Fluoxetine is one of the top ten prescribed antidepressants. Other therapeutic applications were approved for
fluoxetine including, anxiety disorders, bulimia nervosa, and premature ejaculation. However, the role of
fluoxetine in nociceptive pain management is still unclear. In this review, we discuss an overview of five possible
roles of fluoxetine in pain management: intrinsic antinociceptive effect, enhancement of acute opioid analgesia,
attenuation of tolerance development to opioid analgesia, attenuation of dependence development and abstinence
syndrome, and attenuation of opioid induced hyperalgesia.
Conflicting data were reported about fluoxetine intrinsic anti-nociceptive effect in preclinical and clinical
studies except for inflammatory pain. Similar controversy was described in preclinical and clinical studies which
explored the possible enhancement of opioid analgesia by fluoxetine co-administration. However, fluoxetine was
found to have a promising effect on opioid tolerance and dependence in animal and human studies. Regarding
opioid induced hyperalgesia, no studies examined fluoxetine effects in this regard.
Our literature review revealed that, the most likely beneficial use of fluoxetine in nociceptive pain management
is for alleviation of inflammatory pain and attenuation of opioid tolerance and dependence. Nonsteroidal
anti-inflammatory and corticosteroids carry many adverse effects and toxicities. Effective alleviation of
opioid tolerance and dependence represents a huge health burden and growing unmet medical need. Moreover,
most agents used to attenuate these phenomena are either experimental or poorly tolerable drugs which limit
their transitional value. Fluoxetine offers an effective, safe, and tolerable alternative for management of both
inflammatory pain and opioid tolerance and dependence presently available to clinicians.