Physical and emotional
pain deteriorates the quality of well-being. Also, numerous non-invasive and invasive treatments for diagnosed diseases such as
cancer medications and
surgical procedures cause various types of
pain. Despite the multidisciplinary approaches available to manage
pain, the unmet needs for medication with minimal side effects are substantial. Especially with the surge of opioid crisis during the last decades,
non-opioid analgesics may reduce life-threatening overdosing and addictive liability. Although many clinical trials supported the potential potency of cannabis and
cannabidiol (CBD) in
pain management or treatment, the long-term benefits of cannabis or CBD are still not evident. At the same time, growing evidence shows the risk of overusing cannabis and CBD. Therefore, it is urgent to develop novel
analgesic medications that minimize side effects. All four well-identified
adenosine receptors, A1, A2A, A2B, and A3, are implicated in
pain. Recently, a report demonstrated that an
adenosine A1R-specific positive allosteric modulator (PAM) is a potent
analgesic without noticeable side effects. Also, several A3R agonists are being considered as promising
analgesic agent. However, the importance of
adenosine in
pain is relatively underestimated. To help readers understand, first, we will summarize the historical perspective of the
adenosine system in preclinical and clinical studies. Then, we will discuss possible interactions of
adenosine and
opioids or the cannabis system focusing on
pain. Overall, this review will provide the potential role of
adenosine and
adenosine receptors in
pain treatment.