<p><a href="https://rd.springer.com/article/10.2165/00002018-200124150-00004" rel="nofollow noreferrer">Zhang (2001)</a> reports that the analgesic activity of caffeine is due to </p>

<ul>
<li>a blockade of peripheral pro-nociceptive actions of adenosine;</li>
<li>the activation of the central noradenosine, pain-suppressing pathways;</li>
<li>stimulation of the central nervous system with subsequent actions on pain perception;</li>
<li>inhibition of PG (prostaglandine) E<sub>2</sub> synthesis, just like the primary mechanism of paracetamol and caffeine by blocking the COX enzyme; </li>
<li>disinhibition of inhibitory adenosine actions on central cholinergic nerve terminals, leading to increased acetylcholine release and activation of cholinergic mechanisms involved in analgesia;</li>
<li>lastly, caffeine-induced changes in mood may help in in pain relief.</li>
</ul>

<p>Concerning the direct COX inhibitory action (which highly surprised me, personally) - Aspirin-like drugs act on the catalytic site of the COX enzyme. Paracetamol is believed to act at a different site, such as the peroxidation site of COX, while caffeine may block synthesis of the COX-2 protein, probably at the transcriptional level,thereby leading to enhanced COX-2 inhibition. Caffeine is a nonselective antagonist of adenosine A1 and A2 receptors. Adenosine A2a receptors induce intracellular signalling events that cause an upregulation of the COX-2 gene and the release of PGE2 in rat microglia, which is antagonized by caffeine. </p>

<p><a href="http://www.scielo.br/pdf/rba/v62n3/en_v62n3a11.pdf" rel="nofollow noreferrer">Tavares &amp; Sakata (2012)</a> also provide an interesting review on the analgesic effects of caffeine, without it being used in conjunction with other medications.</p>

<p><sub><strong>References</strong><br>
<strong>-</strong> <a href="http://www.scielo.br/pdf/rba/v62n3/en_v62n3a11.pdf" rel="nofollow noreferrer">Tavares &amp; Sakata, <em>Rev Bras Anestesiol</em> (2012); <strong>62</strong>(3): 387-401</a><br>
<strong>-</strong> <a href="https://rd.springer.com/article/10.2165/00002018-200124150-00004" rel="nofollow noreferrer">Zhang, <em>Drug Safety</em> (2001); <strong>24</strong>(15): 1127–42</a></sub>  </p>

CC BY-SA 4.0
2018-09-24T08:37:32.330Z
2018-09-24T08:37:32.330Z
AliceD
<p>Caffeine <a href="https://www.cochrane.org/CD009281/SYMPT_caffeine-analgesic-adjuvant-acute-pain-adults" rel="nofollow noreferrer">is used an adjuvant</a> in over-the-couner pain medication, e.g. added to paracetamol <a href="https://en.wikipedia.org/wiki/Aspirin/paracetamol/caffeine" rel="nofollow noreferrer">and/or</a> aspirin.</p>

<p>A brief look at the <a href="https://en.wikipedia.org/wiki/Caffeine" rel="nofollow noreferrer">Wikipedia page on caffeine</a> doesn't indicate any analgesic effect of caffeine itself. So, what mechanism/pathway allows it to attain this adjuvant effect for pain relief?</p>

<neurophysiology><psychopharmacology><pain>
How does caffeine work as an analgesic adjuvant?
got trolled too much this week
# How does caffeine work as an analgesic adjuvant?

(Asked by: username_0 on 2018-09-22)

Caffeine [is used an adjuvant](https://www.cochrane.org/CD009281/SYMPT_caffeine-analgesic-adjuvant-acute-pain-adults) in over-the-couner pain medication, e.g. added to paracetamol [and/or](https://en.wikipedia.org/wiki/Aspirin/paracetamol/caffeine) aspirin.

A brief look at the [Wikipedia page on caffeine](https://en.wikipedia.org/wiki/Caffeine) doesn't indicate any analgesic effect of caffeine itself. So, what mechanism/pathway allows it to attain this adjuvant effect for pain relief?

**Tags:** neurophysiology, psychopharmacology, pain


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## 1 answers

### Answer by username_1 on 2018-09-24. Score: 3 | Accepted answer

[Zhang (2001)](https://rd.springer.com/article/10.2165/00002018-200124150-00004) reports that the analgesic activity of caffeine is due to

* a blockade of peripheral pro-nociceptive actions of adenosine;
* the activation of the central noradenosine, pain-suppressing pathways;
* stimulation of the central nervous system with subsequent actions on pain perception;
* inhibition of PG (prostaglandine) E2 synthesis, just like the primary mechanism of paracetamol and caffeine by blocking the COX enzyme;
* disinhibition of inhibitory adenosine actions on central cholinergic nerve terminals, leading to increased acetylcholine release and activation of cholinergic mechanisms involved in analgesia;
* lastly, caffeine-induced changes in mood may help in in pain relief.

Concerning the direct COX inhibitory action (which highly surprised me, personally) - Aspirin-like drugs act on the catalytic site of the COX enzyme. Paracetamol is believed to act at a different site, such as the peroxidation site of COX, while caffeine may block synthesis of the COX-2 protein, probably at the transcriptional level,thereby leading to enhanced COX-2 inhibition. Caffeine is a nonselective antagonist of adenosine A1 and A2 receptors. Adenosine A2a receptors induce intracellular signalling events that cause an upregulation of the COX-2 gene and the release of PGE2 in rat microglia, which is antagonized by caffeine.

[Tavares & Sakata (2012)](http://www.scielo.br/pdf/rba/v62n3/en_v62n3a11.pdf) also provide an interesting review on the analgesic effects of caffeine, without it being used in conjunction with other medications.

**References**  
**-** [Tavares & Sakata, *Rev Bras Anestesiol* (2012); **62**(3): 387-401](http://www.scielo.br/pdf/rba/v62n3/en_v62n3a11.pdf)  
**-** [Zhang, *Drug Safety* (2001); **24**(15): 1127–42](https://rd.springer.com/article/10.2165/00002018-200124150-00004)


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