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Painkillers: short-term gain, long-term pain

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Aches and pains seem to be the lot of humanity. Doctors can testify that they treat more patients for pain than for any other ailment, and the remedy is invariably the same: a prescription for a painkiller, such as a powerful and reliable NSAID (nonsteroidal, anti-inflammatory drug), a steroid or an opioid.

Around a third of all American adults suffer constant chronic pain, and many of them never bother the doctor; instead, they self-medicate with an OTC (over-the-counter) painkiller from their pharmacy, choosing either an acetaminophen, marketed as Panadol and Tylenol, or an NSAID, a family of drugs that includes ibuprofen and aspirin and is designed to stop inflammation in the body.

Aspirin started the rush for analgesics in 1917 when it became the first OTC painkiller. Since then, painkillers have become big business, with revenues from OTC remedies set to hit $27.7 billion by the end of 2028, while sales of prescription painkillers are predicted to reach $91.6 billion a year earlier.1

Do they work?

With all this pill-popping, medical researchers have kept a watchful eye on painkillers, assessing their effectiveness and safety. Cochrane reviewers, an independent group of researchers, took another look at 10 of their own reviews that had assessed the effectiveness of 21 OTC painkillers taken either singly or as a combination. Acetaminophen (paracetamol) and aspirin, two of the most popular OTC remedies, were the least effective at reducing acute pain, helping in as few as 11 percent of cases. But taken with ibuprofen, acetaminophen’s effectiveness rose to 70 percent.2 Other researchers dismiss even these modest successes, claiming that the effect of painkillers is no better than that of placebos. In other words, the sufferer thinks the pill will ease their pain, and so it does. This may also have something to do with the characteristics of pain, as it seems to have physical, psychological and emotional aspects.

But researchers from McGill University in Canada discovered something quite strange: any difference between the effects of a painkiller and those of a placebo has been narrowing over the years, due to increases in the placebo effect. When once there was a clear distinction between the actual drug and a placebo, today there is hardly any difference at all. The phenomenon has been a problem for drug companies trying to bring a new painkiller onto the market as they struggle to demonstrate a significant effect beyond what a placebo offers. Stranger still, this narrowing has been witnessed only in US drug trials.3

Are they safe?

Painkillers aren’t the harmless lifestyle pills you’re encouraged to have with your breakfast. Aspirin and other NSAIDs play havoc with the gut, showing associations with anything from ulcers to stomach bleeds. In one study of 713 patients who had died, 244 had been taking an NSAID; in postmortem studies, 30 percent of the drug group had stomach or intestinal ulcers compared to 13 percent in the non-drug group.4

They can also be killers. According to the FDA’s Adverse Events Reporting System (FAERS), the drugs were responsible for 64,354 serious reactions in 2015 and 2016, including nearly 13,000 deaths, and “serious adverse reactions,” including death, occurred in 67 percent of such cases.5 

Acute to chronic

When pain has persisted for two or more weeks, it’s reclassified from acute to chronic. If painkillers are marginally effective in acute cases, they are virtually useless at combating chronic pain. The UK’s NICE (National Institute for Health and Care Excellence), which assesses the cost and effectiveness of drugs before they can be prescribed by the National Health Service, says the standard painkillers—including aspirin and ibuprofen, benzodiazepines and opioids—should not be offered to a chronic pain sufferer. Even antidepressants may be more effective than painkillers, as they can at least deal with some of the psychological aspects of pain. Instead, doctors should be suggesting group exercise programs, psychological therapies or acupuncture.6 

There’s a further twist to the tale. Acute pain may become chronic because the sufferer has taken painkillers, a new study has discovered. Painkillers, such as NSAIDs, acetaminophen and steroids, interfere with the immune system’s natural abilities to deal with pain, extending the time the sufferer is in pain.

A history of pain management

  • 1600s Doctors offer opium to ease pain
  • 1806 Morphine is isolated from opium
  • 1820s Morphine is made in German factories and used to treat pain, anxiety, tuberculosis (TB) and “female disease”
  • 1860s Morphine is used as a painkiller to treat soldiers in the American Civil War
  • 1898 Bayer produces heroin, a derivative of morphine, to reduce the risk of addiction, and markets it as a cough remedy
  • 1899 Bayer develops aspirin from acetylated salicylic acid, a compound derived from plants
  • 1900s Morphine and heroin become the most commonly used painkillers, the first of the opioids
  • 1917 Aspirin becomes the first OTC painkiller, replacing opiates to treat mild to moderate pain
  • 1920s Chronic pain sufferers are still characterized as deluded, malingerers or drug abusers
  • 1960s Pain management becomes a recognized field of medicine; by the 1970s, it has its own research journal, Pain, and association, the International Association for the Study of Pain
  • 1965 Psychologists Ronald Melzack and Patrick Wall publish their theory of “gate control,” which postulates pain is associated with the spinal cord sending pain signals to the brain
  • 1980s Medicine pronounces a “low risk” of addiction to opioids
  • 1985 Although NSAIDS have been heralded as “safe” painkillers, one of the first on the market, phenylbutazone, is banned after it is found to cause aplastic anemia
  • 1999 The first COX-2 painkillers are launched as a safer option than NSAIDs as they don’t cause stomach ulcers and bleeding but target inflammatory mediators and bypass the gut
  • 2000s Coping mechanisms, such as cognitive behavioral therapy (CBT), grow in popularity as alternatives to painkillers

Fighting the body

The anti-inflammatory painkillers could be the biggest culprit. People suffering from lower back pain, one of the most common areas for pain, are nearly twice as likely to be chronic sufferers if they used an NSAID in the early stages, compared to others who used a different type of painkiller.Overall, around 40 percent of people who take painkillers for lower back pain are still in pain a year later, and researchers from McGill University think they know why this is happening. The drugs block the production of neutrophils, white blood cells that are the immune system’s first line of defense to combat inflammation and repair damaged tissue.7

The researchers analyzed the genetic profiles of 98 people with acute lower back pain and noted changes in the expression of over 5,500 genes in those whose pain was  gone three months later, but  no gene expression changes in those whose pain persisted. These findings suggest the painkillers had stopped the body’s natural responses to pain.

Inflammation isn’t the bad guy that needs to be stopped by anti-inflammatories; instead, it’s the start of a process to heal the cause of pain, and blocking it may provide some short-term relief to acute pain but will also cause chronic, long-term problems. 

“Inflammation occurs for a reason, and it looks like it’s dangerous to interfere with it,” said Jeffrey Mogil, a McGill researcher. “For many decades it’s been standard medical practice to treat pain with anti-inflammatory drugs, but we found that this short-term fix could lead to longer-term problems.”

Pain, pain, don’t go away 

Most of us will suffer pain at some time or another. “Pain is a constant companion for humanity,” says Marcia Meldrum, a researcher at the University of California at Los Angeles (UCLA). But despite pain’s prevalence, medicine has struggled to understand what is really happening or how to effectively treat it, if treatment is needed at all.8

So far, medicine has come up with a number of false trails to handle pain. Through the years, it has offered morphine and heroin and, more recently, the opioids, which have resulted in one of the biggest scandals of modern medicine, with entire towns debilitated by addiction.

The NSAIDs seemed to be a safer way forward, but they appear to be more a part of the problem than the solution, transforming an acute problem into a chronic one. However, Meldrum is under no illusions that anything will change soon; pills are easy and have become a way of life for many Americans. 

“We are in this culture now where too many people see drugs as the answer not only to pain, but to improving their lives,” she writes.

Making them see that the painkillers are condemning them to a lifetime of pain will take an enormous cultural shift that won’t happen overnight. 




Globe Newswire, “Over-the-Counter Pain Medication Market Is Estimated to Attain a Valuation of US $27.7 Bn by the End of 2028,” Apr 11, 2022.; MarketWatch, “Pain Management Drugs Market Share, Key Players Profiles, Revenue, Regional Analysis and Forecast 2027,” press release, May 13, 2022. 


Cochrane Database Syst Rev, 2015 (11): CD010794


Pain, 2015; doi: 10.1097/j.pain.0000000000000333


Postgrad Med J, 2001; 77: 82–8


Drug Saf, 2018; 41: 313–20


NICE draft clinical guidelines, August 3, 2020


Sci Transl Med, 2022; 14(644): eabj9954


JAMA, 2003; 290: 2470–2

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