Abstract
Duloxetine, a serotonin and noradrenaline reuptake inhibitor, and celecoxib, a non-steroidal anti-inflammatory drug, are commonly used analgesics for persistent pain, however with moderate gastrointestinal side effects or analgesia tolerance. One promising analgesic strategy is to give a combined prescription, allowing the maximal or equal efficacy with fewer side effects. In the current study, the efficacy and side effects of combined administration of duloxetine and celecoxib were tested in the mouse formalin pain model. The subcutaneous (s.c.) injection of formalin into the left hindpaw induced significant somatic and emotional pain evaluated by the biphasic spontaneous flinching of the injected hindpaw and interphase ultrasonic vocalizations (USVs) during the 1 h after formalin injection, respectively. Pretreatment with intraperitoneal (i.p.) injection of duloxetine or celecoxib at 1 h before formalin injection induced the dose-dependent inhibition on the second but not first phase pain responses. Combined administration of duloxetine and celecoxib showed significant analgesia for the second phase pain responses. Combination analgesia on the first phase was observed only with higher dose combination. A statistical difference between the theoretical and experimental ED50 for the second phase pain responses was observed, which indicated synergistic interaction of the two drugs. Concerning the emotional pain responses revealed with USVs, we assumed that the antinociceptive effects were almost completely derived from duloxetine, since celecoxib was ineffective when administered alone or reduced the dosage of duloxetine when given in combination. Based on the above findings, acute concomitant administration of duloxetine and celecoxib showed synergism on the somatic pain behavior but not emotional pain behaviors.
Highlights
Synergistic, additive or antagonistic interactions can be observed when two analgesics are given at the same time
I.p. drug pretreatment did not alter the motor coordination [Figure 7C; one way ANOVA F(3, 23) = 0.148, p = 0.930]. This is the first report showing combination analgesia for duloxetine and celecoxib on inflammatory pain induced by s.c. injection of formalin into the hind paw
Duloxetine and celecoxib have been commonly used in the treatment of pain, especially for inflammatory or neuropathic pain, the gastrointestinal side effects and the desensitization phenomenon of celecoxib as well as the serotonin (5-HT)-norepinephrine reuptake inhibitor (SNRI) side effects limit the clinic application of both drugs
Summary
Synergistic, additive or antagonistic interactions can be observed when two analgesics are given at the same time. One of the selective cyclooxygenase (COX)-2 inhibitors, has been extensively used in the treatment of osteoarthritis and rheumatoid arthritis [19,20] This compound exhibits 3 featured biological activities -antipyretic, antiinflammatory and analgesic [21] activities attributed to their inhibition of prostaglandin biosynthesis [22]. The celecoxib analgesia faces the gastrointestinal side effects [25] and tolerance as observed in a rat model of inflammatory pain [26] Because both duloxetine and celecoxib are associated with increased risk of side effects, the synergistic effect at a lower dosage might be a better analgesic strategy. In the current study, we observed the potential combination analgesic effect between duloxetine and celecoxib on the inflammatory pain induced by s.c. injection of formalin into one hindpaw of mice with isobolographic analysis
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