Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) for Chronic Pain: Caution and Side Effects Related to Long-Term Use

Most people are familiar with different forms of acute or short-term pain such as headache, fever, and joint pain. While some may be more susceptible to acute pain than others, this type of pain is incredibly common among people of all ages and generally does not interfere with a person’s overall quality of life. 

The Prevalence of Chronic Pain

However, according to the Canadian Pain Task Force (CPTF), almost 8 million Canadians deal with chronic pain, a staggering number. Per the CPTF’s 2021 findings, about 1 in 5 people live with chronic pain – noticeable pain that occurs on a regular basis or with frequency. What’s more, a small but significant percentage of this group has even reported this to be severe pain. Since pain is a commonplace and even daily concern for many individuals, it comes as no surprise that there is also a notable amount of pain relief options readily available, both over-the-counter (OTC) and by prescription. In the case of both acute and chronic pain, the most conventionally reached for pain medication is the NSAID.

What are NSAIDs?

Non-Steroidal Anti-Inflammatory Drugs, or NSAIDs, are a common type of pain reliever and anti-inflammatory drugs. Categorized more broadly as non-opioid analgesics, NSAIDs are approved by Health Canada for use as anti-inflammatory/analgesics (pain relievers), as well as antipyretics (fever reducers). There are several different types of NSAIDs on the market, but the most traditionally used NSAIDs are acetylsalicylic acid (ASA or aspirin), ibuprofen, and naproxen sodium. NSAIDs can often be found over-the-counter as generic medicines, or under common brand monikers like Bayer and St. Joseph (Aspirin), Advil and Motrin (ibuprofen), and Aleve (naproxen). Some NSAIDs are even critical components of multi-ingredient medicines such as Excedrin.

How Do Non-Steroidal Anti-Inflammatory Drugs Work?

The basic function of NSAIDs is fairly simple to understand. Broadly acknowledged as a class of general pain relievers, NSAIDs are used to treat a range of conditions both acute and chronic. With the capacity to be taken orally, topically, or as an injection, NSAIDs can be used to reduce inflammation (similar to drugs such as corticosteroids), treat pain, and reduce fever.

Separated into various groups based on their chemical structure and how they operate in the body, NSAIDs primarily function to inhibit cyclooxygenase. Cyclooxygenase (COX) is a family of enzymes that controls the body’s production of eicosanoids: signaling molecules with a variety of physiological and pathological processes. More specifically, the COX enzyme converts arachidonic acid into a subclass called prostanoids, which includes prostaglandins (mediators of inflammation and anaphylaxis), thromboxanes (mediators of vasoconstriction), and prostacyclins (mediators of vasodilation). By blocking the COX enzyme, NSAIDs ultimately help to slow the production of certain eicosanoids in the body, thus affecting the body’s natural response to trauma.

How Do NSAIDS and COX Inbitors Work?

Cyclooxygenase presents in the body as two different enzymes: COX-1 and COX-2. COX-1 is an essential enzyme constantly being expressed in the body, while COX-2 is only expressed during an inflammatory response. The ubiquity of COX-1 contributes to a more significant role in the body than COX-2: the maintenance of crucial functions in the gastrointestinal system, the kidneys, and the bloodstream. Since the COX-1 and COX-2 enzymes function in different capacities in the body, the inhibition of these enzymes by NSAIDs will have varying interactions and side effects. Most NSAIDs fall under the category of non-selective COX-inhibitors, meaning they affect both COX-1 and COX-2, while a few NSAIDs are categorized as selective COX-2 inhibitors, which means they bypass the more widely present COX-1 enzyme. The lack of selectivity in most commonly used NSAIDs like acetylsalicylic acid, ibuprofen, and naproxen is the reason there are so many potential side effects with NSAID use. As most NSAIDs are non-selective, COX-1 enzymes are inhibited, which could adversely affect the body.

Selective COX-2 inhibitors (Vioxx – rofecoxib and Celebrex – celecoxib)  were introduced to the market as they were thought to be associated with fewer side effects related to the stomach and gastrointestinal system. However, starting in 2004, this class of products was withdrawn from the market (Vioxx) or severely restricted in their common use based on strong warnings from the FDA and Health Canada because of serious cardiovascular side effects potentially causing death in some people.

What Are NSAIDs Used For?

NSAIDs are used to treat general symptoms like high temperature or fever, inflammation, and pain, all of which commonly occur in a range of conditions. NSAIDs are approved for use in the treatment of various types of pain, so they’re commonly prescribed as pain relievers for acute ailments such as headache, fever, painful menstruation, cold and flu, and muscle and joint pain. While NSAIDs are considered more useful for acute conditions, they have also been known to help treat pain associated with chronic conditions such as arthritis and lupus. However, use of NSAIDs for the treatment of chronic conditions is not generally recommended, as long-term use is more commonly linked to adverse side effects. 

What Are The Four Most Common Side Effects of NSAID Use?

NSAIDs are considered generally safe for use by the majority of people. However, it is still possible to experience side effects, including gastrointestinal issues, headaches, drowsiness, dizziness, allergic reactions, and issues with blood pressure, heart, and liver function. Some side effects are more likely than others, and there are several groups for whom NSAID use might cause more consistent or severe side effects.

NSAIDs may potentially cause issues for people 65 and over, people with preexisting conditions like heart, liver, or bowel issues, people with particular allergies or asthma, people who are pregnant, or people taking other medications that may conflict with NSAIDs. While side effects of NSAID use may not always be of great concern, it is important to understand what side effects are possible and for whom they might be more serious. Additionally, though side effects can result from both short-term and long-term NSAID use, it is speculated that long-term use may put the individual at greater risk for more significant side effects.

1. Gastrointestinal Issues

Of the major side effects attributed to NSAID use, gastrointestinal issues seem to be the most common. These gastrointestinal issues include relatively benign responses such as indigestion and generalized stomach pain, as well as more severe, potentially long-term effects like ulcers and gastrointestinal bleeding. While short-term use can cause temporary upset, it is more significant to discuss the likelihood of high-dose or long-term NSAID use potentially disrupting the overall health of the gastrointestinal system.

Long-term NSAID use may cause serious issues in the gastrointestinal system due to the blockage of of COX-1 enzyme production  in the gastric mucosa lining. Normally, COX-1 enzymes work in the lining of the stomach to produce prostaglandins which, in turn, function to protect the stomach lining by creating mucus. However, when NSAIDs are introduced, COX-1 enzymes are blocked, leading to a slowdown in the production of prostaglandins. While this might not cause issues at first, long-term NSAID use poses a consistent threat against the safety of the stomach lining. Without the proper amount of mucus, the stomach lining is vulnerable to damaging stomach acids. This could cause a perforation of the stomach lining that may lead to a variety of acute and chronic conditions like gastric and peptic ulcers, and even gastrointestinal bleeding. Studies show that older individuals should be more conscious of these types of issues associated with long-term use

2. Rebound Headaches

While NSAIDs are commonly prescribed to treat headaches and migraines, it is not uncommon for users of NSAIDs to experience recurring headaches as an unwanted side effect. Referred to as a medication-overuse headache, this secondary disorder typically manifests in people with headache disorders such as migraine, tension, or cluster headaches. The overuse or rebound headaches occur as a result of the acute medication (NSAIDs) being used for an extended period of time and, more often than not, in excess of the recommended dosage. Simple analgesics like aspirin, ibuprofen, and naproxen may result in medication-overuse headaches when used 15 or more days out of the month, while combination medications (several of which often include NSAIDs) like Excedrin can cause adverse effect after 10 days of use per month. If NSAIDs continue to be used in excess, the symptoms of medication-overuse headache may persist and even worsen. However, overuse headaches can be treated by tapering off use of NSAIDs and, instead, treating the initial disorder with other therapeutic means.

3. High Blood Pressure, Stroke, and Heart Attack

Consistent use of NSAIDs has also been linked to high blood pressure. Similar to the effect they have on the gastrointestinal system, NSAIDs adversely affect the renal system (specifically the kidneys) by inhibiting the production of prostaglandins. A slowdown in the production of prostaglandins causes a domino effect of issues in the body that begins in the kidneys. When prostaglandin production first begins to slow down, so does the amount of blood flowing to the kidneys. With less blood flowing to the kidneys, these vital organs stop working as well as they normally would, leading to a buildup of fluid in the body. This fluid buildup then affects the bloodstream, ultimately leading to an increase in blood pressure. High blood pressure is never a good sign, as it can often lead to more serious complications if left untreated. Most commonly, high blood pressure is often one of the first notable symptoms attributed to heart attack or stroke. High blood pressure caused by overuse of NSAIDs has been known to interfere with vasoconstriction (narrowing of the blood vessels), induce platelet aggregation (blood clotting), and affect sodium excretion in the kidneys, all of which set the stage for a serious health event like heart attack or stroke. It is thus recommended those who use NSAIDs regularly, particularly older individuals, understand the potential ramifications and consider alternatives.

4. Allergic and Similar Reactions

Like any other medication, NSAIDs have the potential to cause allergic reactions in certain individuals. Common allergic reactions associated with NSAIDs include skin rashes, wheezing, and throat swelling. The majority of allergic reactions to NSAIDs are the result of an aspirin sensitivity, which is typically connected to preexisting or underlying airway and respiratory disease (aspirin-exacerbated respiratory disease) or skin disease. For those with aspirin-exacerbated respiratory disease (AERD), NSAIDs are not the cause of allergic reactions but, rather, key instigators in the exacerbation of certain symptoms. For example, NSAIDs can increase the symptoms of severe asthma, such as wheezing and difficulty breathing. Similarly, individuals who are prone to hives and swelling of the skin, NSAIDs may trigger flare ups on occasion.

While allergic reactions to NSAIDs are more common among those with preexisting or underlying conditions, NSAIDs may cause allergic reactions in those without existing sensitivity. Most allergic reactions to NSAIDs are fairly mild, but a sudden allergic reaction may lead to serious anaphylactic shock. Characterized by hives, swelling of the skin and throat, difficulty breathing, and lightheadedness, anaphylaxis as a result of NSAID use is rare, but it is also life-threatening and requires immediate medical attention. Because of the potential severity of allergic reactions to NSAIDs, it is suggested that anyone with a history of allergic reactions be cautious.

Should I be Concerned about the Side Effects?

Normal, intermittent use of NSAIDs is generally considered safe for most individuals. However, as with any medication, it is important to understand both the benefits and potential risks of NSAID use and for whom they might pose additional harm. In short-term use, NSAIDs do not seem to cause serious issues. However, chronic use of NSAIDs has proven troublesome for many groups, including the elderly. In addition, NSAIDs may be an issue for those taking other regular medications such as diuretics, certain antidepressants, methotrexate, and other NSAIDs. Thus, while use of NSAIDs is generally safe, it is always worth considering alternatives and speaking to a health care professional if you are concerned.

What are Alternatives Treatments to NSAIDs?

Arguments continue to grow against the use of NSAIDs for pain, specifically in regards to chronic or long-term conditions. As such, more and more alternative treatments are being introduced to address acute and chronic pain with greater concern for overall wellness. Since NSAIDs are used to treat a broad spectrum of conditions, the alternatives vary as well. Popular alternatives to NSAIDs include non-medicinal treatments like physical therapy, acupuncture, and relaxation and meditation techniques, which are particularly popular treatment methods for conditions like muscular and joint pain, headaches, and stress.

There is also a growing interest in use of alternative medications such as acetaminophen (Tylenol) and naturally-derived supplements like turmeric and CBD (cannabidiol) to control inflammation that can cause pain. These medications have the capacity to target pain or inflammation without the adverse effects of NSAIDs.

While studies continue to be conducted about the efficacy of NSAID alternatives, there is already substantial evidence to prove these treatments should at least be considered. With positive effects on acute and chronic pain and little to no negative ramifications, these alternatives are viable options to pursue, particularly for individuals who have experienced an adverse reaction to NSAIDs or are experiencing chronic pain. NSAIDs, though effective, are all too often connected to negative, potentially life-threatening side effects.

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