hEALTH

PAIN

Pain killer

Treatment of pain: Which common pain reliever is the best?

For moderate pain, there are different pain relievers available: Mostly used are acetylsalicylic acid (ASA, “aspirin”), ibuprofen, naproxen, paracetamol (acetaminophen), and (propy)phenazone. All of them also act on fever, should be taken with a glass of water, and should not be taken over a longer period.

This information is supplied without liability. For further information, pay attention to the package insert of the drug, and ask your doctor.

Do classic pain-killer cause heart attacks?

A meta-analysis of controlled observational studies compared the risks of serious cardiovascular events with non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen and diclofenac. It is known that newer, selective COX-2 inhibitors such as Rofecoxib have an increased risk of heart attack and stroke associated with long-term, high-dosage use (see below). For classic pain-killers, it was shown that diclofenac which is also a relatively COX-2 selective drug increase the risk of heart attack on the long-term (i.e. over years); however, no associated risks were found for ibuprofen or naproxen.

Cardiovascular Risk and Inhibition of Cyclooxygenase.
McGettigan P, Henry D.
JAMA 4:1633-44 (2006).

Modern pain-killer: selective COX-2 inhibitors can cause heart attacks

Selective COX-2 inhibitors are pain-killer that selectively inhibt the enzyme cyclooxygenase-2 (COX-2) while having no effect on cyclooxygenase-1 (COX-1). COX-2 mediates the synthesis of prostaglandins responsible for pain and inflammation, hence it was thought selective COX-2 inhibitors could be superior to classic pain-killer which inhibit both COX-1 and COX-2. Inhibition of COX-1 is associated with a diminshed protection of the stomach lining, therefore selective COX-2 inhibitors were thought to have a superior gastrointestinal adverse effect profile.
However, the selective COX-2 inhibitor Rofecoxib shows an 4-fold increased risk of heart attack and stroke associated with long-term, high-dosage use compared to naproxen. As a consequence, Rofecoxib was withdrawn from the market in 2004, and regulatory authorities worldwide now require warnings about cardiovascular risk of other COX-2 inhibitors.

Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia Events.
Zhang J, Ding EL, Song Y.
JAMA 4:1619-32 (2006).

COX-2 Inhibitor Drug Review.
Supplemental results to the COX-2 inhibitor review in JAMA.

Aspirin instead of antibiotics against Staphylococcal infection?

Staphylococcus aureus infection can lead to the development of serious conditions such as endocarditis, pneumonia, and septicemia and requires intensive antibiotic therapy. The emergence of S. aureus resistance to multiple antibiotics poses major clinical problems.
As an alternative, aspirin may be useful for the treatment of S. aureus: Salicylic acid, the major in vivo metabolite of aspirin, downregulates two key Staphylococcus aureus virulence genes, alpha-hemolysin secretion and fibronectin binding. This eliminates both the bacterial attachment to target cells and the production of the bacterial toxin that destroys blood cells.
This kind of therapy would be less stressful for patients than the present treatment with antibiotics.

Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus.
Kupferwasser LI, Yeaman MR, Nast CC, Kupferwasser D, Xiong YQ, Palma M, Cheung AL, Bayer AS.
J Clin Invest. 112: 222-233 (2003).

Concurrent use of ibuprofen and ASA (“aspirin”) could diminish aspirin's cardiovascular benefit

This study followed more than 7,000 cardiovascular patients who took acetylsalicylic acid to ward off a heart attack or stroke. Those who also took ibuprofen frequently were twice as likely to die during the eight-year study than those taking aspirin alone.
Ibuprofen blocks ASA from thinning the blood. ASA normally binds to an enzyme called cyclooxygenase in blood platelets, which stops them clumping together into vessel-clogging clots. “It would seem prudent not to take the two drugs together.” advises study leader Tom MacDonald of Ninewells Hospital and Medical School in Dundee. He suggests that some patients should use an alternative painkiller such as paracetamol.
In a former study, it could be shown that ibuprofen inhibits the blood thinning effect of aspirin. This is especially true for patients who have to take ibuprofen 3 times per day: in this case aspirin doesn’t prevent platelet aggregation. For low doses of ibuprofen, it may be helpful to take aspirin two hours before ibuprofen.

Effect of ibuprofen on cardioprotective effect of aspirin.
MacDonald TM, Wei L.
Lancet 361: 573-574 (2003).

Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.
Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA.
N Engl J Med 2001 345: 1809-17 (2001).

Healthy kidneys and moderate use of pain killer: no bad risk of damage

In this long-term study (14 years), more than 11,000 healthy men were monitored for potential kidney damage caused by aspirin and other nonsteroidal anti-inflammatory drugs. In contrast to earlier studies, the moderate analgesic use was not associated with increased risk of renal dysfunction. Even the intake of more than 2,500 pills in this period seems to be without negative consequences for kidneys without pre-damages.

Analgesic use and renal function in men.
Rexrode KM, Buring JE, Glynn RJ, Stampfer MJ, Youngman LD, Gaziano JM.
JAMA 286: 315-21 (2001).

Do non-steroidal anti-inflammatory drugs help against Alzheimer’s disease?

There is evidence from epidemiological studies that the chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen reduce the relative risk of Alzheimer’s disease (AD). It is postulated that this mechanism is due to the anti-inflammatory activity of NSAIDs. There may be a second kind of action: Beta-amyloid peptide which is aggregated in Alzheimer’s brain (known as plaques) could be anti-aggregated by NSAIDs. In fact, the authors showed that ibuprofen and naproxen bind to aggregated beta-amyloid peptide.
A similar association between a reduced Alzheimer’s disease risk and long-term use of NSAIDs including aspirin has also been shown by the Cache County Study.
However, another study showed that one-year-treatment with NSAIDs didn’t have the desired effects: There was no difference between patients taking anti-inflammatory drugs (naproxen and a new drug called rofecoxib) and patients who got placebos. In addition, side effects like fatigue, dizziness, and hypertension were more often when using NSAIDs. The authors conclude that these drugs do “not slow cognitive decline in patients with mild-to-moderate AD”.

Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies.
Etminan M, Gill S, Samii A.
BMJ. 327: 128 (2003).

In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the Alzheimer’s brain using the positron emission tomography molecular imaging probe 2-(1-{6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile.
Agdeppa ED, Kepe V, Petri A, Satyamurthy N, Liu J, Huang S, Small GW, Cole GM, Barrio JR.
Neuroscience 31: 723-730 (2003).

Effects of Rofecoxib or Naproxen vs Placebo on Alzheimer Disease Progression: A Randomized Controlled Trial.
Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, Jin S, Thomas RG, Thal LJ.
JAMA 289: 2819-26 (2003).

Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study.
Zandi PP, Anthony JC, Hayden KM, Mehta K, Mayer L, Breitner JC; Cache County Study Investigators.
Neurology 59: 880-6 (2002).

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