The Central Analgesic Effects of Paracetamol on Serotonergic Pathways
Condition: Analgesia
Study type: Interventional

Summary: 
      1. Introduction

           Paracetamol, an analgesic prescribed daily, has been in use for more than 50 years.
           Surprisingly, its mode of action is still unclear. One postulated mechanism is the
           reinforcement of descending inhibitory pathways. A recent publication in a human pain
           model raises the question of whether or not Paracetamol acts according to a central
           serotonergic mechanism. Unfortunately, the chosen model was unable to differentiate
           between overall pain, secondary hyperalgesia and allodynia. In particular, secondary
           hyperalgesia and allodynia are central effects.

           The planned study will examine the central analgesic effects of paracetamol on allodynia
           and hyperalgesia by blocking the central effect by adding tropisetron. It will be based
           on an internationally accepted model for the initiation of secondary hyperalgesia, which
           was developed and tested by colleagues in Erlangen.

        2. Study work plan

           This prospective, randomized, placebo-controlled, double-blinded, cross-over trial in 16
           male volunteers will address pain ratings and the area of secondary
           hyperalgesia/allodynia in a human model of electrically evoked pain and compare four
           different treatment scenarios:

             -  Paracetamol 1 g;

             -  Paracetamol, 1 g and Tropisetron 5 mg;

             -  Tropisetron, 5 mg; and

             -  Saline.

           Each volunteer will be allocated to each scenario in a cross-over fashion. Four separate
           treatment trials, at least two weeks apart, will be performed. Each volunteer will be
           familiarized with the stimulation procedure prior to participation.

        3. Ethical considerations

           Informed consent will be obtained from each volunteer. In addition, each volunteer will
           receive remuneration after participating in the study.

           Paracetamol is considered to be a very safe drug in healthy patients. Tropisetron,
           another safe medication, is routinely used in anaesthetic practice as an antiemetic
           drug. Headache, flush and liver parameter elevation are very rare side effects of minor
           importance in our daily clinical work as anaesthetists.

           This pain provoking procedure was developed at the University Erlangen Germany. It is a
           standardized method and has repeatedly received approval by research ethics committees
           internationally. Furthermore, the investigators applied this model to a recent study in
           Basel (cf your decision "study protocol 330/07;" unpublished data, analysis and writing
           in progress).

        4. Patient number and timetable

           The investigators will examine 16 volunteers and expect the experimental component to
           last 3 months. The investigators plan to complete this study within one year.

        5. Study importance

      The mode of action of paracetamol remains unclear. The investigators think that this study
      will enable them to answer important questions concerning the action of paracetamol. The
      investigators hope that further understanding of this regularly prescribed drug will help us
      to better understand the complex mechanisms of pain.
    


Intervention name(s): Paracetamol; Tropisetron; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Paracetamol 1 g i.v. once; Tropisetron 5 mg i.v. once; Saline
Intervention MeSH terms: Acetaminophen; Tropisetron
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Basic Science
Keywords: Paracetamol; Tropisetron; Central analgesic effect; Area of allodynia; Secondary hyperalgesia