Access to the PPM Journal and newsletters is FREE for clinicians.
11 Articles in Volume 16, Issue #7
A Perspective on Tapentadol Therapy
Acupuncture to Treat Brachial Plexopathy and CRPS
Behavioral Medicine: How to Incorporate CBT Into Pain Management
EpiPens and Opioids: Common Ground
Fibromyalgia and Coexisting Chronic Pain Syndromes
Life-Saving Naloxone: Review of Currently Approved Products
Medical Foods Hold Promise In Chronic Pain Patients
Moving Beyond Pain Scales: Building Better Assessment Tools for Today’s Pain Practitioner
Moving Toward an (Almost) Opioid-Free Emergency Department
No Perfect Medicine—What You Need to Know About NSAIDs and Opioids
Prescribing Opioids: How New Policies Are Affecting Medical Specialties

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.

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

Download PDF to view larger

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.

Reversal of respiratory depression caused by partial mu agonists is more difficult to manage as it is reversed only partially by opioid antagonist. This requires special vigilance and a low threshold for a decision to intubate the patient.12 In addition to respiratory depression, respiratory adverse effects include cough suppression, hoarseness (inhibitory part), bronchospasm, and runny nose (excitatory part). In the author’s clinical experience, methadone is disproportionately associated with hoarseness.

The CNS effects of opioids provide pain control, as well as sedation, fatigue, and confusion, which may or may not be short lived. On the contrary, opioids’ excitatory properties may cause hyperalgesia,13,14 seizures, hallucinations, and paranoia. Partial antagonists (like buprenorphine), in general, are less likely to cause these symptoms. Clinically, oxycodone, oxymorphone (Opana), hydrocodone, and hydromorphone are associated with higher incidence of euphoria, while levorphanol, tramadol, tapentadol (Nucynta), and meperidine more often produce seizures. Methadone, meperidine, and higher doses of oxycodone seem to be more frequently associated with encephalopathy.

Intracranial adverse effects associated with opioids include headaches—these are caused by, and separate from, cerebrospinal spinal fluid (CSF) pressure elevation. This may be a result of both inhibitory and excitatory mechanisms, and the basis of universal and sound advice to avoid use of opioids in headache management. Buprenorphine seems to produce fewer headache complications, but still may be responsible for this serious adverse effect.

Musculoskeletal adverse effects vary from inhibitory muscle weakness, decrease in deep tendon reflexes, and improvement in restless leg syndrome to excitatory muscle twitching, rigidity, myalgia, arthralgia, and bone pain, as well as induction of periodic limb movement disorder. Levorphanol, tramadol, tapentadol, and meperidine, as well as buprenorphine, are observed to disproportionately cause excitatory adverse effects in the musculoskeletal system.

Cutaneous side effects include dry skin, brittle hair and nails (inhibitory), and itching, sweating, flushing, rash, petechiae, photosensitivity, and wrinkle formation (excitatory). Buprenorphine seems to especially cause sweating, and methadone (as well as higher doses of other opioids) has negative cosmetic effect due to wrinkle formation.

Circulatory adverse effects are common and include inhibitory orthostatic hypotension, vasodilatation, and decrease in cardiac output, bradycardia or tachycardia, QT segment prolongation, and cardiac arrhythmias. Excitatory peripheral and pulmonary edema as well as secondary cellulites have been observed with opioid use. Methadone and buprenorphine may have higher incidence of low leg edema (and cellulitis). Methadone and meperidine are especially dangerous for QT prolongation. Methadone carries an FDA “black box” warning in regard to association with QT interval; buprenorphine does not have such a warning, but caution is recommended. In relation to pulmonary edema, special precautions should be considered with fentanyl.

Ocular problems associated with opioid therapy include mydriasis (due to hypoxia or withdrawal) or miosis. Red eyes, tearing, worsening of night vision or increase in light sensitivity, and intraocular hypo- or hypertension may be caused by any opioids.

GI adverse effects are common and are caused by both inhibitory (constipation, bloating, dry mouth and teeth decay, or drooling due to esophageal dysregulation) and excitatory functions (GI spasm, abdominal cramps, spasm of sphincter of Oddi and duodenum, obstruction of the common bile duct, nausea, vomiting, hiccups, and gastroesophageal reflux disease [GERD]). Fentanyl and buprenorphine are associated with lesser risk of GI spasm and may be more practical in patients with GI problems.15,16

Endocrine adverse effects range from inhibitory decrease in testosterone, decrease in estrogen and luteinizing hormone, decrease in sexual drive, infertility, hypothyroidism, hypoadrenalism, weight gain (usually associated with edema or with decrease in metabolic rate), to osteoporosis. Excitatory endocrine effects include prolactinemia, gynecomastia, and thyroid-stimulating hormone elevation independent of thyroid function. Endocrine effects of opioids correspond with sexual adverse effects from decrease in sexual desire, erectile disorder, and anorgasmia, to spontaneous orgasms and erections with opioid withdrawal. Buprenorphine is the most benign opioid in this regard.

Immune system adverse effects are frequently associated with opioids. They range from increase in infectious diseases due to immunosuppression to angiogenesis with corresponding tumor growth. Buprenorphine is safest in an immunocompromised patient.

Urinary adverse effects are well known and include prostatic hypertrophy, urinary retention, and urinary incontinence. Opioids complicate treatment of such conditions.22

Half-life and Metabolism

Opioids greatly vary in their half-life: ranging from 2.3 hours for hydromorphone to 20 to 44 hours for buprenorphine. Especially variable and unpredictable is the half-life of methadone, which may range from 3 to 72 hours. Only clinicians with special training and experience are advised to prescribe or administer methadone.

Opioids may be metabolized by different liver cytochrome P (CYP)-450 enzymes or by glucuronidation. As such, opioid’s metabolism is impacted by other substance that either induce or inhibit corresponding enzymes or by competing metabolites. The majority of opioids are metabolized by CYP-450 2D6 (codeine, hydrocodone, tramadol, oxycodone), 3A4 (fentanyl, methadone, buprenorphine), or through glucuronidation (morphine, hydromorphone, levorphanol). Also the presence of kidney or liver diseases may dictate which opioid is safest to use.


Last updated on: September 19, 2016
Continue Reading:
Medical Foods Hold Promise In Chronic Pain Patients

Join The Conversation

Register or Log-in to Join the Conversation

What others are saying

1 comment.

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.
close X