What do we (not) know about how paracetamol (acetaminophen) works?

Abstract

Summary What is known and background: Although paracetamol (acetaminophen), N‐(4‐Hydroxyphenyl)acetamide, is one of the world’s most widely used analgesics, the mechanism by which it produces its analgesic effect is largely unknown. This lack is relevant because: (i) optimal pain treatment matches the analgesic mechanism to the (patho)physiology of the pain and (ii) modern drug discovery relies on an appropriate screening assay. Objective: To review the clinical profile and preclinical studies of paracetamol as means of gaining insight into its mechanism of analgesic action. Methods: A literature search was conducted of clinical and preclinical literature and the information obtained was organized and reviewed from the perspective of its contribution to an understanding of the mechanism of analgesic action of paracetamol. Results: Paracetamol’s broad spectrum of analgesic and other pharmacological actions is presented, along with its multiple postulated mechanism(s) of action. No one mechanism has been definitively shown to account for its analgesic activity. What is new and conclusion: Further research is needed to uncover the mechanism of analgesic action of paracetamol. The lack of this knowledge affects optimal clinical use and impedes drug discovery efforts.

From painkiller to empathy killer: acetaminophen (paracetamol) reduces empathy for pain

“…Although some research implicates a role of oxytocin in empathy (Barraza and Zak, 2013), there are no documented effects of acetaminophen on oxytocin. Thus, it remains unclear which neurotransmitter system is involved in the effects of acetaminophen, but evidence supports roles for the serotonin, opioid, cannabinoid and prostanoid systems, among others (Toussaint et al, 2010;Graham et al, 2013). Each of these neurochemical systems is poised to affect anterior cingulate and insula activity and thus could be a candidate for explaining the effect of acetaminophen on reduced empathy.…”

Perbandingan Kombinasi Tramadol Parasetamol Intravena dengan Tramadol Ketorolak Intravena terhadap Nilai Numeric Rating Scale dan Kebutuhan Opioid Pascahisterektomi

“…Parasetamol memiliki efek analgesia dan juga antipiretik tanpa efek anti-inflamasi, aman digunakan, efek samping minimal, dan ditoleransi dengan baik. 10,11 Parasetamol juga memiliki efek opioidsparing bila digunakan bersama dengan opioid dosis yang rendah sehingga memberikan efek analgesia yang baik dengan meminimalkan efek samping opioid seperti depresi napas, bradikardia, dan hipoksia. 10,11 Tramadol intravena merupakan salah satu analgetik opioid yang sering dipergunakan di Rumah Sakit Dr. Hasan Sadikin (RSHS)Bandung karena mudah didapatkan serta efektif untuk mengatasi rasa nyeri pascabedah.…”

Acute Pain Management in the Emergency Department: Emphasis on NSAIDs

“…Some selectively at COX-2, [63] or even a third isozyme, the so-called COX-3 isoform, [64] have been speculated, [62] but only COX-1 and COX-2 have been definitively identified [63] and preclinical evidence does not support a COX-3 mechanism of action [64]. A predominant central mechanism of action is likely [61].…”

“…However, acetaminophen alone may not always be effective, particularly in the control of moderate to severe pain. Despite its ubiquity, however, the mechanism of action of acetaminophen remains incompletely understood [61]. An aniline analgesic, it differs from NSAIDs and may rely on multiple, interconnected mechanisms of action for its effect.…”