Actu pharmacol. et zyxwvutsrqp toxicol. zyxwvutsrq 1986, zyxwvut 59, 53-59. From the Department of Physiology, University of Bergen, h t a d v e i e n 19, N-5000 Bergen, Norway zy Orphenadrine Citrate Increases and Prolongs the Antinociceptive Effects of Paracetamol in Mice BY Steinar Hunskaar, Odd-Geir Berge and KjeU Hole (Received January 20, 1986; Accepted April 7, 1986) Abslruct; Orphenadrine. a muscle relaxant with antinociceptive effects, was shown to increase and prolong the antinociceptive effects of paracetamol in mice. Both in the increasing temperature hot plate test and in the formalin test, a combination of the two drugs showed a significantly improved effect compared to either of the drugs alone. The time course of the effects was tested in the increasing temperature hot plate test. The group treated with the drug combination showed a prolonged effect compared to both single drug treated groups, the effect lasting longer than 120 min. for the combination and about 80 min. for the single drugs. Orphenadrine and paracetamol increased antinociception even when orphenadrine was injected 90 min. after paracetamol, which by that time did not exert antinociceptive effects by itself. Thus the combination of orphenadrine and paracetamol enhances the antinociceptive effect of either drug in mice. Key-words: Orphenadrine zyxwvuts - paracetamol - analgesia - pain ~ mice In order to extend their range of usefulness, non- narcotic analgesics are often combined with other drugs of the same group or with muscle relaxants and tranquillizers. Paracetamol seems to be very suitable for such combinations since it is a safe drug that rarely produces side effects in recom- mended dosages. Orphenadrine citrate, a diphenhydramine ana- logue, is a supraspinally acting muscle relaxant (Ginzel 1966). It has well-documented clinical ef- fects in a variety of musculoskeletal conditions involving pain (Mok el zyxwvuts a/. 1979; Winter & Post 1979; McGuinness 1983). Since some clinical studies have indicated that orphenadrine also may have direct analgesic activity (Cass et al. 1964; Valtonen 1975; Gold 1978), we recently tested the drug using four different pain tests in mice (Hunskaar et al. 1985a). Antinociceptive proper- ties were found in the formalin test and the in- creasing temperature hot plate test, but not in the tail-flick and the constant temperature hot plate test. The antinociceptive effects were found at doses we11 below sedative or muscle relaxant levels (Hunskaar et a/. 1985a). It has been suggested that in clinical settings the combination of orphenadrine with paracetamol induced pain relief significantly superior to the single drug regimen (Valtonen 1975; Tervo et al. 1976; Mok et al. 1979; Winter & Post 1979; McGuinness 1983). Clinical data also suggest that orphenadrine citrate is able to prolong the effect of paracetamol and to reduce the need for anal- gesic remedication (Birkeland & Clawson 1968; Mok et al. 1979; Winter & Post 1979). Orphenad- rine also seems superior to other muscle relaxants in the ability to induce analgesia (Valtonen 1975). However, the clinical investigations of orphenad- rine citrate have not demonstrated conclusive re- sults. They have not always had appropriate con- trols and the patients have often been suffering