By Wendy Haaf
Which over-the-counter pain reliever is most likely to offer relief from a toothache? From backache or sore muscles? Are some options safer than others? How about if you have a particular medical condition? What do we know about the risks and benefits of the drugs commonly prescribed for chronic pain?
Our understanding of these issues has evolved in recent years, and it turns out that some of these medications may not be quite as innocuous as they once appeared, while others may be less effective than we once thought. Here’s what we found out when we went looking for answers.
Used in Canada to treat pain and fever for more than 50 years, acetaminophen (Tylenol is one brand name) has long been regarded as one of the safest over-the-counter options for these purposes and is also one of the most popular, with annual sales of more than four billion doses (15 per cent of these are prescription products, such as Tylenol 3, a combination of acetaminophen and codeine). While originally it wasn’t clear exactly how the drug worked, it was thought to have a mechanism different from those of other major over-the-counter pain relievers—perhaps exerting its effect via the brain—and therefore to be in a class by itself.
The drug’s major drawback is the potential for liver damage at very high doses.
While acetaminophen “has a very wide margin of safety in usual use,” says Dr. Michael Rieder, a professor of physiology, pharmacology, and medicine at Western University’s Schulich School of Medicine & Dentistry in London, ON, “an overdose is not so safe.”
For moderate pain, such as toothache or aches due to muscle strain, 500 to 1,000 mg of acetaminophen helps (that is, it reduces pain by 50 per cent or more over a four-to-six-hour period) about four out of 10 people who take it, according to reviews of the medical literature conducted by the UK branch of the Cochrane Collaboration, an independent non-profit group of researchers who weigh the evidence behind various medical interventions. Doses of 1,000 mg are also modestly effective for relieving migraine and tension-type headaches. (In this context, over-the-counter pain relievers are best used only once in a while, since overuse can backfire, causing headaches to occur more frequently.)
For common types of chronic pain, however, the drug doesn’t appear to work very well, if at all. In a May 2016 British Medical Journal (BMJ) article, researchers who sifted through the systematic reviews and meta-analyses on the subject stated that in doses of up to 4,000 mg daily, acetaminophen “is ineffective in back pain,” and, “though marginally better than placebo…has little chance of achieving clinical benefit in osteoarthritis.” (That 4,000 mg dose—equivalent to eight 500 mg extra-strength tablets—is the current recommended daily limit.) The authors add, “There is no review evidence [that the drug is effective] for neck pain, rheumatoid arthritis, or cancer pain.”
Serious side effects are very rare—but less rare than we once believed. For one thing, an in-depth scientific review by Health Canada published in 2014 found that half of the more than 250 cases of serious acetaminophen-related liver injuries that occur in Canada each year, and one in five of the 4,000 annual hospitalizations for acetaminophen overdose, were due to people exceeding the recommended dose unintentionally. This can happen if people take doses too close together or unwittingly take multiple products containing acetaminophen (there are more than 475 on the market in Canada) at the same time—as when, for example, someone takes one product for sinus symptoms, another for cough, and plain acetaminophen for an accompanying headache. (Always check labels: acetaminophen will be listed under “medicinal ingredients,” along with the dose.)
Some people, however, run into problems before reaching the daily maximum dose: the same review found that one-in-five reported acetaminophen-related liver injuries occurred at doses within the recommended range. For that reason, a group within Health Canada is currently considering the possibility of capping the amount of acetaminophen per tablet at 375 mg—which would mean no more “extra- strength”—and lowering the recommended daily maximum dose to 2,600 mg.
But that’s not all. The authors of the BMJ article point out that acetaminophen may not deserve its reputation for being less apt than ibuprofen and its relatives to cause side effects, which perhaps isn’t surprising, given the recent discovery that acetaminophen is, in essence, a weak version of an NSAID (non-steroidal anti-inflammatory drug). (NSAIDs, such as Aspirin, ibuprofen, and naproxen, work by blocking two enzymes involved in promoting pain, fever, and inflammation; the problem is that one of these enzymes also produces chemicals that protect the stomach and intestinal lining and spur blood clotting. This is why NSAIDs can cause side effects such as stomach bleeding.)
The authors of the BMJ paper note that in one study involving people with arthritis, acetaminophen had adverse event rates very similar to those of ibuprofen, while another study found that, for short-term common pain, acetaminophen wasn’t tolerated any better than ibuprofen. The researchers also note that in a systematic review of observational studies comparing people who take acetaminophen with those who don’t, the drug—particularly at higher doses—was linked with increased rates of death and a number of other problems, including heart attack, gastrointestinal ulcers, and marked decrease in kidney function. (It’s worth pointing out that observational studies simply follow two groups of people and are consequently less reliable than randomized controlled trials.)
In yet another study, researchers evaluated the incidence of gastrointestinal events such as bleeding in the stomach or intestine in 600,000 Quebec residents aged 65 or older who received prescriptions for an NSAID, acetaminophen, or both. As expected, NSAIDs were linked with a significant increase in the rate of hospitalization for such problems, but so was acetaminophen in high doses (3,000 mg or more per day). Furthermore, combining a lower dose of acetaminophen with an NSAID more than doubled the rates of gastrointestinal side effects serious enough to warrant hospitalization, compared with low-dose acetaminophen alone.
So should you take acetaminophen? If you’re already doing so and it seems to work well for you, there’s probably no reason to switch. (Just be sure not to exceed the recommended dose, and avoid combining the drug with NSAIDs.) On the other hand, you should avoid taking it for more than a few days at a time if you also regularly consume even modest amounts of alcohol, since there’s some evidence this combination may increase the risk for kidney disease. And if acetaminophen offers you only minimal relief and you’re taking it simply because of its purported safety, consider talking to your doctor or pharmacist about trying ibuprofen instead.
As explained above, ibuprofen (Advil and Motrin are two common brand names) belongs to a group of medications called non-steroidal anti-inflammatory drugs—or NSAIDs—which block enzymes involved in producing pain and inflammation. This is why it’s often the over-the-counter medication many dentists, doctors, and pharmacists recommend as a first-line treatment for problems such as pain from an infected tooth and muscle sprains. And indeed, according to the Cochrane review on over-the-counter pain medications, at least five out of 10 people with such types of acute pain will find relief after taking 200 to 400 mg of fast-acting ibuprofen, or one to two regular-strength capsules. (By contrast, about one in five people who take 220 mg of naproxen achieve similar reductions in pain, while roughly four out of 10 of those who take 440 mg do. In Canada, naproxen is available over-the-counter in 220 mg tablets; Aleve is the most widely known brand.)
“The most worrisome thing about any of these drugs is: Is it going to cause a gastrointestinal bleed?” Schulich School of Medicine & Dentistry’s Dr. Rieder says. “That’s something people worry about, although the jury is still out over whether the over-the-counter NSAIDs cause this problem or not.” Consequently, if you’ve had problems such as ulcers and gastrointestinal bleeding in the past, or you’re taking blood-thinning medications such as Warfarin and rivaroxaban, “you might want to try Tylenol instead,” Rieder says, “because the risk is small, but it may not be zero.”
What if you need pain relief more than occasionally? According to guidelines for people 65 or over from the American Geriatric Society, both prescription-strength NSAIDs and their COX-2-inhibitor cousins (a class that includes celecoxib, or Celebrex) should be considered only rarely and with caution. For one thing, complications from these drugs become more common with age and long-term use: the medications are associated with an increased risk not just for gastrointestinal bleeding but also kidney disease, heart attack, and stroke. (In one study of older adults admitted to the geriatrics department of an Italian hospital, NSAIDs were the culprit in nearly one-quarter of hospitalizations due to adverse drug reactions—half of these cases were considered preventable.)
Consequently, the guidelines recommend that you avoid these drugs entirely if you have an active peptic ulcer, chronic kidney disease, or heart failure, and that you use them cautiously, if at all, if you have a history of ulcers, are taking corticosteroids or SSRI antidepressant medications such as Zoloft (as the combination may boost bleeding risk), or have hypertension (which the drugs can exacerbate).
If your doctor has prescribed low-dose Aspirin to reduce your risk for heart attack, an NSAID other than ibuprofen should be used, since ibuprofen appears to negate Aspirin’s heart-protective effects. Three other recommended cautions: you should combine these drugs with another medication that protects the lining of the stomach and intestine, not take more than one NSAID or COX-2 inhibitor (for example, if you’re taking Celebrex daily for arthritis, don’t take Advil for a headache), and have regular follow-ups to check for health issues such as high blood pressure and kidney injury.
However, for some conditions, there is a way of sidestepping the drawbacks of NSAIDs while reaping their pain-relieving benefits: applying a non-prescription gel containing the NSAID diclofenac (sold under the name Voltaren) to the skin instead. Because the dose needed is relatively small and the medication doesn’t pass through the stomach and intestine, “you can’t have a giant bleed,” Rieder explains, “and it works quite well.”
A Cochrane review found that about 60 per cent of people who used a topical NSAID had reduced pain after six to 12 weeks.
There’s no question these chemical siblings of heroin, which include codeine and morphine, are extremely useful for limited periods following surgery and fractures, during attacks of kidney stones, and for cancer pain. “The best way to prevent chronic pain is to treat acute pain effectively, and that includes pain after surgery,” says Dr. Mary Lynch, a professor in anaesthesia, pain management, and perioperative medicine at Dalhousie University in Halifax.
However, starting around the mid-1990s, doctors began prescribing opioids much more liberally for chronic pain, due in part to drug-company-sponsored “educational sessions” for physicians. “A key message to doctors at that time was that opioids worked well for chronic pain and that we didn’t need to worry about causing addiction because the risk for addiction was well less than one per cent,” says Dr. David Juurlink, a senior scientist with the Chronic Disease and Pharmacotherapy Research program at Toronto’s Institute for Clinical Evaluative Sciences. “As it turns out,” he says, “neither of those two bits of information is supported by data.”
In fact, Juurlink says, studies that compared opioids to placebo conditions were virtually all short-term, lasting a maximum of 12 weeks, and participants were carefully selected to exclude people with risk factors for substance abuse (such as a history of alcohol misuse or a family history of mental illness). Consequently, says Dr. Thomas Perry, a clinical assistant professor and chair of the Education Working Group at the University of British Columbia’s (UBC) Therapeutics Initiative, “we don’t have any experimental evidence on what happens long-term,” or in less carefully chosen patients. (Perry adds that many trials also exclude people who can’t tolerate the medication being studied, which makes many results look better than they really are.) What’s more, Juurlink recalls, for opioids, “we were taught there’s no dose limit: you can go up as much as you need,” while the doses used in the trials were relatively modest.
“I think there are people out there with chronic pain who really do have meaningful improvements in quality of life and function with opioids, particularly when used at low doses,” Juurlink stresses, but he and many other experts have come to believe that the drugs have been widely over-prescribed and that for many people who are currently taking them, the risks may outweigh the benefits.
Within just a few weeks of using opioids, “you become physically dependent,” Juurlink notes, which means that if you miss a dose or stop taking the drugs, you develop unpleasant physical symptoms.
“People get diarrhea; they feel like they have a bad flu,” Juurlink says. “Patients understandably interpret that as, I need these drugs or I’m not going to feel very well, and I think a lot of people who have that opinion don’t realize they’re continuing therapy not because it’s making their underlying problem better, but because they’re on a self-perpetuating path.” Another problem with opioids, Juurlink adds, is that “as you continue to use them, you develop what’s called ‘tolerance’—a fancy name for needing more of the drug to achieve the same effect.” However, the higher the dose, “the more likely the patient is to get into trouble,” he says.
What kind of trouble? “There are huge problems with constipation, and in men, testosterone suppression and impacts on libido,” Juurlink says. “I think that in some people with chronic pain and depression, their opioids may actually play a role in causing their depression. In fact, if you take people on really high-dose opioids and slowly wean them to somewhere around half the dose, their pain scores get better and their depression scores get better.” In some people, long-term opioid use actually worsens pain.
Because opioids can cause drowsiness and impair thinking and balance, they’re linked with an increase in the risk for falls and traffic accidents. “There’s a whole host of side effects from these drugs that are dose-related and more likely in older people, who tend to be taking other drugs” and living with other co-existing health problems, Juurlink adds. For example, opioids can exacerbate difficulty passing urine and stool due to diabetes-related nerve problems.
Opioids can be particularly dangerous when combined with other substances that depress the central nervous system, such as alcohol, anti-anxiety drugs, and sleeping medications. “Sometimes,” Juurlink says, “one plus one isn’t two—it’s 10,” which can increase the risk for events ranging from car accidents to death. As a result, “people who are on high-dose opioids are more likely to die from their medicines than from anything else,” Juurlink says. “We did a study last year that showed one in 27 men who were taking 200 mg of morphine or equivalent per day eventually died of an opioid-related cause. That’s in the vicinity of 60 mg of OxyContin twice a day, which is extremely common,” he explains.
Still, Perry says, under the right circumstances and with “a cautious well-trained patient, opioids can be pretty darned safe.” Juurlink adds, “A cautious trial of opioids, with a planned exit strategy if things aren’t going right, may make some people feel better.” Say that you have terrible hip pain, that the waiting list for a joint replacement is two years, and that neither acetaminophen nor NSAIDs have offered enough relief to allow you to carry out your daily tasks. “I might try medical cannabis in an open-minded patient who maybe uses it periodically anyway. But if I did go to opioids, I would start at a low dose, with the intent of watching over the next couple of weeks to see if the patient is feeling and functioning any better,” Juurlink says. “I’m also going to be watching for side effects. What about the sedation? What about constipation? Do the patients feel as sharp behind the wheel of a car?
“If it becomes clear after a few weeks that it’s not cutting it anymore, that’s not an invitation to increase the dose; that means you kicked at this can but it didn’t work.”
And what if you still have serious ongoing pain while taking the medications? “To me, that marks you as having failed opioids, and the thing to do then is get off of them slowly and in a controlled fashion.”
Anticonvulsants and Antidepressants
Sometimes prescribed for chronic pain stemming from dysfunctional or injured nerves (one example is diabetes-related foot pain), these medications can cause side effects ranging from dry mouth and constipation to difficulty adjusting visual focus from near to far, falls, sedation, and impaired thinking. (Many of these side effects are due to these drugs blocking the chemical messenger acetylcholine, and some observational studies hint that long-term use of medications that act this way may be linked with an increase in dementia risk.) When researchers at UBC’s Therapeutics Initiative examined the evidence supporting the use of anticonvulsants in neuropathic pain, for example, they concluded that most people experience some adverse side effects, while fewer than one in 10 seem to achieve a meaningful reduction in pain.
“I tell patients, If you want to try it, fair enough,” Perry says. In such cases, he suggests a short trial starting with a small dose and watching carefully for side effects. If the drug is going to work, he says, “you can probably tell within a week or two.” Higher doses, the Cochrane review concluded, “are unlikely to achieve greater pain reduction but are more likely to cause harm.”
For chronic pain, Perry says, “the biggest lesson is that none of these drugs works very well. The experiments are short-term, and when you really look at what they show, the results are unimpressive. Physical exercise, fitness, and attitude are more likely to help.”
Dalhousie’s Dr. Mary Lynch also underscores the importance of physical activity. “Working with a well-trained physiotherapist in a very structured way can get you through the initial, difficult period,” she says. “Once you get to the point where you’re doing something physical every day— it doesn’t really matter if it’s a walking program or a strengthening program—you can literally change the physiology of your body so you get analgesia—healing from exercise.”