Drug Therapy

With the variety of drugs available for treating depression, choosing one can be daunting. Different agents have characteristics that may make them a better choice for different types of patients, but even so, treating any kind of mental illness often requires an element of trial and error.

Primary care providers are on the frontline of treating mental illness, often evaluating patients before they are seen by a psychiatrist. The purpose of this article is to provide insight into the art of prescribing antidepressants in the primary care setting. We will discuss common patient presentations, including depressed patients without other medical comorbidities as well as those with common comorbidities, with our recommendations for first-line treatment.

We hope our recommendations will help you to navigate the uncertainty more confidently, resulting in more efficient and tailored treatment for your patients.

BASELINE TESTING

When starting a patient on antidepressant drug therapy, we recommend obtaining a set of baseline laboratory tests to rule out underlying medical conditions that may be contributing to the patient’s depression or that may preclude the use of a given drug. (For example, elevation of liver enzymes may preclude the use of duloxetine.) Tests should include:

• A complete blood cell count
• A complete metabolic panel
• A thyroid-stimulating hormone level.

Electrocardiography may also be useful, as some antidepressants can prolong the QT interval or elevate the blood levels of other drugs with this effect.

GENERAL TREATMENT CONSIDERATIONS

There are several classes of antidepressants, and each class has a number of agents. Research has found little difference in efficacy among agents. So to simplify choosing which one to use, we recommend becoming comfortable with an agent from each class, ie:

• A selective serotonin reuptake inhibitor (SSRI)
• A selective serotonin-norepinephrine reuptake inhibitor (SNRI)
• A tricyclic antidepressant (TCA)
• A monoamine oxidase (MAO) inhibitor.

Each class includes generic agents, many of which are on the discount lists of retail pharmacies. Table 1 shows representative drugs from each class, with their relative costs.

Start low and go slow. In general, when starting an antidepressant, consider starting at half the normal dose, titrating upward as tolerated about every 14 days. This approach can minimize side effects. For example, if prescribing fluoxetine, start with 10 mg and titrate every 2 weeks based on tolerance and patient response. That said, each patient may respond differently, requiring perhaps a lower starting dose or a longer titration schedule.

Anticipate side effects. Most of the side effects of an antidepressant drug can be explained by its mechanism of action. Although side effects should certainly be considered when choosing an agent, patients can be reassured that most are transient and benign. A detailed discussion of side effects of antidepressant drugs is beyond the scope of this article, but a review by Khawam et al¹ was published earlier in this journal.

Reassess. If after 4 to 6 weeks the patient has had little or no response, it is reasonable to switch agents. For a patient who was on an SSRI, the change can be to another SSRI or to an SNRI. However, if two SSRIs have already failed, then choose an SNRI. Agents are commonly cross-tapered during the switch to avoid abrupt cessation of one drug or the increased risk of adverse events such as cytochrome P450 interactions, serotonin syndrome, or hypertensive crisis (when switching to an MAO inhibitor).

Beware of interactions. All SSRIs and SNRIs are metabolized through the P450 system in the liver and therefore have the potential for drug-drug interactions. Care must be taken when giving these agents together with drugs whose metabolism can be altered by P450 inhibition. For TCAs, blood levels can be checked if there is concern about toxicity; however, dosing is not strictly based on this level. Great care should be taken if a TCA is given together with an SNRI or an SSRI, as the TCA blood level can become significantly elevated. This may result in QT interval prolongation, as mentioned earlier.

Refer. Referral to a psychiatrist is appropriate for patients for whom multiple classes have failed, for patients who have another psychiatric comorbidity (such as psychosis, hypomania, or mania), or for patients who may need hospitalization. Referral is also appropriate if the physician is concerned about suicide risk.

PATIENTS WITH MAJOR DEPRESSION ONLY

For a patient presenting with depression but no other significant medical comorbidity, the first-line therapy is often an SSRI. Several generic SSRIs are available, and some are on the discount lists at retail pharmacies.

Symptoms should start to improve in about 2 weeks, and the optimal response should be achieved in 4 to 6 weeks of treatment. If this does not occur, consider either adding an augmenting agent or switching to a different antidepressant.

PATIENTS WITH CHRONIC PAIN

Chronic pain and depression often go hand in hand and can potentiate each other. When considering an antidepressant in a patient who has both conditions, the SNRIs and TCAs are typically preferred. Some SNRIs, namely duloxetine and milnacipran, are approved for certain chronic pain conditions, such as fibromyalgia. SNRIs are frequently used off-label for other chronic pain conditions such as headache and neuropathic pain.²

TCAs such as amitriptyline, nortriptyline, and doxepin are also often used in patients with chronic pain. These agents, like the SNRIs, inhibit the reuptake of serotonin and norepinephrine and are used off-label for neuropathic pain,^3,4 migraine, interstitial cystitis,⁵ and other pain conditions.^6–9

For TCAs and SNRIs, the effective dose range for chronic pain overlaps that for depression. However, TCAs are often given at lower doses to patients without depression. We recommend starting at a low dose and slowly titrating upward to an effective dose. SNRIs are often preferred over TCAs because they do not have anticholinergic side effects and because an overdose is much less likely to be lethal.

PATIENTS WITH SEXUAL DYSFUNCTION

One of the more commonly reported side effects of antidepressants is sexual dysfunction, generally in the form of delayed orgasm or decreased libido.¹⁰ Typically, these complaints are attributed to SSRIs and SNRIs; however, TCAs and MAO inhibitors have also been associated wth sexual dysfunction.

Both erectile dysfunction and priapism have been linked to certain antidepressants. In particular, trazodone is a known cause of priapism. Even if using low doses for sleep, male patients should be made aware of this adverse effect.

Switching from one agent to another in the same class is not likely to improve sexual side effects. In particular, all the SSRIs are similar in their likelihood of causing sexual dysfunction. In a patient taking an SSRI who experiences this side effect, switching to bupropion¹¹ or mirtazapine¹² can be quite useful. Bupropion acts primarily on dopamine and norepinephrine, whereas mirtazapine acts on serotonin and norepinephrine but in a different manner from SSRIs and SNRIs.

Adjunctive treatment such as a cholinergic agonist, yohimbine (contraindicated with MAO inhibitors), a serotonergic agent (eg, buspirone), or a drug that acts on nitric oxide (eg, sildenafil, tadalafil) may have some utility but is often ineffective. Dose reduction, if possible, can be of value.

PATIENTS WITH ANXIETY

Many antidepressants are also approved for anxiety disorders, and still more are used off-label for this purpose. Anxiety and depression often occur together, so being able to treat both conditions with one drug can be quite useful.¹³ In general, the antidepressant effects are seen at lower doses of SSRIs and SNRIs, whereas more of the anxiolytic effects are seen at higher doses, particularly for obsessive-compulsive disorder.¹⁴

First-line treatment would be an SSRI or SNRI. Most anxiety disorders respond to either class, but there are some more-specific recommendations. SSRIs are best studied in panic disorder, generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Fluoxetine, citalopram, escitalopram, and sertraline¹⁵ can all be effective in both major depressive disorder and generalized anxiety disorder. Panic disorder also tends to respond well to SSRIs. SNRIs have been evaluated primarily in generalized anxiety disorder but may also be useful in many of the other conditions.

Additionally, mirtazapine (used off-label)¹² and the TCAs^16–18 can help treat anxiety. Clomipramine is used to treat obsessive-compulsive disorder.¹⁹ These drugs are especially useful for nighttime anxiety, as they can aid sleep. Of note, the anxiolytic effect of mirtazapine may be greater at higher doses.

MAO inhibitors often go unused because of the dietary and medication restrictions involved. However, very refractory cases of certain anxiety disorders may respond preferentially to these agents.

Bupropion tends to be more activating than other antidepressants, so is often avoided in anxious patients. However, some research suggests this is not always necessary.²⁰ If the anxiety is secondary to depression, it will often improve significantly with this agent.

When starting or increasing the dose of an antidepressant, patients may experience increased anxiety or feel “jittery.” This feeling usually passes within the first week of treatment, and it is important to inform patients about this effect. “Start low and go slow” in patients with significant comorbid anxiety. Temporarily using a benzodiazepine such as clonazepam may make the transition more tolerable.

PATIENTS WITH CHRONIC FATIGUE SYNDROME OR FIBROMYALGIA

Increasing recognition of both chronic fatigue syndrome and fibromyalgia has led to more proactive treatment for these disorders. Depression can go hand in hand with these disorders, and certain antidepressants, namely the SNRIs, can be useful in this population.

More data exist for the treatment of fibromyalgia. Both duloxetine and milnacipran are approved by the US Food and Drug Administration (FDA) for the treatment of fibromyalgia.²¹ Venlafaxine is also used off-label for this purpose. SSRIs such as fluoxetine and citalopram have had mixed results.^21–23 TCAs have been used with some success; however, their side effects and lethal potential are often limiting.^21,24,25 A recent study in Spain also suggested there may be benefit from using MAO inhibitors for fibromyalgia, but data are quite limited.²⁶

The data for treating chronic fatigue syndrome with SSRIs, SNRIs, or MAO inhibitors are conflicting.^27–29 However, managing the co-existing depression may provide some relief in and of itself.

PATIENTS WITH FREQUENT INSOMNIA

Insomnia can be a symptom of depression, but it can also be a side effect of certain antidepressants. The SSRIs and SNRIs can disrupt sleep patterns in some patients by shortening the rapid-eye-movement (REM) stage.^30,31

In patients with severe insomnia, it may be best to first recommend taking the antidepressant in the morning if they notice worsening sleep after initiating treatment. Patients can be told with any antidepressant, “If it makes you tired, take it at night, and if it wakes you up, take it in the morning.” Of note, a recent South African study suggested that escitalopram may be able to improve sleep.³²

If that does not solve the problem, there are other options. For instance, mirtazapine, particularly in doses of 15 mg or 30 mg, aids depression and insomnia. At higher doses (45 mg), the sleep-aiding effect may be reduced. Low doses of TCAs, particularly doxepin, maprotiline (technically speaking, a tetracyclic antidepressant), amitriptyline, and nortriptyline can be effective sleep aids. These agents may be used as an adjunct to another antidepressant to enhance sleep and mood. However, the TCAs also shorten the REM stage of sleep.³³

The previously mentioned drug interactions with SSRIs and SNRIs also need to be considered. Caution should be used when discontinuing these medications, as patients may experience rebound symptoms in the form of much more vivid dreams. MAO inhibitors may worsen insomnia because they suppress REM sleep.³⁴

Trazodone is another agent that at lower doses (25–150 mg) can be an effective, nonaddicting sleep aid. When used as an antidepressant, it is generally prescribed at higher doses (300–400 mg), but its sedating effects can be quite limiting at these levels. It is important to remember the possibility of priapism in male patients.

GERIATRIC PATIENTS

Old age brings its own set of concerns when treating depression. Elderly patients are more susceptible to potential bradycardia caused by SSRIs. The TCAs have the more worrisome cardiac side effect of QTc prolongation. TCAs can slow cognitive function, whereas the SSRIs, bupropion, and the SNRIs tend not to affect cognition. Escitalopram and duloxetine have been suggested to be particularly effective in the elderly.^35,36 A study from the Netherlands linked SSRIs with increased risk of falling in geriatric patients with dementia.³⁷ Constipation, which could lead to ileus, is increased with TCAs and certain other agents (ie, paroxetine) in the geriatric population.

Mirtazapine is often very useful in elderly patients for many reasons: it treats both anxiety and depression, stimulates appetite and weight gain, can help with nausea, and is an effective sleep aid. Concerns about weight, appetite, and sleep are particularly common in the elderly, whereas younger patients can be less tolerant of drugs that make them gain weight and sleep more. Normal age-related changes to the sleep cycle contribute to decreased satisfaction with sleep as we age. In addition, depression often further impairs sleep. So, in the elderly, optimizing sleep is key. Research has also shown mirtazapine to be effective in patients with both Alzheimer dementia and depression.³⁸

DIABETIC PATIENTS

One of the more worrisome side effects of psychiatric medications in diabetic patients is weight gain. Certain antidepressants have a greater propensity for weight gain and should likely be avoided as first-line treatments in this population.¹² Typically, these agents include those that have more antihistamine action such as paroxetine and the TCAs. These agents also may lead to constipation, which could potentially worsen gastroparesis. Mirtazapine and the MAO inhibitors are also known to cause weight gain.

Bupropion and nefazodone are the most weight-neutral of all antidepressants. Nefazodone has fallen out of favor because of its potential to cause fulminant liver failure in rare cases. However, it remains a reasonable option for patients with comorbid anxiety and depression who have significant weight gain with other agents.

SSRIs and MAO inhibitors may improve or be neutral toward glucose metabolism, and some data suggest that SNRIs may impair this process.³⁹

PATIENTS WITH CARDIAC CONDITIONS

Major depression often coexists with cardiac conditions. In particular, many patients develop depression after suffering a myocardial infarction, and increasingly they are being treated for it.⁴⁰ Treatment in this situation is appropriate, since depression, if untreated, can increase the risk of recurrence of myocardial infarction.⁴¹

However, there are many concerns that accompany treating depression in cardiac patients. Therefore, a baseline electrocardiogram should be obtained before starting an antidepressant.

TCAs and tetracyclic agents have a tendency to prolong the QTc interval and potentiate ventricular arrhythmias,⁴² so it may be prudent to avoid these in patients at risk. These agents can also significantly increase the pulse rate. This tachycardia increases the risk of angina or myocardial infarction from the anticholinergic effects of these drugs.

In February 2013, the FDA issued a warning about possible arrhythmias with citalopram at doses greater than 40 mg in adult patients⁴³; however, research has suggested citalopram is effective in treating depression in cardiac patients.⁴⁴ Research has not shown an increase in efficacy at doses greater than 40 mg daily, so we recommend following the black-box warning.

TCAs and MAO inhibitors can also cause orthostatic hypotension. On the other hand, consuming large amounts of tyramine, in foods such as aged cheese, can precipitate a hypertensive crisis in patients taking MAO inhibitors.

Which antidepressants tend to be safer in cardiac patients? Sertraline has been shown to be safe in congestive heart failure and coronary artery disease,^45–47 but the SSRIs are typically safe. Fluoxetine has shown efficacy in patients who have had a myocardial infarction.⁴⁸ Mirtazapine has also been shown to be efficacious in cardiac patients.⁴⁹ Nefazodone, mirtazapine, bupropion, SSRIs, and SNRIs have little or no tendency toward orthostatic hypotension.

With the variety of drugs available for treating depression, choosing one can be daunting. Different agents have characteristics that may make them a better choice for different types of patients, but even so, treating any kind of mental illness often requires an element of trial and error.

Primary care providers are on the frontline of treating mental illness, often evaluating patients before they are seen by a psychiatrist. The purpose of this article is to provide insight into the art of prescribing antidepressants in the primary care setting. We will discuss common patient presentations, including depressed patients without other medical comorbidities as well as those with common comorbidities, with our recommendations for first-line treatment.

We hope our recommendations will help you to navigate the uncertainty more confidently, resulting in more efficient and tailored treatment for your patients.

BASELINE TESTING

When starting a patient on antidepressant drug therapy, we recommend obtaining a set of baseline laboratory tests to rule out underlying medical conditions that may be contributing to the patient’s depression or that may preclude the use of a given drug. (For example, elevation of liver enzymes may preclude the use of duloxetine.) Tests should include:

• A complete blood cell count
• A complete metabolic panel
• A thyroid-stimulating hormone level.

Electrocardiography may also be useful, as some antidepressants can prolong the QT interval or elevate the blood levels of other drugs with this effect.

GENERAL TREATMENT CONSIDERATIONS

There are several classes of antidepressants, and each class has a number of agents. Research has found little difference in efficacy among agents. So to simplify choosing which one to use, we recommend becoming comfortable with an agent from each class, ie:

• A selective serotonin reuptake inhibitor (SSRI)
• A selective serotonin-norepinephrine reuptake inhibitor (SNRI)
• A tricyclic antidepressant (TCA)
• A monoamine oxidase (MAO) inhibitor.

Each class includes generic agents, many of which are on the discount lists of retail pharmacies. Table 1 shows representative drugs from each class, with their relative costs.

Start low and go slow. In general, when starting an antidepressant, consider starting at half the normal dose, titrating upward as tolerated about every 14 days. This approach can minimize side effects. For example, if prescribing fluoxetine, start with 10 mg and titrate every 2 weeks based on tolerance and patient response. That said, each patient may respond differently, requiring perhaps a lower starting dose or a longer titration schedule.

Anticipate side effects. Most of the side effects of an antidepressant drug can be explained by its mechanism of action. Although side effects should certainly be considered when choosing an agent, patients can be reassured that most are transient and benign. A detailed discussion of side effects of antidepressant drugs is beyond the scope of this article, but a review by Khawam et al¹ was published earlier in this journal.

Reassess. If after 4 to 6 weeks the patient has had little or no response, it is reasonable to switch agents. For a patient who was on an SSRI, the change can be to another SSRI or to an SNRI. However, if two SSRIs have already failed, then choose an SNRI. Agents are commonly cross-tapered during the switch to avoid abrupt cessation of one drug or the increased risk of adverse events such as cytochrome P450 interactions, serotonin syndrome, or hypertensive crisis (when switching to an MAO inhibitor).

Beware of interactions. All SSRIs and SNRIs are metabolized through the P450 system in the liver and therefore have the potential for drug-drug interactions. Care must be taken when giving these agents together with drugs whose metabolism can be altered by P450 inhibition. For TCAs, blood levels can be checked if there is concern about toxicity; however, dosing is not strictly based on this level. Great care should be taken if a TCA is given together with an SNRI or an SSRI, as the TCA blood level can become significantly elevated. This may result in QT interval prolongation, as mentioned earlier.

Refer. Referral to a psychiatrist is appropriate for patients for whom multiple classes have failed, for patients who have another psychiatric comorbidity (such as psychosis, hypomania, or mania), or for patients who may need hospitalization. Referral is also appropriate if the physician is concerned about suicide risk.

PATIENTS WITH MAJOR DEPRESSION ONLY

For a patient presenting with depression but no other significant medical comorbidity, the first-line therapy is often an SSRI. Several generic SSRIs are available, and some are on the discount lists at retail pharmacies.

Symptoms should start to improve in about 2 weeks, and the optimal response should be achieved in 4 to 6 weeks of treatment. If this does not occur, consider either adding an augmenting agent or switching to a different antidepressant.

PATIENTS WITH CHRONIC PAIN

Chronic pain and depression often go hand in hand and can potentiate each other. When considering an antidepressant in a patient who has both conditions, the SNRIs and TCAs are typically preferred. Some SNRIs, namely duloxetine and milnacipran, are approved for certain chronic pain conditions, such as fibromyalgia. SNRIs are frequently used off-label for other chronic pain conditions such as headache and neuropathic pain.²

TCAs such as amitriptyline, nortriptyline, and doxepin are also often used in patients with chronic pain. These agents, like the SNRIs, inhibit the reuptake of serotonin and norepinephrine and are used off-label for neuropathic pain,^3,4 migraine, interstitial cystitis,⁵ and other pain conditions.^6–9

For TCAs and SNRIs, the effective dose range for chronic pain overlaps that for depression. However, TCAs are often given at lower doses to patients without depression. We recommend starting at a low dose and slowly titrating upward to an effective dose. SNRIs are often preferred over TCAs because they do not have anticholinergic side effects and because an overdose is much less likely to be lethal.

PATIENTS WITH SEXUAL DYSFUNCTION

One of the more commonly reported side effects of antidepressants is sexual dysfunction, generally in the form of delayed orgasm or decreased libido.¹⁰ Typically, these complaints are attributed to SSRIs and SNRIs; however, TCAs and MAO inhibitors have also been associated wth sexual dysfunction.

Both erectile dysfunction and priapism have been linked to certain antidepressants. In particular, trazodone is a known cause of priapism. Even if using low doses for sleep, male patients should be made aware of this adverse effect.

Switching from one agent to another in the same class is not likely to improve sexual side effects. In particular, all the SSRIs are similar in their likelihood of causing sexual dysfunction. In a patient taking an SSRI who experiences this side effect, switching to bupropion¹¹ or mirtazapine¹² can be quite useful. Bupropion acts primarily on dopamine and norepinephrine, whereas mirtazapine acts on serotonin and norepinephrine but in a different manner from SSRIs and SNRIs.

Adjunctive treatment such as a cholinergic agonist, yohimbine (contraindicated with MAO inhibitors), a serotonergic agent (eg, buspirone), or a drug that acts on nitric oxide (eg, sildenafil, tadalafil) may have some utility but is often ineffective. Dose reduction, if possible, can be of value.

PATIENTS WITH ANXIETY

Many antidepressants are also approved for anxiety disorders, and still more are used off-label for this purpose. Anxiety and depression often occur together, so being able to treat both conditions with one drug can be quite useful.¹³ In general, the antidepressant effects are seen at lower doses of SSRIs and SNRIs, whereas more of the anxiolytic effects are seen at higher doses, particularly for obsessive-compulsive disorder.¹⁴

First-line treatment would be an SSRI or SNRI. Most anxiety disorders respond to either class, but there are some more-specific recommendations. SSRIs are best studied in panic disorder, generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Fluoxetine, citalopram, escitalopram, and sertraline¹⁵ can all be effective in both major depressive disorder and generalized anxiety disorder. Panic disorder also tends to respond well to SSRIs. SNRIs have been evaluated primarily in generalized anxiety disorder but may also be useful in many of the other conditions.

Additionally, mirtazapine (used off-label)¹² and the TCAs^16–18 can help treat anxiety. Clomipramine is used to treat obsessive-compulsive disorder.¹⁹ These drugs are especially useful for nighttime anxiety, as they can aid sleep. Of note, the anxiolytic effect of mirtazapine may be greater at higher doses.

MAO inhibitors often go unused because of the dietary and medication restrictions involved. However, very refractory cases of certain anxiety disorders may respond preferentially to these agents.

Bupropion tends to be more activating than other antidepressants, so is often avoided in anxious patients. However, some research suggests this is not always necessary.²⁰ If the anxiety is secondary to depression, it will often improve significantly with this agent.

When starting or increasing the dose of an antidepressant, patients may experience increased anxiety or feel “jittery.” This feeling usually passes within the first week of treatment, and it is important to inform patients about this effect. “Start low and go slow” in patients with significant comorbid anxiety. Temporarily using a benzodiazepine such as clonazepam may make the transition more tolerable.

PATIENTS WITH CHRONIC FATIGUE SYNDROME OR FIBROMYALGIA

Increasing recognition of both chronic fatigue syndrome and fibromyalgia has led to more proactive treatment for these disorders. Depression can go hand in hand with these disorders, and certain antidepressants, namely the SNRIs, can be useful in this population.

More data exist for the treatment of fibromyalgia. Both duloxetine and milnacipran are approved by the US Food and Drug Administration (FDA) for the treatment of fibromyalgia.²¹ Venlafaxine is also used off-label for this purpose. SSRIs such as fluoxetine and citalopram have had mixed results.^21–23 TCAs have been used with some success; however, their side effects and lethal potential are often limiting.^21,24,25 A recent study in Spain also suggested there may be benefit from using MAO inhibitors for fibromyalgia, but data are quite limited.²⁶

The data for treating chronic fatigue syndrome with SSRIs, SNRIs, or MAO inhibitors are conflicting.^27–29 However, managing the co-existing depression may provide some relief in and of itself.

PATIENTS WITH FREQUENT INSOMNIA

Insomnia can be a symptom of depression, but it can also be a side effect of certain antidepressants. The SSRIs and SNRIs can disrupt sleep patterns in some patients by shortening the rapid-eye-movement (REM) stage.^30,31

In patients with severe insomnia, it may be best to first recommend taking the antidepressant in the morning if they notice worsening sleep after initiating treatment. Patients can be told with any antidepressant, “If it makes you tired, take it at night, and if it wakes you up, take it in the morning.” Of note, a recent South African study suggested that escitalopram may be able to improve sleep.³²

If that does not solve the problem, there are other options. For instance, mirtazapine, particularly in doses of 15 mg or 30 mg, aids depression and insomnia. At higher doses (45 mg), the sleep-aiding effect may be reduced. Low doses of TCAs, particularly doxepin, maprotiline (technically speaking, a tetracyclic antidepressant), amitriptyline, and nortriptyline can be effective sleep aids. These agents may be used as an adjunct to another antidepressant to enhance sleep and mood. However, the TCAs also shorten the REM stage of sleep.³³

The previously mentioned drug interactions with SSRIs and SNRIs also need to be considered. Caution should be used when discontinuing these medications, as patients may experience rebound symptoms in the form of much more vivid dreams. MAO inhibitors may worsen insomnia because they suppress REM sleep.³⁴

Trazodone is another agent that at lower doses (25–150 mg) can be an effective, nonaddicting sleep aid. When used as an antidepressant, it is generally prescribed at higher doses (300–400 mg), but its sedating effects can be quite limiting at these levels. It is important to remember the possibility of priapism in male patients.

GERIATRIC PATIENTS

Old age brings its own set of concerns when treating depression. Elderly patients are more susceptible to potential bradycardia caused by SSRIs. The TCAs have the more worrisome cardiac side effect of QTc prolongation. TCAs can slow cognitive function, whereas the SSRIs, bupropion, and the SNRIs tend not to affect cognition. Escitalopram and duloxetine have been suggested to be particularly effective in the elderly.^35,36 A study from the Netherlands linked SSRIs with increased risk of falling in geriatric patients with dementia.³⁷ Constipation, which could lead to ileus, is increased with TCAs and certain other agents (ie, paroxetine) in the geriatric population.

Mirtazapine is often very useful in elderly patients for many reasons: it treats both anxiety and depression, stimulates appetite and weight gain, can help with nausea, and is an effective sleep aid. Concerns about weight, appetite, and sleep are particularly common in the elderly, whereas younger patients can be less tolerant of drugs that make them gain weight and sleep more. Normal age-related changes to the sleep cycle contribute to decreased satisfaction with sleep as we age. In addition, depression often further impairs sleep. So, in the elderly, optimizing sleep is key. Research has also shown mirtazapine to be effective in patients with both Alzheimer dementia and depression.³⁸

DIABETIC PATIENTS

One of the more worrisome side effects of psychiatric medications in diabetic patients is weight gain. Certain antidepressants have a greater propensity for weight gain and should likely be avoided as first-line treatments in this population.¹² Typically, these agents include those that have more antihistamine action such as paroxetine and the TCAs. These agents also may lead to constipation, which could potentially worsen gastroparesis. Mirtazapine and the MAO inhibitors are also known to cause weight gain.

Bupropion and nefazodone are the most weight-neutral of all antidepressants. Nefazodone has fallen out of favor because of its potential to cause fulminant liver failure in rare cases. However, it remains a reasonable option for patients with comorbid anxiety and depression who have significant weight gain with other agents.

SSRIs and MAO inhibitors may improve or be neutral toward glucose metabolism, and some data suggest that SNRIs may impair this process.³⁹

PATIENTS WITH CARDIAC CONDITIONS

Major depression often coexists with cardiac conditions. In particular, many patients develop depression after suffering a myocardial infarction, and increasingly they are being treated for it.⁴⁰ Treatment in this situation is appropriate, since depression, if untreated, can increase the risk of recurrence of myocardial infarction.⁴¹

However, there are many concerns that accompany treating depression in cardiac patients. Therefore, a baseline electrocardiogram should be obtained before starting an antidepressant.

TCAs and tetracyclic agents have a tendency to prolong the QTc interval and potentiate ventricular arrhythmias,⁴² so it may be prudent to avoid these in patients at risk. These agents can also significantly increase the pulse rate. This tachycardia increases the risk of angina or myocardial infarction from the anticholinergic effects of these drugs.

In February 2013, the FDA issued a warning about possible arrhythmias with citalopram at doses greater than 40 mg in adult patients⁴³; however, research has suggested citalopram is effective in treating depression in cardiac patients.⁴⁴ Research has not shown an increase in efficacy at doses greater than 40 mg daily, so we recommend following the black-box warning.

TCAs and MAO inhibitors can also cause orthostatic hypotension. On the other hand, consuming large amounts of tyramine, in foods such as aged cheese, can precipitate a hypertensive crisis in patients taking MAO inhibitors.

Which antidepressants tend to be safer in cardiac patients? Sertraline has been shown to be safe in congestive heart failure and coronary artery disease,^45–47 but the SSRIs are typically safe. Fluoxetine has shown efficacy in patients who have had a myocardial infarction.⁴⁸ Mirtazapine has also been shown to be efficacious in cardiac patients.⁴⁹ Nefazodone, mirtazapine, bupropion, SSRIs, and SNRIs have little or no tendency toward orthostatic hypotension.

With the variety of drugs available for treating depression, choosing one can be daunting. Different agents have characteristics that may make them a better choice for different types of patients, but even so, treating any kind of mental illness often requires an element of trial and error.

Primary care providers are on the frontline of treating mental illness, often evaluating patients before they are seen by a psychiatrist. The purpose of this article is to provide insight into the art of prescribing antidepressants in the primary care setting. We will discuss common patient presentations, including depressed patients without other medical comorbidities as well as those with common comorbidities, with our recommendations for first-line treatment.

We hope our recommendations will help you to navigate the uncertainty more confidently, resulting in more efficient and tailored treatment for your patients.

BASELINE TESTING

When starting a patient on antidepressant drug therapy, we recommend obtaining a set of baseline laboratory tests to rule out underlying medical conditions that may be contributing to the patient’s depression or that may preclude the use of a given drug. (For example, elevation of liver enzymes may preclude the use of duloxetine.) Tests should include:

• A complete blood cell count
• A complete metabolic panel
• A thyroid-stimulating hormone level.

Electrocardiography may also be useful, as some antidepressants can prolong the QT interval or elevate the blood levels of other drugs with this effect.

GENERAL TREATMENT CONSIDERATIONS

There are several classes of antidepressants, and each class has a number of agents. Research has found little difference in efficacy among agents. So to simplify choosing which one to use, we recommend becoming comfortable with an agent from each class, ie:

• A selective serotonin reuptake inhibitor (SSRI)
• A selective serotonin-norepinephrine reuptake inhibitor (SNRI)
• A tricyclic antidepressant (TCA)
• A monoamine oxidase (MAO) inhibitor.

Each class includes generic agents, many of which are on the discount lists of retail pharmacies. Table 1 shows representative drugs from each class, with their relative costs.

Start low and go slow. In general, when starting an antidepressant, consider starting at half the normal dose, titrating upward as tolerated about every 14 days. This approach can minimize side effects. For example, if prescribing fluoxetine, start with 10 mg and titrate every 2 weeks based on tolerance and patient response. That said, each patient may respond differently, requiring perhaps a lower starting dose or a longer titration schedule.

Anticipate side effects. Most of the side effects of an antidepressant drug can be explained by its mechanism of action. Although side effects should certainly be considered when choosing an agent, patients can be reassured that most are transient and benign. A detailed discussion of side effects of antidepressant drugs is beyond the scope of this article, but a review by Khawam et al¹ was published earlier in this journal.

Reassess. If after 4 to 6 weeks the patient has had little or no response, it is reasonable to switch agents. For a patient who was on an SSRI, the change can be to another SSRI or to an SNRI. However, if two SSRIs have already failed, then choose an SNRI. Agents are commonly cross-tapered during the switch to avoid abrupt cessation of one drug or the increased risk of adverse events such as cytochrome P450 interactions, serotonin syndrome, or hypertensive crisis (when switching to an MAO inhibitor).

Beware of interactions. All SSRIs and SNRIs are metabolized through the P450 system in the liver and therefore have the potential for drug-drug interactions. Care must be taken when giving these agents together with drugs whose metabolism can be altered by P450 inhibition. For TCAs, blood levels can be checked if there is concern about toxicity; however, dosing is not strictly based on this level. Great care should be taken if a TCA is given together with an SNRI or an SSRI, as the TCA blood level can become significantly elevated. This may result in QT interval prolongation, as mentioned earlier.

Refer. Referral to a psychiatrist is appropriate for patients for whom multiple classes have failed, for patients who have another psychiatric comorbidity (such as psychosis, hypomania, or mania), or for patients who may need hospitalization. Referral is also appropriate if the physician is concerned about suicide risk.

PATIENTS WITH MAJOR DEPRESSION ONLY

For a patient presenting with depression but no other significant medical comorbidity, the first-line therapy is often an SSRI. Several generic SSRIs are available, and some are on the discount lists at retail pharmacies.

Symptoms should start to improve in about 2 weeks, and the optimal response should be achieved in 4 to 6 weeks of treatment. If this does not occur, consider either adding an augmenting agent or switching to a different antidepressant.

PATIENTS WITH CHRONIC PAIN

Chronic pain and depression often go hand in hand and can potentiate each other. When considering an antidepressant in a patient who has both conditions, the SNRIs and TCAs are typically preferred. Some SNRIs, namely duloxetine and milnacipran, are approved for certain chronic pain conditions, such as fibromyalgia. SNRIs are frequently used off-label for other chronic pain conditions such as headache and neuropathic pain.²

TCAs such as amitriptyline, nortriptyline, and doxepin are also often used in patients with chronic pain. These agents, like the SNRIs, inhibit the reuptake of serotonin and norepinephrine and are used off-label for neuropathic pain,^3,4 migraine, interstitial cystitis,⁵ and other pain conditions.^6–9

For TCAs and SNRIs, the effective dose range for chronic pain overlaps that for depression. However, TCAs are often given at lower doses to patients without depression. We recommend starting at a low dose and slowly titrating upward to an effective dose. SNRIs are often preferred over TCAs because they do not have anticholinergic side effects and because an overdose is much less likely to be lethal.

PATIENTS WITH SEXUAL DYSFUNCTION

One of the more commonly reported side effects of antidepressants is sexual dysfunction, generally in the form of delayed orgasm or decreased libido.¹⁰ Typically, these complaints are attributed to SSRIs and SNRIs; however, TCAs and MAO inhibitors have also been associated wth sexual dysfunction.

Both erectile dysfunction and priapism have been linked to certain antidepressants. In particular, trazodone is a known cause of priapism. Even if using low doses for sleep, male patients should be made aware of this adverse effect.

Switching from one agent to another in the same class is not likely to improve sexual side effects. In particular, all the SSRIs are similar in their likelihood of causing sexual dysfunction. In a patient taking an SSRI who experiences this side effect, switching to bupropion¹¹ or mirtazapine¹² can be quite useful. Bupropion acts primarily on dopamine and norepinephrine, whereas mirtazapine acts on serotonin and norepinephrine but in a different manner from SSRIs and SNRIs.

Adjunctive treatment such as a cholinergic agonist, yohimbine (contraindicated with MAO inhibitors), a serotonergic agent (eg, buspirone), or a drug that acts on nitric oxide (eg, sildenafil, tadalafil) may have some utility but is often ineffective. Dose reduction, if possible, can be of value.

PATIENTS WITH ANXIETY

Many antidepressants are also approved for anxiety disorders, and still more are used off-label for this purpose. Anxiety and depression often occur together, so being able to treat both conditions with one drug can be quite useful.¹³ In general, the antidepressant effects are seen at lower doses of SSRIs and SNRIs, whereas more of the anxiolytic effects are seen at higher doses, particularly for obsessive-compulsive disorder.¹⁴

First-line treatment would be an SSRI or SNRI. Most anxiety disorders respond to either class, but there are some more-specific recommendations. SSRIs are best studied in panic disorder, generalized anxiety disorder, social anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder. Fluoxetine, citalopram, escitalopram, and sertraline¹⁵ can all be effective in both major depressive disorder and generalized anxiety disorder. Panic disorder also tends to respond well to SSRIs. SNRIs have been evaluated primarily in generalized anxiety disorder but may also be useful in many of the other conditions.

Additionally, mirtazapine (used off-label)¹² and the TCAs^16–18 can help treat anxiety. Clomipramine is used to treat obsessive-compulsive disorder.¹⁹ These drugs are especially useful for nighttime anxiety, as they can aid sleep. Of note, the anxiolytic effect of mirtazapine may be greater at higher doses.

MAO inhibitors often go unused because of the dietary and medication restrictions involved. However, very refractory cases of certain anxiety disorders may respond preferentially to these agents.

Bupropion tends to be more activating than other antidepressants, so is often avoided in anxious patients. However, some research suggests this is not always necessary.²⁰ If the anxiety is secondary to depression, it will often improve significantly with this agent.

When starting or increasing the dose of an antidepressant, patients may experience increased anxiety or feel “jittery.” This feeling usually passes within the first week of treatment, and it is important to inform patients about this effect. “Start low and go slow” in patients with significant comorbid anxiety. Temporarily using a benzodiazepine such as clonazepam may make the transition more tolerable.

PATIENTS WITH CHRONIC FATIGUE SYNDROME OR FIBROMYALGIA

Increasing recognition of both chronic fatigue syndrome and fibromyalgia has led to more proactive treatment for these disorders. Depression can go hand in hand with these disorders, and certain antidepressants, namely the SNRIs, can be useful in this population.

More data exist for the treatment of fibromyalgia. Both duloxetine and milnacipran are approved by the US Food and Drug Administration (FDA) for the treatment of fibromyalgia.²¹ Venlafaxine is also used off-label for this purpose. SSRIs such as fluoxetine and citalopram have had mixed results.^21–23 TCAs have been used with some success; however, their side effects and lethal potential are often limiting.^21,24,25 A recent study in Spain also suggested there may be benefit from using MAO inhibitors for fibromyalgia, but data are quite limited.²⁶

The data for treating chronic fatigue syndrome with SSRIs, SNRIs, or MAO inhibitors are conflicting.^27–29 However, managing the co-existing depression may provide some relief in and of itself.

PATIENTS WITH FREQUENT INSOMNIA

Insomnia can be a symptom of depression, but it can also be a side effect of certain antidepressants. The SSRIs and SNRIs can disrupt sleep patterns in some patients by shortening the rapid-eye-movement (REM) stage.^30,31

In patients with severe insomnia, it may be best to first recommend taking the antidepressant in the morning if they notice worsening sleep after initiating treatment. Patients can be told with any antidepressant, “If it makes you tired, take it at night, and if it wakes you up, take it in the morning.” Of note, a recent South African study suggested that escitalopram may be able to improve sleep.³²

If that does not solve the problem, there are other options. For instance, mirtazapine, particularly in doses of 15 mg or 30 mg, aids depression and insomnia. At higher doses (45 mg), the sleep-aiding effect may be reduced. Low doses of TCAs, particularly doxepin, maprotiline (technically speaking, a tetracyclic antidepressant), amitriptyline, and nortriptyline can be effective sleep aids. These agents may be used as an adjunct to another antidepressant to enhance sleep and mood. However, the TCAs also shorten the REM stage of sleep.³³

The previously mentioned drug interactions with SSRIs and SNRIs also need to be considered. Caution should be used when discontinuing these medications, as patients may experience rebound symptoms in the form of much more vivid dreams. MAO inhibitors may worsen insomnia because they suppress REM sleep.³⁴

Trazodone is another agent that at lower doses (25–150 mg) can be an effective, nonaddicting sleep aid. When used as an antidepressant, it is generally prescribed at higher doses (300–400 mg), but its sedating effects can be quite limiting at these levels. It is important to remember the possibility of priapism in male patients.

GERIATRIC PATIENTS

Old age brings its own set of concerns when treating depression. Elderly patients are more susceptible to potential bradycardia caused by SSRIs. The TCAs have the more worrisome cardiac side effect of QTc prolongation. TCAs can slow cognitive function, whereas the SSRIs, bupropion, and the SNRIs tend not to affect cognition. Escitalopram and duloxetine have been suggested to be particularly effective in the elderly.^35,36 A study from the Netherlands linked SSRIs with increased risk of falling in geriatric patients with dementia.³⁷ Constipation, which could lead to ileus, is increased with TCAs and certain other agents (ie, paroxetine) in the geriatric population.

Mirtazapine is often very useful in elderly patients for many reasons: it treats both anxiety and depression, stimulates appetite and weight gain, can help with nausea, and is an effective sleep aid. Concerns about weight, appetite, and sleep are particularly common in the elderly, whereas younger patients can be less tolerant of drugs that make them gain weight and sleep more. Normal age-related changes to the sleep cycle contribute to decreased satisfaction with sleep as we age. In addition, depression often further impairs sleep. So, in the elderly, optimizing sleep is key. Research has also shown mirtazapine to be effective in patients with both Alzheimer dementia and depression.³⁸

DIABETIC PATIENTS

One of the more worrisome side effects of psychiatric medications in diabetic patients is weight gain. Certain antidepressants have a greater propensity for weight gain and should likely be avoided as first-line treatments in this population.¹² Typically, these agents include those that have more antihistamine action such as paroxetine and the TCAs. These agents also may lead to constipation, which could potentially worsen gastroparesis. Mirtazapine and the MAO inhibitors are also known to cause weight gain.

Bupropion and nefazodone are the most weight-neutral of all antidepressants. Nefazodone has fallen out of favor because of its potential to cause fulminant liver failure in rare cases. However, it remains a reasonable option for patients with comorbid anxiety and depression who have significant weight gain with other agents.

SSRIs and MAO inhibitors may improve or be neutral toward glucose metabolism, and some data suggest that SNRIs may impair this process.³⁹

PATIENTS WITH CARDIAC CONDITIONS

Major depression often coexists with cardiac conditions. In particular, many patients develop depression after suffering a myocardial infarction, and increasingly they are being treated for it.⁴⁰ Treatment in this situation is appropriate, since depression, if untreated, can increase the risk of recurrence of myocardial infarction.⁴¹

However, there are many concerns that accompany treating depression in cardiac patients. Therefore, a baseline electrocardiogram should be obtained before starting an antidepressant.

TCAs and tetracyclic agents have a tendency to prolong the QTc interval and potentiate ventricular arrhythmias,⁴² so it may be prudent to avoid these in patients at risk. These agents can also significantly increase the pulse rate. This tachycardia increases the risk of angina or myocardial infarction from the anticholinergic effects of these drugs.

In February 2013, the FDA issued a warning about possible arrhythmias with citalopram at doses greater than 40 mg in adult patients⁴³; however, research has suggested citalopram is effective in treating depression in cardiac patients.⁴⁴ Research has not shown an increase in efficacy at doses greater than 40 mg daily, so we recommend following the black-box warning.

TCAs and MAO inhibitors can also cause orthostatic hypotension. On the other hand, consuming large amounts of tyramine, in foods such as aged cheese, can precipitate a hypertensive crisis in patients taking MAO inhibitors.

Which antidepressants tend to be safer in cardiac patients? Sertraline has been shown to be safe in congestive heart failure and coronary artery disease,^45–47 but the SSRIs are typically safe. Fluoxetine has shown efficacy in patients who have had a myocardial infarction.⁴⁸ Mirtazapine has also been shown to be efficacious in cardiac patients.⁴⁹ Nefazodone, mirtazapine, bupropion, SSRIs, and SNRIs have little or no tendency toward orthostatic hypotension.

Early thrombus removal for lower-extremity deep venous thrombosis (DVT) is at present only modestly supported by evidence and so remains controversial. It is largely aimed at preventing postthrombotic syndrome.

The decision to pursue early thrombus removal demands weighing the patient’s risk of postthrombotic syndrome against the risks and costs associated with thrombolysis and thrombectomy, such as bleeding complications. In the final analysis, this remains a subjective decision.

With these caveats in mind, the best candidate for early thrombus removal is a young patient with iliofemoral DVT with symptoms lasting fewer than 14 days.

POSTTHROMBOTIC SYNDROME IS COMMON

Anticoagulation with heparin and warfarin is the mainstay of DVT therapy. Indeed, the safety of this therapy and its effectiveness in reducing thrombus propagation and DVT recurrence are well established. Neither heparin nor warfarin, however, actively reduces the thrombus burden. Rather, both prevent the clot from propagating while it is, hopefully, gradually reabsorbed through endogenous mechanisms.

Up to 50% of DVT patients develop postthrombotic syndrome. A variety of mechanisms are involved, including persistent obstructive thrombosis and valvular injury.¹ But much remains unknown about the etiology, and some patients develop the condition in the absence of abnormalities on objective testing.

Symptoms of postthrombotic syndrome can range from mild heaviness, edema, erythema, and cramping in the affected limb to debilitating pain with classic signs of venous hypertension (eg, venous ectasia and ulcers). It accounts for significant health care costs and has a detrimental effect on quality of life.¹ Thus, there has been interest in early thrombus removal as initial therapy for DVT.

THROMBUS REMOVAL

Venous clots can be removed with open surgery or, more typically, with percutaneous catheter-based thrombolysis and thrombectomy devices that use high-velocity saline jets, ultrasonic energy, or wire oscillation to mechanically fragment the venous clot. All of these mechanisms help with drug delivery and pose a minimal risk of pulmonary embolism.

Evidence is weak

Patients with DVT of the iliac venous system or common femoral vein are at highest risk of postthrombotic syndrome. Therefore, the Society for Vascular Surgery and the American Venous Forum have issued a grade 2C (ie, weak) recommendation in favor of early thrombus removal in patients with a first-time episode of iliofemoral DVT with fewer than 14 days of symptoms.² Moreover, patients must have a low risk of bleeding complications, be ambulatory, and have reasonable life expectancy.

The recommendation is buttressed by a Cochrane meta-analysis that included 101 patients.³ It concluded that there was a significant decrement in the development of postthrombotic syndrome with thrombolysis (but without mechanical thrombectomy) compared with standard therapy: the rate was 48% (29/61) with thrombolysis, and 65% (26/40) with standard therapy.³

More recently, the Catheter-Directed Thrombolysis Versus Standard Treatment for Acute Iliofemoral Deep Vein Thrombosis (CaVenT) study, a randomized prospective trial in 189 patients, demonstrated a lower rate of postthrombotic syndrome at 24 months and increased iliofemoral patency at 6 months with catheter-directed thrombolysis with alteplase (41.1% and 65.9%) vs anticoagulation with heparin and warfarin alone (55.6% and 47.4%).⁴

The Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial is an ongoing prospective randomized multicenter trial of the effect of thrombolysis on postthrombotic syndrome that also hopes to clarify the relative benefits of different methods of pharmacomechanical clot removal.

While CaVenT has not been criticized extensively in the literature, other studies supporting early intervention for iliofemoral venous thrombosis generally have been noted to have a number of shortcomings, including a lack of randomization, and consequent bias, and the use of surrogate end points instead of a direct assessment of postthrombotic syndrome.

Reflecting the weakness of the evidence, the American College of Chest Physicians has issued a grade 2C recommendation against catheter-directed thrombolysis and against thrombectomy in favor of anticoagulant therapy.⁵

A subjective, case-by-case decision

The decision on standard vs interventional therapy must be made case by case. For example, thrombus removal may be more appropriate for a physically active young patient who is more likely to be impaired by postthrombotic syndrome, whereas standard warfarin therapy may be preferable for a sedentary patient. We are also more inclined to offer thrombus removal to patients who have worse symptoms.

Complicating the issue, many patients present with a mix of variables that support and oppose intervention—eg, a moderately active elderly patient with an unclear life expectancy and a history of gastrointestinal bleeding. At present, there is no way to quantitatively evaluate the risks and rewards of thrombus removal, and the final decision is essentially subjective.

Additional facts warranting consideration include the possibility that thrombolysis may require several days of therapy with daily venography for evaluation. Monitoring in the intensive care unit is normally required during the period of thrombolysis. Patients should be apprised of these elements of therapy beforehand; obviously, those who are unwilling to comply are not candidates.

Not a substitute for anticoagulation

It is important to recognize that thrombus removal is not a substitute for standard heparin-warfarin anticoagulation, which must also be prescribed.⁵ Thus, patients who cannot tolerate standard post-DVT anticoagulation should not undergo thrombus removal. Furthermore, the current evidence supports the use of standard anticoagulation over early thrombus removal of DVTs that are more distal in the lower extremity, such as those in the popliteal vein.⁵

PHLEGMASIA CERULEA DOLENS IS A SPECIAL CASE

Phlegmasia cerulea dolens—acute venous outflow obstruction associated with edema, cyanosis, and pain that in the worst cases may lead to shock, limb loss, and death—constitutes a special case. Although we lack robust supporting evidence, phlegmasia is a commonly accepted indication for early thrombus removal as a means of limb salvage.^2,6

Early thrombus removal for lower-extremity deep venous thrombosis (DVT) is at present only modestly supported by evidence and so remains controversial. It is largely aimed at preventing postthrombotic syndrome.

The decision to pursue early thrombus removal demands weighing the patient’s risk of postthrombotic syndrome against the risks and costs associated with thrombolysis and thrombectomy, such as bleeding complications. In the final analysis, this remains a subjective decision.

With these caveats in mind, the best candidate for early thrombus removal is a young patient with iliofemoral DVT with symptoms lasting fewer than 14 days.

POSTTHROMBOTIC SYNDROME IS COMMON

Anticoagulation with heparin and warfarin is the mainstay of DVT therapy. Indeed, the safety of this therapy and its effectiveness in reducing thrombus propagation and DVT recurrence are well established. Neither heparin nor warfarin, however, actively reduces the thrombus burden. Rather, both prevent the clot from propagating while it is, hopefully, gradually reabsorbed through endogenous mechanisms.

Up to 50% of DVT patients develop postthrombotic syndrome. A variety of mechanisms are involved, including persistent obstructive thrombosis and valvular injury.¹ But much remains unknown about the etiology, and some patients develop the condition in the absence of abnormalities on objective testing.

Symptoms of postthrombotic syndrome can range from mild heaviness, edema, erythema, and cramping in the affected limb to debilitating pain with classic signs of venous hypertension (eg, venous ectasia and ulcers). It accounts for significant health care costs and has a detrimental effect on quality of life.¹ Thus, there has been interest in early thrombus removal as initial therapy for DVT.

THROMBUS REMOVAL

Venous clots can be removed with open surgery or, more typically, with percutaneous catheter-based thrombolysis and thrombectomy devices that use high-velocity saline jets, ultrasonic energy, or wire oscillation to mechanically fragment the venous clot. All of these mechanisms help with drug delivery and pose a minimal risk of pulmonary embolism.

Evidence is weak

Patients with DVT of the iliac venous system or common femoral vein are at highest risk of postthrombotic syndrome. Therefore, the Society for Vascular Surgery and the American Venous Forum have issued a grade 2C (ie, weak) recommendation in favor of early thrombus removal in patients with a first-time episode of iliofemoral DVT with fewer than 14 days of symptoms.² Moreover, patients must have a low risk of bleeding complications, be ambulatory, and have reasonable life expectancy.

The recommendation is buttressed by a Cochrane meta-analysis that included 101 patients.³ It concluded that there was a significant decrement in the development of postthrombotic syndrome with thrombolysis (but without mechanical thrombectomy) compared with standard therapy: the rate was 48% (29/61) with thrombolysis, and 65% (26/40) with standard therapy.³

More recently, the Catheter-Directed Thrombolysis Versus Standard Treatment for Acute Iliofemoral Deep Vein Thrombosis (CaVenT) study, a randomized prospective trial in 189 patients, demonstrated a lower rate of postthrombotic syndrome at 24 months and increased iliofemoral patency at 6 months with catheter-directed thrombolysis with alteplase (41.1% and 65.9%) vs anticoagulation with heparin and warfarin alone (55.6% and 47.4%).⁴

The Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial is an ongoing prospective randomized multicenter trial of the effect of thrombolysis on postthrombotic syndrome that also hopes to clarify the relative benefits of different methods of pharmacomechanical clot removal.

While CaVenT has not been criticized extensively in the literature, other studies supporting early intervention for iliofemoral venous thrombosis generally have been noted to have a number of shortcomings, including a lack of randomization, and consequent bias, and the use of surrogate end points instead of a direct assessment of postthrombotic syndrome.

Reflecting the weakness of the evidence, the American College of Chest Physicians has issued a grade 2C recommendation against catheter-directed thrombolysis and against thrombectomy in favor of anticoagulant therapy.⁵

A subjective, case-by-case decision

The decision on standard vs interventional therapy must be made case by case. For example, thrombus removal may be more appropriate for a physically active young patient who is more likely to be impaired by postthrombotic syndrome, whereas standard warfarin therapy may be preferable for a sedentary patient. We are also more inclined to offer thrombus removal to patients who have worse symptoms.

Complicating the issue, many patients present with a mix of variables that support and oppose intervention—eg, a moderately active elderly patient with an unclear life expectancy and a history of gastrointestinal bleeding. At present, there is no way to quantitatively evaluate the risks and rewards of thrombus removal, and the final decision is essentially subjective.

Additional facts warranting consideration include the possibility that thrombolysis may require several days of therapy with daily venography for evaluation. Monitoring in the intensive care unit is normally required during the period of thrombolysis. Patients should be apprised of these elements of therapy beforehand; obviously, those who are unwilling to comply are not candidates.

Not a substitute for anticoagulation

It is important to recognize that thrombus removal is not a substitute for standard heparin-warfarin anticoagulation, which must also be prescribed.⁵ Thus, patients who cannot tolerate standard post-DVT anticoagulation should not undergo thrombus removal. Furthermore, the current evidence supports the use of standard anticoagulation over early thrombus removal of DVTs that are more distal in the lower extremity, such as those in the popliteal vein.⁵

PHLEGMASIA CERULEA DOLENS IS A SPECIAL CASE

Phlegmasia cerulea dolens—acute venous outflow obstruction associated with edema, cyanosis, and pain that in the worst cases may lead to shock, limb loss, and death—constitutes a special case. Although we lack robust supporting evidence, phlegmasia is a commonly accepted indication for early thrombus removal as a means of limb salvage.^2,6

Early thrombus removal for lower-extremity deep venous thrombosis (DVT) is at present only modestly supported by evidence and so remains controversial. It is largely aimed at preventing postthrombotic syndrome.

The decision to pursue early thrombus removal demands weighing the patient’s risk of postthrombotic syndrome against the risks and costs associated with thrombolysis and thrombectomy, such as bleeding complications. In the final analysis, this remains a subjective decision.

With these caveats in mind, the best candidate for early thrombus removal is a young patient with iliofemoral DVT with symptoms lasting fewer than 14 days.

POSTTHROMBOTIC SYNDROME IS COMMON

Anticoagulation with heparin and warfarin is the mainstay of DVT therapy. Indeed, the safety of this therapy and its effectiveness in reducing thrombus propagation and DVT recurrence are well established. Neither heparin nor warfarin, however, actively reduces the thrombus burden. Rather, both prevent the clot from propagating while it is, hopefully, gradually reabsorbed through endogenous mechanisms.

Up to 50% of DVT patients develop postthrombotic syndrome. A variety of mechanisms are involved, including persistent obstructive thrombosis and valvular injury.¹ But much remains unknown about the etiology, and some patients develop the condition in the absence of abnormalities on objective testing.

Symptoms of postthrombotic syndrome can range from mild heaviness, edema, erythema, and cramping in the affected limb to debilitating pain with classic signs of venous hypertension (eg, venous ectasia and ulcers). It accounts for significant health care costs and has a detrimental effect on quality of life.¹ Thus, there has been interest in early thrombus removal as initial therapy for DVT.

THROMBUS REMOVAL

Venous clots can be removed with open surgery or, more typically, with percutaneous catheter-based thrombolysis and thrombectomy devices that use high-velocity saline jets, ultrasonic energy, or wire oscillation to mechanically fragment the venous clot. All of these mechanisms help with drug delivery and pose a minimal risk of pulmonary embolism.

Evidence is weak

Patients with DVT of the iliac venous system or common femoral vein are at highest risk of postthrombotic syndrome. Therefore, the Society for Vascular Surgery and the American Venous Forum have issued a grade 2C (ie, weak) recommendation in favor of early thrombus removal in patients with a first-time episode of iliofemoral DVT with fewer than 14 days of symptoms.² Moreover, patients must have a low risk of bleeding complications, be ambulatory, and have reasonable life expectancy.

The recommendation is buttressed by a Cochrane meta-analysis that included 101 patients.³ It concluded that there was a significant decrement in the development of postthrombotic syndrome with thrombolysis (but without mechanical thrombectomy) compared with standard therapy: the rate was 48% (29/61) with thrombolysis, and 65% (26/40) with standard therapy.³

More recently, the Catheter-Directed Thrombolysis Versus Standard Treatment for Acute Iliofemoral Deep Vein Thrombosis (CaVenT) study, a randomized prospective trial in 189 patients, demonstrated a lower rate of postthrombotic syndrome at 24 months and increased iliofemoral patency at 6 months with catheter-directed thrombolysis with alteplase (41.1% and 65.9%) vs anticoagulation with heparin and warfarin alone (55.6% and 47.4%).⁴

The Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial is an ongoing prospective randomized multicenter trial of the effect of thrombolysis on postthrombotic syndrome that also hopes to clarify the relative benefits of different methods of pharmacomechanical clot removal.

While CaVenT has not been criticized extensively in the literature, other studies supporting early intervention for iliofemoral venous thrombosis generally have been noted to have a number of shortcomings, including a lack of randomization, and consequent bias, and the use of surrogate end points instead of a direct assessment of postthrombotic syndrome.

Reflecting the weakness of the evidence, the American College of Chest Physicians has issued a grade 2C recommendation against catheter-directed thrombolysis and against thrombectomy in favor of anticoagulant therapy.⁵

A subjective, case-by-case decision

The decision on standard vs interventional therapy must be made case by case. For example, thrombus removal may be more appropriate for a physically active young patient who is more likely to be impaired by postthrombotic syndrome, whereas standard warfarin therapy may be preferable for a sedentary patient. We are also more inclined to offer thrombus removal to patients who have worse symptoms.

Complicating the issue, many patients present with a mix of variables that support and oppose intervention—eg, a moderately active elderly patient with an unclear life expectancy and a history of gastrointestinal bleeding. At present, there is no way to quantitatively evaluate the risks and rewards of thrombus removal, and the final decision is essentially subjective.

Additional facts warranting consideration include the possibility that thrombolysis may require several days of therapy with daily venography for evaluation. Monitoring in the intensive care unit is normally required during the period of thrombolysis. Patients should be apprised of these elements of therapy beforehand; obviously, those who are unwilling to comply are not candidates.

Not a substitute for anticoagulation

It is important to recognize that thrombus removal is not a substitute for standard heparin-warfarin anticoagulation, which must also be prescribed.⁵ Thus, patients who cannot tolerate standard post-DVT anticoagulation should not undergo thrombus removal. Furthermore, the current evidence supports the use of standard anticoagulation over early thrombus removal of DVTs that are more distal in the lower extremity, such as those in the popliteal vein.⁵

PHLEGMASIA CERULEA DOLENS IS A SPECIAL CASE

Phlegmasia cerulea dolens—acute venous outflow obstruction associated with edema, cyanosis, and pain that in the worst cases may lead to shock, limb loss, and death—constitutes a special case. Although we lack robust supporting evidence, phlegmasia is a commonly accepted indication for early thrombus removal as a means of limb salvage.^2,6

A March 2013 warning by the US Food and Drug Administration that azithromycin (Zithromax, Zmax, Z-pak) may increase the risk of sudden cardiac death does not mean we must abandon using it. We should, however, try to determine if our patients have cardiovascular risk factors for this extreme side effect and take appropriate precautions.

AZITHROMYCIN: THE SAFEST OF THE MACROLIDES?

Azithromycin, a broad-spectrum macrolide antibiotic, is used to treat or prevent a range of common bacterial infections, including upper and lower respiratory tract infections and certain sexually transmitted diseases.

In terms of overall toxicity, azithromycin has been considered the safest of the macrolides, as it neither undergoes CYP3A4 metabolism nor inhibits CYP3A4 to any clinically meaningful degree, and therefore does not interfere with the array of commonly used medications that undergo CYP3A4 metabolism.

Also, in vitro, azithromycin shows only limited blockade of the potassium channel hERG. This channel is critically involved in cardiomyocyte repolarization, and if it is blocked or otherwise malfunctioning, the result can be a prolonged QT interval, ventricular arrhythmias, and even sudden cardiac death.^1–4 Therefore, lack of blockade, as reflected by a high inhibitory concentration (Table 1), boded well for the safety of azithromycin in terms of QT liability. However, we should be cautious in interpreting in vitro data.

With its broad antibiotic spectrum and perceived favorable safety profile, azithromycin has become one of the top 15 most prescribed drugs and the best-selling antibiotic in the United States, accounting for 55.4 million prescriptions in 2012, according to the IMS Institute for Healthcare Informatics.

THE FDA RECEIVES 203 REPORTS OF ADVERSE EVENTS IN 8 YEARS

However, beginning with a report of azithromycin-triggered torsades de pointes in 2001,⁵ a growing body of evidence, derived from postmarketing surveillance, has linked azithromycin to cardiac arrhythmias such as pronounced QT interval prolongation and associated torsades de pointes (which can progress to life-threatening ventricular fibrillation). Other, closely related macrolides such as clarithromycin and erythromycin are also linked to these effects.

Furthermore, in the 8-year period from 2004 to 2011, the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) received a total of 203 reports of azithromycin-associated QT prolongation, torsades de pointes, ventricular arrhythmia, or, in 65 cases, sudden cardiac death (Table 1).⁶

At face value, the number of FAERS reports appears to be similar between the various macrolide antibiotics. However, it is important to remember that these drugs differ substantially in the number of prescriptions written for them, with azithromycin being prescribed more often. Also, the FAERS numbers are subject to a number of well-known limitations such as confounding variables, uneven quality and completeness of reports, duplication, and underreporting. These limitations preclude the use of such adverse reporting databases in calculating and thereby comparing the true incidence of adverse events associated with the various macrolide antibiotics.^6–9

RAY ET AL FIND A HIGHER RISK OF CARDIOVASCULAR DEATH

Despite these inherent flaws, initial postmarketing surveillance reports cast enough doubt on the long-standing notion that azithromycin is the safest macrolide antibiotic to prompt Ray et al¹⁰ to assess its safety in an observational, nonrandomized study of people enrolled in the Tennessee Medicaid program.

They found that, over the typical 5 days of therapy, people taking azithromycin had a rate of cardiovascular death 2.88 times higher than in people taking no antibiotic, and 2.49 times higher than in people taking amoxicillin (Table 2).

However, the absolute excess risk compared with amoxicillin varied considerably according to baseline risk score for cardiovascular disease, with 1 excess cardiovascular death per 4,100 in the highest-risk decile compared with 1 excess cardiovascular death per 100,000 in the lowest-risk decile.^10,11

Moreover, the increase in deaths did not persist after the 5 days of therapy. This time-limited pattern directly correlated with expected peak azithromycin plasma levels during a standard 5-day course.

Ray et al used appropriate analytic methods to attempt to correct for any confounding bias intrinsic to the observational, nonrandomized study design. Nevertheless, the patients were Medicaid beneficiaries, who have a higher prevalence of comorbid conditions and higher mortality rates than the general population. Therefore, legitimate questions were raised about whether the results of the study could be generalized to populations with substantially lower baseline risk of cardiovascular disease and if differences in the baseline characteristics of the treatment groups were adequately controlled.^12,13

THE FDA REVISES AZITHROMYCIN’S WARNINGS AND PRECAUTIONS

The striking observations by Ray et al,¹⁰ coupled with the concerns raised by postmarketing surveillance reports, compelled the FDA to review the labels of azithromycin and other macrolide antibiotics.

Ultimately, the FDA opted to revise the “warning and precautions” section of the azithromycin drug label to include a warning about the potential risk of fatal arrhythmias, specifically QT interval prolongation and torsades de pointes. In a March 2013 safety announcement, it also urged health care professionals to use caution when prescribing azithromycin to patients known to have risk factors for drug-related arrhythmias, including congenital long QT syndrome, acquired QT interval prolongation, hypokalemia, hypomagnesia, bradycardia, and concurrent use of other medications known to prolong the QT interval, specifically the class IA (eg, quinidine and procainamide) and class III (eg, amiodarone, sotalol, and dofetilide) antiarrhythmics.

SVANSTRÖM ET AL FIND NO INCREASED RISK

However, just when the medical community appeared ready to accept that azithromycin may not be as safe as we thought it was, a large prospective study by Svanström et al, published in early May 2013, found no increased risk of cardiovascular death associated with azithromycin (Table 2).¹⁴

The patients were a representative population of young to middle-aged Danish adults at low baseline risk of underlying cardiovascular disease.

Interestingly, Svanström et al were careful to point out that their study was only powered to rule out a moderate-to-high (> 55%) increase in the relative risk of cardiovascular death. Furthermore, profound differences existed in the baseline risk of death and cardiovascular risk factors between their patients and the Tennessee Medicaid patients studied by Ray et al.¹⁴ Therefore, the authors suggested that their study complements rather than contradicts the study by Ray et al. They attributed the differences in the findings to treatment-effect heterogeneity, in which the risk of azithromycin-associated cardiovascular mortality is largely limited to high-risk patients, namely those with multiple preexisting cardiovascular risk factors.¹⁴

ACC/AHA RECOMMENDATION: IDENTIFY THOSE AT RISK

Collectively, the data reviewed above provide compelling evidence that azithromycin is not completely free of the QT-prolonging and torsadogenic effects that have long been associated with other macrolide antibiotics. However, the findings from both the study by Ray et al and that of Svanström et al suggest that preexisting cardiovascular risk factors play a prominent role in determining the incidence of azithromycin-associated cardiovascular death in a given population (Table 2).^10,14

These findings should prompt physicians to carefully reassess the risks and benefits of azithromycin use in their clinical practices. They also reinforce a recent call by the American Heart Association (AHA) and American College of Cardiology (ACC) to better identify, early on, patients at risk of drug-induced ventricular arrhythmias and sudden death and to subsequently improve how these patients are monitored when the use of QT-prolonging and torsadogenic drugs is medically necessary.¹⁵

AN ELECTRONIC MEDICAL RECORD FLAGS QTc ≥ 500 MS

On the heels of these AHA/ACC suggestions, our hospital has adopted an institution-wide QT alert system. Here, the electronic medical record system (Centricity EMR; GE Healthcare) uses a proprietary algorithm to detect and electronically alert ordering physicians when a patient has a prolonged QT interval, and gives information about the potential clinical significance of this electrocardiographic finding.¹⁶ Physicians also receive a warning when ordering QT-prolonging drugs in patients at risk.

This system is still in its infancy, but it has already confirmed that a prolonged QT interval (QTc ≥ 500 ms) is a powerful predictor of death from any cause and has demonstrated that mortality rates in those with prolonged QT intervals increase in a dose-dependent fashion with the patient’s number of modifiable risk factors (eg, electrolyte disturbances or QT-prolonging medications) and nonmodifiable risk factors (eg, genetic disposition, female sex, structural heart disease, diabetes mellitus).¹⁶ We have also found evidence that modifiable risk factors may have a more pronounced effect on mortality risk than non-modifiable risk factors.¹⁶

These findings suggest that information technology-based QT alert systems may one day provide physicians with an important tool to efficiently identify and possibly even modify the risk of cardiovascular death in patients at high risk, for example, by correcting electrolyte abnormalities or reducing the burden of QT-prolonging medications.

CONSIDER RISK OF QT PROLONGATION WHEN PRESCRIBING AZITHROMYCIN

For most institutions and clinical practices, such electronic QT alert systems are still years if not decades away. However, in light of the information summarized above, all physicians should begin considering risk factors for QT prolongation and torsades de pointes (summarized in Table 3) and weighing the risks and benefits of prescribing azithromycin vs alternative antibiotics with minimal QT liability. This should be relatively simple to do. Things to keep in mind:

• Although azithromycin may increase the relative risk of a cardiovascular event, for most otherwise-healthy patients, the absolute risk is miniscule.
• In a patient at risk (eg, with baseline QT prolongation or multiple risk factors for it), if azithromycin or another QT-prolonging antibiotic such as a macrolide or fluoroquinolone is medically necessary due to preferential bacterial susceptibility or patient allergies, every effort should be made to correct modifiable risk factors (eg, electrolyte abnormalities) and, if possible, to avoid polypharmacy with multiple QT-prolonging drugs.
• For patients who have multiple risk factors for QT prolongation in whom treatment with a known QT-prolonging medication is still deemed in the patient’s best interest, strong consideration should be given to inpatient administration and monitoring until the treatment has been completed.

With careful consideration of modifiable and nonmodifiable risk factors as well as a little extra caution when prescribing potential QT-prolonging medications such as azithromycin, the clinical benefit of these often-advantageous medications can be maximized and the incidence of these tragic but rare drug-induced sudden cardiac deaths can be reduced.

A March 2013 warning by the US Food and Drug Administration that azithromycin (Zithromax, Zmax, Z-pak) may increase the risk of sudden cardiac death does not mean we must abandon using it. We should, however, try to determine if our patients have cardiovascular risk factors for this extreme side effect and take appropriate precautions.

AZITHROMYCIN: THE SAFEST OF THE MACROLIDES?

Azithromycin, a broad-spectrum macrolide antibiotic, is used to treat or prevent a range of common bacterial infections, including upper and lower respiratory tract infections and certain sexually transmitted diseases.

In terms of overall toxicity, azithromycin has been considered the safest of the macrolides, as it neither undergoes CYP3A4 metabolism nor inhibits CYP3A4 to any clinically meaningful degree, and therefore does not interfere with the array of commonly used medications that undergo CYP3A4 metabolism.

Also, in vitro, azithromycin shows only limited blockade of the potassium channel hERG. This channel is critically involved in cardiomyocyte repolarization, and if it is blocked or otherwise malfunctioning, the result can be a prolonged QT interval, ventricular arrhythmias, and even sudden cardiac death.^1–4 Therefore, lack of blockade, as reflected by a high inhibitory concentration (Table 1), boded well for the safety of azithromycin in terms of QT liability. However, we should be cautious in interpreting in vitro data.

With its broad antibiotic spectrum and perceived favorable safety profile, azithromycin has become one of the top 15 most prescribed drugs and the best-selling antibiotic in the United States, accounting for 55.4 million prescriptions in 2012, according to the IMS Institute for Healthcare Informatics.

THE FDA RECEIVES 203 REPORTS OF ADVERSE EVENTS IN 8 YEARS

However, beginning with a report of azithromycin-triggered torsades de pointes in 2001,⁵ a growing body of evidence, derived from postmarketing surveillance, has linked azithromycin to cardiac arrhythmias such as pronounced QT interval prolongation and associated torsades de pointes (which can progress to life-threatening ventricular fibrillation). Other, closely related macrolides such as clarithromycin and erythromycin are also linked to these effects.

Furthermore, in the 8-year period from 2004 to 2011, the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) received a total of 203 reports of azithromycin-associated QT prolongation, torsades de pointes, ventricular arrhythmia, or, in 65 cases, sudden cardiac death (Table 1).⁶

At face value, the number of FAERS reports appears to be similar between the various macrolide antibiotics. However, it is important to remember that these drugs differ substantially in the number of prescriptions written for them, with azithromycin being prescribed more often. Also, the FAERS numbers are subject to a number of well-known limitations such as confounding variables, uneven quality and completeness of reports, duplication, and underreporting. These limitations preclude the use of such adverse reporting databases in calculating and thereby comparing the true incidence of adverse events associated with the various macrolide antibiotics.^6–9

RAY ET AL FIND A HIGHER RISK OF CARDIOVASCULAR DEATH

Despite these inherent flaws, initial postmarketing surveillance reports cast enough doubt on the long-standing notion that azithromycin is the safest macrolide antibiotic to prompt Ray et al¹⁰ to assess its safety in an observational, nonrandomized study of people enrolled in the Tennessee Medicaid program.

They found that, over the typical 5 days of therapy, people taking azithromycin had a rate of cardiovascular death 2.88 times higher than in people taking no antibiotic, and 2.49 times higher than in people taking amoxicillin (Table 2).

However, the absolute excess risk compared with amoxicillin varied considerably according to baseline risk score for cardiovascular disease, with 1 excess cardiovascular death per 4,100 in the highest-risk decile compared with 1 excess cardiovascular death per 100,000 in the lowest-risk decile.^10,11

Moreover, the increase in deaths did not persist after the 5 days of therapy. This time-limited pattern directly correlated with expected peak azithromycin plasma levels during a standard 5-day course.

Ray et al used appropriate analytic methods to attempt to correct for any confounding bias intrinsic to the observational, nonrandomized study design. Nevertheless, the patients were Medicaid beneficiaries, who have a higher prevalence of comorbid conditions and higher mortality rates than the general population. Therefore, legitimate questions were raised about whether the results of the study could be generalized to populations with substantially lower baseline risk of cardiovascular disease and if differences in the baseline characteristics of the treatment groups were adequately controlled.^12,13

THE FDA REVISES AZITHROMYCIN’S WARNINGS AND PRECAUTIONS

The striking observations by Ray et al,¹⁰ coupled with the concerns raised by postmarketing surveillance reports, compelled the FDA to review the labels of azithromycin and other macrolide antibiotics.

Ultimately, the FDA opted to revise the “warning and precautions” section of the azithromycin drug label to include a warning about the potential risk of fatal arrhythmias, specifically QT interval prolongation and torsades de pointes. In a March 2013 safety announcement, it also urged health care professionals to use caution when prescribing azithromycin to patients known to have risk factors for drug-related arrhythmias, including congenital long QT syndrome, acquired QT interval prolongation, hypokalemia, hypomagnesia, bradycardia, and concurrent use of other medications known to prolong the QT interval, specifically the class IA (eg, quinidine and procainamide) and class III (eg, amiodarone, sotalol, and dofetilide) antiarrhythmics.

SVANSTRÖM ET AL FIND NO INCREASED RISK

However, just when the medical community appeared ready to accept that azithromycin may not be as safe as we thought it was, a large prospective study by Svanström et al, published in early May 2013, found no increased risk of cardiovascular death associated with azithromycin (Table 2).¹⁴

The patients were a representative population of young to middle-aged Danish adults at low baseline risk of underlying cardiovascular disease.

Interestingly, Svanström et al were careful to point out that their study was only powered to rule out a moderate-to-high (> 55%) increase in the relative risk of cardiovascular death. Furthermore, profound differences existed in the baseline risk of death and cardiovascular risk factors between their patients and the Tennessee Medicaid patients studied by Ray et al.¹⁴ Therefore, the authors suggested that their study complements rather than contradicts the study by Ray et al. They attributed the differences in the findings to treatment-effect heterogeneity, in which the risk of azithromycin-associated cardiovascular mortality is largely limited to high-risk patients, namely those with multiple preexisting cardiovascular risk factors.¹⁴

ACC/AHA RECOMMENDATION: IDENTIFY THOSE AT RISK

Collectively, the data reviewed above provide compelling evidence that azithromycin is not completely free of the QT-prolonging and torsadogenic effects that have long been associated with other macrolide antibiotics. However, the findings from both the study by Ray et al and that of Svanström et al suggest that preexisting cardiovascular risk factors play a prominent role in determining the incidence of azithromycin-associated cardiovascular death in a given population (Table 2).^10,14

These findings should prompt physicians to carefully reassess the risks and benefits of azithromycin use in their clinical practices. They also reinforce a recent call by the American Heart Association (AHA) and American College of Cardiology (ACC) to better identify, early on, patients at risk of drug-induced ventricular arrhythmias and sudden death and to subsequently improve how these patients are monitored when the use of QT-prolonging and torsadogenic drugs is medically necessary.¹⁵

AN ELECTRONIC MEDICAL RECORD FLAGS QTc ≥ 500 MS

On the heels of these AHA/ACC suggestions, our hospital has adopted an institution-wide QT alert system. Here, the electronic medical record system (Centricity EMR; GE Healthcare) uses a proprietary algorithm to detect and electronically alert ordering physicians when a patient has a prolonged QT interval, and gives information about the potential clinical significance of this electrocardiographic finding.¹⁶ Physicians also receive a warning when ordering QT-prolonging drugs in patients at risk.

This system is still in its infancy, but it has already confirmed that a prolonged QT interval (QTc ≥ 500 ms) is a powerful predictor of death from any cause and has demonstrated that mortality rates in those with prolonged QT intervals increase in a dose-dependent fashion with the patient’s number of modifiable risk factors (eg, electrolyte disturbances or QT-prolonging medications) and nonmodifiable risk factors (eg, genetic disposition, female sex, structural heart disease, diabetes mellitus).¹⁶ We have also found evidence that modifiable risk factors may have a more pronounced effect on mortality risk than non-modifiable risk factors.¹⁶

These findings suggest that information technology-based QT alert systems may one day provide physicians with an important tool to efficiently identify and possibly even modify the risk of cardiovascular death in patients at high risk, for example, by correcting electrolyte abnormalities or reducing the burden of QT-prolonging medications.

CONSIDER RISK OF QT PROLONGATION WHEN PRESCRIBING AZITHROMYCIN

For most institutions and clinical practices, such electronic QT alert systems are still years if not decades away. However, in light of the information summarized above, all physicians should begin considering risk factors for QT prolongation and torsades de pointes (summarized in Table 3) and weighing the risks and benefits of prescribing azithromycin vs alternative antibiotics with minimal QT liability. This should be relatively simple to do. Things to keep in mind:

• Although azithromycin may increase the relative risk of a cardiovascular event, for most otherwise-healthy patients, the absolute risk is miniscule.
• In a patient at risk (eg, with baseline QT prolongation or multiple risk factors for it), if azithromycin or another QT-prolonging antibiotic such as a macrolide or fluoroquinolone is medically necessary due to preferential bacterial susceptibility or patient allergies, every effort should be made to correct modifiable risk factors (eg, electrolyte abnormalities) and, if possible, to avoid polypharmacy with multiple QT-prolonging drugs.
• For patients who have multiple risk factors for QT prolongation in whom treatment with a known QT-prolonging medication is still deemed in the patient’s best interest, strong consideration should be given to inpatient administration and monitoring until the treatment has been completed.

With careful consideration of modifiable and nonmodifiable risk factors as well as a little extra caution when prescribing potential QT-prolonging medications such as azithromycin, the clinical benefit of these often-advantageous medications can be maximized and the incidence of these tragic but rare drug-induced sudden cardiac deaths can be reduced.

A March 2013 warning by the US Food and Drug Administration that azithromycin (Zithromax, Zmax, Z-pak) may increase the risk of sudden cardiac death does not mean we must abandon using it. We should, however, try to determine if our patients have cardiovascular risk factors for this extreme side effect and take appropriate precautions.

AZITHROMYCIN: THE SAFEST OF THE MACROLIDES?

Azithromycin, a broad-spectrum macrolide antibiotic, is used to treat or prevent a range of common bacterial infections, including upper and lower respiratory tract infections and certain sexually transmitted diseases.

In terms of overall toxicity, azithromycin has been considered the safest of the macrolides, as it neither undergoes CYP3A4 metabolism nor inhibits CYP3A4 to any clinically meaningful degree, and therefore does not interfere with the array of commonly used medications that undergo CYP3A4 metabolism.

Also, in vitro, azithromycin shows only limited blockade of the potassium channel hERG. This channel is critically involved in cardiomyocyte repolarization, and if it is blocked or otherwise malfunctioning, the result can be a prolonged QT interval, ventricular arrhythmias, and even sudden cardiac death.^1–4 Therefore, lack of blockade, as reflected by a high inhibitory concentration (Table 1), boded well for the safety of azithromycin in terms of QT liability. However, we should be cautious in interpreting in vitro data.

With its broad antibiotic spectrum and perceived favorable safety profile, azithromycin has become one of the top 15 most prescribed drugs and the best-selling antibiotic in the United States, accounting for 55.4 million prescriptions in 2012, according to the IMS Institute for Healthcare Informatics.

THE FDA RECEIVES 203 REPORTS OF ADVERSE EVENTS IN 8 YEARS

However, beginning with a report of azithromycin-triggered torsades de pointes in 2001,⁵ a growing body of evidence, derived from postmarketing surveillance, has linked azithromycin to cardiac arrhythmias such as pronounced QT interval prolongation and associated torsades de pointes (which can progress to life-threatening ventricular fibrillation). Other, closely related macrolides such as clarithromycin and erythromycin are also linked to these effects.

Furthermore, in the 8-year period from 2004 to 2011, the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) received a total of 203 reports of azithromycin-associated QT prolongation, torsades de pointes, ventricular arrhythmia, or, in 65 cases, sudden cardiac death (Table 1).⁶

At face value, the number of FAERS reports appears to be similar between the various macrolide antibiotics. However, it is important to remember that these drugs differ substantially in the number of prescriptions written for them, with azithromycin being prescribed more often. Also, the FAERS numbers are subject to a number of well-known limitations such as confounding variables, uneven quality and completeness of reports, duplication, and underreporting. These limitations preclude the use of such adverse reporting databases in calculating and thereby comparing the true incidence of adverse events associated with the various macrolide antibiotics.^6–9

RAY ET AL FIND A HIGHER RISK OF CARDIOVASCULAR DEATH

Despite these inherent flaws, initial postmarketing surveillance reports cast enough doubt on the long-standing notion that azithromycin is the safest macrolide antibiotic to prompt Ray et al¹⁰ to assess its safety in an observational, nonrandomized study of people enrolled in the Tennessee Medicaid program.

They found that, over the typical 5 days of therapy, people taking azithromycin had a rate of cardiovascular death 2.88 times higher than in people taking no antibiotic, and 2.49 times higher than in people taking amoxicillin (Table 2).

However, the absolute excess risk compared with amoxicillin varied considerably according to baseline risk score for cardiovascular disease, with 1 excess cardiovascular death per 4,100 in the highest-risk decile compared with 1 excess cardiovascular death per 100,000 in the lowest-risk decile.^10,11

Moreover, the increase in deaths did not persist after the 5 days of therapy. This time-limited pattern directly correlated with expected peak azithromycin plasma levels during a standard 5-day course.

Ray et al used appropriate analytic methods to attempt to correct for any confounding bias intrinsic to the observational, nonrandomized study design. Nevertheless, the patients were Medicaid beneficiaries, who have a higher prevalence of comorbid conditions and higher mortality rates than the general population. Therefore, legitimate questions were raised about whether the results of the study could be generalized to populations with substantially lower baseline risk of cardiovascular disease and if differences in the baseline characteristics of the treatment groups were adequately controlled.^12,13

THE FDA REVISES AZITHROMYCIN’S WARNINGS AND PRECAUTIONS

The striking observations by Ray et al,¹⁰ coupled with the concerns raised by postmarketing surveillance reports, compelled the FDA to review the labels of azithromycin and other macrolide antibiotics.

Ultimately, the FDA opted to revise the “warning and precautions” section of the azithromycin drug label to include a warning about the potential risk of fatal arrhythmias, specifically QT interval prolongation and torsades de pointes. In a March 2013 safety announcement, it also urged health care professionals to use caution when prescribing azithromycin to patients known to have risk factors for drug-related arrhythmias, including congenital long QT syndrome, acquired QT interval prolongation, hypokalemia, hypomagnesia, bradycardia, and concurrent use of other medications known to prolong the QT interval, specifically the class IA (eg, quinidine and procainamide) and class III (eg, amiodarone, sotalol, and dofetilide) antiarrhythmics.

SVANSTRÖM ET AL FIND NO INCREASED RISK

However, just when the medical community appeared ready to accept that azithromycin may not be as safe as we thought it was, a large prospective study by Svanström et al, published in early May 2013, found no increased risk of cardiovascular death associated with azithromycin (Table 2).¹⁴

The patients were a representative population of young to middle-aged Danish adults at low baseline risk of underlying cardiovascular disease.

Interestingly, Svanström et al were careful to point out that their study was only powered to rule out a moderate-to-high (> 55%) increase in the relative risk of cardiovascular death. Furthermore, profound differences existed in the baseline risk of death and cardiovascular risk factors between their patients and the Tennessee Medicaid patients studied by Ray et al.¹⁴ Therefore, the authors suggested that their study complements rather than contradicts the study by Ray et al. They attributed the differences in the findings to treatment-effect heterogeneity, in which the risk of azithromycin-associated cardiovascular mortality is largely limited to high-risk patients, namely those with multiple preexisting cardiovascular risk factors.¹⁴

ACC/AHA RECOMMENDATION: IDENTIFY THOSE AT RISK

Collectively, the data reviewed above provide compelling evidence that azithromycin is not completely free of the QT-prolonging and torsadogenic effects that have long been associated with other macrolide antibiotics. However, the findings from both the study by Ray et al and that of Svanström et al suggest that preexisting cardiovascular risk factors play a prominent role in determining the incidence of azithromycin-associated cardiovascular death in a given population (Table 2).^10,14

These findings should prompt physicians to carefully reassess the risks and benefits of azithromycin use in their clinical practices. They also reinforce a recent call by the American Heart Association (AHA) and American College of Cardiology (ACC) to better identify, early on, patients at risk of drug-induced ventricular arrhythmias and sudden death and to subsequently improve how these patients are monitored when the use of QT-prolonging and torsadogenic drugs is medically necessary.¹⁵

AN ELECTRONIC MEDICAL RECORD FLAGS QTc ≥ 500 MS

On the heels of these AHA/ACC suggestions, our hospital has adopted an institution-wide QT alert system. Here, the electronic medical record system (Centricity EMR; GE Healthcare) uses a proprietary algorithm to detect and electronically alert ordering physicians when a patient has a prolonged QT interval, and gives information about the potential clinical significance of this electrocardiographic finding.¹⁶ Physicians also receive a warning when ordering QT-prolonging drugs in patients at risk.

This system is still in its infancy, but it has already confirmed that a prolonged QT interval (QTc ≥ 500 ms) is a powerful predictor of death from any cause and has demonstrated that mortality rates in those with prolonged QT intervals increase in a dose-dependent fashion with the patient’s number of modifiable risk factors (eg, electrolyte disturbances or QT-prolonging medications) and nonmodifiable risk factors (eg, genetic disposition, female sex, structural heart disease, diabetes mellitus).¹⁶ We have also found evidence that modifiable risk factors may have a more pronounced effect on mortality risk than non-modifiable risk factors.¹⁶

These findings suggest that information technology-based QT alert systems may one day provide physicians with an important tool to efficiently identify and possibly even modify the risk of cardiovascular death in patients at high risk, for example, by correcting electrolyte abnormalities or reducing the burden of QT-prolonging medications.

CONSIDER RISK OF QT PROLONGATION WHEN PRESCRIBING AZITHROMYCIN

For most institutions and clinical practices, such electronic QT alert systems are still years if not decades away. However, in light of the information summarized above, all physicians should begin considering risk factors for QT prolongation and torsades de pointes (summarized in Table 3) and weighing the risks and benefits of prescribing azithromycin vs alternative antibiotics with minimal QT liability. This should be relatively simple to do. Things to keep in mind:

• Although azithromycin may increase the relative risk of a cardiovascular event, for most otherwise-healthy patients, the absolute risk is miniscule.
• In a patient at risk (eg, with baseline QT prolongation or multiple risk factors for it), if azithromycin or another QT-prolonging antibiotic such as a macrolide or fluoroquinolone is medically necessary due to preferential bacterial susceptibility or patient allergies, every effort should be made to correct modifiable risk factors (eg, electrolyte abnormalities) and, if possible, to avoid polypharmacy with multiple QT-prolonging drugs.
• For patients who have multiple risk factors for QT prolongation in whom treatment with a known QT-prolonging medication is still deemed in the patient’s best interest, strong consideration should be given to inpatient administration and monitoring until the treatment has been completed.

With careful consideration of modifiable and nonmodifiable risk factors as well as a little extra caution when prescribing potential QT-prolonging medications such as azithromycin, the clinical benefit of these often-advantageous medications can be maximized and the incidence of these tragic but rare drug-induced sudden cardiac deaths can be reduced.

“Change is the only constant.”

—Heraclitus (c 535–475 bce)

With the cost of health care rising and money to pay for it shrinking, there has never been a greater need to reduce waste.

See related article

Ineffective treatments and adverse drug effects account for much preventable morbidity and expense. New treatments, touted as more potent, are often introduced as replacements for traditional ones that are still effective in many patients, adding to costs and the potential for harm. For the pharmaceutical industry, the search for new “blockbuster” drugs seems to have hit a wall, at least in cardiovascular medicine.¹ Advances often come at the cost of adverse effects, such as bleeding with triple antiplatelet therapy and diabetes with potent statin drugs.

The path to maximizing benefit and reducing harm now appears to lie in stratifying populations and appreciating patient individuality in response to treatment. For many decades we have known that patients vary widely in their response to drugs, owing to personal factors such as body surface area, age, environment, and genetics. And indeed, we treat our patients as individuals, for example by tailoring aminoglycoside dose to weight and renal function.

However, clinical trials typically give us an idea of the benefits only to the average patient. While subgroup analyses identify groups that may benefit more or less from treatment, the additional information they provide is not easily integrated into the clinical model of prescribing, in which one size fits all.

THE PROMISE OF PHARMACOGENETICS

The emerging field of pharmacogenetics promises to give clinicians the tools to make informed treatment decisions based on predictive genetic testing. This genetic testing aims to match treatment to an individual’s genetic profile. This often involves analyzing single-nucleotide polymorphisms in genes for enzymes that metabolize drugs, such as the cytochrome P450 enzymes, to predict efficacy or an adverse event with treatment.

Pharmacogenetics is playing an increasing role in clinical trials, particularly in the early stages of drug development, by helping to reduce the number of patients needed, prove efficacy, and identify subgroups in which alternative treatment can be targeted. At another level, a molecular understanding of disease is leading to truly targeted treatments based on genomics.

Over recent years, genetic testing has been increasingly used in clinical practice, thanks to a convergence of factors such as rapid, low-cost tests, a growing evidence base, and emerging interest among doctors and payers.

An advantage to using genetic testing as opposed to other types of laboratory testing, such as measuring the concentration of the drug in the blood during treatment, is that genetic tests can predict the response to treatment before the treatment is started. Moreover, with therapeutic drug monitoring after treatment has begun, there are sometimes no detectable measures of toxicity. For example, both carbamazepine and the antiviral drug abacavir can—fortunately only rarely—cause Stevens-Johnson syndrome. But before genetic markers were discovered, there was no method of estimating this risk apart from taking a family history.^2,3 Considering the numbers of people involved, it was not feasible until recently to suggest genetic screening for patients starting on these drugs. However, the cost of genotyping and gene sequencing has been falling at a rate inversely faster than Moore’s law (an approximate annual doubling in computer power), and population genomics is becoming a reality.⁴

The US Food and Drug Administration (FDA) recognizes the current and future value of pharmacogenetics in drug safety and development. A number of approved pharmacogenetic biomarkers are listed on the FDA website (Table 1). Black box warnings have been mandated for a number of drugs on the basis of observational evidence.

The FDA also promotes rapid approval for novel drugs with pharmacogenetic “companion diagnostics.” A recent example of this was the approval of ivacaftor for cystic fibrosis patients who have the G551D mutation.⁵ Here, a molecular understanding of the condition led to the development of a targeted treatment. Although the cost of developing this drug was high, the path is now paved for similar advances. Oncologists are familiar with these advances with the emergence of new molecularly targeted treatments, eg, BRAF inhibitors in metastatic melanoma, imatinib in chronic myeloid leukemia, and gefitinib in non-small-cell lung cancer.

PHARMACOGENETICS IN CARDIOVASCULAR MEDICINE

Cardiovascular medicine also stands to benefit from rapid advances in pharmacogenetics.

While no treatment has been developed that targets the molecular basis of cardiovascular disease, a number of genomic biomarkers have emerged that identify patients at risk of adverse reactions or treatment failure. These include genetic tests to predict the maintenance dose and risk of bleeding with warfarin,⁶ the likelihood of myopathy and myositis with simvastatin,⁷ and the risk of recurrent thrombotic events with clopidogrel.^8–10

Using pharmacogenetics in prescribing warfarin and its alternatives

The pharmacogenetics of warfarin has been extensively researched, but genotyping before prescribing this drug is not yet widely done.

In 2007, the FDA updated the labeling of warfarin to include information about the influence of two genes, VKORC1 and CYP2C9, on a patient’s response to this drug. In 2010 this was updated to add that testing for these genes could be used to predict the maintenance dose of the drug. Difficulties with algorithms used to integrate this into clinical practice have hindered adoption of this testing.

With the advent of new anticoagulants such as dabigatran, rivaroxaban, and apixaban, many have expected warfarin and its pharmacogenetics to become obsolete. However, the new agents cost considerably more. Further, they may not offer a very great advantage over warfarin: in the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial, the absolute risk reduction in intracranial hemorrhage with dabigatran vs warfarin was small.¹¹ Therefore, dabigatran is probably not cost-effective in populations at low risk of bleeding.¹² A cost-effectiveness analysis comparing warfarin with dabigatran in patients with uncomplicated atrial fibrillation has suggested that dabigatran is, however, cost-effective in patients at moderate risk.¹²

In the RE-LY trial, the international normalized ratios (INRs) of the patients in the warfarin group were in the therapeutic range only 64% of the time. The advantages of dabigatran over warfarin become less pronounced as warfarin control is tightened.¹³ Of note, pharmacogenetics and home monitoring of the INR have both been shown to lead to tighter control of the INR, with greater time within the therapeutic range.^14,15

Moreover, genetic testing can help us reduce the number of bleeding events in patients taking warfarin.¹⁶ Patients who carry the CYP2C9*2 or CYP2C9*3 polymorphism metabolize S-warfarin slower and therefore have a threefold higher risk of hemorrhage after starting warfarin.¹⁷ We could speculate that patients carrying these variants may be better served by the newer anticoagulants, though this has not been tested in any clinical trial.

It is also worth appreciating that the conditions requiring anticoagulation, such as atrial fibrillation, also have a strong genetic basis. Variants in chromosomes 4q25, 1q21, and 16q22 have all been associated with atrial fibrillation.¹⁸ The risk of atrial fibrillation is five to six times higher in carriers of multiple variants within all of these loci.¹⁹ Genetic variants at 4q25 have been associated with the response to specific antiarrhythmic drug treatments,²⁰ response to pulmonary vein isolation, ^21,22 and direct-current cardioversion.²³ One can imagine a future in which patients with palpitations, carrying multiple gene risk variants, will choose prolonged monitoring at home to confirm a diagnosis. They would then be provided with a personalized best management strategy, using their personal preferences, clinical data, and genetic profile to make a treatment decision.

Using pharmacogenetics in prescribing clopidogrel and its alternatives

The pharmacogenetics of clopidogrel is of particular interest, as it has the potential of establishing a rational basis for using newer antiplatelet drugs such as ticagrelor and prasugrel, which are considerably more expensive than generic clopidogrel.

Most of the people who do not respond to clopidogrel carry the common cytochrome P450 2C19 variants CYP2C19*2 or CYP2C19*3.⁹ These variants are present in particularly high frequency in Asians and African Americans, who often do not feature in large randomized trials.

Newer antiplatelet agents have failed to demonstrate consistent superiority to clopidogrel without a tradeoff of more bleeding. However, in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 39 (TRITON TIMI-38),^24,25 patients with the *2 variant receiving prasugrel had lower cardiovascular event rates than *2 carriers receiving clopidogrel.

Similarly, the patients who benefit the most from ticagrelor are carriers of the 2C19 nonresponder variants. In a large study, clopidogrel responders who did not carry either 2C19 nonresponder genetic variants or ABCB1 variants had cardiovascular outcomes similar to those of patients receiving ticagrelor.²⁶

Clinicians have been cautious in prescribing potent antiplatelet agents to all patients because of the risk of bleeding. One could assume that by reserving newer agents for clopidogrel nonresponders, the bleeding risk could be minimized and overall benefit could be preserved with this strategy.

Cost may also be contained. The cost-effectiveness of such an approach with prasugrel has been tested with computer modeling and appears favorable.²⁷ On the other hand, a similar yet limited analysis did not find genotype-driven use of ticagrelor to be cost-effective.²⁸ This was mostly due to fewer deaths in patients receiving ticagrelor. However, the cost estimate for genotype-guided therapy was overestimated, as heterozygotes in the model were treated with ticagrelor instead of a high dose of clopidogrel.

It now appears that heterozygotes, ie, patients with one copy of the nonresponder variant, can achieve similar platelet inhibition with clopidogrel 225 mg daily as noncarriers on 75 mg daily.²⁹ Since genotype-guided antiplatelet therapy has not been tested in a randomized outcomes trial, this tailored strategy has not been widely accepted.

THE FUTURE

The barriers to adoption of pharmacogenetics are considerable. Clinicians need to be educated about it, reimbursement needs to be worked out, and the pharmaceutical industry needs to get behind it. Nevertheless, the future of pharmacogenetics is extremely promising.

Research networks are forming to support the use of pharmacogenetics in clinical practice. The Pharmgkb (www.pharmgkb.org) database serves as a hub for educating clinicians and researchers as well as curating data for reference. Vanderbilt University is piloting the BioVu project, in which DNA and genotype data on patients are being stored and matched to the electronic clinical records.³⁰ These projects not only provide clinically useful information on the current state of the art of pharmacogenetics, they also aid in disseminating new information about genotype-phenotype relationships.

Analytical software that uses “natural language processing” is being applied to clinician-generated notes to derive new observations and associations between genetic variants and clinical phenotypes. Integrating this information in real-time decision-support modules in the electronic health record provides a feedback loop for a rapid assimilation of new knowledge. Similar innovative decision-support modules are being established by Cleveland Clinic’s Center for Personalized Healthcare.³¹

The rise of ‘omic’ sciences

Pharmacogenetics and pharmacogenomics are part of a larger set of “omic” sciences. The suffix “-omics” implies a larger, more holistic view and is being applied to a number of fields—for example, the study of proteins (proteomics) and the study of metabolites (metabolomics). Profiling proteins and metabolites delivers a deluge of information on a patient that can be clustered, using pattern-recognition software, into population subgroups. Patterns of multiple proteins or metabolites are extracted from this spectral data to identify disease or response to treatment (pharmacometabolomics).

Metabolomics has been shown to predict the response to statins,³² diagnose myocardial infarction,³³ and reclassify cardiovascular risk status.³⁴ In addition, whereas traditional laboratory chemistry is reductionist, using single biomarkers for single-disease diagnosis, omic technologies hold the potential to reveal information on a number of possible health or disease states. The identification of “healthy” profiles using these technologies can potentially provide positive feedback to patients undertaking lifestyle changes and treatment.

The instrument costs for proteomic and metabolomic profiling are relatively high. However, the ongoing running costs are minimal, estimated at as low as less than $13 per test, as there are no expensive reagents.³³ High-volume testing therefore becomes very cost-effective.

Although omic science appears futuristic, proteomics and metabolomics are already used in many clinical laboratories to rapidly identify bacteria. These methods have already revolutionized the way laboratories identify microbes, since they are automated, reduce workload, and give very fast results.

The cost of genetic testing is falling

Critics of pharmacogenetics claim that the predictive value of genetic testing is poor, that evidence is lacking, and that the cost is too high. In all new technologies, the first iteration is coarse, but performance improves with use. The first major barrier is adoption. Projects like BioVu are establishing the infrastructure for a feedback loop to iteratively improve upon the status quo and provide the evidence base clinicians demand.

The cost of genetic testing is falling rapidly, with whole-genome sequencing and annotation now costing less than $5,000. The cost of a pharmacogenetic test can be as low as $100 using low-cost nanotechnology, and the test needs to be performed only once in a patient’s lifetime.²⁷

As other related molecular technologies such as proteomics and metabolomics become available and are integrated with genomics, the predictive ability of this science will improve.

AWAY FROM ONE-SIZE-FITS-ALL MEDICINE

Over the last decade there has been a trend away from “one size fits all” to customized “markets of one” in everything from consumer products to education to medicine. Mass customizing, also known as personalization, has been embraced by the internet community as a means to increase efficiency and reduce cost. This occurs by eliminating waste in redundant work or production of ineffective products.

Personalization on the Internet has been enabled through the use of informatics, mathematics, and supercomputing. The same tools that have personalized the delivery of consumer products are also being applied to the field of pharmacogenetics. Applied in an evidence-based fashion, these new technologies should profoundly improve patient care now and in the future.

“Change is the only constant.”

—Heraclitus (c 535–475 bce)

With the cost of health care rising and money to pay for it shrinking, there has never been a greater need to reduce waste.

See related article

Ineffective treatments and adverse drug effects account for much preventable morbidity and expense. New treatments, touted as more potent, are often introduced as replacements for traditional ones that are still effective in many patients, adding to costs and the potential for harm. For the pharmaceutical industry, the search for new “blockbuster” drugs seems to have hit a wall, at least in cardiovascular medicine.¹ Advances often come at the cost of adverse effects, such as bleeding with triple antiplatelet therapy and diabetes with potent statin drugs.

The path to maximizing benefit and reducing harm now appears to lie in stratifying populations and appreciating patient individuality in response to treatment. For many decades we have known that patients vary widely in their response to drugs, owing to personal factors such as body surface area, age, environment, and genetics. And indeed, we treat our patients as individuals, for example by tailoring aminoglycoside dose to weight and renal function.

However, clinical trials typically give us an idea of the benefits only to the average patient. While subgroup analyses identify groups that may benefit more or less from treatment, the additional information they provide is not easily integrated into the clinical model of prescribing, in which one size fits all.

THE PROMISE OF PHARMACOGENETICS

The emerging field of pharmacogenetics promises to give clinicians the tools to make informed treatment decisions based on predictive genetic testing. This genetic testing aims to match treatment to an individual’s genetic profile. This often involves analyzing single-nucleotide polymorphisms in genes for enzymes that metabolize drugs, such as the cytochrome P450 enzymes, to predict efficacy or an adverse event with treatment.

Pharmacogenetics is playing an increasing role in clinical trials, particularly in the early stages of drug development, by helping to reduce the number of patients needed, prove efficacy, and identify subgroups in which alternative treatment can be targeted. At another level, a molecular understanding of disease is leading to truly targeted treatments based on genomics.

Over recent years, genetic testing has been increasingly used in clinical practice, thanks to a convergence of factors such as rapid, low-cost tests, a growing evidence base, and emerging interest among doctors and payers.

An advantage to using genetic testing as opposed to other types of laboratory testing, such as measuring the concentration of the drug in the blood during treatment, is that genetic tests can predict the response to treatment before the treatment is started. Moreover, with therapeutic drug monitoring after treatment has begun, there are sometimes no detectable measures of toxicity. For example, both carbamazepine and the antiviral drug abacavir can—fortunately only rarely—cause Stevens-Johnson syndrome. But before genetic markers were discovered, there was no method of estimating this risk apart from taking a family history.^2,3 Considering the numbers of people involved, it was not feasible until recently to suggest genetic screening for patients starting on these drugs. However, the cost of genotyping and gene sequencing has been falling at a rate inversely faster than Moore’s law (an approximate annual doubling in computer power), and population genomics is becoming a reality.⁴

The US Food and Drug Administration (FDA) recognizes the current and future value of pharmacogenetics in drug safety and development. A number of approved pharmacogenetic biomarkers are listed on the FDA website (Table 1). Black box warnings have been mandated for a number of drugs on the basis of observational evidence.

The FDA also promotes rapid approval for novel drugs with pharmacogenetic “companion diagnostics.” A recent example of this was the approval of ivacaftor for cystic fibrosis patients who have the G551D mutation.⁵ Here, a molecular understanding of the condition led to the development of a targeted treatment. Although the cost of developing this drug was high, the path is now paved for similar advances. Oncologists are familiar with these advances with the emergence of new molecularly targeted treatments, eg, BRAF inhibitors in metastatic melanoma, imatinib in chronic myeloid leukemia, and gefitinib in non-small-cell lung cancer.

PHARMACOGENETICS IN CARDIOVASCULAR MEDICINE

Cardiovascular medicine also stands to benefit from rapid advances in pharmacogenetics.

While no treatment has been developed that targets the molecular basis of cardiovascular disease, a number of genomic biomarkers have emerged that identify patients at risk of adverse reactions or treatment failure. These include genetic tests to predict the maintenance dose and risk of bleeding with warfarin,⁶ the likelihood of myopathy and myositis with simvastatin,⁷ and the risk of recurrent thrombotic events with clopidogrel.^8–10

Using pharmacogenetics in prescribing warfarin and its alternatives

The pharmacogenetics of warfarin has been extensively researched, but genotyping before prescribing this drug is not yet widely done.

In 2007, the FDA updated the labeling of warfarin to include information about the influence of two genes, VKORC1 and CYP2C9, on a patient’s response to this drug. In 2010 this was updated to add that testing for these genes could be used to predict the maintenance dose of the drug. Difficulties with algorithms used to integrate this into clinical practice have hindered adoption of this testing.

With the advent of new anticoagulants such as dabigatran, rivaroxaban, and apixaban, many have expected warfarin and its pharmacogenetics to become obsolete. However, the new agents cost considerably more. Further, they may not offer a very great advantage over warfarin: in the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial, the absolute risk reduction in intracranial hemorrhage with dabigatran vs warfarin was small.¹¹ Therefore, dabigatran is probably not cost-effective in populations at low risk of bleeding.¹² A cost-effectiveness analysis comparing warfarin with dabigatran in patients with uncomplicated atrial fibrillation has suggested that dabigatran is, however, cost-effective in patients at moderate risk.¹²

In the RE-LY trial, the international normalized ratios (INRs) of the patients in the warfarin group were in the therapeutic range only 64% of the time. The advantages of dabigatran over warfarin become less pronounced as warfarin control is tightened.¹³ Of note, pharmacogenetics and home monitoring of the INR have both been shown to lead to tighter control of the INR, with greater time within the therapeutic range.^14,15

Moreover, genetic testing can help us reduce the number of bleeding events in patients taking warfarin.¹⁶ Patients who carry the CYP2C9*2 or CYP2C9*3 polymorphism metabolize S-warfarin slower and therefore have a threefold higher risk of hemorrhage after starting warfarin.¹⁷ We could speculate that patients carrying these variants may be better served by the newer anticoagulants, though this has not been tested in any clinical trial.

It is also worth appreciating that the conditions requiring anticoagulation, such as atrial fibrillation, also have a strong genetic basis. Variants in chromosomes 4q25, 1q21, and 16q22 have all been associated with atrial fibrillation.¹⁸ The risk of atrial fibrillation is five to six times higher in carriers of multiple variants within all of these loci.¹⁹ Genetic variants at 4q25 have been associated with the response to specific antiarrhythmic drug treatments,²⁰ response to pulmonary vein isolation, ^21,22 and direct-current cardioversion.²³ One can imagine a future in which patients with palpitations, carrying multiple gene risk variants, will choose prolonged monitoring at home to confirm a diagnosis. They would then be provided with a personalized best management strategy, using their personal preferences, clinical data, and genetic profile to make a treatment decision.

Using pharmacogenetics in prescribing clopidogrel and its alternatives

The pharmacogenetics of clopidogrel is of particular interest, as it has the potential of establishing a rational basis for using newer antiplatelet drugs such as ticagrelor and prasugrel, which are considerably more expensive than generic clopidogrel.

Most of the people who do not respond to clopidogrel carry the common cytochrome P450 2C19 variants CYP2C19*2 or CYP2C19*3.⁹ These variants are present in particularly high frequency in Asians and African Americans, who often do not feature in large randomized trials.

Newer antiplatelet agents have failed to demonstrate consistent superiority to clopidogrel without a tradeoff of more bleeding. However, in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 39 (TRITON TIMI-38),^24,25 patients with the *2 variant receiving prasugrel had lower cardiovascular event rates than *2 carriers receiving clopidogrel.

Similarly, the patients who benefit the most from ticagrelor are carriers of the 2C19 nonresponder variants. In a large study, clopidogrel responders who did not carry either 2C19 nonresponder genetic variants or ABCB1 variants had cardiovascular outcomes similar to those of patients receiving ticagrelor.²⁶

Clinicians have been cautious in prescribing potent antiplatelet agents to all patients because of the risk of bleeding. One could assume that by reserving newer agents for clopidogrel nonresponders, the bleeding risk could be minimized and overall benefit could be preserved with this strategy.

Cost may also be contained. The cost-effectiveness of such an approach with prasugrel has been tested with computer modeling and appears favorable.²⁷ On the other hand, a similar yet limited analysis did not find genotype-driven use of ticagrelor to be cost-effective.²⁸ This was mostly due to fewer deaths in patients receiving ticagrelor. However, the cost estimate for genotype-guided therapy was overestimated, as heterozygotes in the model were treated with ticagrelor instead of a high dose of clopidogrel.

It now appears that heterozygotes, ie, patients with one copy of the nonresponder variant, can achieve similar platelet inhibition with clopidogrel 225 mg daily as noncarriers on 75 mg daily.²⁹ Since genotype-guided antiplatelet therapy has not been tested in a randomized outcomes trial, this tailored strategy has not been widely accepted.

THE FUTURE

The barriers to adoption of pharmacogenetics are considerable. Clinicians need to be educated about it, reimbursement needs to be worked out, and the pharmaceutical industry needs to get behind it. Nevertheless, the future of pharmacogenetics is extremely promising.

Research networks are forming to support the use of pharmacogenetics in clinical practice. The Pharmgkb (www.pharmgkb.org) database serves as a hub for educating clinicians and researchers as well as curating data for reference. Vanderbilt University is piloting the BioVu project, in which DNA and genotype data on patients are being stored and matched to the electronic clinical records.³⁰ These projects not only provide clinically useful information on the current state of the art of pharmacogenetics, they also aid in disseminating new information about genotype-phenotype relationships.

Analytical software that uses “natural language processing” is being applied to clinician-generated notes to derive new observations and associations between genetic variants and clinical phenotypes. Integrating this information in real-time decision-support modules in the electronic health record provides a feedback loop for a rapid assimilation of new knowledge. Similar innovative decision-support modules are being established by Cleveland Clinic’s Center for Personalized Healthcare.³¹

The rise of ‘omic’ sciences

Pharmacogenetics and pharmacogenomics are part of a larger set of “omic” sciences. The suffix “-omics” implies a larger, more holistic view and is being applied to a number of fields—for example, the study of proteins (proteomics) and the study of metabolites (metabolomics). Profiling proteins and metabolites delivers a deluge of information on a patient that can be clustered, using pattern-recognition software, into population subgroups. Patterns of multiple proteins or metabolites are extracted from this spectral data to identify disease or response to treatment (pharmacometabolomics).

Metabolomics has been shown to predict the response to statins,³² diagnose myocardial infarction,³³ and reclassify cardiovascular risk status.³⁴ In addition, whereas traditional laboratory chemistry is reductionist, using single biomarkers for single-disease diagnosis, omic technologies hold the potential to reveal information on a number of possible health or disease states. The identification of “healthy” profiles using these technologies can potentially provide positive feedback to patients undertaking lifestyle changes and treatment.

The instrument costs for proteomic and metabolomic profiling are relatively high. However, the ongoing running costs are minimal, estimated at as low as less than $13 per test, as there are no expensive reagents.³³ High-volume testing therefore becomes very cost-effective.

Although omic science appears futuristic, proteomics and metabolomics are already used in many clinical laboratories to rapidly identify bacteria. These methods have already revolutionized the way laboratories identify microbes, since they are automated, reduce workload, and give very fast results.

The cost of genetic testing is falling

Critics of pharmacogenetics claim that the predictive value of genetic testing is poor, that evidence is lacking, and that the cost is too high. In all new technologies, the first iteration is coarse, but performance improves with use. The first major barrier is adoption. Projects like BioVu are establishing the infrastructure for a feedback loop to iteratively improve upon the status quo and provide the evidence base clinicians demand.

The cost of genetic testing is falling rapidly, with whole-genome sequencing and annotation now costing less than $5,000. The cost of a pharmacogenetic test can be as low as $100 using low-cost nanotechnology, and the test needs to be performed only once in a patient’s lifetime.²⁷

As other related molecular technologies such as proteomics and metabolomics become available and are integrated with genomics, the predictive ability of this science will improve.

AWAY FROM ONE-SIZE-FITS-ALL MEDICINE

Over the last decade there has been a trend away from “one size fits all” to customized “markets of one” in everything from consumer products to education to medicine. Mass customizing, also known as personalization, has been embraced by the internet community as a means to increase efficiency and reduce cost. This occurs by eliminating waste in redundant work or production of ineffective products.

Personalization on the Internet has been enabled through the use of informatics, mathematics, and supercomputing. The same tools that have personalized the delivery of consumer products are also being applied to the field of pharmacogenetics. Applied in an evidence-based fashion, these new technologies should profoundly improve patient care now and in the future.

“Change is the only constant.”

—Heraclitus (c 535–475 bce)

With the cost of health care rising and money to pay for it shrinking, there has never been a greater need to reduce waste.

See related article

Ineffective treatments and adverse drug effects account for much preventable morbidity and expense. New treatments, touted as more potent, are often introduced as replacements for traditional ones that are still effective in many patients, adding to costs and the potential for harm. For the pharmaceutical industry, the search for new “blockbuster” drugs seems to have hit a wall, at least in cardiovascular medicine.¹ Advances often come at the cost of adverse effects, such as bleeding with triple antiplatelet therapy and diabetes with potent statin drugs.

The path to maximizing benefit and reducing harm now appears to lie in stratifying populations and appreciating patient individuality in response to treatment. For many decades we have known that patients vary widely in their response to drugs, owing to personal factors such as body surface area, age, environment, and genetics. And indeed, we treat our patients as individuals, for example by tailoring aminoglycoside dose to weight and renal function.

However, clinical trials typically give us an idea of the benefits only to the average patient. While subgroup analyses identify groups that may benefit more or less from treatment, the additional information they provide is not easily integrated into the clinical model of prescribing, in which one size fits all.

THE PROMISE OF PHARMACOGENETICS

The emerging field of pharmacogenetics promises to give clinicians the tools to make informed treatment decisions based on predictive genetic testing. This genetic testing aims to match treatment to an individual’s genetic profile. This often involves analyzing single-nucleotide polymorphisms in genes for enzymes that metabolize drugs, such as the cytochrome P450 enzymes, to predict efficacy or an adverse event with treatment.

Pharmacogenetics is playing an increasing role in clinical trials, particularly in the early stages of drug development, by helping to reduce the number of patients needed, prove efficacy, and identify subgroups in which alternative treatment can be targeted. At another level, a molecular understanding of disease is leading to truly targeted treatments based on genomics.

Over recent years, genetic testing has been increasingly used in clinical practice, thanks to a convergence of factors such as rapid, low-cost tests, a growing evidence base, and emerging interest among doctors and payers.

An advantage to using genetic testing as opposed to other types of laboratory testing, such as measuring the concentration of the drug in the blood during treatment, is that genetic tests can predict the response to treatment before the treatment is started. Moreover, with therapeutic drug monitoring after treatment has begun, there are sometimes no detectable measures of toxicity. For example, both carbamazepine and the antiviral drug abacavir can—fortunately only rarely—cause Stevens-Johnson syndrome. But before genetic markers were discovered, there was no method of estimating this risk apart from taking a family history.^2,3 Considering the numbers of people involved, it was not feasible until recently to suggest genetic screening for patients starting on these drugs. However, the cost of genotyping and gene sequencing has been falling at a rate inversely faster than Moore’s law (an approximate annual doubling in computer power), and population genomics is becoming a reality.⁴

The US Food and Drug Administration (FDA) recognizes the current and future value of pharmacogenetics in drug safety and development. A number of approved pharmacogenetic biomarkers are listed on the FDA website (Table 1). Black box warnings have been mandated for a number of drugs on the basis of observational evidence.

The FDA also promotes rapid approval for novel drugs with pharmacogenetic “companion diagnostics.” A recent example of this was the approval of ivacaftor for cystic fibrosis patients who have the G551D mutation.⁵ Here, a molecular understanding of the condition led to the development of a targeted treatment. Although the cost of developing this drug was high, the path is now paved for similar advances. Oncologists are familiar with these advances with the emergence of new molecularly targeted treatments, eg, BRAF inhibitors in metastatic melanoma, imatinib in chronic myeloid leukemia, and gefitinib in non-small-cell lung cancer.

PHARMACOGENETICS IN CARDIOVASCULAR MEDICINE

Cardiovascular medicine also stands to benefit from rapid advances in pharmacogenetics.

While no treatment has been developed that targets the molecular basis of cardiovascular disease, a number of genomic biomarkers have emerged that identify patients at risk of adverse reactions or treatment failure. These include genetic tests to predict the maintenance dose and risk of bleeding with warfarin,⁶ the likelihood of myopathy and myositis with simvastatin,⁷ and the risk of recurrent thrombotic events with clopidogrel.^8–10

Using pharmacogenetics in prescribing warfarin and its alternatives

The pharmacogenetics of warfarin has been extensively researched, but genotyping before prescribing this drug is not yet widely done.

In 2007, the FDA updated the labeling of warfarin to include information about the influence of two genes, VKORC1 and CYP2C9, on a patient’s response to this drug. In 2010 this was updated to add that testing for these genes could be used to predict the maintenance dose of the drug. Difficulties with algorithms used to integrate this into clinical practice have hindered adoption of this testing.

With the advent of new anticoagulants such as dabigatran, rivaroxaban, and apixaban, many have expected warfarin and its pharmacogenetics to become obsolete. However, the new agents cost considerably more. Further, they may not offer a very great advantage over warfarin: in the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial, the absolute risk reduction in intracranial hemorrhage with dabigatran vs warfarin was small.¹¹ Therefore, dabigatran is probably not cost-effective in populations at low risk of bleeding.¹² A cost-effectiveness analysis comparing warfarin with dabigatran in patients with uncomplicated atrial fibrillation has suggested that dabigatran is, however, cost-effective in patients at moderate risk.¹²

In the RE-LY trial, the international normalized ratios (INRs) of the patients in the warfarin group were in the therapeutic range only 64% of the time. The advantages of dabigatran over warfarin become less pronounced as warfarin control is tightened.¹³ Of note, pharmacogenetics and home monitoring of the INR have both been shown to lead to tighter control of the INR, with greater time within the therapeutic range.^14,15

Moreover, genetic testing can help us reduce the number of bleeding events in patients taking warfarin.¹⁶ Patients who carry the CYP2C9*2 or CYP2C9*3 polymorphism metabolize S-warfarin slower and therefore have a threefold higher risk of hemorrhage after starting warfarin.¹⁷ We could speculate that patients carrying these variants may be better served by the newer anticoagulants, though this has not been tested in any clinical trial.

It is also worth appreciating that the conditions requiring anticoagulation, such as atrial fibrillation, also have a strong genetic basis. Variants in chromosomes 4q25, 1q21, and 16q22 have all been associated with atrial fibrillation.¹⁸ The risk of atrial fibrillation is five to six times higher in carriers of multiple variants within all of these loci.¹⁹ Genetic variants at 4q25 have been associated with the response to specific antiarrhythmic drug treatments,²⁰ response to pulmonary vein isolation, ^21,22 and direct-current cardioversion.²³ One can imagine a future in which patients with palpitations, carrying multiple gene risk variants, will choose prolonged monitoring at home to confirm a diagnosis. They would then be provided with a personalized best management strategy, using their personal preferences, clinical data, and genetic profile to make a treatment decision.

Using pharmacogenetics in prescribing clopidogrel and its alternatives

The pharmacogenetics of clopidogrel is of particular interest, as it has the potential of establishing a rational basis for using newer antiplatelet drugs such as ticagrelor and prasugrel, which are considerably more expensive than generic clopidogrel.

Most of the people who do not respond to clopidogrel carry the common cytochrome P450 2C19 variants CYP2C19*2 or CYP2C19*3.⁹ These variants are present in particularly high frequency in Asians and African Americans, who often do not feature in large randomized trials.

Newer antiplatelet agents have failed to demonstrate consistent superiority to clopidogrel without a tradeoff of more bleeding. However, in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 39 (TRITON TIMI-38),^24,25 patients with the *2 variant receiving prasugrel had lower cardiovascular event rates than *2 carriers receiving clopidogrel.

Similarly, the patients who benefit the most from ticagrelor are carriers of the 2C19 nonresponder variants. In a large study, clopidogrel responders who did not carry either 2C19 nonresponder genetic variants or ABCB1 variants had cardiovascular outcomes similar to those of patients receiving ticagrelor.²⁶

Clinicians have been cautious in prescribing potent antiplatelet agents to all patients because of the risk of bleeding. One could assume that by reserving newer agents for clopidogrel nonresponders, the bleeding risk could be minimized and overall benefit could be preserved with this strategy.

Cost may also be contained. The cost-effectiveness of such an approach with prasugrel has been tested with computer modeling and appears favorable.²⁷ On the other hand, a similar yet limited analysis did not find genotype-driven use of ticagrelor to be cost-effective.²⁸ This was mostly due to fewer deaths in patients receiving ticagrelor. However, the cost estimate for genotype-guided therapy was overestimated, as heterozygotes in the model were treated with ticagrelor instead of a high dose of clopidogrel.

It now appears that heterozygotes, ie, patients with one copy of the nonresponder variant, can achieve similar platelet inhibition with clopidogrel 225 mg daily as noncarriers on 75 mg daily.²⁹ Since genotype-guided antiplatelet therapy has not been tested in a randomized outcomes trial, this tailored strategy has not been widely accepted.

THE FUTURE

The barriers to adoption of pharmacogenetics are considerable. Clinicians need to be educated about it, reimbursement needs to be worked out, and the pharmaceutical industry needs to get behind it. Nevertheless, the future of pharmacogenetics is extremely promising.

Research networks are forming to support the use of pharmacogenetics in clinical practice. The Pharmgkb (www.pharmgkb.org) database serves as a hub for educating clinicians and researchers as well as curating data for reference. Vanderbilt University is piloting the BioVu project, in which DNA and genotype data on patients are being stored and matched to the electronic clinical records.³⁰ These projects not only provide clinically useful information on the current state of the art of pharmacogenetics, they also aid in disseminating new information about genotype-phenotype relationships.

Analytical software that uses “natural language processing” is being applied to clinician-generated notes to derive new observations and associations between genetic variants and clinical phenotypes. Integrating this information in real-time decision-support modules in the electronic health record provides a feedback loop for a rapid assimilation of new knowledge. Similar innovative decision-support modules are being established by Cleveland Clinic’s Center for Personalized Healthcare.³¹

The rise of ‘omic’ sciences

Pharmacogenetics and pharmacogenomics are part of a larger set of “omic” sciences. The suffix “-omics” implies a larger, more holistic view and is being applied to a number of fields—for example, the study of proteins (proteomics) and the study of metabolites (metabolomics). Profiling proteins and metabolites delivers a deluge of information on a patient that can be clustered, using pattern-recognition software, into population subgroups. Patterns of multiple proteins or metabolites are extracted from this spectral data to identify disease or response to treatment (pharmacometabolomics).

Metabolomics has been shown to predict the response to statins,³² diagnose myocardial infarction,³³ and reclassify cardiovascular risk status.³⁴ In addition, whereas traditional laboratory chemistry is reductionist, using single biomarkers for single-disease diagnosis, omic technologies hold the potential to reveal information on a number of possible health or disease states. The identification of “healthy” profiles using these technologies can potentially provide positive feedback to patients undertaking lifestyle changes and treatment.

The instrument costs for proteomic and metabolomic profiling are relatively high. However, the ongoing running costs are minimal, estimated at as low as less than $13 per test, as there are no expensive reagents.³³ High-volume testing therefore becomes very cost-effective.

Although omic science appears futuristic, proteomics and metabolomics are already used in many clinical laboratories to rapidly identify bacteria. These methods have already revolutionized the way laboratories identify microbes, since they are automated, reduce workload, and give very fast results.

The cost of genetic testing is falling

Critics of pharmacogenetics claim that the predictive value of genetic testing is poor, that evidence is lacking, and that the cost is too high. In all new technologies, the first iteration is coarse, but performance improves with use. The first major barrier is adoption. Projects like BioVu are establishing the infrastructure for a feedback loop to iteratively improve upon the status quo and provide the evidence base clinicians demand.

The cost of genetic testing is falling rapidly, with whole-genome sequencing and annotation now costing less than $5,000. The cost of a pharmacogenetic test can be as low as $100 using low-cost nanotechnology, and the test needs to be performed only once in a patient’s lifetime.²⁷

As other related molecular technologies such as proteomics and metabolomics become available and are integrated with genomics, the predictive ability of this science will improve.

AWAY FROM ONE-SIZE-FITS-ALL MEDICINE

Over the last decade there has been a trend away from “one size fits all” to customized “markets of one” in everything from consumer products to education to medicine. Mass customizing, also known as personalization, has been embraced by the internet community as a means to increase efficiency and reduce cost. This occurs by eliminating waste in redundant work or production of ineffective products.

Personalization on the Internet has been enabled through the use of informatics, mathematics, and supercomputing. The same tools that have personalized the delivery of consumer products are also being applied to the field of pharmacogenetics. Applied in an evidence-based fashion, these new technologies should profoundly improve patient care now and in the future.

The answer is not clear. There is evidence in favor of pharmacogenetic testing, but not yet enough to strongly recommend it. However, we do believe that physicians should consider it when starting patients on warfarin therapy.

See related commentary

WARFARIN HAS A NARROW THERAPEUTIC WINDOW

Although newer drugs are available, warfarin is still the most commonly used oral anticoagulant for preventing and treating thromboembolism.¹ It is highly effective but has a narrow therapeutic window and wide interindividual variability in dosage requirements, which poses challenges to achieving adequate anticoagulation.^1–3 Inappropriate dosing contributes to a high rate of bleeding events and emergency room visits.⁴

Warfarin is monitored using the prothrombin time. Because the prothrombin time varies depending on the assay used, the standardized value called the international normalized ratio (INR) is more commonly used.

Clinical factors such as age, body size, and drug interactions affect warfarin dosage requirements and are important to consider,⁵ even though they account for only 15% to 20% of the variability in warfarin dose.⁶

Genetic factors also affect warfarin dosage requirements. The combination of genetic and clinical factors accounts for up to 47% of the dose variability.⁷

GENES THAT AFFECT WARFARIN

Several genes are known to influence warfarin’s pharmacokinetics and pharmacodynamics. Of these, the two most clinically relevant and well studied are CYP2C9 (which codes for cytochrome P450 2C9) and VKORC1 (which codes for vitamin K epoxide reductase).⁷ These genes are polymorphic, with some variants producing less-active enzymes that allow warfarin to be more active. Therefore, patients who carry these variants need lower doses of this drug (see below).

CYP2C9 variants

The CYP2C9 gene has several variants. Of these, CYP2C9*2 and CYP2C9*3 are associated with the lowest enzyme activity.

Patients with either of these variants require significantly lower warfarin doses to reach therapeutic levels than those with the wild-type gene (ie, CYP2C9*1). CYP2C9*2 reduces warfarin clearance by 40%, and the CYP2C9*3 variant reduces it by 75%.⁷ Having a *2 or *3 allele increases the risk of bleeding during warfarin therapy and the time needed to achieve a stable dose.⁸ Other variants associated with lower warfarin dose requirements are *5, *6, and *11.

The prevalence of these variants is significantly higher in people of European ancestry (roughly one-third) than in Asian people and African Americans,⁷ although no one has recommended not testing in these low-prevalence populations. Limdi et al⁹ reported that by including the *5, *6, and *11 variants in genetic testing (in addition to *2 and *3), they could identify more African Americans (9.7%) who carried at least one of these abnormal variants than reported previously. Differences among ethnic groups need to be taken into account when interpreting pharmacogenetic studies.

VKORC1 variants

Patients also need lower doses of warfarin if they carry the VKORC1 −1639G>A variant, and they spend more time with an INR above the therapeutic range and have higher overall INR values. However, having this variant does not appear to increase the risk of bleeding.

The −1639G>A variant is the most common variant of VKORC1. Rarer ones have also been described, but most commercially available tests do not detect them.

Racial differences exist in the prevalence rates of the various VKORC1 polymorphisms, with the most sensitive (low-dose) genotype predominating in Asians and the least sensitive (high-dose) genotype predominating in African Americans. Over 50% of people of European ancestry carry the intermediate-sensitivity genotype (typical dose).⁷

CURRENT RECOMMENDATIONS FOR OR AGAINST TESTING

FDA labeling

In 2007, the US Food and Drug Administration (FDA) required that the warfarin package insert carry information about initial dosing based on CYP2C9 and VKORC1 testing. This recommendation was revised in 2010 to include a table to help clinicians select an initial warfarin dose if CYP2C9 and VKORC1 genotype information is available. However, the FDA does not require pharmacogenetic testing, leaving the decision to the discretion of the clinician.⁷

American College of Chest Physicians

The American College of Chest Physicians recommends against routine pharmacogenetic testing (grade 1B) because of a lack of evidence that it improves clinical end points or that it is cost-effective.⁵

WHAT EVIDENCE SUPORTS GENETIC TESTING TO GUIDE WARFARIN THERAPY?

To date, no large randomized, controlled trial has been published that looked at clinical outcomes with warfarin dosing based on pharmacogenetic testing. However, several smaller studies have suggested it is beneficial.

One trial found that when dosing was informed by pharmacogenetic testing, patients had significantly more time in the therapeutic range, a lower percentage of INRs greater than 4 or less than 1.5, and fewer serious adverse events (death, myocardial infarction, stroke, thromboembolism, and clinically significant bleeding events).¹⁰ Patients whose dosage was determined using pharmacogenetic algorithms as opposed to traditional clinical algorithms maintained a therapeutic INR more consistently.¹¹

In addition, compared with historical controls, patients whose physician used pharmacogenetic testing to guide warfarin dosing had a rate of hospitalization 31% lower and a rate of hospitalization specifically for bleeding or thromboembolism 28% lower during 6 months of follow-up.^12,13

Several studies have attempted to assess the cost-effectiveness and utility of pharmacogenetic testing in warfarin therapy. As yet, the results have been inconclusive.¹⁴ Larger prospective trials are under way and are estimated to be completed in late 2013.¹⁵ These include:

• COAG (Clarification of Optimal Anticoagulation Through Genetics)
• GIFT (Genetics Informatics Trial of Warfarin to Prevent Venous Thrombosis)
• EU-PACT (European Pharmacogenetics of Anticoagulant Therapy-Warfarin).

We hope these studies will provide greater clarity on the clinical utility and cost-effectiveness of pharmacogenetic testing to guide warfarin dosing.

HOW SHOULD GENETIC INFORMATION BE USED TO GUIDE OR ALTER THERAPY?

Algorithms are available for estimating initial and maintenance warfarin doses based on genetic information (CYP2C9 and VKORC1), race or ethnicity, age, sex, body mass index, smoking status, and other medications taken. In addition, models incorporating the INR on day 4 and days 6 to 11 have been developed for dose refinement.¹⁵ The algorithms explain 30% to 60% of the variability of the data, with lower values for African Americans.⁷

A well-developed dosing model that includes traditional clinical factors and patient genetic status is publicly available online at www.warfarindosing.org.⁴

CPIC: A leader in applied pharmacogenetics

In late 2009, PharmGKB joined forces with the Pharmacogenomics Research Network of the National Institutes of Health to form the Clinical Pharmacogenetics Implementation Consortium (CPIC). This organization issues guidelines that are written by expert clinicians and scientists and then are peer-reviewed, published in leading journals, and simultaneously posted to the PharmGKB website along with supplemental information and updates.

CPIC’s goal is to review the current evidence and to address barriers to the adoption of pharmacogenetic testing into clinical practice. Its guidelines do not advise when or which pharmacogenetic tests should be ordered. Rather, they provide guidance on interpreting and applying such testing, should the test results be available.⁷

CPIC has guidelines on CYP2C9 and VKORC1 genotypes and warfarin dosing.⁸ If a patient’s genetic information is available, CPIC strongly recommends the use of pharmacogenetic algorithm-based dosing. If such an algorithm is not accessible, use of a genotype dosing table is recommended.⁸

Monitoring is still needed

Many factors can affect an individual’s response to warfarin above and beyond the above-noted clinical and genetic traits. These include diet, concomitant medications (both prescription and over-the-counter and herbal), and disease state. There may also be additional genetic polymorphisms not yet identified in various racial and ethnic groups that may affect dosing requirements. And as with all medications, patient compliance and dosing errors have a large potential to affect individual response. Therefore, clinicians should still be diligent about clinical monitoring.¹⁵

Most useful for initial dose

As with most pharmacogenetic information, the greatest benefit can be achieved when this information is used to guide the initial dose, although there is also some effect noted when this information is known and acted upon into the 2nd week of treatment.⁸

Patients on long-term warfarin treatment with stable doses and those unable to achieve stable dosing because of variable adherence or dietary vitamin K intake are less likely to benefit from genetic testing.

There are no published guidelines on the utility of pharmacogenetic testing if a patient is already on a stable dose of warfarin or has a known historical stable dose. There are also no published guidelines on changing the frequency of monitoring based on known genotype.

In children, the data are sparse at this time regarding the utility of pharmacogenetically informed dosing.

HOW DOES ONE ORDER TESTING, AND WHAT IS THE COST?

The FDA has approved four warfarin pharmacogenetic test kits. To be used in clinical decision-making, these tests must be done in a laboratory certified by the Clinical Laboratory Improvement Amendments (CLIA) program.

Testing typically costs a few hundred dollars and may take days for results to be returned if not available on site.¹⁵ At Cleveland Clinic, CYP2C9 and VKORC1 testing can be run in-house at a cost of about $700. Generally, many third-party payers do not reimburse for testing without a prior-approval process.

TO TEST OR NOT TO TEST

Pharmacogenetic testing is available and may help optimize warfarin dosing early in treatment, as well as help maintain therapeutic INRs more consistently. There is preliminary evidence that using this information to guide dosing improves clinical outcomes. Several large trials are under way to address additional questions of clinical utility, with results expected in the next year. There are also readily available decision-support tools to guide therapeutic dosing, and when pharmacogenetic test results are available, utilization of a warfarin dosing algorithm is recommended.

The largest barrier remaining appears to be cost (relative to perceived benefit), and until larger trials of clinical utility and cost-effectiveness are completed and analyzed, hurdles exist to obtaining coverage for such testing.

If it is readily available (and can be paid for by insurance companies or out-of-pocket) and test results can be obtained within 24 to 48 hours or before prescribing, pharmacogenetic testing can be a valuable tool to guide and manage warfarin dosing. Particularly for patients who want to be as proactive as possible, warfarin pharmacogenetic testing offers the ability to participate in this decision-making and to potentially reduce their risk of adverse drug events. And in view of the evidence and FDA recommendations, we propose that the discussion with our patients is not whether we should consider pharmacogenetic testing, but that we have considered pharmacogenetic testing, and why we have decided for or against it.

The answer is not clear. There is evidence in favor of pharmacogenetic testing, but not yet enough to strongly recommend it. However, we do believe that physicians should consider it when starting patients on warfarin therapy.

See related commentary

WARFARIN HAS A NARROW THERAPEUTIC WINDOW

Although newer drugs are available, warfarin is still the most commonly used oral anticoagulant for preventing and treating thromboembolism.¹ It is highly effective but has a narrow therapeutic window and wide interindividual variability in dosage requirements, which poses challenges to achieving adequate anticoagulation.^1–3 Inappropriate dosing contributes to a high rate of bleeding events and emergency room visits.⁴

Warfarin is monitored using the prothrombin time. Because the prothrombin time varies depending on the assay used, the standardized value called the international normalized ratio (INR) is more commonly used.

Clinical factors such as age, body size, and drug interactions affect warfarin dosage requirements and are important to consider,⁵ even though they account for only 15% to 20% of the variability in warfarin dose.⁶

Genetic factors also affect warfarin dosage requirements. The combination of genetic and clinical factors accounts for up to 47% of the dose variability.⁷

GENES THAT AFFECT WARFARIN

Several genes are known to influence warfarin’s pharmacokinetics and pharmacodynamics. Of these, the two most clinically relevant and well studied are CYP2C9 (which codes for cytochrome P450 2C9) and VKORC1 (which codes for vitamin K epoxide reductase).⁷ These genes are polymorphic, with some variants producing less-active enzymes that allow warfarin to be more active. Therefore, patients who carry these variants need lower doses of this drug (see below).

CYP2C9 variants

The CYP2C9 gene has several variants. Of these, CYP2C9*2 and CYP2C9*3 are associated with the lowest enzyme activity.

Patients with either of these variants require significantly lower warfarin doses to reach therapeutic levels than those with the wild-type gene (ie, CYP2C9*1). CYP2C9*2 reduces warfarin clearance by 40%, and the CYP2C9*3 variant reduces it by 75%.⁷ Having a *2 or *3 allele increases the risk of bleeding during warfarin therapy and the time needed to achieve a stable dose.⁸ Other variants associated with lower warfarin dose requirements are *5, *6, and *11.

The prevalence of these variants is significantly higher in people of European ancestry (roughly one-third) than in Asian people and African Americans,⁷ although no one has recommended not testing in these low-prevalence populations. Limdi et al⁹ reported that by including the *5, *6, and *11 variants in genetic testing (in addition to *2 and *3), they could identify more African Americans (9.7%) who carried at least one of these abnormal variants than reported previously. Differences among ethnic groups need to be taken into account when interpreting pharmacogenetic studies.

VKORC1 variants

Patients also need lower doses of warfarin if they carry the VKORC1 −1639G>A variant, and they spend more time with an INR above the therapeutic range and have higher overall INR values. However, having this variant does not appear to increase the risk of bleeding.

The −1639G>A variant is the most common variant of VKORC1. Rarer ones have also been described, but most commercially available tests do not detect them.

Racial differences exist in the prevalence rates of the various VKORC1 polymorphisms, with the most sensitive (low-dose) genotype predominating in Asians and the least sensitive (high-dose) genotype predominating in African Americans. Over 50% of people of European ancestry carry the intermediate-sensitivity genotype (typical dose).⁷

CURRENT RECOMMENDATIONS FOR OR AGAINST TESTING

FDA labeling

In 2007, the US Food and Drug Administration (FDA) required that the warfarin package insert carry information about initial dosing based on CYP2C9 and VKORC1 testing. This recommendation was revised in 2010 to include a table to help clinicians select an initial warfarin dose if CYP2C9 and VKORC1 genotype information is available. However, the FDA does not require pharmacogenetic testing, leaving the decision to the discretion of the clinician.⁷

American College of Chest Physicians

The American College of Chest Physicians recommends against routine pharmacogenetic testing (grade 1B) because of a lack of evidence that it improves clinical end points or that it is cost-effective.⁵

WHAT EVIDENCE SUPORTS GENETIC TESTING TO GUIDE WARFARIN THERAPY?

To date, no large randomized, controlled trial has been published that looked at clinical outcomes with warfarin dosing based on pharmacogenetic testing. However, several smaller studies have suggested it is beneficial.

One trial found that when dosing was informed by pharmacogenetic testing, patients had significantly more time in the therapeutic range, a lower percentage of INRs greater than 4 or less than 1.5, and fewer serious adverse events (death, myocardial infarction, stroke, thromboembolism, and clinically significant bleeding events).¹⁰ Patients whose dosage was determined using pharmacogenetic algorithms as opposed to traditional clinical algorithms maintained a therapeutic INR more consistently.¹¹

In addition, compared with historical controls, patients whose physician used pharmacogenetic testing to guide warfarin dosing had a rate of hospitalization 31% lower and a rate of hospitalization specifically for bleeding or thromboembolism 28% lower during 6 months of follow-up.^12,13

Several studies have attempted to assess the cost-effectiveness and utility of pharmacogenetic testing in warfarin therapy. As yet, the results have been inconclusive.¹⁴ Larger prospective trials are under way and are estimated to be completed in late 2013.¹⁵ These include:

• COAG (Clarification of Optimal Anticoagulation Through Genetics)
• GIFT (Genetics Informatics Trial of Warfarin to Prevent Venous Thrombosis)
• EU-PACT (European Pharmacogenetics of Anticoagulant Therapy-Warfarin).

We hope these studies will provide greater clarity on the clinical utility and cost-effectiveness of pharmacogenetic testing to guide warfarin dosing.

HOW SHOULD GENETIC INFORMATION BE USED TO GUIDE OR ALTER THERAPY?

Algorithms are available for estimating initial and maintenance warfarin doses based on genetic information (CYP2C9 and VKORC1), race or ethnicity, age, sex, body mass index, smoking status, and other medications taken. In addition, models incorporating the INR on day 4 and days 6 to 11 have been developed for dose refinement.¹⁵ The algorithms explain 30% to 60% of the variability of the data, with lower values for African Americans.⁷

A well-developed dosing model that includes traditional clinical factors and patient genetic status is publicly available online at www.warfarindosing.org.⁴

CPIC: A leader in applied pharmacogenetics

In late 2009, PharmGKB joined forces with the Pharmacogenomics Research Network of the National Institutes of Health to form the Clinical Pharmacogenetics Implementation Consortium (CPIC). This organization issues guidelines that are written by expert clinicians and scientists and then are peer-reviewed, published in leading journals, and simultaneously posted to the PharmGKB website along with supplemental information and updates.

CPIC’s goal is to review the current evidence and to address barriers to the adoption of pharmacogenetic testing into clinical practice. Its guidelines do not advise when or which pharmacogenetic tests should be ordered. Rather, they provide guidance on interpreting and applying such testing, should the test results be available.⁷

CPIC has guidelines on CYP2C9 and VKORC1 genotypes and warfarin dosing.⁸ If a patient’s genetic information is available, CPIC strongly recommends the use of pharmacogenetic algorithm-based dosing. If such an algorithm is not accessible, use of a genotype dosing table is recommended.⁸

Monitoring is still needed

Many factors can affect an individual’s response to warfarin above and beyond the above-noted clinical and genetic traits. These include diet, concomitant medications (both prescription and over-the-counter and herbal), and disease state. There may also be additional genetic polymorphisms not yet identified in various racial and ethnic groups that may affect dosing requirements. And as with all medications, patient compliance and dosing errors have a large potential to affect individual response. Therefore, clinicians should still be diligent about clinical monitoring.¹⁵

Most useful for initial dose

As with most pharmacogenetic information, the greatest benefit can be achieved when this information is used to guide the initial dose, although there is also some effect noted when this information is known and acted upon into the 2nd week of treatment.⁸

Patients on long-term warfarin treatment with stable doses and those unable to achieve stable dosing because of variable adherence or dietary vitamin K intake are less likely to benefit from genetic testing.

There are no published guidelines on the utility of pharmacogenetic testing if a patient is already on a stable dose of warfarin or has a known historical stable dose. There are also no published guidelines on changing the frequency of monitoring based on known genotype.

In children, the data are sparse at this time regarding the utility of pharmacogenetically informed dosing.

HOW DOES ONE ORDER TESTING, AND WHAT IS THE COST?

The FDA has approved four warfarin pharmacogenetic test kits. To be used in clinical decision-making, these tests must be done in a laboratory certified by the Clinical Laboratory Improvement Amendments (CLIA) program.

Testing typically costs a few hundred dollars and may take days for results to be returned if not available on site.¹⁵ At Cleveland Clinic, CYP2C9 and VKORC1 testing can be run in-house at a cost of about $700. Generally, many third-party payers do not reimburse for testing without a prior-approval process.

TO TEST OR NOT TO TEST

Pharmacogenetic testing is available and may help optimize warfarin dosing early in treatment, as well as help maintain therapeutic INRs more consistently. There is preliminary evidence that using this information to guide dosing improves clinical outcomes. Several large trials are under way to address additional questions of clinical utility, with results expected in the next year. There are also readily available decision-support tools to guide therapeutic dosing, and when pharmacogenetic test results are available, utilization of a warfarin dosing algorithm is recommended.

The largest barrier remaining appears to be cost (relative to perceived benefit), and until larger trials of clinical utility and cost-effectiveness are completed and analyzed, hurdles exist to obtaining coverage for such testing.

If it is readily available (and can be paid for by insurance companies or out-of-pocket) and test results can be obtained within 24 to 48 hours or before prescribing, pharmacogenetic testing can be a valuable tool to guide and manage warfarin dosing. Particularly for patients who want to be as proactive as possible, warfarin pharmacogenetic testing offers the ability to participate in this decision-making and to potentially reduce their risk of adverse drug events. And in view of the evidence and FDA recommendations, we propose that the discussion with our patients is not whether we should consider pharmacogenetic testing, but that we have considered pharmacogenetic testing, and why we have decided for or against it.

The answer is not clear. There is evidence in favor of pharmacogenetic testing, but not yet enough to strongly recommend it. However, we do believe that physicians should consider it when starting patients on warfarin therapy.

See related commentary

WARFARIN HAS A NARROW THERAPEUTIC WINDOW

Although newer drugs are available, warfarin is still the most commonly used oral anticoagulant for preventing and treating thromboembolism.¹ It is highly effective but has a narrow therapeutic window and wide interindividual variability in dosage requirements, which poses challenges to achieving adequate anticoagulation.^1–3 Inappropriate dosing contributes to a high rate of bleeding events and emergency room visits.⁴

Warfarin is monitored using the prothrombin time. Because the prothrombin time varies depending on the assay used, the standardized value called the international normalized ratio (INR) is more commonly used.

Clinical factors such as age, body size, and drug interactions affect warfarin dosage requirements and are important to consider,⁵ even though they account for only 15% to 20% of the variability in warfarin dose.⁶

Genetic factors also affect warfarin dosage requirements. The combination of genetic and clinical factors accounts for up to 47% of the dose variability.⁷

GENES THAT AFFECT WARFARIN

Several genes are known to influence warfarin’s pharmacokinetics and pharmacodynamics. Of these, the two most clinically relevant and well studied are CYP2C9 (which codes for cytochrome P450 2C9) and VKORC1 (which codes for vitamin K epoxide reductase).⁷ These genes are polymorphic, with some variants producing less-active enzymes that allow warfarin to be more active. Therefore, patients who carry these variants need lower doses of this drug (see below).

CYP2C9 variants

The CYP2C9 gene has several variants. Of these, CYP2C9*2 and CYP2C9*3 are associated with the lowest enzyme activity.

Patients with either of these variants require significantly lower warfarin doses to reach therapeutic levels than those with the wild-type gene (ie, CYP2C9*1). CYP2C9*2 reduces warfarin clearance by 40%, and the CYP2C9*3 variant reduces it by 75%.⁷ Having a *2 or *3 allele increases the risk of bleeding during warfarin therapy and the time needed to achieve a stable dose.⁸ Other variants associated with lower warfarin dose requirements are *5, *6, and *11.

The prevalence of these variants is significantly higher in people of European ancestry (roughly one-third) than in Asian people and African Americans,⁷ although no one has recommended not testing in these low-prevalence populations. Limdi et al⁹ reported that by including the *5, *6, and *11 variants in genetic testing (in addition to *2 and *3), they could identify more African Americans (9.7%) who carried at least one of these abnormal variants than reported previously. Differences among ethnic groups need to be taken into account when interpreting pharmacogenetic studies.

VKORC1 variants

Patients also need lower doses of warfarin if they carry the VKORC1 −1639G>A variant, and they spend more time with an INR above the therapeutic range and have higher overall INR values. However, having this variant does not appear to increase the risk of bleeding.

The −1639G>A variant is the most common variant of VKORC1. Rarer ones have also been described, but most commercially available tests do not detect them.

Racial differences exist in the prevalence rates of the various VKORC1 polymorphisms, with the most sensitive (low-dose) genotype predominating in Asians and the least sensitive (high-dose) genotype predominating in African Americans. Over 50% of people of European ancestry carry the intermediate-sensitivity genotype (typical dose).⁷

CURRENT RECOMMENDATIONS FOR OR AGAINST TESTING

FDA labeling

In 2007, the US Food and Drug Administration (FDA) required that the warfarin package insert carry information about initial dosing based on CYP2C9 and VKORC1 testing. This recommendation was revised in 2010 to include a table to help clinicians select an initial warfarin dose if CYP2C9 and VKORC1 genotype information is available. However, the FDA does not require pharmacogenetic testing, leaving the decision to the discretion of the clinician.⁷

American College of Chest Physicians

The American College of Chest Physicians recommends against routine pharmacogenetic testing (grade 1B) because of a lack of evidence that it improves clinical end points or that it is cost-effective.⁵

WHAT EVIDENCE SUPORTS GENETIC TESTING TO GUIDE WARFARIN THERAPY?

To date, no large randomized, controlled trial has been published that looked at clinical outcomes with warfarin dosing based on pharmacogenetic testing. However, several smaller studies have suggested it is beneficial.

One trial found that when dosing was informed by pharmacogenetic testing, patients had significantly more time in the therapeutic range, a lower percentage of INRs greater than 4 or less than 1.5, and fewer serious adverse events (death, myocardial infarction, stroke, thromboembolism, and clinically significant bleeding events).¹⁰ Patients whose dosage was determined using pharmacogenetic algorithms as opposed to traditional clinical algorithms maintained a therapeutic INR more consistently.¹¹

In addition, compared with historical controls, patients whose physician used pharmacogenetic testing to guide warfarin dosing had a rate of hospitalization 31% lower and a rate of hospitalization specifically for bleeding or thromboembolism 28% lower during 6 months of follow-up.^12,13

Several studies have attempted to assess the cost-effectiveness and utility of pharmacogenetic testing in warfarin therapy. As yet, the results have been inconclusive.¹⁴ Larger prospective trials are under way and are estimated to be completed in late 2013.¹⁵ These include:

• COAG (Clarification of Optimal Anticoagulation Through Genetics)
• GIFT (Genetics Informatics Trial of Warfarin to Prevent Venous Thrombosis)
• EU-PACT (European Pharmacogenetics of Anticoagulant Therapy-Warfarin).

We hope these studies will provide greater clarity on the clinical utility and cost-effectiveness of pharmacogenetic testing to guide warfarin dosing.

HOW SHOULD GENETIC INFORMATION BE USED TO GUIDE OR ALTER THERAPY?

Algorithms are available for estimating initial and maintenance warfarin doses based on genetic information (CYP2C9 and VKORC1), race or ethnicity, age, sex, body mass index, smoking status, and other medications taken. In addition, models incorporating the INR on day 4 and days 6 to 11 have been developed for dose refinement.¹⁵ The algorithms explain 30% to 60% of the variability of the data, with lower values for African Americans.⁷

A well-developed dosing model that includes traditional clinical factors and patient genetic status is publicly available online at www.warfarindosing.org.⁴

CPIC: A leader in applied pharmacogenetics

In late 2009, PharmGKB joined forces with the Pharmacogenomics Research Network of the National Institutes of Health to form the Clinical Pharmacogenetics Implementation Consortium (CPIC). This organization issues guidelines that are written by expert clinicians and scientists and then are peer-reviewed, published in leading journals, and simultaneously posted to the PharmGKB website along with supplemental information and updates.

CPIC’s goal is to review the current evidence and to address barriers to the adoption of pharmacogenetic testing into clinical practice. Its guidelines do not advise when or which pharmacogenetic tests should be ordered. Rather, they provide guidance on interpreting and applying such testing, should the test results be available.⁷

CPIC has guidelines on CYP2C9 and VKORC1 genotypes and warfarin dosing.⁸ If a patient’s genetic information is available, CPIC strongly recommends the use of pharmacogenetic algorithm-based dosing. If such an algorithm is not accessible, use of a genotype dosing table is recommended.⁸

Monitoring is still needed

Many factors can affect an individual’s response to warfarin above and beyond the above-noted clinical and genetic traits. These include diet, concomitant medications (both prescription and over-the-counter and herbal), and disease state. There may also be additional genetic polymorphisms not yet identified in various racial and ethnic groups that may affect dosing requirements. And as with all medications, patient compliance and dosing errors have a large potential to affect individual response. Therefore, clinicians should still be diligent about clinical monitoring.¹⁵

Most useful for initial dose

As with most pharmacogenetic information, the greatest benefit can be achieved when this information is used to guide the initial dose, although there is also some effect noted when this information is known and acted upon into the 2nd week of treatment.⁸

Patients on long-term warfarin treatment with stable doses and those unable to achieve stable dosing because of variable adherence or dietary vitamin K intake are less likely to benefit from genetic testing.

There are no published guidelines on the utility of pharmacogenetic testing if a patient is already on a stable dose of warfarin or has a known historical stable dose. There are also no published guidelines on changing the frequency of monitoring based on known genotype.

In children, the data are sparse at this time regarding the utility of pharmacogenetically informed dosing.

HOW DOES ONE ORDER TESTING, AND WHAT IS THE COST?

The FDA has approved four warfarin pharmacogenetic test kits. To be used in clinical decision-making, these tests must be done in a laboratory certified by the Clinical Laboratory Improvement Amendments (CLIA) program.

Testing typically costs a few hundred dollars and may take days for results to be returned if not available on site.¹⁵ At Cleveland Clinic, CYP2C9 and VKORC1 testing can be run in-house at a cost of about $700. Generally, many third-party payers do not reimburse for testing without a prior-approval process.

TO TEST OR NOT TO TEST

Pharmacogenetic testing is available and may help optimize warfarin dosing early in treatment, as well as help maintain therapeutic INRs more consistently. There is preliminary evidence that using this information to guide dosing improves clinical outcomes. Several large trials are under way to address additional questions of clinical utility, with results expected in the next year. There are also readily available decision-support tools to guide therapeutic dosing, and when pharmacogenetic test results are available, utilization of a warfarin dosing algorithm is recommended.

The largest barrier remaining appears to be cost (relative to perceived benefit), and until larger trials of clinical utility and cost-effectiveness are completed and analyzed, hurdles exist to obtaining coverage for such testing.

If it is readily available (and can be paid for by insurance companies or out-of-pocket) and test results can be obtained within 24 to 48 hours or before prescribing, pharmacogenetic testing can be a valuable tool to guide and manage warfarin dosing. Particularly for patients who want to be as proactive as possible, warfarin pharmacogenetic testing offers the ability to participate in this decision-making and to potentially reduce their risk of adverse drug events. And in view of the evidence and FDA recommendations, we propose that the discussion with our patients is not whether we should consider pharmacogenetic testing, but that we have considered pharmacogenetic testing, and why we have decided for or against it.

It seems anachronistic that we still debate how best to fix the plumbing of clogged arteries. Our understanding of the pathogenesis of acute coronary syndromes has evolved in leaps and bounds since the first attempts at coronary revascularization. And yet, as Aggarwal et al discuss in their analysis of the FREEDOM trial,¹ practical and technical questions about how best to open coronary blockages remain clinically relevant, even as we develop strategies to reverse the atherosclerotic processes that created those blockages.

Many acute coronary events arise not from coronary stenoses but from unstable, vulnerable plaques, which may be a distance away from the stable stenoses and thus undetectable. These unstable plaques, embedded within the remodeled arterial wall and without a protective fibrous cap, may rupture and cause an acute thrombotic occlusion. Statins, aspirin, and perhaps anti-inflammatory drugs (now including colchicine) decrease acute coronary events, likely by interfering with the chain of events initiated by plaque rupture.

So why should coronary artery bypass grafting (CABG) be superior to drug-eluting stents (with antiplatelet therapy) in some diabetic patients, as the FREEDOM trial¹ found?

Stenting and balloon dilation repair discrete areas of critical narrowing presumed to be contributing to downstream myocardial ischemia. But areas of vulnerable, non-calcified plaque (with outward remodeling of the vessel wall but generally preserved lumen integrity) may be geographically separated from the identified stenosis and thus be left untreated by stenting. On the other hand, CABG may circumvent “silent” areas of nascent vulnerable plaque that, if left in place, might later rupture and cause acute syndromes or death.

This explanation is clearly hypothetical and one of many possibilities. But paying attention to the new biology of the atherosclerotic process should lead us all to be more aggressive in using treatments shown to reduce the progression of coronary artery disease and the occurrence of acute coronary syndromes. This is especially true in patients with diabetes who are known to have diffuse coronary involvement. So even as we more fully recognize the value of CABG in these patients, perhaps if we intervene earlier—with statins, hypertension control, improved diet, smoking cessation, prevention of chronic kidney disease, antiplatelet therapy, and anti-inflammatory therapy—we will not need it.

It seems anachronistic that we still debate how best to fix the plumbing of clogged arteries. Our understanding of the pathogenesis of acute coronary syndromes has evolved in leaps and bounds since the first attempts at coronary revascularization. And yet, as Aggarwal et al discuss in their analysis of the FREEDOM trial,¹ practical and technical questions about how best to open coronary blockages remain clinically relevant, even as we develop strategies to reverse the atherosclerotic processes that created those blockages.

Many acute coronary events arise not from coronary stenoses but from unstable, vulnerable plaques, which may be a distance away from the stable stenoses and thus undetectable. These unstable plaques, embedded within the remodeled arterial wall and without a protective fibrous cap, may rupture and cause an acute thrombotic occlusion. Statins, aspirin, and perhaps anti-inflammatory drugs (now including colchicine) decrease acute coronary events, likely by interfering with the chain of events initiated by plaque rupture.

So why should coronary artery bypass grafting (CABG) be superior to drug-eluting stents (with antiplatelet therapy) in some diabetic patients, as the FREEDOM trial¹ found?

Stenting and balloon dilation repair discrete areas of critical narrowing presumed to be contributing to downstream myocardial ischemia. But areas of vulnerable, non-calcified plaque (with outward remodeling of the vessel wall but generally preserved lumen integrity) may be geographically separated from the identified stenosis and thus be left untreated by stenting. On the other hand, CABG may circumvent “silent” areas of nascent vulnerable plaque that, if left in place, might later rupture and cause acute syndromes or death.

This explanation is clearly hypothetical and one of many possibilities. But paying attention to the new biology of the atherosclerotic process should lead us all to be more aggressive in using treatments shown to reduce the progression of coronary artery disease and the occurrence of acute coronary syndromes. This is especially true in patients with diabetes who are known to have diffuse coronary involvement. So even as we more fully recognize the value of CABG in these patients, perhaps if we intervene earlier—with statins, hypertension control, improved diet, smoking cessation, prevention of chronic kidney disease, antiplatelet therapy, and anti-inflammatory therapy—we will not need it.

It seems anachronistic that we still debate how best to fix the plumbing of clogged arteries. Our understanding of the pathogenesis of acute coronary syndromes has evolved in leaps and bounds since the first attempts at coronary revascularization. And yet, as Aggarwal et al discuss in their analysis of the FREEDOM trial,¹ practical and technical questions about how best to open coronary blockages remain clinically relevant, even as we develop strategies to reverse the atherosclerotic processes that created those blockages.

Many acute coronary events arise not from coronary stenoses but from unstable, vulnerable plaques, which may be a distance away from the stable stenoses and thus undetectable. These unstable plaques, embedded within the remodeled arterial wall and without a protective fibrous cap, may rupture and cause an acute thrombotic occlusion. Statins, aspirin, and perhaps anti-inflammatory drugs (now including colchicine) decrease acute coronary events, likely by interfering with the chain of events initiated by plaque rupture.

So why should coronary artery bypass grafting (CABG) be superior to drug-eluting stents (with antiplatelet therapy) in some diabetic patients, as the FREEDOM trial¹ found?

Stenting and balloon dilation repair discrete areas of critical narrowing presumed to be contributing to downstream myocardial ischemia. But areas of vulnerable, non-calcified plaque (with outward remodeling of the vessel wall but generally preserved lumen integrity) may be geographically separated from the identified stenosis and thus be left untreated by stenting. On the other hand, CABG may circumvent “silent” areas of nascent vulnerable plaque that, if left in place, might later rupture and cause acute syndromes or death.

This explanation is clearly hypothetical and one of many possibilities. But paying attention to the new biology of the atherosclerotic process should lead us all to be more aggressive in using treatments shown to reduce the progression of coronary artery disease and the occurrence of acute coronary syndromes. This is especially true in patients with diabetes who are known to have diffuse coronary involvement. So even as we more fully recognize the value of CABG in these patients, perhaps if we intervene earlier—with statins, hypertension control, improved diet, smoking cessation, prevention of chronic kidney disease, antiplatelet therapy, and anti-inflammatory therapy—we will not need it.

A 32-year-old man presents to the emergency department with excruciating abdominal pain associated with multiple episodes of vomiting for the past 2 days. He reports no fevers, headaches, diarrhea, constipation, hematochezia, melena, musculoskeletal symptoms, or weight loss. His abdominal pain is generalized and crampy. It does not radiate and has no precipitating factors. The pain is relieved only with intravenous narcotics.

See related editorial

He does not smoke, drink alcohol, or use illicit drugs. He has no known drug or food allergies. He says that his current condition causes him emotional stress that affects his performance at work.

About a year ago, after a complicated surgical procedure, he needed chronic high-dose narcotics. A few months later, he developed multiple bouts of abdominal pain and vomiting that required hospital visits. He now takes oral oxycodone 10–15 mg every 4–6 hours.

On admission, his vital signs are stable, but he is in excruciating pain. He is alert and oriented to person, place, and time. His sclera are anicteric, and the pupils are equal, round, and reactive to light. Lung and heart examinations are normal. The abdomen is soft and nondistended but tender in all four quadrants without guarding; the liver and spleen are not palpable, and no abdominal masses are detected. He has no skin rash, joint swelling or tenderness, or peripheral edema. The neurologic examination is normal. Computed tomography (CT) of the abdomen with contrast shows no signs of bowel obstruction, pancreatic calcifications or edema, cholecystitis, or hepatobiliary disease. Results of initial laboratory testing are shown in Table 1.

1. Based on the information available, which is the least likely cause of his symptoms?

• Acute pancreatitis
• Cyclic vomiting syndrome
• Acute intermittent porphyria
• Gastroparesis

Acute pancreatitis

Acute pancreatitis is the least likely cause of his symptoms. It is commonly caused by gallstones, alcohol, hypertriglyceridemia, and certain drugs.¹ The associated abdominal pain is usually epigastric, radiates to the back, and is accompanied by nausea or vomiting, or both. The onset of pain is sudden and rapidly increases in severity within 30 minutes. CT shows enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections.¹ The diagnosis is based on two of the following three criteria: abdominal pain characteristic of acute pancreatitis; a serum amylase or lipase concentration three or more times the upper limit of normal; and characteristic findings of acute pancreatitis on CT.¹

Cyclic vomiting syndrome

Cyclic vomiting syndrome is thought to be caused by episodic dysautonomia, mitochondrial DNA mutations, and hypothalamic emetic response oversensitivity,^2–4 but the exact pathogenesis is unknown. The syndrome has been strongly linked to migraine and to the chronic excessive use of cannabinoids.^5–9 The Rome III diagnostic criteria¹⁰ are the following: the vomiting episodes are stereotypical, ie, they are acute and last for less than 1 week; the patient has had three or more episodes in the previous year; and the patient has no nausea or vomiting between episodes. The patient must meet all three criteria. A history of migraine or a family history of migraine further supports the diagnosis.

Acute intermittent porphyria

Acute intermittent porphyria is characterized by neurovisceral symptoms such as convulsions, paresis, autonomic dysfunction, constipation, and diarrhea that result from the overproduction of porphyrin precursors and deficiency of porphobilinogen deaminase.¹¹

Most patients have poorly localized, severe, steady abdominal pain that develops over hours to days and that may persist for days to weeks.¹¹ Since the pain is neuropathic, abdominal tenderness is usually minimal during an acute attack. Other clues include signs of ileus, such as constipation, nausea, abdominal distention, or decreased bowel sounds; bladder dysfunction, eg, urinary retention, incontinence, or dysuria; reddish-brown urine; and sensory neuropathy of the chest, back, and extremities.¹¹ Blistering skin lesions are usually not seen. The presence of porphobilinogen in the urine confirms the diagnosis.¹¹

Gastroparesis

Gastroparesis is a result of discoordination between the sympathetic and parasympathetic nervous systems, neurons, and smooth muscles within the stomach, causing a decrease in gastric motility. Common causes are diabetes,¹² scleroderma,¹³ and neurologic disorders.¹⁴ It can also be iatrogenic,¹⁵ resulting from visceral nerve injury and drug treatment with narcotics, calcium channel blockers, muscarinic cholinergic antagonists, or certain antidepressants. Symptoms are related to gastric stasis, ie, abdominal pain from gastric distention, bloating, vomiting, and early satiety.¹⁵ Abdominal pain may worsen after eating, and vomitus usually consists of recently ingested food. These patients may have abdominal distension or tenderness and succussion splash. After excluding possible mechanical obstruction, a gastric-emptying study may be necessary to make the diagnosis.¹⁵

CASE CONTINUED

A serum and urine drug screen in our patient is positive only for opioids. Urine measures of delta-aminolevulinic acid and porphobilinogen are normal. CT angiography of the abdomen shows no signs of mesenteric vascular occlusion. Esophagogastroduodenoscopy shows antral gastritis, but the esophagus and duodenum appear normal, and colonoscopy is normal as well. Histologic study of biopsy specimens obtained during endoscopy is unrevealing. A gastric-emptying study shows delayed emptying. The patient’s abdominal pain and vomiting persist with the initial dose of intravenous narcotic but resolve with escalating doses. When asked, the patient denies an excessive need for hot baths.

2. Which is the most likely diagnosis at this point?

• Narcotic bowel syndrome
• Opioid withdrawal
• Crohn disease
• Chronic pancreatitis
• Chronic mesenteric ischemia
• Cannabinoid hyperemesis

Narcotic bowel syndrome

Narcotic bowel syndrome is the most likely diagnosis. Grunkemeier et al¹⁶ described it as chronic or frequently recurring abdominal pain that is treated with narcotics, either chronically or acutely with high doses, and that includes all the following features¹⁶:

• The pain worsens or resolves incompletely with continued or increasing doses of narcotics
• The pain markedly worsens when the narcotic dose is decreased, and decreases when the drug is reinstituted (the “soarand-crash” effect)
• The frequency, duration, and intensity of the pain episodes gradually increase
• The nature of the pain and its intensity are not explained by a current or previous gastrointestinal diagnosis.¹⁶

This syndrome is common in patients who receive high doses of narcotics for postoperative pain or for other, nonmalignant causes of pain. Patients eventually become dependent on the drugs but are not aware that chronic use activates and facilitates areas in the brain that enhance the perception of pain.¹⁶ A study of a rat model of narcotic bowel syndrome¹⁷ showed that morphine-induced hyperalgesia depends on central sensitization involving the activation of spinal microglia. This eventually results in concomitant peripheral sensitization involving the colonic mucosal neuroimmune system, and also in central or peripheral activation of opioid kappa-receptors by dynorphin release.¹⁷

Patients tend to present with chronic or intermittent colicky abdominal pain that requires escalating doses of narcotics. Eventually, they develop tachyphylaxis and shortened pain-free periods and will require even higher doses of narcotics. This ultimately enhances the perception of pain and worsens opioid bowel symptoms, causing a vicious circle of pain and more narcotic use.¹⁶

Laboratory tests are usually normal, and imaging may show only ileus. Gastric emptying may be delayed in patients who have either narcotic bowel syndrome or gastroparesis, but since abdominal pain from narcotic bowel syndrome is a result of central and visceral hypersensitivity, these patients perceive more severe abdominal pain than patients with gastroparesis alone.

Opioid withdrawal

Symptoms of opioid withdrawal may appear as soon as 6 to 24 hours after cessation of the opioid in patients known to be dependent on opioids. These patients present with crampy abdominal pain with nausea.¹⁸ Other symptoms include agitation, rhinorrhea, lacrimation, excessive yawning, arthralgias, papillary dilation, and piloerection.¹⁸

Our patient did not have the typical signs of opioid withdrawal.

Crohn disease

Crohn disease is a multisystem disorder with specific clinical and pathologic features. It is characterized by focal, asymmetric, transmural, and occasionally granulomatous inflammation primarily affecting the gastrointestinal tract.¹⁹ Characteristic symptoms include abdominal pain, chronic diarrhea with or without rectal bleeding, and weight loss. Extraintestinal signs may include anemia and inflammatory changes in the eyes, skin, and joints. The diagnosis is based on endoscopic, radiographic, and pathologic findings.¹⁹

Our patient did not have diarrhea or signs of Crohn disease on CT, endoscopy, or histology.

Chronic pancreatitis

Chronic pancreatitis involves progressive inflammatory changes resulting in permanent structural damage to the pancreas and subsequent exocrine and endocrine dysfunction.²⁰ Patients have epigastric abdominal pain that often radiates to the back²⁰; it is associated with eating and is partly relieved with leaning forward. Symptoms of pancreatic insufficiency such as fat malabsorption (resulting in steatorrhea and fat-soluble vitamin deficiency) and diabetes are common. Calcifications within the pancreas on CT suggest chronic pancreatitis.²⁰ Serum lipase and amylase levels may be normal or slightly elevated.²⁰

Our patient’s abdominal pain was not typical of pancreatitis. He had no signs or symptoms of pancreatic insufficiency and no calcifications within the pancreas.

Chronic mesenteric ischemia

Chronic mesenteric ischemia (“intestinal angina”) is caused by a reduction in intestinal blood flow as a result of occlusion, vasospasm, or hypoperfusion of the mesenteric vasculature.²¹ It is commonly seen in patients who smoke or who have atherosclerotic vascular disease. These patients have chronic dull or crampy abdominal pain that usually occurs within 1 hour after eating.²¹ To avoid pain, patients avoid eating, resulting in weight loss.²¹ CT angiography with multi-detector CT is as effective as angiography (the gold standard) in depicting splanchnic arterial anatomy.²²

Our patient is young and has no known risk factors for atherosclerosis such as smoking. His abdominal pain is more intermittent than chronic and is not associated with eating.

Cannabinoid hyperemesis

Cannabinoid hyperemesis should be considered in patients with long-term cannabis use presenting with cyclic vomiting, abdominal pain, compulsive use of hot showers, and improvement of symptoms with cannabis cessation.²³ Although cannabinoids have been recognized for their antiemetic effects, long-term use may eventually cause autonomic instability and disturbances in the hypothalamic-pituitary-adrenal axis, resulting in cyclic vomiting and thermoregulatory impairment.²³

Although our patient presented with multiple episodes of vomiting and abdominal pain, he denied using marijuana, he tested negative for tetrahydrocannabinol, and he did not associate any relief of his symptoms with hot baths.

CASE CONTINUED

Our patient receives intravenous hydration, antiemetics, and a narcotic in tapering intravenous doses, and his symptoms gradually improve. He is discharged from the hospital. However, a few weeks later he is readmitted with the same symptoms of abdominal pain and nausea.

3. What is the cornerstone of treatment for narcotic bowel syndrome?

• Establishing a therapeutic relationship
• Detoxification
• Supportive management with intravenous fluids, antiemetics, and stool-softeners
• Medical management with a short-acting narcotic, clonidine, lorazepam, and desipramine

MANAGEMENT OF NARCOTIC BOWEL SYNDROME

An effective therapeutic relationship with the patient is the cornerstone of treatment and should be established before starting detoxification.¹⁷ The physician must first learn to accept that the patient’s condition is real and must show genuine empathy as well as provide information about the pathophysiologic basis of the condition, the rationale for withholding narcotics, and the detrimental role narcotics play in the vicious circle of pain.

Detoxification involves gradually withdrawing the narcotic and substituting a nonnarcotic such as an antidepressant for pain control, as well as prescribing a drug such as a benzodiazepine or clonidine to prevent withdrawal symptoms and a laxative to prevent constipation.^17,24 The physician must reassure the patient that he or she will not be abandoned in pain and that all medications will be continuously adjusted as needed to keep him or her comfortable throughout the detoxification process.^17,24 The physician must continuously gauge the patient’s willingness to continue with treatment and must also be readily available to address the patient’s concerns in a timely manner.^17,24 Involving family members and friends may provide additional support to the patient. Referral to a functional gastrointestinal motility program, a pain specialist, and a psychologist may also be considered.^17,24 Follow-up care is essential, even after the withdrawal program has ended.^17,24

BACK TO THE PATIENT

After successfully establishing a therapeutic relationship and discussing the treatment plan with our patient, we started him on the same dosage of narcotic that he had been receiving, calculated in intravenous morphine equivalents to achieve maximal comfort, and then decreased the dosage by 10% to 33% daily until he was completely off narcotics. An antidepressant and a benzodiazepine were given simultaneously with narcotic tapering. Oral clonidine (0.1–0.4 mg/day) was given after the narcotic dosage was reduced to about half, and polyethylene glycol was given as needed for constipation. The total duration of detoxification was 7 days.

The patient was referred to a psychologist for cognitive-behavioral and relaxation therapy, as well as for encouragement and support. At 6 months, he had had no recurrence of symptoms.

TAKE-HOME MESSAGE

In the United States, the number of patients taking a narcotic for nonmalignant pain is increasing, ²⁵ and physicians should be more aware of complications such as narcotic bowel syndrome.

Narcotic bowel syndrome should be suspected in any patient with prolonged narcotic use presenting with multiple recurrent episodes of abdominal pain after other causes are ruled out.

Establishing a good therapeutic relationship with the patient is the cornerstone of successful treatment. Patients who understand their condition and are willing to be treated tend to have better outcomes.

Supportive treatment, symptom relief, and emotional support during detoxification increase compliance.

A 32-year-old man presents to the emergency department with excruciating abdominal pain associated with multiple episodes of vomiting for the past 2 days. He reports no fevers, headaches, diarrhea, constipation, hematochezia, melena, musculoskeletal symptoms, or weight loss. His abdominal pain is generalized and crampy. It does not radiate and has no precipitating factors. The pain is relieved only with intravenous narcotics.

See related editorial

He does not smoke, drink alcohol, or use illicit drugs. He has no known drug or food allergies. He says that his current condition causes him emotional stress that affects his performance at work.

About a year ago, after a complicated surgical procedure, he needed chronic high-dose narcotics. A few months later, he developed multiple bouts of abdominal pain and vomiting that required hospital visits. He now takes oral oxycodone 10–15 mg every 4–6 hours.

On admission, his vital signs are stable, but he is in excruciating pain. He is alert and oriented to person, place, and time. His sclera are anicteric, and the pupils are equal, round, and reactive to light. Lung and heart examinations are normal. The abdomen is soft and nondistended but tender in all four quadrants without guarding; the liver and spleen are not palpable, and no abdominal masses are detected. He has no skin rash, joint swelling or tenderness, or peripheral edema. The neurologic examination is normal. Computed tomography (CT) of the abdomen with contrast shows no signs of bowel obstruction, pancreatic calcifications or edema, cholecystitis, or hepatobiliary disease. Results of initial laboratory testing are shown in Table 1.

1. Based on the information available, which is the least likely cause of his symptoms?

• Acute pancreatitis
• Cyclic vomiting syndrome
• Acute intermittent porphyria
• Gastroparesis

Acute pancreatitis

Acute pancreatitis is the least likely cause of his symptoms. It is commonly caused by gallstones, alcohol, hypertriglyceridemia, and certain drugs.¹ The associated abdominal pain is usually epigastric, radiates to the back, and is accompanied by nausea or vomiting, or both. The onset of pain is sudden and rapidly increases in severity within 30 minutes. CT shows enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections.¹ The diagnosis is based on two of the following three criteria: abdominal pain characteristic of acute pancreatitis; a serum amylase or lipase concentration three or more times the upper limit of normal; and characteristic findings of acute pancreatitis on CT.¹

Cyclic vomiting syndrome

Cyclic vomiting syndrome is thought to be caused by episodic dysautonomia, mitochondrial DNA mutations, and hypothalamic emetic response oversensitivity,^2–4 but the exact pathogenesis is unknown. The syndrome has been strongly linked to migraine and to the chronic excessive use of cannabinoids.^5–9 The Rome III diagnostic criteria¹⁰ are the following: the vomiting episodes are stereotypical, ie, they are acute and last for less than 1 week; the patient has had three or more episodes in the previous year; and the patient has no nausea or vomiting between episodes. The patient must meet all three criteria. A history of migraine or a family history of migraine further supports the diagnosis.

Acute intermittent porphyria

Acute intermittent porphyria is characterized by neurovisceral symptoms such as convulsions, paresis, autonomic dysfunction, constipation, and diarrhea that result from the overproduction of porphyrin precursors and deficiency of porphobilinogen deaminase.¹¹

Most patients have poorly localized, severe, steady abdominal pain that develops over hours to days and that may persist for days to weeks.¹¹ Since the pain is neuropathic, abdominal tenderness is usually minimal during an acute attack. Other clues include signs of ileus, such as constipation, nausea, abdominal distention, or decreased bowel sounds; bladder dysfunction, eg, urinary retention, incontinence, or dysuria; reddish-brown urine; and sensory neuropathy of the chest, back, and extremities.¹¹ Blistering skin lesions are usually not seen. The presence of porphobilinogen in the urine confirms the diagnosis.¹¹

Gastroparesis

Gastroparesis is a result of discoordination between the sympathetic and parasympathetic nervous systems, neurons, and smooth muscles within the stomach, causing a decrease in gastric motility. Common causes are diabetes,¹² scleroderma,¹³ and neurologic disorders.¹⁴ It can also be iatrogenic,¹⁵ resulting from visceral nerve injury and drug treatment with narcotics, calcium channel blockers, muscarinic cholinergic antagonists, or certain antidepressants. Symptoms are related to gastric stasis, ie, abdominal pain from gastric distention, bloating, vomiting, and early satiety.¹⁵ Abdominal pain may worsen after eating, and vomitus usually consists of recently ingested food. These patients may have abdominal distension or tenderness and succussion splash. After excluding possible mechanical obstruction, a gastric-emptying study may be necessary to make the diagnosis.¹⁵

CASE CONTINUED

A serum and urine drug screen in our patient is positive only for opioids. Urine measures of delta-aminolevulinic acid and porphobilinogen are normal. CT angiography of the abdomen shows no signs of mesenteric vascular occlusion. Esophagogastroduodenoscopy shows antral gastritis, but the esophagus and duodenum appear normal, and colonoscopy is normal as well. Histologic study of biopsy specimens obtained during endoscopy is unrevealing. A gastric-emptying study shows delayed emptying. The patient’s abdominal pain and vomiting persist with the initial dose of intravenous narcotic but resolve with escalating doses. When asked, the patient denies an excessive need for hot baths.

2. Which is the most likely diagnosis at this point?

• Narcotic bowel syndrome
• Opioid withdrawal
• Crohn disease
• Chronic pancreatitis
• Chronic mesenteric ischemia
• Cannabinoid hyperemesis

Narcotic bowel syndrome

Narcotic bowel syndrome is the most likely diagnosis. Grunkemeier et al¹⁶ described it as chronic or frequently recurring abdominal pain that is treated with narcotics, either chronically or acutely with high doses, and that includes all the following features¹⁶:

• The pain worsens or resolves incompletely with continued or increasing doses of narcotics
• The pain markedly worsens when the narcotic dose is decreased, and decreases when the drug is reinstituted (the “soarand-crash” effect)
• The frequency, duration, and intensity of the pain episodes gradually increase
• The nature of the pain and its intensity are not explained by a current or previous gastrointestinal diagnosis.¹⁶

This syndrome is common in patients who receive high doses of narcotics for postoperative pain or for other, nonmalignant causes of pain. Patients eventually become dependent on the drugs but are not aware that chronic use activates and facilitates areas in the brain that enhance the perception of pain.¹⁶ A study of a rat model of narcotic bowel syndrome¹⁷ showed that morphine-induced hyperalgesia depends on central sensitization involving the activation of spinal microglia. This eventually results in concomitant peripheral sensitization involving the colonic mucosal neuroimmune system, and also in central or peripheral activation of opioid kappa-receptors by dynorphin release.¹⁷

Patients tend to present with chronic or intermittent colicky abdominal pain that requires escalating doses of narcotics. Eventually, they develop tachyphylaxis and shortened pain-free periods and will require even higher doses of narcotics. This ultimately enhances the perception of pain and worsens opioid bowel symptoms, causing a vicious circle of pain and more narcotic use.¹⁶

Laboratory tests are usually normal, and imaging may show only ileus. Gastric emptying may be delayed in patients who have either narcotic bowel syndrome or gastroparesis, but since abdominal pain from narcotic bowel syndrome is a result of central and visceral hypersensitivity, these patients perceive more severe abdominal pain than patients with gastroparesis alone.

Opioid withdrawal

Symptoms of opioid withdrawal may appear as soon as 6 to 24 hours after cessation of the opioid in patients known to be dependent on opioids. These patients present with crampy abdominal pain with nausea.¹⁸ Other symptoms include agitation, rhinorrhea, lacrimation, excessive yawning, arthralgias, papillary dilation, and piloerection.¹⁸

Our patient did not have the typical signs of opioid withdrawal.

Crohn disease

Crohn disease is a multisystem disorder with specific clinical and pathologic features. It is characterized by focal, asymmetric, transmural, and occasionally granulomatous inflammation primarily affecting the gastrointestinal tract.¹⁹ Characteristic symptoms include abdominal pain, chronic diarrhea with or without rectal bleeding, and weight loss. Extraintestinal signs may include anemia and inflammatory changes in the eyes, skin, and joints. The diagnosis is based on endoscopic, radiographic, and pathologic findings.¹⁹

Our patient did not have diarrhea or signs of Crohn disease on CT, endoscopy, or histology.

Chronic pancreatitis

Chronic pancreatitis involves progressive inflammatory changes resulting in permanent structural damage to the pancreas and subsequent exocrine and endocrine dysfunction.²⁰ Patients have epigastric abdominal pain that often radiates to the back²⁰; it is associated with eating and is partly relieved with leaning forward. Symptoms of pancreatic insufficiency such as fat malabsorption (resulting in steatorrhea and fat-soluble vitamin deficiency) and diabetes are common. Calcifications within the pancreas on CT suggest chronic pancreatitis.²⁰ Serum lipase and amylase levels may be normal or slightly elevated.²⁰

Our patient’s abdominal pain was not typical of pancreatitis. He had no signs or symptoms of pancreatic insufficiency and no calcifications within the pancreas.

Chronic mesenteric ischemia

Chronic mesenteric ischemia (“intestinal angina”) is caused by a reduction in intestinal blood flow as a result of occlusion, vasospasm, or hypoperfusion of the mesenteric vasculature.²¹ It is commonly seen in patients who smoke or who have atherosclerotic vascular disease. These patients have chronic dull or crampy abdominal pain that usually occurs within 1 hour after eating.²¹ To avoid pain, patients avoid eating, resulting in weight loss.²¹ CT angiography with multi-detector CT is as effective as angiography (the gold standard) in depicting splanchnic arterial anatomy.²²

Our patient is young and has no known risk factors for atherosclerosis such as smoking. His abdominal pain is more intermittent than chronic and is not associated with eating.

Cannabinoid hyperemesis

Cannabinoid hyperemesis should be considered in patients with long-term cannabis use presenting with cyclic vomiting, abdominal pain, compulsive use of hot showers, and improvement of symptoms with cannabis cessation.²³ Although cannabinoids have been recognized for their antiemetic effects, long-term use may eventually cause autonomic instability and disturbances in the hypothalamic-pituitary-adrenal axis, resulting in cyclic vomiting and thermoregulatory impairment.²³

Although our patient presented with multiple episodes of vomiting and abdominal pain, he denied using marijuana, he tested negative for tetrahydrocannabinol, and he did not associate any relief of his symptoms with hot baths.

CASE CONTINUED

Our patient receives intravenous hydration, antiemetics, and a narcotic in tapering intravenous doses, and his symptoms gradually improve. He is discharged from the hospital. However, a few weeks later he is readmitted with the same symptoms of abdominal pain and nausea.

3. What is the cornerstone of treatment for narcotic bowel syndrome?

• Establishing a therapeutic relationship
• Detoxification
• Supportive management with intravenous fluids, antiemetics, and stool-softeners
• Medical management with a short-acting narcotic, clonidine, lorazepam, and desipramine

MANAGEMENT OF NARCOTIC BOWEL SYNDROME

An effective therapeutic relationship with the patient is the cornerstone of treatment and should be established before starting detoxification.¹⁷ The physician must first learn to accept that the patient’s condition is real and must show genuine empathy as well as provide information about the pathophysiologic basis of the condition, the rationale for withholding narcotics, and the detrimental role narcotics play in the vicious circle of pain.

Detoxification involves gradually withdrawing the narcotic and substituting a nonnarcotic such as an antidepressant for pain control, as well as prescribing a drug such as a benzodiazepine or clonidine to prevent withdrawal symptoms and a laxative to prevent constipation.^17,24 The physician must reassure the patient that he or she will not be abandoned in pain and that all medications will be continuously adjusted as needed to keep him or her comfortable throughout the detoxification process.^17,24 The physician must continuously gauge the patient’s willingness to continue with treatment and must also be readily available to address the patient’s concerns in a timely manner.^17,24 Involving family members and friends may provide additional support to the patient. Referral to a functional gastrointestinal motility program, a pain specialist, and a psychologist may also be considered.^17,24 Follow-up care is essential, even after the withdrawal program has ended.^17,24

BACK TO THE PATIENT

After successfully establishing a therapeutic relationship and discussing the treatment plan with our patient, we started him on the same dosage of narcotic that he had been receiving, calculated in intravenous morphine equivalents to achieve maximal comfort, and then decreased the dosage by 10% to 33% daily until he was completely off narcotics. An antidepressant and a benzodiazepine were given simultaneously with narcotic tapering. Oral clonidine (0.1–0.4 mg/day) was given after the narcotic dosage was reduced to about half, and polyethylene glycol was given as needed for constipation. The total duration of detoxification was 7 days.

The patient was referred to a psychologist for cognitive-behavioral and relaxation therapy, as well as for encouragement and support. At 6 months, he had had no recurrence of symptoms.

TAKE-HOME MESSAGE

In the United States, the number of patients taking a narcotic for nonmalignant pain is increasing, ²⁵ and physicians should be more aware of complications such as narcotic bowel syndrome.

Narcotic bowel syndrome should be suspected in any patient with prolonged narcotic use presenting with multiple recurrent episodes of abdominal pain after other causes are ruled out.

Establishing a good therapeutic relationship with the patient is the cornerstone of successful treatment. Patients who understand their condition and are willing to be treated tend to have better outcomes.

Supportive treatment, symptom relief, and emotional support during detoxification increase compliance.

A 32-year-old man presents to the emergency department with excruciating abdominal pain associated with multiple episodes of vomiting for the past 2 days. He reports no fevers, headaches, diarrhea, constipation, hematochezia, melena, musculoskeletal symptoms, or weight loss. His abdominal pain is generalized and crampy. It does not radiate and has no precipitating factors. The pain is relieved only with intravenous narcotics.

See related editorial

He does not smoke, drink alcohol, or use illicit drugs. He has no known drug or food allergies. He says that his current condition causes him emotional stress that affects his performance at work.

About a year ago, after a complicated surgical procedure, he needed chronic high-dose narcotics. A few months later, he developed multiple bouts of abdominal pain and vomiting that required hospital visits. He now takes oral oxycodone 10–15 mg every 4–6 hours.

On admission, his vital signs are stable, but he is in excruciating pain. He is alert and oriented to person, place, and time. His sclera are anicteric, and the pupils are equal, round, and reactive to light. Lung and heart examinations are normal. The abdomen is soft and nondistended but tender in all four quadrants without guarding; the liver and spleen are not palpable, and no abdominal masses are detected. He has no skin rash, joint swelling or tenderness, or peripheral edema. The neurologic examination is normal. Computed tomography (CT) of the abdomen with contrast shows no signs of bowel obstruction, pancreatic calcifications or edema, cholecystitis, or hepatobiliary disease. Results of initial laboratory testing are shown in Table 1.

1. Based on the information available, which is the least likely cause of his symptoms?

• Acute pancreatitis
• Cyclic vomiting syndrome
• Acute intermittent porphyria
• Gastroparesis

Acute pancreatitis

Acute pancreatitis is the least likely cause of his symptoms. It is commonly caused by gallstones, alcohol, hypertriglyceridemia, and certain drugs.¹ The associated abdominal pain is usually epigastric, radiates to the back, and is accompanied by nausea or vomiting, or both. The onset of pain is sudden and rapidly increases in severity within 30 minutes. CT shows enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections.¹ The diagnosis is based on two of the following three criteria: abdominal pain characteristic of acute pancreatitis; a serum amylase or lipase concentration three or more times the upper limit of normal; and characteristic findings of acute pancreatitis on CT.¹

Cyclic vomiting syndrome

Cyclic vomiting syndrome is thought to be caused by episodic dysautonomia, mitochondrial DNA mutations, and hypothalamic emetic response oversensitivity,^2–4 but the exact pathogenesis is unknown. The syndrome has been strongly linked to migraine and to the chronic excessive use of cannabinoids.^5–9 The Rome III diagnostic criteria¹⁰ are the following: the vomiting episodes are stereotypical, ie, they are acute and last for less than 1 week; the patient has had three or more episodes in the previous year; and the patient has no nausea or vomiting between episodes. The patient must meet all three criteria. A history of migraine or a family history of migraine further supports the diagnosis.

Acute intermittent porphyria

Acute intermittent porphyria is characterized by neurovisceral symptoms such as convulsions, paresis, autonomic dysfunction, constipation, and diarrhea that result from the overproduction of porphyrin precursors and deficiency of porphobilinogen deaminase.¹¹

Most patients have poorly localized, severe, steady abdominal pain that develops over hours to days and that may persist for days to weeks.¹¹ Since the pain is neuropathic, abdominal tenderness is usually minimal during an acute attack. Other clues include signs of ileus, such as constipation, nausea, abdominal distention, or decreased bowel sounds; bladder dysfunction, eg, urinary retention, incontinence, or dysuria; reddish-brown urine; and sensory neuropathy of the chest, back, and extremities.¹¹ Blistering skin lesions are usually not seen. The presence of porphobilinogen in the urine confirms the diagnosis.¹¹

Gastroparesis

Gastroparesis is a result of discoordination between the sympathetic and parasympathetic nervous systems, neurons, and smooth muscles within the stomach, causing a decrease in gastric motility. Common causes are diabetes,¹² scleroderma,¹³ and neurologic disorders.¹⁴ It can also be iatrogenic,¹⁵ resulting from visceral nerve injury and drug treatment with narcotics, calcium channel blockers, muscarinic cholinergic antagonists, or certain antidepressants. Symptoms are related to gastric stasis, ie, abdominal pain from gastric distention, bloating, vomiting, and early satiety.¹⁵ Abdominal pain may worsen after eating, and vomitus usually consists of recently ingested food. These patients may have abdominal distension or tenderness and succussion splash. After excluding possible mechanical obstruction, a gastric-emptying study may be necessary to make the diagnosis.¹⁵

CASE CONTINUED

A serum and urine drug screen in our patient is positive only for opioids. Urine measures of delta-aminolevulinic acid and porphobilinogen are normal. CT angiography of the abdomen shows no signs of mesenteric vascular occlusion. Esophagogastroduodenoscopy shows antral gastritis, but the esophagus and duodenum appear normal, and colonoscopy is normal as well. Histologic study of biopsy specimens obtained during endoscopy is unrevealing. A gastric-emptying study shows delayed emptying. The patient’s abdominal pain and vomiting persist with the initial dose of intravenous narcotic but resolve with escalating doses. When asked, the patient denies an excessive need for hot baths.

2. Which is the most likely diagnosis at this point?

• Narcotic bowel syndrome
• Opioid withdrawal
• Crohn disease
• Chronic pancreatitis
• Chronic mesenteric ischemia
• Cannabinoid hyperemesis

Narcotic bowel syndrome

Narcotic bowel syndrome is the most likely diagnosis. Grunkemeier et al¹⁶ described it as chronic or frequently recurring abdominal pain that is treated with narcotics, either chronically or acutely with high doses, and that includes all the following features¹⁶:

• The pain worsens or resolves incompletely with continued or increasing doses of narcotics
• The pain markedly worsens when the narcotic dose is decreased, and decreases when the drug is reinstituted (the “soarand-crash” effect)
• The frequency, duration, and intensity of the pain episodes gradually increase
• The nature of the pain and its intensity are not explained by a current or previous gastrointestinal diagnosis.¹⁶

This syndrome is common in patients who receive high doses of narcotics for postoperative pain or for other, nonmalignant causes of pain. Patients eventually become dependent on the drugs but are not aware that chronic use activates and facilitates areas in the brain that enhance the perception of pain.¹⁶ A study of a rat model of narcotic bowel syndrome¹⁷ showed that morphine-induced hyperalgesia depends on central sensitization involving the activation of spinal microglia. This eventually results in concomitant peripheral sensitization involving the colonic mucosal neuroimmune system, and also in central or peripheral activation of opioid kappa-receptors by dynorphin release.¹⁷

Patients tend to present with chronic or intermittent colicky abdominal pain that requires escalating doses of narcotics. Eventually, they develop tachyphylaxis and shortened pain-free periods and will require even higher doses of narcotics. This ultimately enhances the perception of pain and worsens opioid bowel symptoms, causing a vicious circle of pain and more narcotic use.¹⁶

Laboratory tests are usually normal, and imaging may show only ileus. Gastric emptying may be delayed in patients who have either narcotic bowel syndrome or gastroparesis, but since abdominal pain from narcotic bowel syndrome is a result of central and visceral hypersensitivity, these patients perceive more severe abdominal pain than patients with gastroparesis alone.

Opioid withdrawal

Symptoms of opioid withdrawal may appear as soon as 6 to 24 hours after cessation of the opioid in patients known to be dependent on opioids. These patients present with crampy abdominal pain with nausea.¹⁸ Other symptoms include agitation, rhinorrhea, lacrimation, excessive yawning, arthralgias, papillary dilation, and piloerection.¹⁸

Our patient did not have the typical signs of opioid withdrawal.

Crohn disease

Crohn disease is a multisystem disorder with specific clinical and pathologic features. It is characterized by focal, asymmetric, transmural, and occasionally granulomatous inflammation primarily affecting the gastrointestinal tract.¹⁹ Characteristic symptoms include abdominal pain, chronic diarrhea with or without rectal bleeding, and weight loss. Extraintestinal signs may include anemia and inflammatory changes in the eyes, skin, and joints. The diagnosis is based on endoscopic, radiographic, and pathologic findings.¹⁹

Our patient did not have diarrhea or signs of Crohn disease on CT, endoscopy, or histology.

Chronic pancreatitis

Chronic pancreatitis involves progressive inflammatory changes resulting in permanent structural damage to the pancreas and subsequent exocrine and endocrine dysfunction.²⁰ Patients have epigastric abdominal pain that often radiates to the back²⁰; it is associated with eating and is partly relieved with leaning forward. Symptoms of pancreatic insufficiency such as fat malabsorption (resulting in steatorrhea and fat-soluble vitamin deficiency) and diabetes are common. Calcifications within the pancreas on CT suggest chronic pancreatitis.²⁰ Serum lipase and amylase levels may be normal or slightly elevated.²⁰

Our patient’s abdominal pain was not typical of pancreatitis. He had no signs or symptoms of pancreatic insufficiency and no calcifications within the pancreas.

Chronic mesenteric ischemia

Chronic mesenteric ischemia (“intestinal angina”) is caused by a reduction in intestinal blood flow as a result of occlusion, vasospasm, or hypoperfusion of the mesenteric vasculature.²¹ It is commonly seen in patients who smoke or who have atherosclerotic vascular disease. These patients have chronic dull or crampy abdominal pain that usually occurs within 1 hour after eating.²¹ To avoid pain, patients avoid eating, resulting in weight loss.²¹ CT angiography with multi-detector CT is as effective as angiography (the gold standard) in depicting splanchnic arterial anatomy.²²

Our patient is young and has no known risk factors for atherosclerosis such as smoking. His abdominal pain is more intermittent than chronic and is not associated with eating.

Cannabinoid hyperemesis

Cannabinoid hyperemesis should be considered in patients with long-term cannabis use presenting with cyclic vomiting, abdominal pain, compulsive use of hot showers, and improvement of symptoms with cannabis cessation.²³ Although cannabinoids have been recognized for their antiemetic effects, long-term use may eventually cause autonomic instability and disturbances in the hypothalamic-pituitary-adrenal axis, resulting in cyclic vomiting and thermoregulatory impairment.²³

Although our patient presented with multiple episodes of vomiting and abdominal pain, he denied using marijuana, he tested negative for tetrahydrocannabinol, and he did not associate any relief of his symptoms with hot baths.

CASE CONTINUED

Our patient receives intravenous hydration, antiemetics, and a narcotic in tapering intravenous doses, and his symptoms gradually improve. He is discharged from the hospital. However, a few weeks later he is readmitted with the same symptoms of abdominal pain and nausea.

3. What is the cornerstone of treatment for narcotic bowel syndrome?

• Establishing a therapeutic relationship
• Detoxification
• Supportive management with intravenous fluids, antiemetics, and stool-softeners
• Medical management with a short-acting narcotic, clonidine, lorazepam, and desipramine

MANAGEMENT OF NARCOTIC BOWEL SYNDROME

An effective therapeutic relationship with the patient is the cornerstone of treatment and should be established before starting detoxification.¹⁷ The physician must first learn to accept that the patient’s condition is real and must show genuine empathy as well as provide information about the pathophysiologic basis of the condition, the rationale for withholding narcotics, and the detrimental role narcotics play in the vicious circle of pain.

Detoxification involves gradually withdrawing the narcotic and substituting a nonnarcotic such as an antidepressant for pain control, as well as prescribing a drug such as a benzodiazepine or clonidine to prevent withdrawal symptoms and a laxative to prevent constipation.^17,24 The physician must reassure the patient that he or she will not be abandoned in pain and that all medications will be continuously adjusted as needed to keep him or her comfortable throughout the detoxification process.^17,24 The physician must continuously gauge the patient’s willingness to continue with treatment and must also be readily available to address the patient’s concerns in a timely manner.^17,24 Involving family members and friends may provide additional support to the patient. Referral to a functional gastrointestinal motility program, a pain specialist, and a psychologist may also be considered.^17,24 Follow-up care is essential, even after the withdrawal program has ended.^17,24

BACK TO THE PATIENT

After successfully establishing a therapeutic relationship and discussing the treatment plan with our patient, we started him on the same dosage of narcotic that he had been receiving, calculated in intravenous morphine equivalents to achieve maximal comfort, and then decreased the dosage by 10% to 33% daily until he was completely off narcotics. An antidepressant and a benzodiazepine were given simultaneously with narcotic tapering. Oral clonidine (0.1–0.4 mg/day) was given after the narcotic dosage was reduced to about half, and polyethylene glycol was given as needed for constipation. The total duration of detoxification was 7 days.

The patient was referred to a psychologist for cognitive-behavioral and relaxation therapy, as well as for encouragement and support. At 6 months, he had had no recurrence of symptoms.

TAKE-HOME MESSAGE

In the United States, the number of patients taking a narcotic for nonmalignant pain is increasing, ²⁵ and physicians should be more aware of complications such as narcotic bowel syndrome.

Narcotic bowel syndrome should be suspected in any patient with prolonged narcotic use presenting with multiple recurrent episodes of abdominal pain after other causes are ruled out.

Establishing a good therapeutic relationship with the patient is the cornerstone of successful treatment. Patients who understand their condition and are willing to be treated tend to have better outcomes.

Supportive treatment, symptom relief, and emotional support during detoxification increase compliance.