Summary Non-steroidal anti-inflammatory drugs (NSAIDs) are the first line treatment of acute or recurrent pain and often remain the prerogative of the primary care physician if not the patient himself on self-administration. The beneficial and side effects are widely known, however in recent years scientific evidence has made new and interesting contributions that deserve to be made known also and especially in the specialistic field. Rational use and patient selection criteria are important to optimize clinical outcome and minimize risk.
Riassunto Gli antinfiammatori non steroidei (FANS) sono in prima linea nel trattamento del dolore acuto o ricorrente e spesso restano appannaggio del medico di medicina generale se non del paziente stesso in automedicazione. Gli effetti benefici e quelli collaterali sono ampiamente noti; tuttavia, negli ultimi anni, l’evidenza scientifica ha apportato nuovi e interessanti contributi che meritano di essere resi noti anche e soprattutto in ambito specialistico. L’uso razionale e i criteri di selezione del paziente sono importanti per ottimizzare il risultato clinico e minimizzare i rischi.
Key words NSAID, nociceptive pain, side effects, pain management
Parole chiave FANS, dolore nocicettivo, effetti collaterali, trattamento del dolore
In the last decade, studies on analgesics have placed the emphasis on opioids and their problems, and the research in cannabinoids field has recently become popular again. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most studied and most used/abused drugs, especially through self-medication; because of this, NSAIDs have lost importance in specialized medicine and now are almost exclusively of general practitioners. In this review we try to identify target and rationale for the use of NSAIDs relying onthe latest scientific evidence.
As early as 19711we are aware on prostanoids’ effects and the main NSAIDs adverse effects; its depend on inhibition (more or less marked) of constitutive cyclooxygenases (COX-1) or inducible cyclooxygenases (COX-2). The criteria that lead the choice of an antinflammatory drug are often based on clinician experience, being usually the first pharmacological line against pain event. The duration of treatment has contracted due to the phenomena of abuse found, especially in the elderly population.3 It therefore seems appropriate to reflect on criteria to be used to optimize the benefit and minimize the risks: when, why and how.
Spinal degeneration and osteoarthritis are the most common causes of pain in elderly. They are often treated with NSAIDs,4although it is not always correct to use these drugs.
NSAIDs are antinociceptive drugs and therefore their peripheral action is prevalent. The use of Fans should therefore be reserved for forms of nociceptive inflammatory pain, then the forms in which prostaglandin release occurs.4-6,26
The inflammation of a tissue determines release of various mediators including cytokines, bradykinins, H + ions and prostaglandins. This involves a series of effects on nociceptors;7for example, activation of protein Kinasi C, which in turn phosphorylates the TRPV1 receptor channel, reducing its activation threshold and protein Kinasi A which reduces the activation threshold of voltage channels dependent on the Na +. These processes have in common the increased probability of generating nociceptor hyperexcitability and therefore the appearance of primary allodynia, which can lead to the spontaneous activation of the nociceptor: an example of this process is nociceptor activation by body temperature.
Hyperexcitabilitycondition can be reduced by specific drugs reducing prostanoidssynthesis and restoring the physiological threshold: they are NSAIDs and steroids. However, the mediators produced by phlogosis are not just prostaglandins: therefore an antiprostaglandin drug does not always return a nociceptor to a normal threshold; in fact there are monoclonal antibodies, such as anti-TNFα, 6 which act on other components but which can only be used for certain pathologies.
Steroids also work on cytokines production; then their anti-inflammatory activity is certainly greater8as well as anti-edema and anti-chemotactic effects.
In rheumatic disease chronic pain, it should also reflect on treatment with NSAIDs (prevalent action on prostaglandins) instead of steroid therapy, thus favoring action on cytokines.
The effect of NSAIDs does not end in the nociceptive terminal, but occurs in central nervous system (CNS). For example, at pre and post-synaptic level, PgE2 facilitates glutamate release and spinal neuron activation and reduces glycine release from inhibitory neurons.9-18
Many studies have demonstrated the central effects of Fans: among these, those have placed the emphasis9-18 on tolerance to Nsaids and on cross-tolerance to opioids in raphe magno, amygdala, hippocampus, periaqueductal gray (PAG) and - more recently - in the anterior cingulate cortex (CCA).18In this last study the pre-treatment with naloxone prevents the analgesic effect induced by NSAIDs in CCA, indicating that part of NSAIDseffect is mediated by endogenous opioid pathway, with a possible role of descending inhibitory system.
Despite these findings, the use of these drugs in neuropathic pain is controversial: a recent study19indicates that the evidence remains very mild, confirming the results of previous studies. Two of them tested the efficacy on neuropathic pain of GW406381, a very effective NSAID in inflammatory pain and some NSAIDs in combination or not with pregabalin: the results are unfavorable for use in neuropathic pain. The discrete response in some forms of neuropathic pain may be linked to inflammatory reaction that in some cases occurs: prostaglandins amplify Na + currents and Ca2 + intake in peripheral nociceptors, facilitating neurotransmittersrelease and depolarization. The result is peripheral and central hypersensitization that occurs in nerve lesions associated with inflammation; indeed, in animal models, NSAIDs have shown they can reduce central hypersensitization.
Therefore, in neuropathic pain the Fans could be used in the presence of an ectopic site along the somatosensory pathway involved in an inflammatory process; an example is the exit of nucleus pulposus from intervertebral disc with consequent radicular/peridural irritation and the onset of inflammation.19
NSAIDs are justified by pathophysiological mechanism (reduced nociceptors threshold on phlogistic basis), but also by evidence of efficacy. The latest studies on patients suffering from rheumatic diseases and degenerative pathologies are favorable to their use.20-23The reason is simple: joint inflammation leads to increased pain, disability and joint damage. Chronic inflammation (persistent stimulus, carried by C fibers) leads to central sensitization,24involves the limbic system and can determine dysfunction of descending inhibitory pathways.25These factors worsen prognosis and quality of life of patients suffering from osteoarthritis and rheumatic diseases, and who attend pain therapy centers.26
The same guidelines are agreed in the step-by-step approach:27start with paracetamol; test the response to topical NSAIDs first, use combination therapy to reduce the side effects of individual drugs related to higher doses.About to topical drugs, diclofenac patch showed greater effectiveness (pain reduction) and piroxicam greater benefit (functional outcome);28topical NSAIDs have mild systemic effect.
Some studies indicate that NSAIDs seem to work better than opioids to alleviate pain in some diseases. The randomized SPACE study29compared chronic pain management in patients with back pain, hip arthrosis and knee in two groups: opioid therapy and non-opioid therapy (NSAIDs + adjuvants)..Results at 12 months indicate better pain control and a slight improvement in BPI (Brief Pain Inventory) with non-opioids, and functionality is similar in two groups.These results require a reflection on pharmacological chronic pain management. It must be considered that some preliminary studies on resolvins, protectins and maresines -lipid mediators derived from polyunsaturated fatty acids (PUFAs) with key role in phlogosis resolution- seem to indicate that some NSAIDs may interfere with wound healing process.30
NSAIDs have specific mechanism of action and should be used in the right context; current international guidelines are favorable to their use and one last assessment remains: how to prescribe them. The latest scientific evidences confirm the known side effects, partially deny or reconsider the others.
Bone healing is guaranteed by remodeling, between osteoblasts and osteoclasts, which allows the generation of a completely new healthy bone tissue.31An hematoma is formed in the lesion; here an inflammatory and coagulative response takes place and allows repair: an early phase characterized by high concentrations of granulocytes and monocytes/macrophages and by elevated levels of cytokines (in particular IL-6, IL-8 and TGF), which in turn stimulate the differentiation of mesenchymal cells (condro and osteogenic lines) leading to the formation of a soft and then calcareous callus. This process can be inhibited or become incomplete due to various factors including NSAIDs as demonstrated by various studies.32Studies on knockout mice for gene that codes COX-1 show no change in healing bone; instead mices lacking COX-2 gene exhibit a worsening of bone welding, or a failure to merge the stumps.33 COX-2 enzyme plays an important role in osteoblast differentiation during healing of bone tissue.32,33
Inhibition of COX-2 prevents β-catenin production, important for osteoblast precursors differentiation and proliferation.34 Then, phlogosis can reduce the damage (ex articular) but it could make facilitate the onset of microfractures (ex Modic of vertebral bodies)or more serious injuries. In particular, a short-term treatment (7 days) can delay healing, and a prolonged treatment could prevent bone welding.35At the same time, NSAIDs seem to improve tissue healing around the fracture by stimulating collagen synthesis;36,37furthermore, prostaglandin inhibition reduces pathological bone growth and heterotopic ossification,39particularly important for example after hip surgery. A study seems to indicate that ibuprofen improves bone trabeculation.39It must be considered that opioids also seem to reduce the strength of the callus.40,41
In bone fractures, it may be prudent to limit the use of NSAIDs to a few days and in low doses, not only for what has been said about the mediated COX-2 mechanism, but also to allow resolvines to carry out their work correctly.30
NSAIDs interfere with mitochondrial respiration and beta-oxidation by converting non-esterified fatty acids to triglycerides. Thus it is possible to have steatosis and the production of Reactive Oxygen Species (R.O.S.), which can happen if it is pre-existing hepatosis: in the most severe cases hepatic necrosis can develop.42 We must remember that hepatotoxicity does not only concern acetaminophen.
Renal risks are widely known: water retention, arterial hypertension, heart failure and acute renal failure. COX-1 is omnipresent and plays an important role at the level of the glomerulus and in the afferent and efferent arteries (in particular there may be changes in the glomerular filtration rate) and in the distal tubules. Patients especially the elderly, nephropaths and heart patients are at risk.
Indomethacin appears to have a higher incidence of renal side effects, with a relative risk (RR) of 2.23 followed by ibuprofen RR 1.73; naproxen RR 1.37 and celecoxib RR 1.00.43
In recent years, several studies have been published on the inflammatory pathogenesis of some degenerative pathologies: the use of NSAIDs, for example, has been associated with a delay in the onset of Alzheimer's in high-risk families44despite some conflicting studies on the use of Fans long term.45 Parkinson's disease also appears to benefit from coxib therapy.46
Waddell and Hsu have shown anti-cancerous activity of NSAIDs, for example the protective effect on colorectal cancer of sulindac and indomethacin47 and induction of celecoxib apoptosis in prostate cancer cell lines.48 COX-2 is found in high doses in many cancerous tissues and appears to control several cellular processes.49
Gastrointestinal risks (GI) related to COX-1 inhibition are also known:50, 51 reduction of mucous blood flow and mucus and bicarbonate secretion, together with the alteration of platelet aggregation, increase the risk of bleeding. These risks affect all NSAIDs. Elderly patients with history of dyspepsia or peptic ulcer bleeding have more risks of acute bleeding events. The risk is dose-dependent.51 Lanas and Bhatt detected that 60-80% of acute hospitalized emergency bleedings did not show any warning signs: therefore a protective approach should be adopted.52, 53 Proton pump inhibitors (IPP) significantly reduce the risk of gastroduodenal ulcer during chronic NSAID therapy;54 in 2006 celecoxib and IPP in patients with high risk of bleeding was recommended (follow-up for bleeding at 13 months: 8.9% in patients with celecoxib, 0% in patients adding PPIs).55
However, also PPIs are not risk-free (C. difficile infection, interstitial nephritis, increased fractures in women, impaired vitamin and mineral absorption, increased CV risk and drug interactions due to action on hepatic cytochromes). Anti-H2 and misoprostol are also potential protectors of gastric mucosa; standard anti-H2 doses did not show statistically significant efficacy56and misoprostol had a high incidence of diarrhea.57
It is useful to distinguish between upper gastrointestinal tract bleeding(UGI) and lower (LGI): in fact PPIs (but also anti-H2 and sucralftate) do not provide any protection from LGI noxoius risks.50-54 NSAIDs are weak acids, lipophilic and therefore with detergent properties (due to the interaction with membrane phospholipids); these properties cause direct damage to intestinal epithelial surface.58 A capsular endoscopy study has shown macroscopic lesions in 70% of healthy volunteers after 2 weeks of diclofenac therapy;59 we must add that LGI complications are more frequent and more serious (mortality rate, extension of hospital stay and required diagnostic tests).
The randomized CONCERN study61 compared celecoxib and naproxen in patients with cardiothrombotic diseases and arthritis who had presented bleeding UGI: celecoxib had a 50% GI risk compared to naproxen, while the cardiovascular risk (CV) was similar; celecoxib is always indicated as the safest drug by the PRECISION study,62from CV point of view. A 2016 meta-analysis63 compared NSAIDs and placebos. The results indicate diclofenac (RR 1.89) and coxibs (RR 1.81) as less harmful than ibuprofen (RR 3.97) and naproxen (RR 4.22); however for the LGI etoricoxib tract it has the same risks as non-selective NSAIDs.58A recent review are extremely protective: a PPI would be necessary whenever it is possible and it always advisable using celecoxib except when GI and CV risksare low: only in this case the clinician would be authorized to use any other FANS.50We must also evaluate other aspects, including efficacy: pain relief and anti-inflammatory effect to chose NSAID, as we will see later.
One of the main problems in using these drugs is the co-presence of CV diseases and pain in the elderly. It needs to be clarified whether patients use cardioaspirin (ASAc). Six large multicenter studies64 have shown a reduction in mortality in those who use ASAc (although the latest recent opinion is conflicting),65 so all reference guidelines recommend it for cardio-brain prevention. Many elderly take it in conjunction with other NSAIDs and in the USA 16% of ASAc users take chronic NSAIDs.66 The pharmacodynamic interaction between ASAc and NSAIDs exists but the interactions vary depending on the timing of doses, the dose of ASAc and of NSAIDs.66-70
Arachidonic acid accesses the COX-1 platelet catalytic site from a hydrophobic channel and ASAc irreversibly acetylates a serine residue inside the COX-1 and close to the catalytic site, blocking access to arachidonic acid and thus preventing platelet aggregation.71Most NSAIDs (except diclofenac, ketorolac and acetaminophen72) inhibit catalytic site, but unlike ASAc they do so reversibly. When a NSAID is present in platelet ASAc fails to access the serine target.71The half-life of ASAc is 15-20 minutes;73 within one hour with 100 mg dose is able to inhibit 98% of thromboxanic activity.71 If ASAc is taken after a single dose NSAID, for example ibuprofen 400mg two hours before75(or this drug is taken daily) the result will be the lack of anti-aggregation effect. If single NSAID is administered 2 hours after ASAc the effect of the latter remains unchanged. The data is relevant: in case of ineffectiveness CV and cerebral protective effect (thrombosis) is missing,75,76 despite two meta-analyzes have not replicated these results.77,78The half-life of ASAc is 15-20 minutes;73 within one hour a 100 mg dose is able to inhibit 98% of thromboxanic activity.66 An additional possibility is to use aspirin with anti-inflammatory dosages instead of anti-aggregation agents.79
Another consideration is about coxibs (selective COX-2 inhibitors).
Mechanisms of platelet aggregation and vasoconstriction that lead to the prothrombotic effect of thromboxane (TxA2)are well known,80 as known is the release of nitric oxide (NO), vasodilation and inhibition of platelet aggregation of prostaglandin I2 (Pg2) with the resulting antithrombotic effect. The TxA2 produced by COX-1 in platelets is inhibited by ASAc, endothelial PgI2 is inhibited by coxibs (action on COX-2, not present in platelets) with consequent imbalance between the two enzymes and therefore increased thrombotic risk. Nevertheless some recent studies indicate that this increase in risk is not so marked.60,61
There are many differences from drug to drug and not just on the basis of selectivity. In vitro etodolac is more “coxib” than celecoxib,81 but has a chemical structure of a carbo- or heterocyclic acid such as indomethacin or ketorolac.82 The same selectivity for COX-2 varies from drug to drug: for example etoricoxib, valdecoxib and lumiracoxib are more selective than the progenitor celecoxib. Other mechanisms may also influence the CV risk: rofecoxib has pro-oxidative activity (potentially pro-atherosclerotic) and in part etoricoxib,83 and celecoxib presents a sulfonamide group that reduces the expression of endothelial tissue factor with potentially protective effect on the risk of thrombosis.
All NSAIDs are inducers of R.O.S. (Reactive Oxygen Species) in cardiac cells, with potential cardiotoxicity.84
The latest studies indicate that NSAIDs and coxib CV events are similar, but coxibs are more tolerated under the GI profile (Precision study);62 in addition celecoxib generally has fewer side effects than other NSAIDs (Concern study)61 also in case of renal risk.43 Celecoxib on the tolerability profile remains among the first places.85-87 The Medal program study87 had already focused on the absence of differences in CV risk between etoricoxib and diclofenac, as far as etoricoxib lead to a rise in blood pressure.
CV risk of selective NSAIDs seems to depend on doses rather than on the duration of treatment.50This is an important point, as usually the prescription of Fans, because of the risks mentioned above, is always reduced to a few days therapy: although the principle of "primum non nocere" remains valid, we have to evaluate the risk-benefit ratio for each patient; for example the risk of AMI is similar in patients on therapy for a few days or for more than a month and increases significantly with the increase in dosage.50,62 In Precision study the safety profile in the long term in NYHA class patients I and II was acceptable,62 and joint damage should not be overlooked in rheumatic diseases such as rheumatoid arthritis, where the functional prognosis is severely impaired and therefore long-term use is often decisive. Finally it should be remembered that ketorolac has shown a greater incidence of AMI compared to other NSAIDs and in other European and non-European countries it has been banned; diclofenac also has a higher risk of AMI than other NSAIDs, but less than ketorolac.88
Effectiveness and final algorithm
The latest studies indicate celecoxib as one of the safest and most tolerant gastrointestinal NSAIDs and naproxen seems safe enough for CV risk, despite the conflicting results of some studies such as CONCERN,61,88in which the authors suggest avoiding naproxen in case of high GI risk and associated CV.
A large meta-analysis of 201789 compares NSAIDs in a forrest plot: diclofenac 150 mg appears to be one of the most effective NSAIDs in reducing perceived pain and function, followed by etoricoxib (but already with a lower statistical reliability); with regard to diclofenac, the study on topical NSAIDs28 had already demonstrated its validity.
If we wanted to hypothesize an algorithm to combine efficacy and prudence, an important metanalysis90(Table 1) highlighted the lower number of GI complications in patients on diclofenac and coxib therapy, while CV risk seems to increase with all NSAIDs in a similar way except for naproxen: on this basis it has indicated a flow chart that divides the therapy to be administered based on the GI and CV risk (Figure 1).
Low risk GI patients
CV risk low: you can use any NSAID; CV risk high: NSAIDs are not recommended; if necessary, no ASAc patient can take naproxen (or celecoxib, NdA) max 18 months therapy; patient who takes ASAc: diclofenac with IPP, max 18 months.
Intermediate risk GI patients
Risk factors: previous acute events of upper GI tract, >65 years, chronic use of NSAIDs and concomitant therapy with ASAc/anticoagulants /corticosteroids:
CV risk low: any NSAID with IPP or alternatively coxib or diclofenac without IPP; CV risk high: NSAIDs should be avoided; if really necessary in no ASAc patient: naproxen with IPP (or celecoxib with IPP, N.d.A.) max 18 months; if patient uses ASAc: diclofenac with IPP max 18 months.
High risk GI patients
CV risk low: diclofenac or coxib with IPP; CV risk high: avoid NSAIDs or if indispensable and not in therapy with ASAc: diclofenac or celecoxib with PPI for a duration less than 18 months; if in therapy with ASAc, avoid NSAIDs.
NSAIDs are among the most widely used anti-inflammatory and analgesic drugs, but the criterion is not always the most appropriate. The elective indication of NSAIDs is acute inflammatory nociceptive pain or during exacerbation; however rheumatic diseases often require the doctor to use these drugs chronically. If necessary (so whenever there are one or more gastrointestinal risk factors) you must protect the stomach if not contraindicated and remember the risks to the intestine, which are not preventable. NSAIDs that do not interact with antiplatelet activity can be used in patients taking cardioaspirin. In patients with gastrointestinal and / or cardiovascular risk it appears prudent to follow an algorithm as already mentioned, more generally, in case of high risk it is always better to avoid them. Finally, new technologies are being studied in an attempt to increase security; NSAIDs that release nitric oxide (NO) and hydrogen sulfide (H2S) protecting the gastric mucosa; NSAIDs that use nanotechnology for better absorption and lower toxicity.91
Conflict of interests
The authors certify the scientific work was conducted without conflicts of interests and that they actively contributed to its realization.
8) Schimmer B et al. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In : Hardman JG, Limbird LE : Goodman & Gilman’s - The Pharmacological Basis of Therapeutics 10th Edition. New York: McGraw-Hill 2001. p.1649-1677.
14) Vanegas H et al. The periaqueductal gray as critical site for antinociception and tolerance induced by non-steroidal anti-inflammatory drugs. In: Maione S, Di Marzo V, editors. Neurotransmission in the Antinociceptive descending pathway. Kerala: Research Signpost 2007. p. 69–80.
53) Bhatt DL et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2008; 52(18):1502–1517.
79) Fornasari DMM et al. Dolore infiammatorio acuto in pazienti a rischio cardiovascolare in terapia con aspirina a basse dosi: una possibile opzione e un’ipotesi suggestiva. Rivista SIMG 2017; (5):56-64.
80) Antman EM et al. Cyclooxygenase inhibition and cardiovascular risk. Circulation 2005 Aug 2; 112(5):759-70.