Every day you can see or read commercials for over-the-counter antipyretics and pain killers that you have reason to believe are safe to take, otherwise they would not be available without prescription.
Pain such as headaches, low back pain, and joint and muscle pain is very common, and many people take medication regularly and in an unaccountable way, particularly for chronic pain, often occurring frequently in the elderly.
The most popular over-the-counter antipyretic drugs and painkillers belong to the class of nonsteroidal anti-inflammatory drugs (abbreviated as NSAIDs). This class is designated as 'nonsteroidal' because the mode of action is different from that of anti-inflammatory steroids, the synthetic version of hormones from the adrenal gland. These are now used in only in fully-justified cases, due to their severe side effects.
Heart attack instead of ulcer?
This question was raised by the author of a study, which analyzed the greatest drug scandal of all time (1). The nonsteroidal painkiller Rofecoxib received marketing approval in 1999, despite the manufacturer's awareness that its intake was associated with serious risk of heart attack. The drug was withdrawn from the market in 2004; however during 5 years of trading the estimated number of heart attacks caused by the drug may have reached 140,000 in the U.S. alone, of which 60,000 cases were fatal (2). Valdecoxib also had a short tenure; with the manufacturer having to pay compensation of 2.3 billion dollars after withdrawal (3).
Unfortunately the intake of NSAIDs remaining on the market is not free of risks either. Since such painkillers are usually taken by elderly people who often already have some heart disease, data from patients with heart disease therefore provides valuable information on their effects.
Painkillers with the active substance diclofenac (e.g. Voltaren) may be prescribed at doses of up to 100-150 mg; however the risk of death is twofold even at small doses, and at doses above 100 mg, the risk of heart attack and mortality is already 2.5-fold and 5.5-fold , respectively. For painkillers with the active ingredient celecoxib (Celebrex), a threefold mortality risk should be considered above doses of even 200 mg. Tablets and creams containing the active substance ibuprofen can also be purchased without prescription: a popular tablet (Algoflex forte) contains 600 mg of the active ingredient. Such a tablet increases the risk of death by 31%, but as its effect ceases after 6 hours, up to 1,800 mg may be taken, according to the recommendations, despite the threefold increase in the risk of death above doses of 1200 mg. Painkillers with the active substance naproxen (e.g. Naprosyn) contain 200-250 mg of the active ingredient. Taking one tablet increases mortality risk by 22% and doses exceeding 500 mg are associated with a twofold risk of death (4).
Based on results from 26 studies in elderly people conducted by the pharmaceutical industry, stroke risk could be assessed separately. It increased by 76%, 236% and 186% for Naproxen, Ibuprofen and Diclofenac, respectively (5).
In trials conducted to observe everyday use, people of different ages and with varied health status participated. For such a mixed population regarding health status, it is evident that the intake of such medications poses less risk on average. Analyzing the cardiovascular consequences of NSAID intake for 2.7 million people, it could be established that Naproxen is associated with a minor risk at both small and large doses. Ibuprofen increased the risk of stroke or heart attack by 78% only at high doses. Diclofenac increased cardiovascular risk by 22% and 100% at small and large doses respectively, and the intake of Celebrex showed similar hazards (6).
Several studies confirmed that NSAIDs increase blood pressure. Individual painkillers elevate blood pressure by 5 mmHg on average, but 'on average' means that some people experience minimal, while others much greater, blood pressure increase (7). Influencing factors include altered renal function (see below), but there are also other contributing mechanisms since NSAIDs largely neutralize the effect of blood pressure lowering drugs (except calcium channel blockers and low-dose Aspirin) (8).
Of course it is difficult to translate statistical data into everyday life. You can never know who will develop a heart attack from a single pill, and who can take it without any concerns for years. Nevertheless one conclusion can definitely be drawn: the availability of many painkillers as over-the-counter drugs does not mean that they may be taken without any risk.
Selective and non-selective NSAIDs
The first NSAID was Aspirin, known for a long time. Researchers explored the mode of action of Aspirin and further NSAIDs were designed based on their findings. Prostaglandins produced by the so-called COX (cyclooxygenase) enzymes are mostly responsible for inflammation in the body. The COX-1 enzyme has many important functions including protection of the mucous membrane of the stomach, has an important role in kidney function, and a vital role in blood clotting. Essentially COX-2 will appear in the body only if infection or inflammation develops anywhere.
NSAIDs developed in the 50s and 70s were non-selective, i.e. they inhibited both the enzymes COX-1 and COX-2. It was soon discovered that COX-1 inhibition may result in increased acid production and ulcer formation in the gastrointestinal system, it may impair the kidneys, and blocks platelet adhesion. This latter feature is exploited therapeutically: the formation of dangerous blood clots can be blocked by taking Aspirin at a low dose. To eliminate side effects of early NSAIDs due to COX-1 inhibition, researchers developed selective NSAIDs, i.e. they only inhibit COX-2.
Gastrointestinal bleeds
Non-selective NSAIDs, blocking both COX-1 and COX-2, pose an increased risk in the development of stomach and intestinal ulcers since COX-1 has a protective effect on the gastric and intestinal mucosa (see text in box for details). This is the rationale for the development of selective NSAIDs, which only inhibit the enzyme COX-2. These indeed proved to be less dangerous for ulcer formation; yet, contrary to expectations, they are not completely safe to use. For example, although Rofecoxib, subsequently withdrawn from the market, was less prone to ulcer symptoms compared to the non-selective Naproxen, there was nevertheless a fivefold increased rate of ulcers in the study versus placebo (7). Many elderly people take drugs like Aspirin at low doses to inhibit blood clot formation. Co-administration of these with non-selective NSAIDs is also associated with an increased risk of ulcer formation (8).
Non-selective NSAIDs still remain popular drugs (Aspirin, Diclofenac, Ibuprofen, Naproxen, mefenamic acid, indomethacin, ketoprofen, piroxicam, flurbiprofen, etc.), and their prolonged intake is associated with a significant threefold risk of ulcers. Analyses found that age >65 and a previous ulcer are aggravating factors: the risk of developing new ulcers was respectively 5.5-fold and 5-fold for old age and having had a previous ulcer (9). There are certain conditions where NSAIDs still remain the best choice; in such cases it is important to provide protection against the predisposing effect of these drugs on ulcers, e.g. by giving antacids. Unfortunately these are not free from risk either, especially those in the drug class of proton pump inhibitors (10).
Renal function and NSAIDs
For normal kidney function, we continuously need prostaglandins produced by COX-1, which dilate blood vessels in the kidneys and thereby enhance their excretory function. As non-selective NSAIDs (see above) inhibit the function of COX-1, blood vessels in the kidneys become narrowed, therefore impairing renal function. The first signs of this impairment in lab test results include elevated creatinine, potassium and sodium levels, and somatic symptoms such as swollen tissues, reduced urine excretion, high blood pressure, frequent headaches, muscle cramps and, in more severe cases, nausea, vomiting and loss of appetite. The risk of renal impairment due to NSAIDs is markedly increased by poor circulation occurring, for example, because of heart disease, or by natural deterioration of renal function in the elderly (11).
Fortunately NSAID intake generally causes 'only' acute renal impairment, which rapidly starts to improve after discontinuation of taking the NSAID (11). Acute renal failure, which might even be fatal without treatment, is a rare condition generally affecting 2 people out of 100,000. However in patients taking NSAIDs, there is a fourfold risk of acute renal failure, which becomes tenfold in those taking high doses (12). Renal function may be impaired for various other reasons (high blood pressure, diabetes, etc.) and if permanently declined renal function is coupled with NSAID use, there is an increased risk of chronic kidney disease (13). Dehydration is also a serious hazard during NSAID intake because, due to thickened urine, the drug can reach particularly high concentrations in the kidneys. In a 99 km ultramarathon race organized annually in South Africa, 19 runners developed acute renal failure over an 18 year period, and of those 19 runners, 15 took NSAIDs (14).
Modern NSAIDs selectively blocking COX-2 are considered less dangerous regarding the kidneys, but, as it turns out, COX-2 also participates in normal kidney function, so taking these pain killers is also not free of hazard (14, 16).
A decline in renal function due to NSAIDs is also risky because of the initially unnoticeable nature, and even in severe cases the condition can easily be considered as a viral infection causing nausea and vomiting.
Pregnancy
NSAIDs taken during the early stages of pregnancy have been found to carry small risk, but they may cause serious problems in the third trimester. A bridging artery called the ductus arteriosus develops in the fetus, which switches off the not yet functioning lungs from the bloodstream. The artery needs to be closed after birth so that normal circulation of the baby can be started. During fetal life, prostaglandins produced by the placenta keep this artery open but their production is blocked by NSAIDs, so as a result of NSAIDs taken in the third trimester, there is a 15-fold risk of premature closure of the ductus arteriosus, which may cause serious heart problems, and even fetal death (19).
Other side effects meriting surveillance
Antidepressants alone carry a twofold risk of stomach bleeding (1), but when taken together with NSAIDs, this risk becomes six-fold (1). Co-administration of the two types of drug will lead to increased bleeding even during minor surgery (2) and the risk of intracranial bleeding also rises by 60% (3). For patients on anticoagulants, NSAIDs should be given with caution because they can even double INR values (4).
- NSAIDs, particularly salicylates taken in high doses, may cause ringing in the ears and hearing loss; fortunately, these problems generally cease after discontinuation of the drug (5).
- NSAIDs, although rarely, may cause meningitis which is more common in patients with autoimmune diseases (6).
- In older age some of the NSAIDs may induce psychotic symptoms (paranoid thoughts, confusion), Attention Deficit Disorder, or mental deterioration (6).
- NSAIDs may slow down the healing of bone fractures (7). Since NSAIDs may, although rarely, lead to quite varied allergic and immunological disorders as well, attention should be paid to all unusual symptoms initiating after onset of NSAID use.
Pain is part of our everyday life. Thus it is no coincidence that painkillers are one of the most popular medications. As nearly all persistently taken painkillers have side effects, it is better to prevent the pain, and this is absolutely not as hopeless as it may first seem. Studies show unequivocal correlation between metabolic syndrome (symptoms including abdominal obesity, high blood pressure, high fasting blood glucose levels, high triglyceride levels) and various types of pain. The cause is simple: abdominal obesity leads to inflammation all over the body, which added to the local inflammatory process (e.g. in joints or muscles) reaches the threshold level of triggering pain (20). Therefore the most effective way to fight pain is to lose weight.
References
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20, Toates: http://www.steffentoatesdc.com/2015/04/22/metabolic-syndrome-and-pain/
References to section 'Other side effects...'
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2, Mahdanian: Ther Adv Psychopharmacol. 2015 Dec;5(6):332-8.
3, Shin: BMJ. 2015 Jul 14;351:h3517.
4, van Dijk: Thromb Haemost. 2004 Jan;91(1):95-101.
5, Simon: N Engl J Med. 1980 May 22;302(21):1179-85
6, Hoppmann: Arch Intern Med. 1991 Jul;151(7):1309-13.
7, Dodwell: Calcif Tissue Int. 2010 Sep;87(3):193-202.