People taking high daily doses of two common painkillers are at increased risk of heart attack and stroke, say Oxford researchers.
NSAIDs are used to treat chronic pain in conditions such as arthritis
But the British Medical Journal study says the risk is moderate, with only an extra three people in every thousand suffering from an adverse reaction.
Long term use of non-steroidal anti-inflammatories like ibuprofen and diclofenac have raised fears before.
They are standard drugs for those with chronic pain, like arthritis sufferers.
Concern had focused on the newer COX-2 drugs, but there are now also fears over NSAIDs.
The doses given for chronic pain conditions are much higher than those used by people taking the drugs as occasional painkillers.
The newer COX-2 inhibitors were developed to avoid the side effects of gastric bleeding and ulcers which sometimes occurred with traditional NSAIDs.
One COX-2, Vioxx, was taken off the market after concerns about the risk of heart attack.
Some studies have shown the risk of heart attacks and strokes might also be associated with other NSAIDs, but the results have not been clear-cut.
By analysing data from all randomised trials that recorded serious vascular events in patients on NSAIDs, the researchers from Oxford University found that, in patients taking COX-2s, the odds of a heart attack or stroke increased by 42% compared with placebo.
The odds were increased by 51% for high-dose ibuprofen (800mg three times a day) and 63% for high-dose diclofenac (75mg twice a day).
Another NSAID - naproxen - was found not to be associated with an increased risk of cardiovascular events.
The researchers stressed that the overall risk was small - for every 1,000 patients taking a COX-2 or an NSAID around three extra people a year would have a heart attack.
Dr Colin Baigent, lead researcher said: "With this data we now have a complete picture of the effects of COX-2s and NSAIDs.
"The important point is that for most people who don't have a history of heart attack or stroke the risk is very small.
"These drugs are very important in helping people to control their pain and it is for patients to discuss with their doctors whether this risk is acceptable for them.
He added that more studies were needed on other effects of naproxen before any recommendations could be made on its use.
Professor Peter Weissberg, Medical Director of the British Heart Foundation said there was mounting evidence that taking high doses of NSAIDs increases the chances of heart attack.
"However, the increased risk is small and many patients with chronic debilitating pain may well feel that this small risk is worth taking to relieve their symptoms," he said.
Dr Jim Kennedy, chair of the Royal College of General Practitioners' prescribing committee said: "We would first try patients on simple analgesics such as paracetamol and then treatments with codeine in.
"COX-2s and NSAIDs are a third-line option, and the patient has to make an informed choice about that."
"A lot of patients say the drugs are the difference between having independence and not being able get out of the house."
A spokesperson for Arthritis Care agreed that patients should be left to make the choice: "Millions of people take NSAIDs, and those taking higher doses do so because they're in a significant amount of pain.
"Provided they have accurate information, they can make an informed choice about whether it's the right one for them."
Professor Rob Moots, consultant rheumatologist at University Hospital Aintree, Liverpool said: "It's important patients take them when they need them rather than taking a high dose every day - that way the risk is absolutely minimised."
A spokesperson for the International Ibuprofen Foundation emphasised the study specifically referred to high dose prescription treatment of patients with painful conditions, particularly osteoarthritis.
"The occasional and short-term use of ibuprofen for minor pain conditions - the way the majority of consumers in the UK use over-the-counter ibuprofen products, is not shown to be a risk factor."