Nonsteroidal Anti-Inflammatory Medications

Author(s): Ritika Oberoi-Jassal, MD, Navdeep Singh Jassal, MD, Jaspreet Singh, MD, Young Chang, MD, Joshua Smith, MD

Originally published:11/05/2012

Last updated:09/30/2016

1. DISEASE/DISORDER:

Definition

Nonsteroidal anti-inflammatory drugs (NSAIDs) are medications used to reduce inflammation and to relieve pain. They are one of the most commonly used medications in adults. All NSAIDs have analgesic, anti-inflammatory, and antipyretic properties.1 The Center for Disease Control (CDC) and Prevention and World Health Organization (WHO) pain ladder recommends NSAIDs should be considered first line for the treatment of mild to moderate, acute, chronic, post-operative, cancer and non-cancer related pain.2,3

Etiology

NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and/or inflammation are present. These drugs also are effective in some neuropathic pain syndromes when used as adjuvants with other analgesics.

NSAIDs are generally indicated for the symptomatic relief of the following conditions:

  1. rheumatoid arthritis
  2. osteoarthritis (OA)
  3. acute gout, inflammatory arthropathies
  4. dysmenorrhea
  5. headache and migraine
  6. postoperative pain
  7. mild to moderate pain because of inflammation and tissue injury
  8. back pain and radiculopathy
  9. sprains
  10. strains
  11. kidney stones
  12. fever
  13. other conditions

Epidemiology including risk factors and primary prevention

According to the American Academy of Pain Medicine, market research reports indicate that more than 1.5 billion people worldwide suffer from chronic pain.4 Long the mainstay of chronic pain management, NSAIDs are known to be associated with gastrointestinal (GI), cardiovascular issues, and for some NSAIDs renal toxicities.

Expert consensus guidelines for the management of hip and knee osteoarthritis by the Osteoarthritis Research Society International (OARSI) recommend the lowest effective dose of NSAIDs should be used but, if possible, long term use should be avoided.5

Patho-anatomy/physiology

NSAIDs work by inhibiting prostaglandin synthase or cyclooxygenase (COX). They impair the transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxanes.6 The different NSAIDs inhibit COX at different extents. However, there are no studies relating the degree of COX inhibition with anti-inflammatory efficacy in patients.7

Multiple randomized clinical trials show there is no evidence that a specific NSAID is superior to another.

COX enzymes: Two related isoforms of the COX enzyme have been described: COX-1 (prostaglandin-H-synthase-1) and COX-2 (prostaglandin-H-synthase-2).8

  • COX-1 is variably expressed in most tissues. It regulates normal cellular processes (e.g., gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function) and is stimulated by hormones or growth factors.
  • COX-2 is usually undetectable in most tissues; its expression is increased during states of inflammation. It is expressed in the brain, kidney, bones, and probably in the female reproductive system. Also, COX-2 expression is inhibited by glucocorticoids. This observation may contribute to the significant anti-inflammatory effects of the glucocorticoids.

Thus, differences in the effectiveness with which a particular NSAID inhibits an isoform of COX may affect both its activity and toxicity. It has been proposed that an NSAID inhibiting only COX-2 should decrease inflammation without having any effect on the constitutive COX-1 isoform (thereby minimizing toxicity). Such an agent would maximize effectiveness without inducing toxicity, particularly GI erosions.

The selective COX-2 inhibitors demonstrate at least a 200- to 300-fold selectivity for inhibition of COX-2 over COX-1 at therapeutic doses. They provide comparable analgesia with the nonspecific NSAIDs with a reduction in GI side effects. An additional possible benefit is protection against the development of colon cancer.9 Unfortunately, there is a possible increase in complications because of heart attack, thrombosis, and stroke by a relative increase in thromboxane in these medications, which caused rofecoxib to be pulled from the marked in 2004, and valdecoxib in 2005. 

Specific secondary or associated conditions and complications

Common adverse effects of NSAID use:

GI
  • dyspepsia
  • peptic ulcer disease
  • bleeding
Risk factors for GI associated gastroduodenal ulcers include:

 

  • advanced age
  • history of ulcers
  • concomitant use of corticosteroids
  • higher doses of NSAID use
  • concomitant use of anticoagulants 10

 

Hepatic
  • elevations of serum aminotransferases
Renal
  • development of acute renal failure due to COX mediated inhibition of prostaglandin causing unopposed constriction, therefore vasodilation, of the afferent arteriole leading to decreased renal perfusion
Cardiovascular
  • NSAIDs carry a cardiovascular risk, non-aspirin containing NSAIDs can cause heart attacks or strokes and can modestly exacerbate heart failure, especially with COX-2 selective agents 11
  • cause a modest worsening of underlying hypertension.
  • electrolyte and fluid abnormalities can occur

 

Pulmonary
  • bronchospasm may result in susceptible individuals. The mechanism of action is via the arachidonic pathway, NSAID induced inhibition of COX causes in an increase in lipoxygenase resulting in bronchospasm.
Hematologic
  • NSAIDs have antiplatelet effects and can interact with warfarin; although it is not strictly prohibited, a clinically significant increase in international normalized ratio may occur.
Allergy
  • reactions include urticaria, angioedema, generalized pruritus

COX-2 selective NSAIDs have less GI toxicity side effects. 3 In patients with increased GI risk, either a COX-2 selective agent or a non-selective COX with co-prescription of a proton pump inhibitor for gastroprotection may be considered, but NSAIDs, including both non-selective and COX-2 selective agents, should be used with caution in patients with cardiovascular risk factors. 5 

Toxicity

  1. NSAID ingestions of less than 100 mg/kg are unlikely to cause significant symptoms in adults.
    1. Ingestions greater than approximately 400 mg/kg can cause severe symptoms; usually this is related to an increased anion gap.
    2. Metabolic acidosis may be seen after large ingestions.
  2. Renal failure and renal papillary necrosis are rare and occur most often in patients with decreased effective arterial volume, underlying renal dysfunction, or excessive overdose.
  3. Acute central nervous system toxicity related to NSAIDs might range from drowsiness to seizure to coma.
  4. NSAIDs might affect patients who suffer from asthma and chronic urticarial by causing anaphylactic and anaphylactoid reactions.
  5. In the event of an overdose, it is important to secure the airway, breathing, and circulation. Aggressive intervention is usually unnecessary. Sometimes decontamination with activated charcoal might be enough, because no antidote exists.

2. ESSENTIALS OF ASSESSMENT

Functional assessment

Patients who are taking NSAIDs should be asked to report the effectiveness of analgesia, functional improvement with activities of daily living, as well as potential side effects of the medications. It is not uncommon to see patients who fail to get relief with one family of NSAIDs, but find relief after switching to another family. Finally, doses of NSAIDs should be optimized according to patient symptoms and side effects.

Laboratory studies

  1. None needed unless the patient has a history of renal failure, for which its use must be based on an individualized assessment of the risks of acute decline in the glomerular filtration rate versus the therapeutic benefits of treatment.
  2. A heart condition or use of warfarin needs to be closely monitored as well.

Professional Issues

Physicians should educate patients who are on long-term use of NSAIDs about the potential increased risk of medical complications related to its use.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Chronic pain is one of the most common reasons for seeking medical attention. A number of pharmacologic and non-pharmacologic therapies are available for patients with chronic pain.

Treatment options for chronic pain generally fall into six major categories:

  1. pharmacologic
  2. physical therapy
  3. behavioral medicine
  4. neuromodulation
  5. interventional procedures
  6. surgical approaches

Optimal patient outcomes employ a multidisciplinary approach. Medication should not be the sole focus of treatment, but should be used when needed, in conjunction with other treatment modalities.

Neuropathic pain – NSAIDs are used as adjuvant medications in the treatment of neuropathic pain.

Nociceptive pain – When pharmacotherapy for nociceptive pain is required, acetaminophen is typically recommended as a first-line therapy for pain related to OA-related pain and chronic low back pain.

Coordination of care

NSAIDs can be delivered orally or topically. An alternative first line for localized arthritis, acute conditions such as sprains, strains, and overuse injuries is topical NSAIDs, as these do not have the systemic side effects of oral NSAIDs. 3,12 A systematic Cochrane Review of topical NSAIDs for acute musculoskeletal pain in adults revealed gel formulations of diclofenac, ibuprofen, and ketoprofen, and some diclofenac patches provide the best effects.12 In 2 trials that directly compared diclofenac 1.5% topical solution to oral diclofenac, incidence of dry skin at the application site was significantly greater for topical diclofenac, whereas incidence of GI adverse events was significantly greater for oral diclofenac; however, withdrawals because of adverse events were similar in the topical and oral diclofenac treatment groups.13,14

Patient & family education

Patient and family education is important, because some of these medications are prescribed over-the-counter, and occasionally a patient might combine medications. Patients should be educated on the possible side effects of the medications and should notify physicians if they are taking other medications, such as warfarin and clopidrogel, because they can increase bleeding time.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

With consideration of opioid abuse and misuse, NSAIDs are considered first line agents for acute and chronic pain management; however, the side effect profile must be weighed against the benefit of starting treatment in certain patient populations. In recent years, cardiovascular risk has become increasingly evident.

The Institute of Medicine reports cultural change is needed regarding pain management to gain a better understanding of pain of all types and improving efforts to prevent, assess and treat pain. 15

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

Not applicable at this time.

REFERENCES

  1. Björkman R. Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Experimental studies in the rat. Acta Anaesthesiol Scand Suppl. 1995;103:1-44.
  2. World Health Organization. WHO Analgesic Ladder. Available at:  http://www.who.int/cancer/palliative/painladder/en/  Accessed April 14, 2016.
  3. Centers for Disease Control and Prevention. Nonopioid treatments for chronic pain. http://www.cdc.gov/drugoverdose/pdf/alternative_treatments-a.pdf Accessed April 14, 2016.
  4. The American Academy of Pain Medication. AAPM facts and figures on pain medicine. Available at: http://www.painmed.org/patientcenter/facts_on_pain.aspx. Accessed April 14, 2016.
  5. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16:137–62
  6. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs–differences and similarities. N Engl J Med. 1991;324:1716-1725.
  7. Abramson SB, Weissmann G. The mechanisms of action of nonsteroidal antiinflammatory drugs. Arthritis Rheum. 1989;32:1-9.
  8. DeWitt DL, Meade EA, Smith WL. PGH synthase isoenzyme selectivity: the potential for safer nonsteroidal antiinflammatory drugs. Am J Med. 1993;95:40S-44S.
  9. Giovannucci E, Egan KM, Hunter DJ, et al. Aspirin and the risk of colorectal cancer in women. N Engl J Med. 1995;333:609-614.
  10. Wolfe MM, Lichtenstein DR, Singh G.  Review Article: Gastrointestinal Toxicity of Nonsteroidal Antiinflammatory Drugs.  New England J Med.  1999; 340:1888-1899.
  11. Food and Drug Administration.  FDA Drug and Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes.  Rockville, MD: Food and Drug Administration; 2015.        http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm.  Accessed April 14th, 2016.
  12. Derry S,Moore RA, Gaskell H,McIntyre M,Wiffen PJ. Topical NSAIDs for acute musculoskeletal pain in adults. Cochrane Database of Systematic Reviews 2015, Issue 6. Art. No.: CD007402. DOI: 10.1002/14651858.CD007402.pub3.
  13. Roth SH, Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Int Med. 2004;164:2017-2023.
  14. Altman RD, Dreiser RL, Fisher CL, Chase WF, Dreher DS, Zacher J. Diclofenac sodium gel in patients with primary hand osteoarthritis: a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2009;36:1991-1999.
  15. Institute of Medicine. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington, DC: The National Academies Press; 2011.

Original Version of the Topic:

Jose Mena, MD. Nonsteroidal Anti-Inflammatory Medications. Publication Date:2012/11/05.

Author Disclosure

Navdeep Singh Jassal, MD
Nothing to Disclose

Ritika Oberoi-Jassal, MD
Nothing to Disclose

Jaspreet Singh, MD
Nothing to Disclose

Young Chang, MD
Nothing to Disclose

Joshua Smith, MD
Nothing to Disclose

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