Accurate Education - NSAIDs

NSAIDs (Non-Steroid Anti-Inflammatory Drugs)

Examples:

Non-selective NSAIDs (ns-NSAID):

Ibuprofen (Motrin)

Naproxen (Aleve, Naprosyn)

Diclofenac (Voltaren)

Meloxicam (Mobic)

and others

Selective NSAIDs:

Celebrex (celecoxib)

Definitions and Terms Related to Pain

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NSAIDs (Non-Steroid Anti-Inflammatory Drugs)

Types of NSAIDs

NSAIDs that are available over the counter (OTC) without prescription include ibuprofen (Advil, Motrin) and naproxen (Naprosyn, Anaprox, Aleve) and aspirin. Prescription versions of the OTC NSAIDs are available and usually covered by insurance. Other common prescription NSAIDs include diclofenac (Voltaren), Mobic (meloxicam) and others.

Selective and Non-selective NSAIDs:

NSAIDs work by inhibiting two enzymes that are responsible for inflammation and pain, cyclooxygenase-1 and cyclooxygenase-2 (Cox-1 and Cox-2). NSAIDs that inhibit both Cox-1 and Cox-2 are considered non-selective NSAIDs (ns-NSAIDs) whereas NSAIDs that inhibit only Cox-2 are referred to as selective Cox-2 inhibitors.

Cox-1 vs Cox-2 NSAIDs

Inhibition of Cox-1 results in decreased levels of prostaglandins in the gastrointestinal tract that are protective of the lining of the gastrointestinal (GI) tract which is why NSAIDs can lead to gastritis and ulcers. Selective Cox-2 inhibitors offer the advantage of reduced risk of GI side effects but unfortunately they raise the risk of cardiovascular (CV) side effects, including heart attack and stroke. Most selective Cox-2 inhibitors (i.e Vioxx) have been taken off the market due to their increased CV risks, but Celebrex (celecoxib) is still available and does not appear to have increased CV risks over the ns-NSAIDs.

Topical NSAIDs:

Topical NSAIDs in many cases are equally effective for pain control and are the recommended first choice to begin treatment with an NSAID. There are many effective OTC topical creams with NSAIDs. Prescription NSAIDs include diclofenac (Voltaren Gel, Pennsaid and Flector Patches). Compounded topical medications used for pain usually consist of a combination of different medications with analgesic properties, in addition to diclofenac.

Benefits of NSAIDs

NSAIDs are sometimes overlooked and underutilized in the management of chronic pain.

NSAIDs offer 3 benefits:

Pain relief for mild to moderate pain
Anti-inflammatory benefit for inflammation and arthritis
Reduce fever

Pain relief:

The NSAIDs are particularly effective for toothaches and other oral pain, often superior to opioids. They are also very effective for headaches, even when tylenol or opioids are not. For menstrual pain NSAIDs are frequently found to be more effective than opioids. Overall, NSAIDs are very effective in acute pain such as trauma and post-operative pain. Interestingly, there is recent research that suggests taking B vitamin complex with NSAIDs improves their pain relieving benefits. The mechanism for this benefit is unknown.

Inflammation:

NSAIDs are perhaps best known for their effectiveness in treating arthritis pain because of their anti- inflammatory properties. NSAIDs also have a role in treating many sources of chronic pain. Since chronic pain is very often due at least in part to inflammation, the anti-inflammatory benefit of the NSAIDs can be very helpful. A common but under-appreciated source of arthritis pain is the facet joint in the spine which is the primary source of neck and back pain in as many as 40% of patients with chronic neck and back pain.

While the pain relief provided by the NSAIDs is generally fairly fast in onset – within an hour after a dose – the anti-inflammatory benefits may take as long as 2-4 weeks to take full effect and may require multiple doses/day. Failure to understand this leads to premature discontinuation of NSAIDs due to the incorrect conclusion that the NSAID offers no benefit after being taken only once or twice a day for brief time periods. It may be necessary to maintain regular dosing of an NSAID for at least 2-4 weeks to fully appreciate their benefit.

Dosing of NSAIDs

Determining the best, or optimal, dose of an NSAID is based on a few variables. First, each person may respond differently to one NSAID vs. another. Secondly, one person may require higher doses than another to achieve the same benefit.

Genetic testing:

Your physician may obtain genetic tests of your DNA by an oral swab of your cheek to help guide your NSAID management towards the best choice and dose of NSAID. Some people are slower than others to metabolize and eliminate NSAIDs from their system. These people may need to reduce their dose by 50-75% or more compared to usual doses of an NSAID in order to avoid higher risk of side effects. Ask your physician about genetic testing and NSAIDs.

NSAIDs for Pain – A Ceiling Effect

The dose needed to reduce pain, particularly acute pain, is often less than the dose needed to reduce inflammation. With ibuprofen and diclofenac, there is a ceiling effect for the pain benefit. In one study comparing analgesia (pain relief) with 400 mg, 600 mg, and 800 mg doses of ibuprofen, there was no significant difference in pain relief among these doses. Although higher doses have been shown to further reduce inflammation, doses above 400mg do not equate to additional pain reduction. In a systematic review, oral diclofenac 50 mg was associated with greater analgesia in postoperative pain than diclofenac 25 mg; however, diclofenac 100 mg did not show improved effectiveness over diclofenac 50 mg, suggesting a ceiling effect at 50 mg.

For example, the maximum beneficial analgesic (pain relieving) dose of ibuprofen is 400mg. Thus, when taken for a toothache, if 400mg of ibuprofen doesn’t provide relief, taking 800mg may not be expected to do so either. Taking higher doses in this case would only place one at greater risk of side effects with little expected greater pain relief.

TreatIng inflammation:

With arthritis, the maximum anti-inflammatory dose is often higher – up to 800mg ibuprofen per dose, up to 4 doses/day. It may require at least two weeks of multiple daily doses to achieve full benefit.

How to determine the best dose of an NSAID:

First, understand the basic principal regarding all medications: the optimal dose is the smallest dose that provides the maximum benefit (with no side effects). To determine the optimal dose, start your dosing low. In general, ibuprofen is considered one of the safest of the NSAIDs, so start with ibuprofen (Advil, Motrin).

NSAIDs for Acute Pain

For short term or intermittent use, simply start with a 200mg dose (one OTC tablet) and if this is ineffective proceed to the 400mg dose. If the 400mg dose is ineffective, consider trying a 600-800mg dose, but it is unlikely the higher dose will be more effective and you should find an alternative analgesic rather than continue taking more than a 400mg dose of ibuprofen.

NSAIDs for Chronic Pain

For managing chronic pain associated with inflammation, begin your dosing at 200mg every 6 hours (four times a day). Stay at this dose for a week or two, then assess the benefit achieved at this dosing. Next, increase your dose to 400mg every 6 hours for another week or two. If increasing the dose from 200mg to 400mg did not provide additional benefit, go back to the 200mg dose. If the 400mg dose did provide additional benefit, proceed to the 600mg dose and repeat the process up to 800mg 4x/day. Because chronic pain is often associated with inflammation, the argument is that the higher doses may offer greater benefit. But it should be understood that the time required to reduce inflammation may be 2-4 weeks and therefor the pain benefit from reducing inflammation may also take 2-4 weeks before it can be fully appreciated.

Due to the many factors contributing to pain, it may be somewhat difficult to determine which dosing regimen always works best – the optimal dose may vary from time to time even in the same individual. But it is always best to maintain your dosing at the lowest dose that provides the most benefit.

NSAIDs for Chronic Low Back Pain (LBP)

Due to their ease of availability, affordability and perceived safety along with recently growing concerns regarding the use of opioids for chronic low back pain, NSAIDs are commonly prescribed long term for chronic low back pain. The wisdom of doing so should be based on the determination of safety and effectiveness of this practice.

A recent review article published in 2016 evaluated the safety and effectiveness of NSAIDs for chronic LBP and reported that less than half of the random controlled trials (RCT) showed that NSAIDs are more effective than placebo regarding pain intensity. NSAIDs were determined to be only slightly more effective than placebo regarding disability. However, the magnitude of the benefits were small, and the quality of evidence was low. When only the hightest quality RCTs were included, differences in effect between NSAIDs and placebo were reduced. No difference in effectiveness between NSAIDs of different types, including selective versus non-selective NSAIDs were identified. In regard to the safety of long-term NSAID use for LBP, researchers concluded “we cannot make firm statements about the occurrence of adverse events or whether NSAIDs are safe for long-term use.”

NSAIDs vs. Opioids for Pain

In comparing the effectiveness of oral NSAIDs, a 2016 study reviewed research that evaluated celecoxib, diclofenac, naproxen and piroxicam with tramadol, hydromorphone and oxycodone and concluded that NSAIDs and opioids offer similar benefits in reducing knee osteoarthritis (OA) pain. The decision as to which class of medication to engage should be based on individual safety and effectiveness variables.

Which NSAID is Best?

If “best” means the most pain relief, there is no definitive research to show that one NSAID is generally more effective than another. However, an individual may find one NSAID does work better than another so it doesn’t hurt to experiment a little amongst the NSAIDs. Genetic testing may provide information for identifying the most effective NSAID for an individual.

If “best” means the safest drug, a recent publication described some differences in risks between the different NSAIDs. Specifically, oral diclofenac, ibuprofen, and celecoxib have been associated with high cardiovascular (CV) risk, while naproxen has been associated with the lowest risk for adverse cardiovascular events. From a gastrointestinal perspective, agents such as ketorolac (Toradol) and piroxicam demonstrate a high risk for gastrointestinal bleeding and perforation, while celecoxib, diclofenac, and ibuprofen are associated with fewer gastrointestinal (GI) adverse events at equivalent doses.

Keeping it Simple:

If topical NSAIDs are effective, practical and affordable, use only topical NSAIDs.

As with any decision, the benefits of taking NSAIDs must be weighed against the risks. When the decision is to treat with NSAIDs, it is wisest to limit the dose and duration of use as much as possible. Cardiovascular risk appears to be associaed only with chronic use of NSAIDs, not occasional, episodic use. The following suggestions may prove helpful:

For those patients at relatively low risk for both GI and CV problems, any non-selective NSAID (ns-NSAID) alone should be acceptable. However, for long-term or high frequency use of NSAIDs, or for those patients with a positive family history of NSAID-induced GI side effects, supplementing with a proton pump inhibitor (PPI) such as Nexium (esomeprazole) or Prilosec (omeprazole) might be advisable.

For those patients with relatively low GI and high CV risk, naproxen is preferred because of its minimal CV risk compared with other ns-NSAIDs or COX-2 selective inhibitors, but Celebrex (celecoxib) at the lowest approved dose (200 mg once daily) might be acceptable. The degree of CV risk appears related to the level of Cox-2 inhibition, with naproxen having the least activity. For a graph of Cox-2 activities of different NSAIDs, see here.

For those patients with relatively high GI risk, and low CV risk, a COX-2 selective inhibitor alone or ns-NSAID with a proton pump inhibitor (PPI) such as Nexium (esomeprazole) or Prilosec (omeprazole), appears to offer similar protection from upper GI bleeding. However, only Celebrex (celecoxib) will reduce gastrointestinal lining harm throughout the entire GI tract.

One note regarding celecoxib:

Concerns have been raised that there may be cross-reactivity between allergies to sulfa antibiotics and celecoxib, due to a structural element of the celecoxib shared with sulfa antibiotics. Because of this, it is often advised to avoid celecoxib if one has an allergy to sulfa antibiotics because a history of sulfa allergy may be associated with an increased risk of adverse reactions to a wide range of nonantibacterial sulfonamides, including celecoxib, loop and thiazide diuretics, certain antivirals, carbonic anhydrase inhibitors, and sulfonylureas. Concerns have also been raised that patients who have experienced an allergic reaction to one nonantibacterial sulfonamide may be at risk for an adverse reaction to others. However, there is good evidence that none of the nonantibiotic sulfonamides exhibit both of the features shown to be responsible for sulfonamide allergic reactions. The weight of evidence suggests that withholding nonantibacterial sulfonamides such as celecoxib from patients with prior reactions to antibacterial sulfonamides or other nonantibacterial sulfonamides is not clinically justified.

For those patients with relatively both high GI risk, and high CV risk, the optimal strategy is to avoid NSAID therapy.

If “best” means the safest form, the use of a topical form of NSAID is the preferred means of using an NSAID. Applied topically in the form of a cream, gel or patch, the NSAID will penetrate to the affected area only where applied, lessening the blood levels and exposure to the kidney and liver therefore reducing the risk of systemic side effects (fewer cardiovascular and gastrointestinal adverse events) and treatment complications. Topical NSAIDs in many cases are equally effective for pain control and are the recommended first choice to begin treatment with an NSAID.

Combining Oral and Topical NSAIDs

A recent study looked at combining oral and topical NSAIDs at the same time and found oral or topical diclofenac individual effectiveness was similar to combination of both therapy in all pain and physical function endpoints. In other words, adding oral diclofenac to topical diclofenac treatment offered no benefits but did increase the risk of side effects.

There are many effective OTC topical creams with NSAIDs. Prescription NSAIDs include diclofenac (Voltaren Gel, Pennsaid and Flector Patches) as well as others available by prescription from a compounding pharmacy. Compounded topical medications used for pain usually consist of a combination of different medications with analgesic properties, including an NSAID.

Safety and Precautions with NSAIDs

Gastrointestinal (GI):

While the NSAIDs are usually quite safe, they can cause problems – most commonly nausea or abdominal pain, but sometimes ulcers or bleeding in the stomach or intestinge that may result in black or tarry stools. People at higher risk for g.i. side effects include those with recent history of ulcers, smokers and those who use NSAIDs frequently (>10 doses/month). The use of alcohol may also increase risk for g.i. side effects with NSAIDs. For those who are at higher risk, it is recommended that they also take a medicine to reduce stomach acid such as a PPI (e.g. prilosec, Nexium, Prevacid) or an H2 blockers (e.g. ranitidine (Zantac) or Pepcid). PPIs are thought to be more effective than H2 blockers for protection against NSAIDs. It may also be helpful to take NSAIDs with food although research suggests this may not be an effective strategy.

Other conditions at elevated risk of gastrointestinal bleeding include the elderly and people who have hemorrhoids, duodenal and gastric ulcers, ulcerative colitis, Crohn’s disease, esophageal varices, esophagitis, intestinal polyps and tumors, celiac sprue, intestinal vasculitis, cow’s milk allergy, and anal fissures.

Liver:

Studies have found liver toxicity (hepatotoxicity) from NSAIDs to be very low. The incidence rate of hepatotoxicity associated with NSAIDs is in the range of 1.4–23.4/100000 patient-years. A review article published in 2018 that evaluated 698 studies identified only 8 studies regarding three NSAIDs (celecoxib, etoricoxib, and diclofenac) that demonstrated clinically significant evidence for liver toxicity (hepatotoxicity). The authors assessed hepatotoxicity manifest as liver enzyme (aminotransferases AST & ALT) elevations > 3 × upper limits of normal (ULN), liver-related drug discontinuation, serious hepatic adverse events, liver-related hospitalizations, and liver-related deaths.

Of the three NSAIDs, diclofenac (Voltaren) has the highest proportion of hepatotoxicity, followed by celecoxib (Celebrex), and etoricoxib (not marketed). Hepatotoxic evidence is mostly based on aminotransferase elevation, while liver-related hospitalization or discontinuation was very low.

Kidneys:

NSAIDs can also cause nephritis (inflammation in the kidneys), which may result in abdominal pain, back pain, blood in the urine and/or fever. If you develop any of these symptoms, discontinue NSAIDs and notify your physician. If you have any previous history of kidney disease, it probably best to avoid NSAIDs.

Cardiovascular:

Recent research has also determined that there is increased risk of heart attack, stroke, blood clots and high blood pressure associated with long term use of NSAIDs. In 2015, the FDA strengthened a previous warning for the increased risk for myocardial infarction (heart attack) and stroke with the use of NSAIDs. The American Heart Association recommends naproxen as the NSAID of choice for patients with high cardiovascular risk.

A “safe” time frame for the use of NSAIDs is not well defined but should be limited to a maximum of two to three weeks to limit cardiovascular risk. If you are at increased risk for these conditions you may not be a good candidate for the use of NSAIDs even for short term use so you should talk with your physician before taking NSAIDS.

Surgery:

It is commonly advised that NSAIDs be discontinued a week or more prior to surgery, based on the concerns that increased bleeding may occur. However, evaluating this further, the concern is based on NSAIDs coating platelets and reducing their capacity to form blood clots. Because this effect of NSAIDs is temporary and based on the rate at which the NSAID is metabolized and eliminated by the liver, the actual time for witholding dosing prior to surgery is likely needed for only 24 hours before surgery for short acting NSAIDs like ibuprofen (Advil, Motrin) and diclofenac (Voltaren). Longer acting NSAIDs like naproxen (Aleve) and meloxicam (Mobic) are likely to be safe when discontinued only 4-5 days preoperatively.

Healing of Bone Fractures

It is also commonly advised to avoid NSAIDs in the setting of bone healing from surgery or fractures. This is based on studies limited to animals, with no apparent human studies yet completed and a lack of ability to . As such, the need for witholding NSAIDs in these circumstances is yet to be confirmed.

Genetic Testing

Through the use of genetic testing via an oral saliva swab, it can be determined if you are a normal metabolizer of NSAIDs or not and this can provide important information to improve the safety of taking NSAIDs. For example, if it is determined that you are a slow metabolizer, lower doses may provide greater than average benefits for a particular dose but also greater likelihood of developing the side effects listed above. This especially applies to the use of high dose NSAIDs which would likely represent a significant risk to a slow metabolizer with no likely benefit. Genetic testing also provides insights as to the likely potential benefits of NSAIDs such as in cardiovascular risk reduction. Discuss this with your physician.

Drug Interactions

Aspirin and NSAIDs

Low dose aspirin is frequently advised as a protective measure against heart attack and/or stroke. The mechanism for this benefit comes from aspirin coating platelets, the cells that form blood clots, which makes them less likely to form an unwanted blood clot. When aspirin coats platelets, it does so permanently for the life of the platelet which is about 10-14 days. The use of some NSAIDs may interfere with this benefit, especially ibuprofen, because ibuprofen also coats platelets, but only temporarily. Therefore, if you take ibuprofen at the same time as aspirin, the ibuprofen may competitively interfere with aspirin and counteract the benefit obtained by taking aspirin. Celecoxib (Celebrex) may not coat platelets and may be a better choice of NSAID for those taking aspirin to reduce the risk of heart attack or stroke. The data on naproxen (Aleve & Naprosyn) is ambiguous but is likely to interfere aspirin benefits.

To avoid the interaction with aspirin, It is advised to wait for 2-4 hours after taking your aspirin before takng an ibuprofen and wait 12 hours after taking the naproxen before taking the aspirin. This recommendation does not apply when taking aspirin for headache or pain, only when taking it to reduce risk of heart attack, blood clots or stroke.

It is always important to weigh the benefits against the risks when taking any medications. Always discuss the use of NSAIDs with your physician.

Antidepressants (SSRIs & SNRIs) and NSAIDs

The classes of antidepressants, SSRIs (Selective Serotonin Reuptake Inhibitors) and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors) improve depression by blocking the reuptake (removal) of serotonin from nerve synapses (space between nerve cells) and prolonging the effect of the serotonin which is believed to act to reduce depression. However, this inhibition of serotonin can impact other functions besides nerves.

Platelets are the protective cells in blood that form blood clots in the event of injury or damage to tissues that results in bleeding. Platelets store and release serotonin as part of the process of stimulating clot formation and it is believed that the SSRIs (and possibly the SNRIs) interfere with this process resulting in impaired blood clot formation. While this apparently does not have clinically significant systemic affects, it does appear to increase the risk of gastrointestinal (GI) bleeding in those taking NSAIDs.

Certain individuals are at higher risk of suffering from GI bleeding, including the elderly and people who have hemorrhoids, duodenal and gastric ulcers, ulcerative colitis, Crohn’s disease, esophageal varices, esophagitis, intestinal polyps and tumors, celiac sprue, intestinal vasculitis, cow’s milk allergy, and anal fissures. These individuals should be especially cautious taking NSAIDs, if at all, and should also considering avoiding these SSRIs and SNRIs if taking NSAIDs.

A recent study indicated that 5.3 percent of the subjects who had GI bleeding were taking SSRIs, compared to only 3 percent of those not taking SSRIs, an increased risk of 60 percent. There was an almost fivefold increased risk of GI bleeding among users of SSRIs also using corticosteroids (such as prednisone). Among those taking corticosteroids, NSAIDs and SSRIs, there was a ninefold increased risk of gastrointestinal bleeding. Other studies have found that even low-dose aspirin, when combined with SSRIs, can increase the GI risk of bleeding, although the risk is slightly less than with other NSAIDs.

SSRIs commonly prescribed include:

Prozac (Fluoxetine), Celexa (Citalopram), Paxil (Paroxetine), Lexapro (Escitalopram) and Zoloft (Sertraline).

SNRIs commonly prescribed include:

Cymbalta (duloxetine), Effexor (venlafaxine) and Savella (milnaciprin).

Allergy to NSAIDs

If you have had an allergic reaction to aspirin or any of the NSAIDs, it is likely that you will also have an allergic reaction to any other NSAID – so all NSAIDs should be avoided.

Final Comment

In the battle against chronic pain, do not forget to consider some of the simple solutions such as the NSAIDs, warm soaks and massage, especially when experiencing a flare-up of your usual pain. While the NSAIDs may not have the immediate, powerful impact that the opioids do, in fact they may provide quite significant reduction in pain when taken appropriately. Just stay at the smallest dose with the most benefit.

References:

NSAIDs – Overviews

NSAIDs – Safety

NSAIDs – Sulfa Allergy and Cross-Reactivity with Celecoxib (Celebrex)

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Accurate Education – NSAIDs

NSAIDs (Non-Steroid Anti-Inflammatory Drugs)

Key to Links:

NSAIDs (Non-Steroid Anti-Inflammatory Drugs)

Types of NSAIDs

Benefits of NSAIDs

Dosing of NSAIDs

Which NSAID is Best?

Safety and Precautions with NSAIDs

Drug Interactions

References:

NSAIDs – Overviews

NSAIDs – Safety

NSAIDs – Sulfa Allergy and Cross-Reactivity with Celecoxib (Celebrex)

Emphasis on Education

For more information, please contact Accurate Clinic.

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