Abstract Aim of investigation: Guaifenesin is used as an expectorant and it has been reported to possess muscle re- laxant and sedative activity. Guaifenesin has been used as a component of composite OTC analgesics containing paracetamol for many years. The aim of our study was to ascertain effects of guaifenesin on paracetamol analgesic activity and locomotor performance. Methods: Antinoci- ceptive efficacy was tested in mice using an acetic acid (0.7%) writhing test. Locomotor performance was tested in rota-rod test and activity cage. All drugs were given orally and tested in mice. Results: In combination with a subeffective dose of guaifenesin (200 mg/kg), the ED 50 for paracetamol in the writhing test was significantly lower (82.2 mg/kg) than that of paracetamol administered alone (233.7 mg/kg). Guaifenesin alone did not show an analgesic effect. Guaifenesin did not produce statistically significant locomotor impairment in the rota-rod test at doses enhancing analgesic activity of paracetamol, although there was a trend for decreased locomotor activity in ac- tivity cage. Conclusion: The present results indicate that guaifenesin may enhance analgesic activity of paraceta- mol. Keywords Paracetamol · Guaifenesin · Analgesic combinations · Writhing · Locomotor performance Introduction Combination analgesics are often prescribed and they con- stitute a substantial portion of the over-the-counter (OTC) analgesic market. The main rationale of analgesic combi- nations is enhancement of analgesia by combining two compounds with different mechanisms of action (additive or synergistic) and different risk profiles. There is good evidence that combinations of paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs) with opioid analgesics have an enhanced (synergistic) analgesic effect (Beaver 1984; Zhang and Po 1997; Po and Zhang 1998). Another drug with well-documented enhancement of potency of analgesics is caffeine (Laska et al. 1984; McQuay et al. 1996). However, there are many other analgesic combina- tions in clinical use with less convincing evidence of ad- ditive or synergistic effects of their components. Composite analgesics containing aspirin or paraceta- mol and guaifenesin were introduced to the market in Czechoslovakia and Central Europe in the early 1980s with the aim to replace older OTC analgesics containing unsafe components (aminophenazone, phenacetine, barbi- turates). Analgesic combinations of paracetamol or aspirin with guaifenesin derivatives (methocarbamol, mephen- esin) are available in many countries. Guaifenesin is also widely used as an expectorant in OTC preparations. It was previously reported to also possess central muscle relax- ant and sedative activity (Carter 1966; Hofrichter et al. 1967; Horn 1967; Gorski and Kuchler 1971) but its mech- anism of action is not understood. Paracetamol is a well- established analgesic with central antinociceptive action. The major aim of this study was to ascertain effects of guaifenesin on paracetamol analgesic activity in an exper- imental model of pain, the writhing test in mice. The sec- ond aim was to evaluate possible neurobehavioral toxicity of guaifenesin in combination with paracetamol, using the rota-rod test and an activity cage. Materials and methods Animals. All studies and procedures were approved by the Com- mittee for Protection of Laboratory Animals of the 3rd Faculty of Medicine, Charles University. Male NMRI mice weighing 24–30 g (VUFB Konarovice, Czech Republic) were used. Food was withheld for 16 h before initiation of experiments to facilitate i.p. administration of acetic acid and to reduce variability, but animals had free access to water. The animals were adapted to the laboratory environment for at least 1 h before being used. The duration of the experiments was as short as possi- T. Doležal · M. Kršiak Guaifenesin enhances the analgesic potency of paracetamol in mice Naunyn-Schmiedeberg’s Arch Pharmacol (2002) 366 : 551–554 DOI 10.1007/s00210-002-0642-y Received: 23 April 2002 / Accepted: 12 August 2002 / Published online: 3 October 2002 ORIGINAL ARTICLE T. Doležal (✉) · M. Kršiak Department of Pharmacology, 3rd Faculty of Medicine, Charles University of Prague, Ruska 87, 100 34 Prague, Czech Republic e-mail: Tomas.Dolezal@lf3.cuni.cz, Tel.: +42-0267102530, Fax: +42-0267102461 © Springer-Verlag 2002