TIPS 1991 No.

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Trends in
Pharmacological Sciences
Science & Society
Rethinking the use of Furthermore, several recent studies show,
however, that NSAIDs can also increase
Glossary
Cyclooxygenases (COX-1 and COX-2): enzymes
NSAIDs in early pain [5] and inflammation [6–8] as a long- that oxygenate the fatty acid arachidonic acid to
synthesize prostaglandin H2 (PGH2). PGH2 is then
acute pain term consequence. More specifically, per-
turbation at the onset of inflammation can
further metabolized by specific prostanoid synthases
to generate the prostanoids.
prolong inflammation and inflammatory Eicosanoids: a group of signaling lipids derived from
Marco Sisignano 1,2,* and pain and can also delay the proper resolu- arachidonic acid with various functions. The name
Gerd Geisslinger1,2 tion of inflammation. Here, we discuss
‘eicosanoids’ refers to their shared property to consist
of 20 carbons (Greek: eicosa).
these findings and suggest alternatives to Neutrophils: innate immune cells that rapidly
Non-steroidal anti-inflammatory the use of NSAIDs in early acute pain at infiltrate damaged or infected tissue.
drugs (NSAIDs) are the most widely the onset of inflammation. Nociceptors: peripheral sensory nerve endings that
detect noxious mechanical, thermal, or chemical
used analgesics to treat inflamma- stimuli and transduce them to electrical signals as
tory pain. Despite their efficacy, Anti-inflammatory properties of action potentials to elicit pain.
recent studies show that NSAID prostanoids and their receptors Non-steroidal anti-inflammatory drugs
(NSAIDs): inhibit cyclooxygenases and by that
use in early acute pain can prolong NSAIDs mediate their analgesic effects by
prostanoid production. They are the most widely
pain and inflammation and delay inhibiting the cyclooxygenases COX-1 used drugs for the treatment of inflammatory
and COX-2, thus limiting the synthesis of pain.
their resolution. We suggest using
prostanoids. The COX products prosta- Prostanoids: a group of signaling lipids that are
analgesics without inflammation- synthesized by COX enzymes and specific
glandin E2 (PGE2) and prostaglandin I2
related properties in early acute prostanoid synthases that are strongly involved in
(PGI2) sensitize nociceptors by activating inflammatory processes. They include
pain instead of NSAIDs. their EP and IP receptors, leading to the prostaglandin D2 (PGD2), prostaglandin E2 (PGE2),
PKA-dependent phosphorylation of neu- prostaglandin I2 (PGI2, also referred to as
prostacyclin), prostaglandin F2α (PGF2α), and
ronal ion channels, such as the transient
thromboxane A2 (TXA2). They can be released to
Pain is one of the cardinal signs of inflam- receptor potential vanilloid 1 (TRPV1) function as signaling mediators via
mation. It protects affected parts of the channel. Likewise, prostanoids can in- activation of their G protein-coupled receptors.
body during inflammation by increasing crease the activity of the sodium channel Transient receptor potential vanilloid 1 (TRPV1):
a ligand-gated ion-channel in sensory neurons
sensory sensitivity and avoiding exposure Na(v)1.9 [9], which can increase neuronal that can be activated by heat (>42°C), capsaicin
to noxious stimuli. But like inflammation, activity and lead to mechanical and ther- (the spicy component of chili peppers), and acidic
pain can lose its protective component mal hypersensitivity during inflammatory conditions (pH < 5.9). Its activity can also be
and become chronic [1]. Approximately pain. Inhibiting the synthesis of PGE2 and modulated by various signaling mediators,
including prostanoids; TRPV1 is strongly involved
20% of the global population is thought PGI2 with NSAIDs prevents the activation in physiological and pathophysiological pain
to be affected by chronic pain [2]. of their receptors, reducing mechanical processing.
and thermal hypersensitivity during inflam-
NSAIDs (see Glossary) are the most widely matory pain [10].
used pharmaceuticals for the treatment
of low to moderate pain, either by self- In early inflammation, prostanoids are
medication as over-the-counter drugs synthesized and released from invading against the transition to chronic pain [5].
or by prescription. The antihyperalgesic neutrophils and macrophages. During this This has been confirmed in preclinical
efficacy of NSAIDs is high compared phase, prostanoids exert their proalgesic pain models showing that treatment with
with other drugs. This is reflected by functions. However, these prostanoids ap- the NSAID diclofenac, but not other (co-)
their low number needed to treat (NNT) pear also to mediate the resolution of inflam- analgesics such as gabapentin, lidocaine,
as tested in acute postoperative pain mation [11]. These observations challenge or morphine, robustly extended the duration
(third molar extraction) [3]. But despite the concept of PGE 2 in particular being of mechanical hypersensitivity in mouse
their efficacy in the treatment of inflam- a strictly proinflammatory and proalgesic models of inflammatory and neuropathic
matory pain, NSAIDs can cause severe lipid mediator, highlighting its role in early pain. This process seems to depend on
side effects, mainly affecting the gastroin- inflammatory processes which then trigger the activity of neutrophils. Finally, the pain
testinal, cardiovascular, and renal sys- resolution of inflammation. trajectories of human patients with acute
tems. The risk of these side effects of back pain identified an elevated risk of pain
NSAIDs increases with higher doses and The transient neutrophil-driven upregula- persistence in patients taking NSAIDs. This
longer-term use [4]. tion of inflammatory responses protects implies that early treatment of acute pain

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with NSAIDs may lead to prolonged and treat pain acutely but on the other may of prostanoid levels in inflamed tissue or
chronic pain [5]. prolong pain and increase the risk of fluid of patients could be used to deter-
developing chronic pain. As a clinical mine the optimal therapeutic time point of
Likewise, PGE2 was found to be essential consequence, it might be helpful to NSAID reduction.
for the resolution of neutrophil-mediated treat early pain with drugs that do not
inflammation, and its activation of EP 4 influence neutrophil migration. This can Concluding remarks
receptors during injury caused a switch be achieved by replacing NSAIDs and We acknowledge that it is difficult, in di-
toward anti-inflammatory eicosanoid other anti-inflammatory drugs with pure an- verse clinical settings, to precisely deter-
signaling [8]. algesics that do not affect inflammatory mine the onset of inflammation before
processes. In later phases of acute inflam- switching analgesics according to the
In the context of neuroinflammation and mation, NSAIDs may be used to reduce treatment schedule suggested previously.
persistent pain, the activation of EP 2 inflammatory hyperalgesia but should then Also, precise threshold concentrations of
and EP4 receptors in spinal microglia by slowly be reduced to allow the proper prostanoids and threshold ratios of neutro-
PGE2 reduced proinflammatory cytokine resolution of inflammation and inflamma- phils to macrophages would be required
secretion in a preclinical model of neuro- tory pain. to enable therapeutic decisions. In many
inflammation [6]. The expression levels cases, it is also difficult to obtain inflamed
of these receptors increase during neu- For the treatment of early acute pain, we tissue or fluid that contains representative
roinflammation, so their activation by therefore suggest that clinicians consider populations of immune cells and media-
PGE2 triggers a negative feedback loop replacing NSAIDs with acetaminophen tors, which would be necessary for precise
to reduce inflammation and promote res- (paracetamol) for low levels of pain, with analysis. These analyses would also take
olution. Blocking PGE2 synthesis, for ex- dipyrone (metamizole) for moderate pain, too much time in case a quick therapeutic
ample, with NSAIDs, would suppress this and with an opioid such as morphine for decision has to be made.
pathway, prolong neuroinflammation, severe pain, as well as with sodium channel
and increase the risk of chronic pain [6]. blockers for local anesthesia (Figure 1). It should be mentioned that the previously
Another study showed that PGE2 - Adhering to this hypothetical therapeutic suggested alternative treatment options
dependent activation of the EP4 receptor scheme and restricting NSAID use to the acetaminophen/paracetamol, dipyrone/
strongly affects innate lymphoid cells, phase of maximum inflammation and in- metamizole, opioids such as tramadol or
promoting homeostasis and the produc- flammatory pain may serve two purposes. morphine, and sodium channel blockers
tion of IL-22, thus reducing systemic in- First, it would shorten the general treatment also have their own risks and side effects.
flammation [7]. Inhibiting this system with duration with NSAIDs, which would benefit For example, high doses of acetamino-
NSAIDs could suppress the PGE2-EP4- patients because most of the severe side phen are associated with liver toxicity [12]
IL-22-mediated anti-inflammatory response. effects of NSAIDs are associated with and dipyrone is banned in several coun-
Furthermore, PGE2 synthesis mediates the their long-term use. Second, it would not tries, because its use is associated with
anti-inflammatory effects during the resolu- influence the activation of neutrophils or agranulocytosis [13]. Moreover, the use of
tion phase of inflammation, which seem to early immune responses, allowing a more opioids can paradoxically lead to opioid-
be mediated by EP2 and EP4 receptors but physiological course of inflammation, in- induced hyperalgesia, [14] or may cause
may also involve other prostanoids [11]. cluding its resolution. The optimal window respiratory depression. These effects de-
In conclusion, there is evidence that of NSAID in patients may be determined mand a rational evaluation of analgesic
NSAID use can prolong inflammation by FACS analysis, for example, to deter- use in the individual clinical context.
and inflammatory pain while delaying res- mine the ratio of neutrophils to macro-
olution by suppressing PGE 2 synthesis phages in biological samples using Ly6G Here, our intention is to sensitize clinicians
and its anti-inflammatory effects. as a neutrophil marker and F4/80 plus and patients, encouraging them to differen-
Ly6C for macrophages. tiate the use of analgesics in early acute
Replacing NSAID therapy in early pain. We strongly recommend more phar-
acute pain In later phases, we suggest that NSAID macological and clinical research on this
In the context of pain, the aforemen- use should also be restricted to allow the subject because the differentiated and
tioned observations imply that interfer- prostanoid-dependent resolution of in- more precise use of analgesics leads
ence in prostanoid synthesis by NSAIDs flammation and inflammatory pain. During to a more personalized therapeutic ap-
in early acute pain, when inflammation is this phase, a second wave of prostanoid proach for the treatment of pain. A clinical
just starting, can on one hand effectively synthesis takes place [11]. The elevation investigation in this context could, for

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Trends in Pharmacological Sciences

Trends in Pharmacological Sciences

Figure 1. Suggested therapeutic scheme of NSAID replacement in early acute pain. Suggested therapeutic scheme for the treatment of early acute pain when
inflammation has not yet been initiated or is just beginning. NSAIDs could be replaced by acetaminophen (paracetamol) for low levels of pain, with dipyrone (metamizole) for
moderate pain, and with an opioid for severe pain, as well as with sodium channel blockers for local anesthesia to allow neutrophil migration and activation. NSAID use
could be restricted to the acute inflammatory phase and slowly decreased in the resolution phase. Abbreviation: NSAID, non-steroidal anti-inflammatory drug.

example, consist of conducting a postoper- Fraunhofer Society and the Hessian Ministry of Higher 5. Parisien, M. et al. (2022) Acute inflammatory response via
neutrophil activation protects against the development of
ative pain management trial giving NSAIDs Education, Research and the Arts. We acknowledge chronic pain. Sci. Transl. Med. 14, eabj9954
Dr Richard M. Twyman for manuscript editing. 6. Brenneis, C. et al. (2011) Anti-inflammatory role of microsomal
or the aforementioned alternative therapeu-
prostaglandin E synthase-1 in a model of neuroinflammation.
tics at different doses to the patients and J. Biol. Chem. 286, 2331–2342
Declaration of interests 7. Duffin, R. et al. (2016) Prostaglandin E2 constrains systemic
monitoring postoperative pain with visual
inflammation through an innate lymphoid cell-IL-22 axis.
analogue scale, questionnaires, or quantita- No interests are declared. Science 351, 1333–1338
tive sensory testing (QST). To assess post- 8. Loynes, C.A. et al. (2018) PGE(2) production at sites of
1
pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, tissue injury promotes an anti-inflammatory neutrophil
operative quality of recovery and the effect Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, phenotype and determines the outcome of inflammation
of each treatment on the transition from Germany resolution in vivo. Sci. Adv. 4, eaar8320
2
Fraunhofer Institute for Translational Medicine and 9. Rush, A.M. and Waxman, S.G. (2004) PGE2 increases the
acute inflammation to resolution, immune Pharmacology ITMP, and Fraunhofer Cluster of Excellence for tetrodotoxin-resistant Nav1.9 sodium current in mouse
cells, cytokines, and chemokines could Immune Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596 DRG neurons via G-proteins. Brain Res. 1023, 264–271
10. Jang, Y. et al. (2020) Molecular mechanisms underlying
also be measured in inflamed tissue in a nar- Frankfurt am Main, Germany the actions of arachidonic acid-derived prostaglandins on
row timespan after surgery. This could be *Correspondence: peripheral nociception. J. Neuroinflammation 17, 30
11. Schmid, T. and Brune, B. (2021) Prostanoids and resolu-
combined with a broader approach to im- Marco.Sisignano@med.uni-frankfurt.de (M. Sisignano). tion of inflammation - beyond the lipid-mediator class
plement multi-omics analysis [15], helping https://doi.org/10.1016/j.tips.2023.01.001 switch. Front. Immunol. 12, 714042
12. Yan, M. et al. (2018) Mechanisms of acetaminophen-
us to understand and manage chronic © 2023 Elsevier Ltd. All rights reserved. induced liver injury and its implications for therapeutic
pain in patients while reducing the individual interventions. Redox Biol. 17, 274–283
13. Hoffmann, F. et al. (2020) Agranulocytosis attributed
burden of this disease. References to metamizole: an analysis of spontaneous reports in
1. Woolf, C.J. (2020) Capturing novel non-opioid pain targets. EudraVigilance 1985-2017. Basic Clin. Pharmacol. Toxicol.
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Acknowledgments 2. Cohen, S.P. et al. (2021) Chronic pain: an update on 14. Colvin, L.A. et al. (2019) Perioperative opioid analgesia-
The work of the authors was supported by the German burden, best practices, and new advances. Lancet 397, when is enough too much? A review of opioid-induced
2082–2097 tolerance and hyperalgesia. Lancet 393, 1558–1568
Research Foundation (DFG) grants SFB1039 A09 3. Jones, P. et al. (2020) Oral non-steroidal anti-inflammatory 15. Diatchenko, L. et al. (2022) Omics approaches to discover
and Z01, from the Fraunhofer Foundation Project drugs versus other oral analgesic agents for acute pathophysiological pathways contributing to human pain.
Neuropathic Pain and the Fraunhofer Cluster of soft tissue injury. Cochrane Database Syst. Rev. 8, Pain 163, S69–S78
CD007789
Excellence for Immune-Mediated Diseases (CIMD).
4. Bindu, S. et al. (2020) Non-steroidal anti-inflammatory
The authors are also supported by the Leistungszentrum drugs (NSAIDs) and organ damage: a current perspective.
Innovative Therapeutics (TheraNova) funded by the Biochem. Pharmacol. 180, 114147

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