Nonsteroidal Anti-Inflammatory Drugs: Balancing Efficacy and Safety

Many conditions require effective pain relief, including renal colic, dysmenorrhea, and musculoskeletal pain. In the United States alone, an estimated 116.5 million episodes of acute low back and neck pain were recorded in 2011, with projections increasing to 128.5 million cases by 2021 [1].

Pain management should always be individualized. Both pharmacological and non-pharmacological approaches may be appropriate, depending on the underlying condition.

In its 2005 recommendations, the U.S. Food and Drug Administration (FDA) advised prescribing the lowest effective dose of a nonsteroidal anti-inflammatory drug (NSAID) for the shortest duration necessary to achieve the patient's treatment goals. These recommendations have also been endorsed by the American College of Rheumatology and the American Heart Association, which continue to recommend NSAIDs as first-line therapy for many painful inflammatory conditions [1].

When selecting an NSAID, clinicians should consider not only its analgesic and anti-inflammatory efficacy but also its cardiovascular, gastrointestinal, and renal safety profile, together with the patient's individual risk factors.

Potential Adverse Effects of NSAIDs

NSAIDs are well known to increase the risk of gastric and duodenal ulcers and their potentially life-threatening complications, including gastrointestinal bleeding and perforation.

In 2012, more patients in the United States died from gastrointestinal complications associated with NSAID use than from many other chronic diseases [2]. Patients taking NSAIDs are hospitalized for gastrointestinal bleeding significantly more often than individuals who do not use these medications [3].

The risk is particularly high when NSAIDs are combined with glucocorticoids or anticoagulants [13].

In recent years, growing evidence has also linked NSAIDs to an increased incidence of cardiovascular complications. These effects appear to depend largely on the degree of cyclooxygenase-2 (COX-2) inhibition in relation to cyclooxygenase-1 (COX-1) inhibition [14].

Both COX-1 and COX-2 participate in the synthesis of prostanoids, including prostaglandin E₂ (PGE₂), prostacyclin (PGI₂), and thromboxane A₂ (TxA₂) [6,7].

These mediators play important roles in hemostasis.

Thromboxane A₂, produced by platelets through COX-1 activity, promotes platelet aggregation, vasoconstriction, and vascular smooth muscle proliferation. Inhibition of platelet COX-1 reduces thromboxane production, decreasing platelet aggregation and thrombus formation—a mechanism underlying the cardioprotective effects of low-dose aspirin.

Although COX-2 was originally believed to be expressed only at sites of inflammation, it is now known to be constitutively present in several tissues, including the brain, kidneys, pancreas, and vascular endothelium.

Within vascular endothelial cells, COX-2 promotes prostacyclin production. Prostacyclin inhibits platelet aggregation, dilates blood vessels, and suppresses vascular smooth muscle proliferation.

Selective inhibition of COX-2 reduces prostacyclin production while leaving thromboxane activity relatively unaffected. This disrupts the physiological balance between thromboxane and prostacyclin, creating a prothrombotic state.

This imbalance may also occur with certain non-selective NSAIDs because they inhibit COX-1 and COX-2 to different degrees.

Selective COX-2 inhibitors produce a greater imbalance and are therefore associated with a higher risk of thrombosis through accelerated clot formation at sites of vascular injury [8].

Earlier regulatory warnings highlighted the cardiovascular risks associated with NSAID use in patients with cardiovascular disease. More robust evidence became available following a comprehensive systematic review of randomized controlled trials published in the British Medical Journal in January 2011.

The analysis included 116,429 patients enrolled in 31 clinical trials evaluating naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, lumiracoxib, rofecoxib, or placebo.

Overall, NSAID use was associated with an increased risk of myocardial infarction, stroke, and cardiovascular mortality.

The highest risk of myocardial infarction was observed with rofecoxib, with a 2.12-fold increase. (Rofecoxib was withdrawn from the market in 2004 because of concerns regarding cardiovascular safety.)

Ibuprofen was associated with the greatest increase in stroke risk (3.36-fold), followed by diclofenac (2.86-fold).

Etoricoxib was associated with the greatest increase in cardiovascular mortality (4.07-fold), followed closely by diclofenac (3.98-fold) [9].

These findings have raised concerns regarding the safety of NSAIDs. Nevertheless, effective alternatives remain limited.

Current recommendations emphasize first assessing gastrointestinal risk. Patients at low gastrointestinal risk may receive non-selective NSAIDs. For those at high gastrointestinal risk, treatment decisions should also consider the patient's cardiovascular risk, particularly the risks of myocardial infarction and stroke [10].

Dexketoprofen (Dolmen) and Its Safety Profile

Like other traditional NSAIDs, dexketoprofen inhibits both COX isoenzymes. Consequently, prolonged treatment may still be associated with the adverse effects described above.

Selective COX-2 inhibitors produce fewer gastrointestinal adverse effects but carry a greater risk of cardiovascular complications.

To minimize adverse effects, patients frequently reduce analgesic doses on their own, which may result in inadequate pain control.

An ideal analgesic should therefore provide effective pain relief at relatively low doses while minimizing adverse effects. This is particularly important for patients with chronic pain requiring repeated treatment and for those recovering from surgery, in whom adequate postoperative analgesia is essential.

Ketoprofen is a widely used NSAID with potent analgesic and anti-inflammatory properties resulting from inhibition of prostaglandin synthesis. However, it is associated with a higher risk of gastrointestinal bleeding than many other NSAIDs [15].

The analgesic activity of ketoprofen resides exclusively in its S(+)-enantiomer, dexketoprofen. The R(−)-enantiomer contributes little or no analgesic effect but retains ulcerogenic properties.

Through stereoselective biotechnological purification, the active S(+)-enantiomer was isolated, resulting in dexketoprofen. Because only the active isomer is administered, equivalent analgesia can be achieved at approximately half the dose required for ketoprofen, potentially reducing adverse effects [15].

Dexketoprofen formulated as the trometamol salt (DKT) is highly water soluble—approximately 100-fold more soluble than dexketoprofen free acid [15].

This enhanced solubility results in rapid gastrointestinal absorption and a faster onset of analgesia.

Injectable dexketoprofen may be used for acute postoperative pain for up to two days, after which treatment may be continued with the oral formulation.

Following oral administration, analgesia begins within 25–35 minutes and lasts approximately 4–6 hours [16].

For optimal absorption, dexketoprofen trometamol should be taken on an empty stomach [11,12,16].

In one clinical trial involving patients with acute low back pain, dexketoprofen trometamol 25 mg three times daily was compared with tramadol 50 mg three times daily.

By the fourth day of treatment, dexketoprofen provided significantly greater relief of movement-related pain (p < 0.04) and was associated with significantly fewer adverse effects (p < 0.03) [15].

Other studies involving patients with arthritis compared dexketoprofen 25 mg three times daily with ketoprofen 150 mg daily and diclofenac 150 mg daily.

After three weeks of treatment, pain relief achieved with dexketoprofen 75 mg/day was comparable to that of diclofenac 150 mg/day and superior to ketoprofen 150 mg/day [15].

In a later study by Marenco and colleagues, treatment with dexketoprofen 25 mg three times daily reduced pain intensity measured by the Visual Analog Scale by 43% after two weeks, compared with 29% among patients receiving diclofenac 50 mg three times daily (p < 0.03).

No cases of gastrointestinal bleeding, myocardial infarction, or death were reported during the study [19].

Summary

• NSAIDs remain first-line therapy for pain relief and the treatment of inflammatory conditions.
• Before prescribing an NSAID, clinicians should assess the patient's risk of gastrointestinal complications. Patients at low gastrointestinal risk may receive non-selective NSAIDs, whereas those at higher risk require individualized treatment that also considers cardiovascular risk.
• Clinical studies have shown that dexketoprofen (Dolmen) provides analgesic efficacy comparable to tramadol and equivalent to twice the dose of ketoprofen while producing fewer gastrointestinal adverse effects [18,19].
• Dexketoprofen may also be combined with opioid analgesics, potentially allowing lower opioid doses and reducing opioid-related adverse effects [18,19].
• Overall, dexketoprofen (Dolmen) has been shown to be an effective option for the short-term symptomatic treatment of acute pain, with fewer gastrointestinal adverse effects than ketoprofen.

Reprinted from Pharmacist Practice

Literature references are available from the editorial office.

No. LT/Dol/2014/44