Nonsteroidal Anti-Inflammatory Medications

Author(s): Karen Morice, MD, Bari Madureira, DO, MPH

Originally published:11/05/2012

Last updated:09/15/2019

1. DISEASE/DISORDER:

Definition

Non-steroidal 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 Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) pain ladder recommend NSAIDs 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 multiple medical conditions, including:

  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/neck pain and radiculopathy
  9. sprains
  10. strains
  11. kidney stones
  12. fever

Epidemiology including risk factors and primary prevention

According to data analyzed from the National Health Interview Survey (NHIS) in 2016 by the CDC, an estimated 20.4% of US adults (approximately 50 million individuals) suffer from chronic pain.4 In addition, market research from the American Academy of Pain Medicine (AAPM) indicate that world-wide this number includes more than 1.5 billion people.5 Long the mainstay of acute & chronic pain management, NSAIDs are known to be associated with gastrointestinal (GI), cardiovascular, and renal toxicities. The risk of adverse events varies between individual drugs and patients. This variability in response can be ascribed to the individual differences in pharmacodynamic, pharmacokinetic & drug metabolism properties.

In order to prevent adverse events, general consensus for most conditions is to start at the lowest effective dose and prescribe for the shortest period possible.

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 NSAIDs are classified according to their relative selectivity of inhibiting COX-1 or COX-2. 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 mucosal integrity, vascular homeostasis, platelet function, and renal blood flow) and is stimulated by hormones or growth factors.
  • COX-2 expression is minimal under basal conditions. It is induced by pro-inflammatory stimuli (i.e., cytokines) in endothelial cells, monocytes/macrophages, tumor cells & plaque-associated cells.9 It is expressed in the brain, kidney, bones, and probably in the female reproductive system.

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.10 Unfortunately, there is a possible increase in risk of heart attack, thrombosis, and stroke by a relative increase in thromboxane in these medications, which caused rofecoxib to be pulled from the market 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 gastroduodenal ulcers include:

  • advanced age
  • history of ulcers
  • concomitant use of corticosteroids
  • higher doses of NSAID use
  • concomitant use of anticoagulants 11
Hepatic
  • elevation of serum aminotransferases
Renal
  • acute renal failure due to COX-mediated inhibition of prostaglandin causing unopposed constriction of the afferent arteriole leading to decreased renal perfusion
Cardiovascular
  • non-aspirin containing NSAIDs can cause heart attacks or strokes and can modestly exacerbate heart failure.12 This risk may begin within a few weeks of starting an NSAID
  • worsening of underlying hypertension
  • electrolyte and fluid abnormalities
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; a clinically significant increase in international normalized ratio may occur.
Allergy
  • urticaria, angioedema, generalized pruritus

COX-2 selective NSAIDs have fewer GI side effects.3 In patients with increased GI risk, either a COX-2 selective agent or a non-selective agent with co-prescription of a proton pump inhibitor for gastroprotection may be considered. However, all NSAIDs, both non-selective and COX-2 selective agents, should be used with caution in patients with cardiovascular risk factors.5 The risks increase with higher doses and longer dosing periods. A black box warning currently exists on all NSAIDs for cardiovascular events & GI ulcers/bleeding.

Toxicity

  1. Ingestions of less than 100 mg/kg of most NSAIDs 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 urticaria by causing anaphylactic and anaphylactoid reactions.
  5. In the event of an overdose, aggressive intervention is usually unnecessary. Decontamination with activated charcoal is suggested within two hours of ingestion. 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 particularly if used for short periods (as in the treatment of acute pain) unless the patient has a history of renal failure. Prescription should 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.
  3. For patients chronically treated with daily NSAIDs, a complete blood count, blood urea nitrogen and creatinine, and aspartate aminotransferase should be obtained at least once yearly. More frequent testing should be considered for patients at increased risk of adverse events.

Professional Issues

As more is understood regarding pain and pain management practices, 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. 13

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Pain is one of the most common reasons for seeking medical attention whether it be acute or chronic. A number of pharmacologic and non-pharmacologic therapies are available for these patients.

Treatment options for 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 osteoarthritis and chronic low back pain.

One algorithm from Ong, CKS et al. suggests the following14:

If pain is mild to moderate, start with acetaminophen. If insufficient for pain relief or if pain is moderate to severe, consider switching/starting with ibuprofen +/- PPI for patients with a risk of GI bleed. If pain remains persistent, first switch from ibuprofen to naproxen and if there is still insufficient analgesia, a combination of NSAID + acetaminophen or opioid can be trialed. Special consideration must be made for those allergic to traditional NSAIDs or in whom there is significant cardiac, renal or hepatic impairment.

Coordination of care

NSAIDs can be delivered orally or topically. Intramuscular formulation is also available, although this is more frequently used in acute settings (i.e., emergency department, urgent care). Topical NSAIDs are a good alternative first line for localized arthritis and superficial acute conditions such as sprains, strains, and overuse injuries, as these are less likely to have the typical systemic side effects of oral NSAIDs.3,15 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.15 In two 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.16,17

Patient & family education

Patient and family education is important for two reasons. One is because some of these medications are prescribed over-the-counter and two is because patients may combine medications without being aware of potential interactions. Patients should be educated on the possible side effects of NSAIDs and should notify physicians if they are taking other medications. This is particularly true of medications such as warfarin and clopidrogel because they can increase bleeding time.

A study by the American Academy of Pain Medicine (AAPM) indicated that approximately 10% of patients exceed the daily limit of NSAIDs.18 Patients may not recognize pain medications as NSAIDs and should be educated on dosing directions to avoid excess dosing and adverse effects. This includes the names of specific NSAIDs as well as strength & dosing schedules.

For reference, commonly prescribed NSAIDs include:

Generic Brand Name (in the US)
ibuprofen Advil, Motrin, IBU
naproxen Aleve, Anaprox, Naprelan, Naprosyn, Flanax
indomethacin Indocin
diclofenac potassium Cambia, Zipsor, Zorvolex, Voltaren
ketoprofen  
ketorolac Toradol
meloxicam Mobic
piroxicam Feldene
sulindac Clinoril
celexoxib Celebrex

Of the above, the only COX-2 selective currently on the market is Celecoxib. The rest are non-selective. Dosing schedules range from once daily (meloxicam, peroxicam) to 3-4x daily (ibuprofen, diclofenac) and have varying starting and maximum doses.

Of note, drug adherence is enhanced when medications are dosed less frequently, which should be taken into consideration when prescribing.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

A 2018 systematic review & meta-analysis indicated that both non-selective & selective NSAIDs were effective as heterotopic ossification (HO) prophylaxis after total hip arthroplasty (THA). The use of NSAIDs also provided the dual benefit of pain relief. Indomethacin (non-selective) & celecoxib (selective) were the benchmark medications in this study19.

That being said, controversy still exists over whether NSAIDs impair bone healing after fracture or fusion. Multiple studies have indicated an increased risk of non-union with the use of NSAIDs.20,21 However, a 2010 systematic review & meta-analysis revealed that when only higher-quality studies were considered, a significant increase in risk of non-union was not observed (OR 2.2 95% CI 0.8-6.3).22 They did not include randomized clinical trials in the analysis, which must be taken into consideration. Although other studies have indicated a similar lack of association, and given that non-union only occurs in approximately 1% of fractures, it is less likely that a short-term course of NSAIDs will lead to significant harm. Overall, the lack of clear consensus means that no clinical recommendation can be made regarding the appropriate use of NSAIDs in this context.

With many providers concerned about the current opioid epidemic, the dose-sparing effect of NSAIDs when provided in combination with opioids should be considered. While the majority of the evidence for opioid-sparing of NSAIDs exists in the post-surgical realm, it can likely be translated into the rehab world.

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

  1. Definition of a dose ceiling. A previous study in 1983 indicated that the dose ceiling of ibuprofen was approximately 1600mg (400mg in 4x daily dosing).23 While it is evident that a dose ceiling likely exists, it is unclear exactly what the ceiling is for many current NSAIDs on the market. Further studies regarding dose response could be performed to provide a clearer understanding and to provide a more evidence-based guideline for prescribing patterns that will benefit patients and help reduce adverse events.
  2. Class-switching. Patients who do not respond to one particular class of NSAID may obtain benefit by switching classes. However, there is limited data in this regard.
  3. Long-term side effects of topical NSAIDs . While several studies indicate fewer GI side effects with topical NSAIDs, we must still consider that topical medications have systemic absorption. More studies are needed in regards to the potential for side effects with long-term use.
  4. Bone healing. As detailed above, there is no clear consensus on the effect of NSAIDs on bone healing. Further studies could elucidate the effect of NSAIDs on bone healing particularly in patients who are more prone to heal poorly (e.g., diabetics, chronic tobacco users).
  5. The effect of NSAIDs in acute musculoskeletal injury. A recent study supported the use of NSAIDs in reducing strength loss, soreness & blood creatine kinase levels after an acute muscle injury.24 However, it is unclear what this means in the clinical setting, such as whether a particular dose regimen could be used to help promote healing after an acute injury.

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 August 4, 2019.
  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. Dahlamer J, et al. Prevalence of Chronic Pain & High-Impact Chronic Pain Among Adults – United States, 2016. CDC Morbidity and Mortality Weekly Report. 2018, September 14.
  5. 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.
  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. Pepine CJ, Gurbel PA. Cardiovascular safety of NSAIDs: Additional insights after PRECISION and point of view. Clin Cardiol. 2017 Dec; 40(12):1352-1356
  10. 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.
  11. Wolfe MM, Lichtenstein DR, Singh G.  Review Article: Gastrointestinal Toxicity of Nonsteroidal Antiinflammatory Drugs.  New England J Med.  1999; 340:1888-1899.
  12. 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.
  13. Institute of Medicine. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington, DC: The National Academies Press; 2011.
  14. Ong CKS, Lirk P, Tan CH, and Seymour RA. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res. 2007 Mar; 5(1):19-34
  15. 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.
  16. 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.
  17. 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.
  18. Kaufman DW, Kelly JP, Battista, DR, Malone MK, Weinstein RB, Shiffman, S. Exceeding the daily dosing limit of nonsteroidal anti-inflammatory drugs among ibuprofen users. Pharmacoepidemiol Drug Saf. 2018 Mar; 27(3):322-331
  19. Joice M, Vaileaidis GI, Amanatullah DF. Non-steroidial anti-inflammatory drugs for heterotopic ossification prophylaxis after total hip arthroplasty: a systematic review & meta-analysis. Bone Joint J. 2018 Jul;100-B(7):915-922.
  20. Sagi HC, Jordan CJ, Barei DP, Serrano-Riera R, Steverson B. Indomethacin prophylaxis for heterotopic ossification after acetabular fracture surgery increases the risk for nonunion of the posterior wall. J Orthop Trauma. 2014 Jul;28(7):377-83
  21. Dodwell ER, Latorre JG, Parsini E, Zwettler E, Chandra D, Mulpuri K, Snyder B. NSAID exposure and risk of nonunion: a meta-analysis of case-control and cohort studies. Calcif Tissue Int. 2010;87(3):193.
  22. Grennan et al. Dose response study with ibuprofen in rheumatoid arthritis: Clinical and pharmacokinetic findings. Br J Clin Pharmac. 1983(15): 311-316.
  23. Morelli KM, Brown LB. Warren GL. Effect of NSAIDs on recovery from acute skeletal muscle injury: a systematic review and meta-analysis. Am J Sports Med. 2019 Jan; 46(1):224-233.

Original Version of the Topic:

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

Previous Revision of the Topic

Ritika Oberoi-Jassal, MD, Navdeep Singh Jassal, MD, Jaspreet Singh, MD, Young Chang, MD, Joshua Smith, MD. Nonsteroidal Anti-Inflammatory Medications. Publication Date: 09/30/2016.

Author Disclosure

Karen Morice, MD
Nothing to Disclose

Bari Madureira, DO, MPH
Nothing to Disclose

 

Related Articles