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12 Articles in Volume 12, Issue #4
Causes of Postoperative Pain Following Inguinal Hernia Repair: What the Literature Shows
Persistent Postsurgical Pain
Managing Adverse Drug Effects in Pain: Focus on Triptans and NSAIDs
Nonsurgical Treatments for Ankle Arthritis
Opioid Disposal: Dos and Don’ts
Survey Shows More Education About Fibromyalgia Needed Among Healthcare Providers
Anxiety in a Headache Patient: Case Challenge
“Centralized Pain”: A New Consensus Phrase
Tooth Loss in the Chronic Pain Population
When Prescribed Opioids Go Unused
May 2012 Pain Research Updates
May 2012 Letters to the Editor

Managing Adverse Drug Effects in Pain: Focus on Triptans and NSAIDs

Reviewing the adverse effects, drug–drug, and drug–disease state interactions of triptans and non-steroidal anti-inflammatory drugs (NSAIDs) may assist clinicians when prescribing these analgesics. Part 2 of this series will explore the drug–drug interaction profiles of muscle relaxants.

Today’s market provides many therapeutic options for treating chronic pain conditions. However, because of the complexity of the patients, and the extent of polypharmacy used in these patients, caution needs to be exercised when prescribing analgesics. Analgesic therapy must be individualized for each patient to maximize symptom control and minimize toxicity. When multiple analgesics are used for pain management, adverse drug effects (ADEs) often develop. This occurs most frequently in patients with multiple providers. Providers may have to compensate for ADEs or exacerbated symptoms created by a new drug that was prescribed by another provider.

In 2003, Gandhi et al reported an average 10% increase in ADEs per patient for each additional medication added to their profile.1 This was the only predictor significantly associated with ADEs in the ambulatory setting. Patients who had serious ADEs in the ambulatory setting were then compared with patients from the inpatient setting. The ambulatory patients were found to have a higher percentage of ADEs due to the higher total rate of ADEs in the ambulatory setting. Additionally, NSAIDs and non-opioid analgesics were two of the eight medication classes highlighted as being associated with ADEs in the article.1

There are few “true” contraindications in the medication management of chronic pain. The majority of warnings and precautions for analgesics include recommendations to monitor for ADEs. Healthcare providers may overlook the patient’s other disease states because the symptoms of chronic pain may be the chief complaints. Just as clinicians are aware that non-selective β-blockers are contraindicated for patients with asthma, they should also be aware of the effects of comorbidities on analgesics. Providers are encouraged to take an extra few minutes to double check the patient’s current medication profile to prevent exacerbation of the patient’s other disease states. Three drug classes commonly used for chronic pain conditions are the triptans for migraines, NSAIDs for somatic pain, and muscle relaxants for spasms associated with low back pain. Muscle relaxants will be explored further in Part 2 of this article series. Several of these commonly used analgesics can negatively impact other disease states, influence the intended response from other drugs, or potentially cause side effects that require additional drug therapy for management. This article will review possible ADEs and drug interactions associated with triptans and NSAIDs when they are used in patients with certain comorbidities.

Triptans
To date, migraine pathophysiology is still not completely understood. A migraine headache is a complex neurological condition that involves dilation of blood vessels, inflammation, fluid retention, and activation of pain receptors. Different medications have been used to target each of these mechanisms. Triptans are a large class of medications used to abort migraines via their vasoconstrictive action. Seven triptans are approved by the FDA for the treatment of acute migraine in adults (Table 1). While they have established efficacy, there are certain situations that require additional consideration before use.

Triptans are recommended as first-line therapy for acute migraine treatment in patients whose attacks do not respond well to simple or combination analgesics.2 The advantage of triptans over most other alternatives is their more favorable ADE profile and more specific mechanism of action. Triptan therapy is most effective when used early in the course of the migraine, in appropriate doses, and while the headache pain is still mild.3

The decision about which triptan, and which formulation to use, depends on the patient’s preference, the characteristics of the headache, convenience, associated symptoms, and cost. Only sumatriptan is available for parenteral administration. Oral triptans are appropriate when nausea and vomiting are not associated with a patient’s migraine. The onset of action of most triptans is 20 to 60 minutes.4 A second dose may be taken 2 to 4 hours after the initial dose. If nausea and vomiting are prominent, subcutaneous sumatriptan is available. The onset of action of subcutaneous therapy is 10 minutes, and it is the most effective mode of administration.4 A needle-free formulation, which uses a blast of air to create a small hole in the skin to deliver the medication into the subcutaneous tissue, also is available.5 Other options are orally disintegrating wafers, as well as intranasal and rectal formulations.

When prescribing triptans, healthcare providers should be aware of several drug interactions. Triptans should not be used within 24 hours after administration of ergotamine medications, such as dihydroergotamine (DHE) or methysergide. A 2006 FDA advisory alerted healthcare providers to the possible development of serotonin syndrome when triptans are used in combination with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin norepinephrine reuptake inhibitors (SNRIs).6

Triptans are contraindicated in patients with poorly controlled hypertension, severe hepatic or renal impairment, and basilar or hemiplegic migraine (uncommon forms of migraine with aura). Extreme caution should be taken when using triptans in men over 40 years of age and women over 50 years of age. These patients should be screened for cardiovascular disease prior to initiation of therapy, since triptans cause vasoconstriction and have been linked to myocardial infarction, arrhythmias, stroke, and even death.7

A cluster of ADEs including paresthesias; flushing; and mild, transient neck tightness or chest pressure have been named the “triptan sensations.”8 In one study, these sensations were reported by almost 50% of the patients who received subcutaneous sumatriptan and in about 25% of those who took the oral formulations.9 These adverse effects appear to be more common in women and younger people and can sometimes be abated by switching triptans or switching to another route of administration. Neck or chest tightness that occurs with triptan use may alarm patients and healthcare providers. When evaluated, most patients with triptan-induced neck or chest pain do not have evidence of decreased myocardial perfusion. Thus, in most cases, triptan-associated chest pain is not caused by coronary vasoconstriction. Unfortunately, serious cardiovascular events, some resulting in death, have been reported with triptan use. Among the patients who died, several had cardiac risk factors and were found to have coronary artery disease on postmortem examination.10 Other options in acute migraine treatment are NSAIDs, combination products such as aspirin/acetaminophen/caffeine, or DHE for severe migraine headaches.11

NSAIDs
NSAIDs are a broad class of analgesics that are among the most commonly prescribed over-the-counter analgesics in the United States (Table 2).12 They are indicated for mild to moderate somatic pain related to osteoarthritis, rheumatoid arthritis, and other disease states, as well as postsurgical pain. Additionally, although often forgotten, they can be useful for cancer pain, either alone or in combination with opioids, particularly in the setting of metastatic bone pain. NSAIDs produce analgesia by inhibiting cyclooxygenase (COX)-1 and COX-2 enzymes, decreasing the production of prostaglandins from the breakdown of arachidonic acid. In addition to its direct effect on reducing inflammation, the decrease in prostaglandins indirectly affects the pain process by inhibiting the sensitization of nociceptors via bradykinin and histamine, thus maintaining the patient’s innate threshold of pain.13,14 COX-1, the constitutive form, is routinely expressed in the gastrointestinal (GI) tract, kidney, and vascular system, and it regulates gastric cytoprotection and vascular homeostasis. COX-2 expression is stimulated by inflammatory mediators and is expressed in the kidney and central nervous system (CNS).15

Drug–drug interactions with NSAIDs are usually pharmacodynamic, as they either potentiate or antagonize the effects of other medications. They potentiate the risk of bruising and bleeding with anticoagulants due to a possible increase in the international normalized ratio (INR), as well as their antiplatelet effects when used with other agents affecting platelet function.16 They may increase nephrotoxicity with cyclosporine, tacrolimus, and aminoglycosides. They decrease the effectiveness of diuretics and cause hyperkalemia with concurrent use of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), potassium-sparing diuretics, and supplements.17,18

Drug–disease state interactions are critical components when considering the use of NSAIDs. Caution should be taken when prescribing NSAIDs for patients who also have hypertension, renal compromise, coronary artery disease, congestive heart failure and edema, diabetes, history of peptic ulcer disease or gastroesophageal reflux disease (GERD), and asthma, as NSAIDs may exacerbate these conditions.17-20

Given the widespread use of NSAIDs, caution must be exercised, especially in patients 60 years or older. In this population, many of these comorbidities exist and the potential for drug–drug and drug–disease interactions is high. Indomethacin, ketorolac, mefenamic acid, and piroxicam are not recommended for use in older persons because of their ADE profile.21 Non-acetylated salicylates and NSAIDs with a shorter half-life, used intermittently and at the lowest effective dose, are preferred for older adults to reduce the risk of peptic ulcer disease.21,22

There are several ADEs associated with NSAIDs. Three of the most concerning ADEs are GI effects, renal effects, and effects on platelet activity with cardiovascular complications. Aspirin, indomethacin, and ketorolac are associated with the most GI ADEs because of their increased COX-1 effects.21,23,24 GI toxicity was found to increase three-fold in elderly patients compared with younger patients treated with NSAIDs.25 Additionally, the incidence of peptic ulcer disease is increased 13-fold when NSAIDs are taken concurrently with warfarin.26 The GI complications of NSAIDs may be reduced with the addition of a proton pump inhibitor (PPI) or misoprostol.20 Tramadol or acetaminophen may be options to consider for the treatment of mild to moderate chronic pain to avoid some of the toxicities mentioned above in at-risk patients.

Inhibition of prostaglandin synthesis also affects kidney function and the cardiovascular system, leading to fluid and electrolyte imbalances.18,19 In the renal vasculature, the vasodilating effects of prostaglandins maintain adequate blood flow to the glomerulus. NSAIDs block this beneficial effect, making the kidneys more prone to the effects of nephrotoxins, low blood volume, and perfusion pressure. In the coronary vessels, COX-1 causes production of thromboxane A2 in platelets, inducing vasoconstriction and platelet aggregation. COX-2 stimulates production of prostacyclin in the endothelium, leading to vasodilation. The NSAIDs (specifically those that are more selective for COX-2) allow COX-1 (and thromboxane A2) to function in the absence of the countering effects of COX-2 (and prostacyclin), leading to ischemic cardiac and cerebrovascular events. Older patients with congestive heart failure have a two-fold increased risk for hospital admission associated with taking concurrent NSAIDs.17 Current data strongly suggest that NSAIDs be used cautiously in patients at risk of cardiovascular and renal effects and manufacturers are required to include the cardiovascular and GI risks on their product labeling.18 The cardiovascular risk (specifically myocardial infarction) with NSAIDs appears to be dose-related; however, to date, there does not seem to be an increased risk with naproxen, which is more COX-1 selective.

Aspirin
Aspirin (acetylsalicylic acid) is a member of the salicylate class and is the most commonly used agent in its class. Due to the GI toxicity associated with aspirin use, the newer NSAIDs have essentially replaced its use as an analgesic. Low-dose aspirin continues to be extensively used for the primary and secondary prevention of cardio- and cerebrovascular events.24

Non-acetylated Salicylates
Non-acetylated salicylates (magnesium salicylate, choline magnesium trisalicylate, salsalate) were developed to reduce the risk of GI ADEs and platelet inhibition associated with aspirin, while retaining the analgesic and some of the anti-inflammatory effects. These drugs may be tolerated better by patients who are allergic to aspirin. There are also topical methyl salicylate products available for localized pain. Although the risk for GI ADEs related to non-acetylated salicylates is less than that of aspirin, these agents are still associated with some risk of gastric injury, mostly due to local irritation.16 They are also known to cause tinnitus, particularly in higher doses and in patients who are at risk.

Non-selective NSAIDs
Non-selective NSAIDs act peripherally to reduce the production of prostaglandins at the site of injury through their inhibition of COX-1 and COX-2. Their selectivity for COX-1 and COX-2 vary but no single agent is more effective than another. Patient response is individualized. If one agent is not effective (such as ibuprofen, which is a propionic acid), the patient may be switched to an agent in a different structural class (such as etodolac in the acetic acid class).

Topical NSAIDs
Topical diclofenac products (patch, topical solution, and gel) are options for select patients with localized pain. These products provide the benefit of NSAIDs with the potential for a reduced ADE profile due to site-specific administration and minimal systemic exposure.27,28 Several studies have shown reduced GI irritation with these products.29 When compared to the diclofenac 50 mg tablet, the patch (Flector) was found to achieve approximately 1% systemic exposure when administered twice daily for 4 days.29 Similarly, the diclofenac gel (Voltaren) achieved 6% of the blood levels compared to the oral formulation (50% to 60%).30 The long-term ADEs of the topical diclofenac products have not yet been studied.

Selective COX-2 Inhibitors
COX-2 inhibitors are NSAIDs that act primarily through selective inhibition of the COX-2 enzyme. COX-2 inhibitors are equally effective as non-selective NSAIDs for management of arthritis pain in clinical trials.31 Due to the selectivity of the COX-2 inhibitors, they are associated with an improved short-term GI safety profile, and decreased risk of bleeding complications when compared with non-selective NSAIDs.32 The platelet-sparing effects of COX-2 inhibitors make them good choices for postoperative pain, where there is concern about bleeding, including oral surgery and arthroplasty. The renal and cardiovascular risks are the same as non-selective NSAIDs.33,34 The only COX-2 selective NSAID on the US market is celecoxib (Celebrex), a sulfonamide that is contraindicated in patients with a sulfa allergy. A 2007 study compared intermittent versus continuous use of celecoxib in patients with osteoarthritis of the knee or hip and found no difference in outcomes based on the Western Ontario and McMaster Universities (WOMAC) osteoarthritis scores, suggesting that treating intermittent flares may be a better approach than chronic daily use to minimize risks.35

Conclusion
In the ambulatory setting, navigating drug interactions, comorbidity considerations, and ADEs can be a challenge, but fortunately there are numerous options. Triptans and NSAIDs are two large classes of commonly used medications, each with the potential to cause various undesired effects. Understanding these effects in the context of the patient’s other disease states is essential to minimize complications that may lead to an exacerbation of symptoms. The many distinct therapeutic options available to treat chronic pain conditions should be considered and used when the potential for complications arises. Part 2 of this article series will explore drug–drug interactions of muscle relaxants, examining antispasmodic and antispasticity agents.

Last updated on: June 19, 2012
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