Can one use ‘any NSAID’ or ‘any painkiller’? – the consequences of poor treatment decisions

In this article, you will learn:

• Why the choice of an NSAID or another painkiller should not be left to chance, and on which characteristics of the patient and the pain it should depend
• What role do multimorbidity, polypharmacy, the patient’s age and organ failure play in the choice of NSAIDs?
• how the volume of distribution of a drug affects its penetration into tissues and its analgesic and anti-inflammatory efficacy
• Why is it necessary to take renal function and cardiovascular diseases into account when using NSAIDs?
• How important are a particular NSAID’s metabolic pathway and potential interactions with other medicines when choosing it?
• Why, in patients with multiple conditions, the choice of analgesic should be tailored to the individual and take into account the patient’s overall medication regimen

Abstract

Non-steroidal anti-inflammatory drugs and painkillers are among the most commonly used groups of medicines, and not only amongst older people. The choice of an anti-inflammatory drug must not be left to chance, whilst the choice of a painkiller must take into account the type of pain, the mechanism by which it arises and its severity. An inappropriate therapeutic decision can lead to serious complications, including kidney damage, adverse effects on the cardiovascular system and, above all, ineffective pharmacotherapy. Poor therapeutic decisions may also result in clinically significant drug interactions, particularly in patients with multiple comorbidities and, consequently, those on multiple medications. It is therefore essential to tailor pharmacotherapy to the individual and not to simply select ‘any’ anti-inflammatory or analgesic drug.

Keywords

NSAIDs, paracetamol, metamizole sodium, cytochrome P450

The results of the analyses carried out indicate that one of the most commonly used groups of OTC medicines by Polish patients includes, amongst others, non-steroidal anti-inflammatory drugs, and that the most popular method of alleviating many ailments ‘on one’s own’, without consulting a doctor, is self-medication. This approach often leads to numerous errors in the administration of medication. The solution to this problem lies in consulting a doctor or pharmacist at an early stage regarding the correct dosages of medicines and permissible, safe combinations of medicines. Unfortunately, NSAIDs are available not only in pharmacies but also in supermarkets and at petrol stations – places where storage conditions are not monitored and where patients are unable to consult a specialist.

The answer seems straightforward – the choice of medicine must take into account the pharmacokinetic and pharmacodynamic profile, the mechanism of pain, its location and intensity, as well as the characteristics of the patient in whom the medicine is to be used. The choice of medication cannot be arbitrary, and ‘just any’ NSAID will often fail to produce the desired effect. Personalisation in the choice of medication is a very important aspect that must always be taken into account, not only to improve the patient’s quality of life, but also to reduce the risk of sensitisation and secondary hyperalgesia, which are associated with the chronicity of pain. Furthermore, the majority of patients with pain who require NSAIDs are those with multiple co-morbidities and the resulting polypharmacy. Medicines used to treat other medical conditions may alter the analgesic and anti-inflammatory effects of the NSAID being taken, as well as increase the risk of clinically significant drug interactions. Therefore, in the case of a patient with multiple comorbidities, any modification to pharmacotherapy (such as the addition of an NSAID) must be considered in the context of their comorbidities; in practice, this means that treating multimorbidity in isolation is a serious error – Table 1 [1]. Other factors that must be taken into account when selecting the most effective and safest drug include the patient’s age and organ failure. Older patients are much more likely to suffer from pain, which is treated with NSAIDs, metamizole sodium or paracetamol. As for the latter, it should be borne in mind that it is not always possible to replace NSAIDs with paracetamol. It will, of course, be ineffective for inflammatory pain, but also
for visceral pain. The latest guidelines also do not recommend the use of paracetamol as a painkiller in patients with osteoarthritis [2].

Of course it does – the value of this pharmacokinetic parameter, amongst others, determines the analgesic and, in particular, the anti-inflammatory efficacy of NSAIDs. The volume of distribution, defined as the hypothetical volume of body fluids in which, after uniform distribution, the administered drug would achieve the same concentration as in the blood, is a pharmacokinetic parameter characterising the distribution of the drug within the body. In practice, if its value is < 7 l (approx. 10% of body weight), this means that the drug is distributed only within the vascular bed; Vd = 7–20 l (approx. 30% of body weight) – indicates that the drug penetrates into the extravascular space and is distributed in extracellular fluids; Vd = 20–40 l (approx. 60% of body weight) – this indicates that the drug is distributed throughout the body’s total water content, whereas when Vd is > 40 l, this indicates that the drug binds extensively to intracellular structures and is distributed to peripheral tissues, where it may accumulate. This parameter is of particular importance when key factors in the selection of NSAIDs include the drug’s penetration into peripheral tissues affected by inflammation and the duration of the drug’s presence in these tissues (the higher the Vd value, the better the drug’s penetration into peripheral compartments), those in which the ongoing inflammatory process is the direct cause of nociception – Table 2 [3].

Among the many adverse effects that may result from frequent use of NSAIDs, renal dysfunction is one of the most notable. Although drugs in this group are relatively safe, their unmonitored use – particularly in patients with hypovolaemia, nephropathy, diabetes, cardiovascular diseases, geriatric patients, and patients taking drugs with nephrotoxic potential, may lead to renal adverse effects – Table 3 [4]. These include: interstitial nephritis, acute tubular necrosis, acute renal failure, chronic renal failure, renal papillary necrosis and asymptomatic renal dysfunction.

It is worth noting here that recent years have seen an increase in the incidence of cardiovascular disease; consequently, the choice of NSAIDs must also take into account patients with these conditions. It is therefore worth bearing in mind that in patients taking acetylsalicylic acid (at antiplatelet doses), there are no pharmacokinetic interactions when ketoprofen or dexketoprofen are used. Drugs characterised by a low risk of interaction with antiplatelet agents include coxibs and nimesulide. Diclofenac and aceclofenac are not recommended for use in patients who have had a stroke, acute coronary syndromes, coronary artery disease or heart failure.

When deciding which specific NSAID to choose, it is also important to bear in mind the pharmacokinetic interactions that may occur. This principle seems obvious, yet we do not always bear it in mind and may, for example, combine NSAIDs with selective serotonin reuptake inhibitors (SSRIs) or serotonin and noradrenaline reuptake inhibitors (SNRIs), even though these combinations should be avoided in clinical practice. Clinically significant interactions arise from the fact that NSAIDs inhibit the activity of cytochrome P450 isoenzymes, which are involved in the metabolism of various medicines, including antidepressants – Table 4 [5].

When selecting the appropriate medicine, it is important to bear in mind that some NSAIDs have a different metabolic pathway to most substances in this group (for example, ketoprofen is mainly conjugated with glucuronic acid and only minimally metabolised by CYP isoenzymes), which naturally reduces the risk of adverse interactions with other medicines being taken. Due to the risk of pharmacokinetic interactions, celecoxib must not be used in combination with tramadol. Celecoxib is a CYP2D6 inhibitor; consequently, this combination inhibits the metabolism of tramadol into one of its metabolites (O-demethyltramadol) responsible for the opioid analgesic effect; this will result in a lack of improvement in pain control, as well as an increased risk of nausea and vomiting due to the increased serotonergic activity of tramadol. The guidelines for the use of NSAIDs with proton pump inhibitors (PPIs) are a broad topic which will not be covered in this text; however, it is worth noting here that if we are dealing with a patient who is taking diclofenac, indomethacin, meloxicam, celecoxib, ibuprofen or naproxen and who requires (in accordance with current standards) concomitant administration of a PPI, this should never be omeprazole or esomeprazole. Both the former and the latter are potent inhibitors of CYP2C9 and CYP2C19, and therefore lead to the inhibition of the metabolism of the aforementioned NSAIDs (when used at doses close to maximum tolerated doses) [6].

NSAIDs are one of the most commonly used classes of medicines. Their selection must never be arbitrary, and one must never simply prescribe ‘any’ NSAID or other painkiller. The choice must always take into account the pharmacokinetic and pharmacodynamic profile, the location of the pain, its mechanism and intensity, as well as the patient’s overall clinical picture (without fragmenting it). A significant proportion of patients who require NSAIDs are those with multiple conditions and are therefore taking numerous medicines which may alter the action profile of the NSAID being used and increase the risk of adverse effects. The choice of medication must therefore be as individualised as possible.

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