Pain (dolor), swelling (tumour), redness (rubor) and overheating (calor) are the cardinal symptoms of inflammation and are therefore found in various locations in most patients with rheumatic diseases.
The effect of willow bark (Salix) against these symptoms was already known in ancient times. However, it was not until the middle of the 19th century that salicin was isolated from willow bark and a little later an oxidised form of salicin, salicylic acid, was widely used clinically.
After Felix Hoffmann succeeded in synthesising acetylsalicylic acid (ASA), better known under the trade name "aspirin", this in turn replaced salicylic acid due to its less bad taste and better tolerability. Over time, other substances (e.g. diclofenac, ibuprofen) with similar effects were discovered and labelled together with ASA as NSAIDs.
However, it was not until 1971 that John Vane discovered the inhibition of the enzyme cyclooxygenase (COX) as a possible mechanism of action of ASA and other NSAIDs. And the discovery that there are two isoforms of COX, namely COX1 and COX2, which differ in that the expression of COX2 is induced by inflammatory stimuli, while COX1 is constitutively present in most cells, has further increased the understanding of the effects and side effects of NSAIDs. Non-selective NSAIDs, which inhibit COX1 and COX2 equally, and these include most of the NSAIDs in use today, therefore differ from selective COX2 inhibitors in terms of their side effect profile. However, the analgesic potency of both substance classes is the same. This is an important indication that prostaglandin synthesis by COX2 is responsible for inflammation and pain.
Effects of NSARs
The main mechanism of action of NSAIDs can be explained by the inhibition of prostaglandin synthesis. Prostaglandins are derivatives of polyunsaturated fatty acids. They are formed in many different tissues, hence the name tissue hormones, in response to all kinds of stimuli and play an important role in pain and inflammatory reactions, among other things. The parent substance of prostaglandins is prostaglandin H2 (PGH2), which is formed from arachidonic acid by the enzyme COX. In a further step, prostaglandin I2, prostaglandin E2 and prostaglandin F2 as well as thromboxane A2 are formed from PGH2. NSAIDs therefore have an anti-inflammatory effect, as they inhibit the binding of arachidonic acid to COX.
Among the prostaglandins, PGE2 is considered to be the most important in the context of inflammatory processes. PGE2 not only leads to an increase in vascular permeability and thus to tissue swelling (tumour) and associated erythema (rubor), but also to hyperalgesia (intensification of pain, dolor) in the context of inflammatory processes.
Fields of application of NSAR
In ankylosing spondylitis, it has been shown that NSAIDs have an influence on the course of the disease in terms of a reduction in radiological changes. They are therefore used in this disease as a basic therapy (= therapy that positively influences the course of the disease). In other rheumatic diseases such as chronic polyarthritis, however, NSAIDs have no influence on the actual course of the disease (e.g. prevention of bone destruction). Here, NSAIDs cannot replace therapies that can stop joint destruction (e.g. methotrexate, leflunomide). However, as methotrexate, as well as the other basic therapies for chronic polyarthritis, only develop their full effect after a few weeks and the disease can be accompanied by massive pain symptoms at the beginning, NSAIDs are important drugs for initial pain control.
Side effects of NSAIDs
NSAIDs can cause side effects in many different organs. Most side effects can be explained by the inhibition of the synthesis of prostaglandins, which not only have a pathogenetic effect in the context of inflammation, but are also important for physiological functions.
Gastrointestinal side effects of NSAIDs
One of the most important side effects of these substances is their potential to damage the mucous membrane of the digestive tract and thus cause ulcers. Several strategies have been developed to combat this side effect. Firstly, it is important to realise that the ulcerogenic effect of NSAIDs depends on the dose and the length of time they are taken. This means that therapy with NSAIDs should be kept at the lowest possible dose and as short as possible. With proton pump inhibitors (PPI) and the prostaglandin analogue misoprostol, there are further therapeutic concepts to counteract the peptic side effects of NSAIDs. With regard to the newer selective COX2 inhibitors, large studies have shown that the risk of developing a gastrointestinal ulcer with these drugs is lower than with non-selective COX inhibitors. However, it should be noted that there is no advantage of COX2 inhibitors with regard to other gastroprotective strategies, e.g. combination of non-selective COX inhibitors with PPIs, and that COX2 inhibitors are by no means recommended for existing ulcers.
Renal side effects of NSAIDs
Prostaglandins are also important for renal blood flow and for the electrolyte and water balance. The inhibition of renal prostaglandins by NSAIDs can therefore lead to the development of peripheral oedema, electrolyte imbalance, an increase in blood pressure or a deterioration in renal function. Patients with pre-existing poor kidney function are particularly at risk of developing acute kidney failure when taking NSAIDs. This also applies to the specific COX2 inhibitors.
Hepatic side effects of NSAIDs
In up to 15% of patients taking NSAIDs there is a minimal, and in up to 1% a significant increase in liver values (up to threefold increase). However, few cases of severe hepatic side effects, such as fatal, fulminant hepatitis, liver necrosis or liver failure have been described. It is therefore recommended to check the liver values shortly after starting treatment with NSAIDs.
Asthma and allergic reactions
In general, all NSAIDs can lead to hypersensitivity, such as skin reactions, angioedema, urticaria and anaphylactic reactions. It is also important to know that 10-20% of patients with asthma have a hypersensitivity to NSAIDs. This can lead to a severe worsening of asthma ("aspirin-exacerbated respiratory disease", AERD). Interestingly, specific COX2 inhibitors have been shown not to lead to worsening in patients with AERD.
Cardiovascular side effects
The development and widespread use of COX2 inhibitors raised major concerns about cardiovascular side effects of NSAIDs after the drug rofecoxib was withdrawn from the market due to cardiovascular side effects. Whether the remaining COX2 inhibitors have a higher risk of cardiovascular side effects than non-selective COX inhibitors is still controversial. In general, however, NSAIDs should be used with caution in patients with heart failure.
In terms of their anti-inflammatory and analgesic potency, NSAIDs are indispensable drugs in rheumatology, taking into account their side effects. However, NSAIDs usually have no influence on the actual course of the disease and can therefore not replace a basic therapy such as methotrexate, which often only develops its full effect after a few weeks, but can initially lead to rapid pain relief due to their rapid onset of action.