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No Perfect Medicine—What You Need to Know About NSAIDs and Opioids

Your guide to safe use of NSAIDs and opioids, and possible drug-drug interactions.
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There are no perfect medications. This applies to both nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. A high level of mortality is associated with both NSAIDs and opioids. An overall mortality incidence rate of 48/1,000 person-years was reported for patients taking nonselective NSAIDs compared with 75/1,000 person-years with opioids.1

In 2015, US Food and Drug Administration (FDA) strengthened the existing label warning for non-aspirin NSAIDs, citing that NSAIDs increase the chance of a heart attack or stroke. Pain patients taking either over-the-counter (OTC) or prescription versions of NSAIDs should be alerted to adverse events, especially those patients with pre-existing cardiovascular conditions and history of gastrointestinal (GI) bleeding (Table 1).2

GI bleeding and cardiovascular problems begin almost immediately after starting a patient on NSAIDs—in fact, the risk is approximately the same whether these agents are used for short- or long-term treatment.3,4 The risk of kidney failure, however, increases the longer NSAIDs are used for pain management.4 And all adverse events increase with higher doses of NSAIDs.5,6

Inhibition of cyclo-oxygenase-1 (COX-1), which is required to synthesize prostaglandins, may be the cause of NSAID-related GI ulcers. Without the mucosal protective prostaglandins, stomach acid, bile salts, and enzymes may be more likely to cause direct damage.7 Pharmaceutical companies have produced COX-2-selective NSAIDs (coxibs) that are less toxic to the GI tract—offering protection from the development of ulcers and GI bleeds. However, when COX-2 NSAIDs are combined with low-dose aspirin (ASA), that mucosal protection is reduced.

The risk of GI bleeds appears to be highest with ketorolac, and then in decreasing order, piroxicam, indomethacin (Indocin, others), naproxen (Aleve), ketoprofen, meloxicam (Mobic, others), diclofenac (Voltaren, Solaraze, others), and ibuprofen (Advil, Motrin, others).8

The relative risk of hypertension also varies depending on the specific NSAID.9 Among NSAIDs, naproxen is generally considered the safest NSAID for patients at risk for cardiovascular adverse effects. The GI benefit of coxibs also must be weighed against a potentially heightened risk of cardiovascular and renal problems.10 Celecoxib (Celebrex) is the only COX-2-selective product still on the market.

Additional and less-known adverse effects include irritability, anxiety, psychosis, menstrual disturbance, and hemolytic anemia (due to induction of antibodies to the Rh antigen). Fluid retention and edema, exfoliative dermatitis, Stevens-Johnson syndrome and epidermal necrolysis, headache, dizziness, hot flashes, and syncope, are additional risks carried by NSAIDs. In pregnancy, this class of medications is labeled Category C and is contraindicated in the third trimester (Category D) due to closure of ductus arteriosus in fetus.

Drug-Drug Interactions

Multiple classes of drugs can potentially interact with NSAIDS. This includes angiotensin-converting enzyme inhibitors (ACE inhibitors), beta-blockers, and angiotensin receptor blockers (ARBs), anticoagulants, selective serotonin reuptake inhibitors (SSRIs), cyclosporine, lithium, loop diuretics, and methotrexate (Table 2).

Various approaches to NSAID risk mitigation (such as enteric coating, using prodrugs, or combining with gastro-protective agents) potentially reduce upper GI events, but do not protect against lower GI, cardiovascular, or renal events.6,11 The most commonly used agents available for prevention of NSAID-related GI ulcers include misoprostol (Cytotec, others), histamine2 receptor antagonists (H2RAs), and proton pump inhibitors (PPIs). As noted, COX-2 inhibitors may reduce GI events but have potential to increase cardiovascular (CV) and renal risks.10

In addition to using lower doses, use of NSAIDs with shorter half-life (such as diclofenac, ketorolac, and ibuprofen) in general offer less GI risks than longer half-life medications (such as naproxen, meloxicam, and piroxicam).

Avoiding these medications in high-risk patients, such as the elderly, patients with congestive heart failure (CHF), coronary artery disease (CAD), hypertension (HTN), renal insufficiency, and liver cirrhosis, remains a prudent approach.

Table 2 offers a practical summary of NSAIDs’ properties and may be a quick reference for medical practitioners who use this class of medications in clinical practice.


Opioids are indispensable in any pain management practice. The class of FDA-approved opioids is diverse and based on one universal principle—action on mu-opioid receptor (MOR). This includes full and partial opioid agonists, agonists-antagonists, and pure antagonists (naloxone and naltrexone). This article describes only full and partial opioid antagonists.

As with any other substances entering the human body, opioids are associated with adverse effects and are influenced by the chemical properties of each medication, as well as by metabolic factors and interaction with other substances. Use of opioids is also regulated by a risk vs benefit assessment due to their addictive nature.

Opioids possess both inhibitory (analgesia, respiratory depression, constipation, etc.) and excitatory properties (hyperalgesia, euphoria, edema, GI spasm, etc.), which vary by medications and by patient (see Table 3).12-22

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Adverse Events

Respiratory depression is one of the most feared adverse events associated with opioids Respiratory inhibition is caused by both full mu agonists and partial mu agonists. Reversal of respiratory inhibition caused by full mu agonists may be achieved by administration of opioid antagonist (eg, naloxone). Once this medication wears off, respiratory depression may return.

Last updated on: September 19, 2016
First published on: September 1, 2016
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By drstephenrodrigues on 10/07/2016
Pain; Plain and Simple: We have always have had treatments for most all pain problems. These physical pain remedies have been under our noses and at our fingertips since the dawn of time. In reality, in the 1960s, the fundamentals of medicine proved beyond doubts; physical pain problems are treated with physical therapy. The basic cause-effect: Life's injuries cause intramuscular scars which trigger pain signals. The primary problem-solution: Therapeutic or hands-on varieties of physical therapy will benefit intramuscular microscars by activating the natural forces from within. The simple treatment mechanism of action: The Healing Cascade of Wound Repair. "Natural forces within us are the true healers of disease." - Hippocrates This whole natural category of the healing construct was given to us by Hippocrates, Hackett, Travell, Simons, Rachlin and Gunn. If one adds or subtracts any ideas over the top of this fundamental scientific equation, then it will not be 100% accurate anymore. Now all you have to do is correctly and completely define the words "pain" and "Physical Therapy PT." Pain is any distress, cry for help or a need for assistance out of your distress. PT is any remedy which applies a force of effort into the muscular tissues enough to power up the healing cascade of wound repair.