperature
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Humans
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / etiology
  • Male
  • Pain Measurement / drug effects
  • Pain Threshold / drug effects
  • Physical Stimulation
  • Regional Blood Flow / drug effects
  • Regional Blood Flow / physiology
  • Sample Size
  • Skin / blood supply
  • Sunburn / complications
  • Sunburn / drug therapy*
  • Tramadol / administration & dosage
  • Tramadol / therapeutic use*
  • Ultraviolet Rays / adverse effects*
  • Young Adult


  • Analgesics, Non-Narcotic
  • Analgesics, Opioid
  • Drug Combinations
  • Acetaminophen
  • Tramadol