Safety and Efficacy Considerations for Chronic Use of NSAIDs for Chronic Pain

by Jie Mei, Olena Polyakova, Sammu Dhaliwall, Kevin McDonald and Alison YJ Wong

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) provide relief for many ailments due to their analgesic, anti-inflammatory and antipyretic effects in multiple health conditions.1-4 As a class of drugs, NSAIDs are the most frequently prescribed medications worldwide, accounting for 10 million prescriptions per year in Canada, 25 million in the United Kingdom, and 70 million in the United States.1,5  Considering the efficacy of NSAIDs for pain relief and their nonaddictive nature, chronic use of NSAIDs is likely to increase, especially given the wide-spread opioid misuse crisis.3,8  Chronic use of NSAIDs has notably been reported for more than 29 million American adults2 (out of about 50 million American adults6,7 who suffer from chronic pain).

For some indications, NSAIDs should be taken on a regularly scheduled basis rather than only “as needed” (e.g., to ensure adequate pain control). Although these agents have similar efficacy and the same mechanism of action (cyclooxygenase-1 and 2 (COX-1, 2) inhibition and prostaglandin generation), the safety profiles, pharmacokinetic and pharmacodynamic properties differ within the class. Additionally, long-term, chronic use of NSAIDs may cause numerous adverse effects, including cardiovascular, gastrointestinal, and renal risks.4

Drug safety-efficacy profiles should be reviewed for every patient’s pain management plans during clinical decision-making. In some cases, the challenge of choosing the correct agent and dose may require several adjustments.3 Accordingly, finding the optimal therapy for a patient often includes dose modification and/or changing agents, which may increase the period with uncontrolled pain and/or the risk of adverse effects.3

Appropriate treatment should also be based on a patient’s individual characteristics, family history, and comorbidities. In recent years, a patient’s pharmacogenetics has been  shown to influence the risk of adverse effects and therefore a patient’s precise, comprehensive profile should be reviewed when selecting an NSAID for a specific patient. On these bases,  a comparison of the long-term safety and efficacy of different NSAIDs will be discussed in detail in this article. We also include a table that highlights the superfamily of Cytochrome P450 (CYP) and other data that can be used to prescribe the precise medicine for a patient.

Recommendations for long-term NSAID use

NSAID use is defined as chronic if these medications are taken more than three times a week for more than three months.2 Health regulated authorities in Canada (Health Canada) and the US FDA (Food  and Drug Administration) have approved the recommendations  to  prescribe NSAIDs for a variety of health conditions summarized in Table 1.10-16

To emphasize a point noted above: NSAIDs have similar efficacy and the same mechanism of action, making the selection of an appropriate NSAID dependent on factors such as the patient’s profile, the potential adverse effects of a drug, pharmacokinetic/pharmacodynamic properties, cost, and availability. Previous studies have shown an increase in cardiovascular, gastrointestinal and renal risk within the first month of chronic use of certain NSAIDs.9

NSAID precautions

In this section, precautions regarding recommendations for patients are reviewed with a focus on the relative toxicity of the different NSAIDs for cardiovascular, gastrointestinal, and renal complications as summarized below and in Table 2.1-5,10–16,23–40

Cardiovascular Risks Associated with NSAIDs

Previous studies showed an increased cardiovascular risk associated with some NSAIDs (diclofenac, ibuprofen, etoricoxib, celecoxib).1,3-5,9,24,26,28–30,38–43  Some agents (rofecoxib, lumiracoxib, ibuprofen) may notably cause or exacerbate heart failure and increase the risk of developing an acute coronary syndrome or other cardiovascular episodes of an atherothrombotic nature.1,5,9,26,28–30,38–40,42  Certain studies suggest that the greater cardiovascular risk may be associated with the mechanism of action of the NSAID, where a greater risk is associated with COX-2 selective NSAIDs compared to nonselective NSAIDs.29–31,38  However, one cohort study suggests that the use of celecoxib, a COX-2 selective NSAID, was not associated with an increased risk of admission for heart failure compared to patients not taking NSAIDs.31

Among traditional nonselective NSAIDs, diclofenac represents the  greatest cardiovascular risk.4  In contrast, naproxen seems to have the safest cardiovascular profile and is the best treatment option in patients with high cardiovascular risk.4  Therefore, patients who require chronic NSAID use should be evaluated for individual cardiovascular risk, as this could influence the choice of the specific NSAID.

Gastrointestinal Risks Associated with NSAIDs

Due to gastrointestinal risks, patients may suffer NSAID adverse effects,  which  can range from dyspepsia to life-threatening gastric bleeding.4,5,9,31,35 COX-2 selective NSAIDs, specifically celecoxib, are associated with a lower gastrointestinal risk.28 It should be noted that an NSAID’s half-life may also affect its gastrointestinal risk (i.e. NSAIDs with longer half-lives represent a greater risk).28 Nevertheless, the risk of experiencing gastrointestinal adverse effects largely depends on the patient’s risk factors (Table 3).4  Accordingly, in patients with existing gastrointestinal risk factors who require an NSAID, celecoxib appears to be safer compared to other agents of its class and may  be used with close monitoring.4  The addition of a proton pump inhibitor (PPI) may further decrease the risk of NSAID-related gastrointestinal adverse effects and should be considered for the duration of NSAID treatment, particularly in patients with high gastrointestinal risk factors.4,24 For example, misoprostol at 800 mcg/day, as well as a double- dose of H2 receptor antagonists (H2RAs), may also help prevent gastroduodenal ulcers and can be considered as alternatives to PPI therapy.49,50

Renal Risks  Associated  with   NSAIDs NSAIDs can induce a myriad of adverse effects for patients at risk for renal dysfunction, ranging from sodium retention (hypertension risk) to decreased glomerular perfusion (risk of kidney failure).32Elderly patients with pre-existing chronic kidney disease, patients taking a diuretic with an angiotensin-converting enzyme inhibitor or an angiotensin receptor antagonist, and patients who use NSAIDs with long half- lives are all at higher risk of NSAID-related nephrotoxicity.9 However, all agents may cause renal dysfunction and the choice of a specific NSAID should be based mostly on an adequate evaluation of the patient’s cardiovascular and gastrointestinal risks (Figure 1).4

Skeletal Muscle Risks Associated with NSAIDs

NSAIDs may interfere with tissue and bone healing; a likely mechanism is the blockade of COX-2, which is involved in the differentiation and response of mesenchymal stem cells. In the bones, NSAID use affects osteoblasts and chondroblasts, which in the context of fractures, could delay healing in short term use and increase the risk of nonunion in long term use. In tendons, NSAID use may decrease tenocyte collagen production: this could lead to reduced tensile strength and ultimately delay tendon healing. In muscles, NSAID use may reduce satellite cell activity, which may interfere with muscle repair and adaptation to exercise.51-52

Liver Risks Associated with NSAIDs

NSAIDs are associated with hepatotoxicity, although the incidence is rare relative to the other risks presented in this article. NSAID-induced hepatotoxicity usually results from an idiosyncratic reaction of either an immunologic or metabolic type. Injury typically occurs during the first six months of treatment, and clinical presentation resembles that of viral hepatitis. Possible risk factors include use of other hepatotoxic drugs and rheumatoid arthritis; alcohol abuse and chronic liver disease were excluded from NSAID hepatotoxicity cohort studies and their risk is consequently unknown. There is no significant difference in the incidence of hepatic injury between nonselective NSAIDs and selective COX-2 inhibitors, with the exception of diclofenac, which was associated with a higher risk of hepatotoxicity than celecoxib. Of the available NSAIDs, ibuprofen seems to present the lower risk of liver injury and may be a preferred option for patients with risk factors for hepatotoxicity. In the context of chronic NSAID use, it is recommended to monitor transaminase concentrations every two to four weeks in the first 6 months of treatment, and to discontinue the NSAID if enzymes show progressive elevation or if there is evidence of liver injury.53-57

The influence of pharmacokinetics, pharmacodynamics and pharmacogenetics

NSAIDs have different  pharmacokinetic properties that may influence the choice of a specific NSAID, especially in light of other drugs a patient may be prescribed. For example, NSAIDs that have a rapid absorption and onset of action (ibuprofen, ASA at anti-inflammatory doses or naproxen) may offer an advantage in migraine attacks, acute pain or other situations where time to onset is important.44 On the other hand, NSAIDs with longer half-lives  may  be more helpful in chronic pain, as they maintain constant drug concentrations with a less frequent dosing scheme. However, as mentioned above, this sustained effect may also lead to increased risk of adverse effects.3,44

A specific NSAID’s distribution in the body and the ability to achieve therapeutic concentrations at the site of action may prove to be an advantage in specific conditions.3,44  For instance, highly protein-bound, acidic NSAIDs (ibuprofen or diclofenac) may accumulate in the synovial compartment, which may provide sustained pain relief beyond themolecules’ plasma half-lives and provide an advantage in the treatment of musculoskeletal pain (OA  and  RA).3,33 Similarly, NSAIDs  that can achieve therapeutic concentrations in the central nervous system may be more effective in decreasing central sensitization associated with the development and maintenance of chronic pain.3  These hypotheses remain mostly theoretical, however, as such pharmacokinetic characteristics have not been demonstrated to have a clear clinical impact.

Another aspect to consider when selecting a specific NSAID is a drug’s metabolism (see, e.g., Metabolism column in Table 2). Several molecules (celecoxib, flurbiprofen, ibuprofen, piroxicam) are notably metabolizedby the CYP2C8 and/or 2C9 enzymes.27  Therefore, a patient’s pharmacogenomic profile may influence the metabolism of these NSAIDs. Several studies have shown that polymorphisms in these enzymes can result in decreased NSAID metabolism, leading to increased exposure which may thereby lead to an increased risk of adverse effects.3,27,36,37  The impact of these polymorphisms depends on each allele variant and the specific NSAID used and are detailed in Table 2 (Metabolism column).

Ibuprofen, for example, is metabolized by both CYP2C9 and CYP2C8 enzymes. The CYP2C9*2 and *3 allele are associated with decreased metabolism of ibuprofen, thereby leading to increased concentrations and an increased risk of NSAID-related gastrointestinal bleeding as compared with the wild-type CYP2C9*1.27,36 In a North American population, both CYP2C9*2 and *3 alleles are common and may affect NSAID exposure. Carriers of these alleles may need to take lower ibuprofen doses or an agent not metabolized by CYP2C9.27,36 Similarly, patients with the CYP2C8*3 allele, which also decreases ibuprofen metabolism, is common in Caucasians (11-14%) but rare in Africans and Asians. Patients carrying this allele may also require lower ibuprofen doses.27,36

Some studies have also investigated the impact of genetic variations in the expression of the drug targets, COX-1 (PTGS1) and COX-2 (PTGS2), on the response to NSAIDs. The Pro17Leu variant of the PTGS1 gene is associated with a failure of inhibition of thromboxane formation by celecoxib and rofecoxib, which are generally considered as COX-2 selective NSAIDs. Patients with this variant of COX-1 enzyme and taking COX-2 selective agents could therefore have a comparable adverse effect profile with COX-2 selective agents and non-selective NSAIDs. As such, patients with the Pro17Leu variant of the PTGS1 gene may have a higher risk of gastrointestinal adverse effects and a lower risk of cardiovascular adverse effects with COX-2 selective agents than patients without this variant.46 On the other hand, independently of NSAID use, the most widely studied PTGS2 pharmacogenetic variant is the 765G>C polymorphism which may be associated with an increase in cardiovascular risks (though this remains open to debate).42,47Some PTGS2 allele variations also appear to affect the efficacy of ibuprofen and rofecoxib for pain relief.3,42,47 These preliminary results may indicate that genetic polymorphisms affecting COX-2 may explain some interindividual variability in NSAID efficacy.

Drug interactions

As over 90% of NSAIDs are used by elderly patients who tend to have a significant number of medications, caution is required to decrease the risk of drug interactions between NSAIDs and the patient’s medications.48 For instance, several NSAIDs, such as ibuprofen and naproxen, may increase the risk of mortality when prescribed with low-dose acetylsalicylic acid (ASA) by competitively inhibiting the latter’s binding site on platelets, which could block the cardioprotective effects of the drug (though this remains in debate).4 Taking the NSAID two hours after ASA could potentially reduce the impact of such interference, however, the effect of such an intervention in the context of chronic use is unknown.4

NSAIDs are also known to interact with several other medications, including warfarin, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, CYP2C9 substrates (e.g. glyburide), cyclosporine, lithium, selective serotonin reuptake inhibitors, tenofovir, trimethoprim-sulfamethoxazole and methotrexate.10-16  Adequate interaction management is therefore also important for optimal NSAID use, especially in chronic cases where the interaction is likely to persist over a long period.

Jie Mei is a 4th year PharmD student at Université de Montréal. In addition to her studies, Jie works at Northwest Telepharmacy Solutions, where she has contributed to the development of a database documenting the impacts of pharmacogenetic variations on patient drug metabolism. Jie also works in community pharmacies in Quebec, where she learned to provide and individualize pharmacotherapy for a wide variety of patients (chronic illnesses, anticoagulotherapy, geriatrics, infectious diseases, OBGYN, paediatrics, methadone, etc).

 

Sammu Dhaliwall graduated from the Faculty of Pharmacy, University of Toronto in 2003 followed by an accredited hospital residency in 2004. Sammu obtained his Pharm D from Skaggs School of Pharmacy at University of Colorado in 2010. Sammu started pharmacy practice at Trillium Health Centre providing care mainly in the Emergency Department before joining Northwest Telepharmacy Solutions in 2008. Since 2008, Sammu has been providing telepharmacy services to several hospitals and a family health team in northern Ontario and has transitioned into the Senior Manager of Business Development position recently. In his new role, Sammu has continued to find new opportunities for pharmacists to provide remote care while overseeing a newly created Research division.

Olena Polyakova graduated with honors from V.N. Karazin Kharkiv National University School of Medicine (Ukraine) in 2002, completed a residency in Pathology, and consequently received her Ph.D. in medicine. Following she secured the position of an Assistant Professor of the Department of General and Clinical Pathology at her Alma Mater along with a staff pathologist position at Regional Cancer Hospital. For a variety of reasons she moved in Canada and later she passed the Medical Council of Canada exams and completed the Applied Clinical Research program at McMaster University (Canada). Being a clinician and researcher, she has participated in numerous projects in areas of genomics, maternal and fetal health, and cancer markers. Olena is a co-author of peer-reviewed articles and conference materials. She has reviewed manuscripts for Clinical Anatomy and JAMA Oncology journals. Her current research interests include clinical utilization of proteomics in oncology, as well as being a resource and the advocate for the patients from multiple ethnical backgrounds in different stages of their life and their illness. Olena is a member of ACRP and USCAP.

Alison Yi Jin Wong is a clinical pharmacist working at Northwest Telepharmacy Solutions and the McGill University Health Centre. Alison’s expertise includes the clinical application of pharmacogenomics, safe and evidence informed cannabis use for medical purposes, care of complex patients living with HIV and other chronic viral illnesses and clinical research. Alison is also involved in the preceptorship of students and residents for Université de Montréal.


Kevin
McDonald, BScPHM is the Founder and Director of North West Telepharmacy Solutions, who set up a new way of providing hospital pharmacy services to a small remote hospital in northern Canada in April 2004. He provided all the services that a pharmacist would provide by being onsite, but from a different city. A banner of The North West Company, LP, telepharmacy is now provided 24/7 to over 65 hospitals Canada-wide. Kevin has been a hospital pharmacist for 27 years. He graduated from the University of Toronto in 1993, completed a hospital residency at the Addiction Research Foundation, then made his way to the far reaches of Canada’s north.


Conclusion

Considering the high prevalence of chronic NSAID use to manage chronic ailments, the choice of the correct NSAID for a specific patient needs to be weighed carefully to optimize drug efficacy and safety. The clinician should consider each patient’s individual characteristics before selecting a therapeutic agent, including the patient’s cardiovascular, gastrointestinal, renal risk factors, pharmacogenetic information (if available), and the use of concomitant medications. The NSAIDs efficacy, safety, pharmacokinetic and pharmacodynamic properties should then be matched with the patient’s characteristics in order to select the best drug for the patient.

Finally, we note that pharmacists are uniquely positioned to aid physicians and patients with drug recommendations  due to their specific expertise in drug properties and knowledge of patient medication history (medications taken in the past, efficacy and toxicity responses to each drug, patient adherence). In addition to counselling on treatment choice, pharmacists can also help relay adequate information to the patient to ensure that the latter adheres to treatment.

Conditions associated with contraindications for NSAIDs

NSAIDs should not be used in patients who have documented creatinine clearance less than 30ml/min/1.73m2, serum potassium higher than 5.5 mmol/L, uncontrolled hypertension, severe or uncontrolled heart failure, third trimester of pregnancy, or an active gastrointestinal bleed.10–16 Additional precautions should be taken in elderly patients, pregnant or breastfeeding women, children, as well as any patient presenting with risk factors in the cardiovascular/gastrointestinal/renal systems.10-16

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