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10 Articles in Volume 15, Issue #10
2015 Has Been a Good Year for Clinical Progress
Addison’s Original 1855 Cases Reveal Stories of Chronic Pain
Can We Prevent Chronic Pain?
Letters to the Editor: Nerve Fiber Testing, Fibromyalgia
Medication Guide for Pain—A Short Primer for Primary Care
Odd Pet Behavior During SCS Trial—Case Report
Opioid-Induced Constipation: New and Emerging Therapies—Update 2015
Palliative Care: Dying With Dignity
PPM Editorial Board: Year in Pain Management 2015
QT Intervals and Antidepressants

QT Intervals and Antidepressants

Ask the Expert: December 2015

Question: Which SSRIs and SNRIs are associated with QT prolongation?

Answer: Pain and depression often go hand and hand. Therefore, primary care physicians and pain specialists often ask pharmacists which of the most popular antidepressants are safe to use for pain patients.

This article will focus on selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), which are consistently among the most commonly prescribed medications in the United States.1,2

The SSRIs are useful for treating depression associated with pain conditions but do not appear to relieve pain on their own. However, fluoxetine (Prozac, others), may boost the analgesic effects of some tricyclic antidepressants (TCAs). Of the SSRIs, sertraline (Zoloft, others), fluoxetine, citalopram (Celexa, others), escitalopram (Lexapro, others), and paroxetine (Paxil, Pexeva, others) all were among the top 200 medications dispensed in 2014.3

The SNRIs play a significant role in the treatment of numerous pain disorders, ranging from fibromyalgia and diabetic peripheral neuropathy to episodic migraine prevention and chronic musculoskeletal pain.4 Among the SNRIs, duloxetine (Cymbalta, Irenka, others), venlafaxine (formerly sold as Effexor, generic), and milnacipran (Savella) are the most commonly prescribed.3

Adverse effects (AEs) of SSRIs and SNRIs include nausea, diarrhea, sexual dysfunction, weight gain, and hyponatremia.4 Although electrocardiogram (ECG) changes, such as QT interval prolongation, are considered more commonplace with the TCAs, SSRIs and SNRIs may warrant cause for concern as well.5

In 2012, the FDA released revised recommendations for citalopram, noting its potential risk for abnormal heart rhythms when prescribed at high doses.6 Specifically, the FDA advised against citalopram use in patients with congenital long QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure. The FDA advised health providers that citalopram doses should not exceed 20 mg daily for patients older than 60 years of age and 40 mg per day for all other patients. In addition, doses of escitalopram should not exceed 20 mg daily. The rationale cited: higher doses of the SSRIs may prolong the QT interval with no additional therapeutic benefit.6 Although routine ECG monitoring is not currently recommended, citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.

Given these FDA recommendations for the SSRI citalopram, and the similarities of SSRIs and SNRIs with respect to other AEs, many pain specialists have asked whether QT prolongation also is a concern with SNRIs?

The QT interval and Torsades de Pointes

On an ECG, the QT interval represents the summation of ventricular myocyte action potentials (APs).7 These APs occur as a result of the flow of ions across the cell membrane through various channels composed of protein complexes. There are 5 phases of this cardiac cycle (Table 1).7 The entirety of this process signifies the progression from cardiac depolarization to repolarization.

The QT interval is measured from the beginning of the QRS complex to the end of the T wave. On a 12-lead ECG, the QT interval generally is measured in lead II. However, the QT interval varies inversely with heart rate, so a correction for heart rate typically is calculated using Bazett’s formula: QTc = QT interval ÷ the square root of the RR interval (in seconds).8 In adults, a QTc interval of more than 450 ms is considered prolonged in men, whereas the normal range for women is generally accepted to be slightly longer—450 to 470 ms.8

Long QT syndrome (LQTS) is a genetic or acquired disorder of myocardial repolarization that results in a prolonged QT interval. Most concerning is the risk of sudden cardiac death (SCD) due to torsades de pointes (TdP), a life-threatening, polymorphic ventricular tachycardia characterized by progressive, sinusoidal, cyclic alteration of the QRS axis. 8 The name torsades de pointes or “twisting of the points” stems from the display of the QRS complexes as they appear to “twist” around the isoelectric line of the recording. TdP often results in an ectopic beat followed by a long pause with a subsequent beat showing pronounced QT prolongation. This short-long-short cycle typically characterizes drug-induced or pause-dependent TdP.7

Common features of TdP include a ventricular rate of approximately 160 to 250 beats per minute, irregular RR intervals, and cycling of the QRS axis through 180 degrees every 5 to 20 beats. Common symptoms in patients with LQTS include palpitations, seizures, syncope, as well as the potential for SCD.8

There are many recognized risk factors for TdP including female gender, genetic predisposition, age over 65 years, electrolyte disturbances, bradycardia, digitalis therapy, and baseline elevation in QT interval.7

SSRI/SNRI-induced QT prolongation primarily occurs as a result of the blockade of potassium channels, most notably the IKr, or “rapid” potassium rectifier channel, and the blockade of cardiac fast sodium channels. This leads to ventricular AP prolongation as well as a decrease in conduction velocity, resulting in prolongation of the QT interval. Additionally, some SNRIs, most notably venlafaxine, have been shown to block the fast inward sodium current in ventricular myocytes in a concentration-dependent manner, which also may contribute to changes in the QT interval.9 When initiated in patients predisposed to QT prolongation (such as those with LQTS) or in combination with other medications that potentially prolong the QT interval, SSRIs and SNRIs may further increase a patient’s risk for QT prolongation and, thus, TdP and SCD.

In October, 2005, the FDA provided definitions of clinically relevant changes in QTc intervals in their guidance for clinical evaluation of QT/QTc interval prolongation for non-antiarrhythmic drugs (Table 2, page 16).10 The document also states that prolongation of QTc to >500 ms during therapy has been a threshold of particular concern and QTc interval increases of greater than 30 to 60 ms from baseline are considered clinically relevant.10 According to the 2011 AHA/ACC scientific statement on prevention of TdP in hospital settings, a QTc over the 99th percentile should be considered abnormally prolonged, which corresponds to a QTc of longer than 470 ms for men and longer than 480 ms for women.11

Literature Search

We conducted a search of the product information of each SSRI and SNRI regarding QT interval prolongation, searching the primary literature using the MeSH terms “serotonin reuptake inhibitors” and “antidepressive agents.” Another source was The Arizona Center for Education and Research on Therapeutics’ website termed CredibleMeds, which lists drugs that have a risk of QT prolongation and cardiac arrhythmias.12 We evaluated these resources collectively to formulate a clinically beneficial overview of SSRI and SNRI agents, their associated effects on QTc prolongation, and their likelihood of causing TdP.

SSRIs

Of the SSRIs, citalopram is most commonly associated with QT prolongation. Citalopram is listed on CredibleMeds as a drug with known TdP risk, and the site lists over 100 studies supporting this classification. Among these studies was a systematic review of 18 case reports of citalopram resulting in QTc prolongation, 10 of which were associated with the development of TdP.13

Escitalopram, the S-isomer of citalopram, also may pose a risk for prolongation of the QT interval. Although only the S-isomer of citalopram (escitalopram) is responsible for its antidepressant activity, it appears that both the S- and R- isomers are responsible for its ECG-altering affects.14 A randomized, double-blind, placebo-controlled study examined the cardiovascular effects of escitalopram doses between 5 and 20 mg per day and concluded that although escitalopram has a statistically significant effect on heart rate, it has no clinically meaningful effect on ECG values.15

The level of evidence of ECG changes with the remaining SSRIs does not parallel that for citalopram and escitalopram. CredibleMeds lists sertraline as a drug with conditional TdP risk, although large randomized studies do not support this. In the SADHART trial, 369 patients with major depressive disorder (MDD) who had an acute myocardial infarction or were hospitalized with unstable angina within 30 days of enrollment were randomized to placebo or sertraline after these events. After 16 weeks, the study resulted in no significant difference in QTc interval between the 2 groups of patients.16 Numerous other studies corroborate these data.17,18

Although CredibleMeds lists fluoxetine as a drug with conditional TdP risk, prospective data does appear to support a clinically relevant concern.12 Several small studies have been performed to assess for the risk of QT prolongation in fluoxetine-treated patients. One trial of 54 depressed patients receiving 20 mg of fluoxetine daily (with flexible dosing up to 60 mg daily) was found to show no significant change in QTc interval at 9 weeks.19 Other trials have been conducted assessing fluoxetine’s effect on the QT interval, but they were not sufficiently powered to draw generalizable conclusions. These trials failed to prove any clinically significant increase in QTc interval as a result of fluoxetine therapy. Although mean QT intervals in these studies were prolonged anywhere from 2 ms to 10 ms, this likely is not clinically significant.20-22

Paroxetine is listed as a drug with conditional TdP risk on CredibleMeds, although many of the studies cited do not clearly illustrate an association.12,23-26

Fluvoxamine (Luvox, others), although not frequently used, does not appear to be associated with QT prolongation or TdP. Two studies, one examining 70 patients taking fluvoxamine at a mean dose of 105.4 mg and the other evaluating 34 patients taking fluvoxamine at an unspecified dose, found that fluvoxamine was not a significant risk factor for QTc prolongation.27,28

Any patient concomitantly taking a medication known or suspected to prolong the QT interval or any patient with known risk factors or conditions that predispose them to a prolonged QT interval may benefit from avoiding SSRI therapy altogether. This includes patients taking thioridazine, pimozide, or digitalis, as well as patients aged 65 years and older, documented LQTS, baseline elevation in QT interval or a documented history of abnormalities in levels of electrolytes, particularly sodium, potassium, and magnesium. In these patients, risk versus benefit must be cautiously weighed.

SNRIs

SNRIs likely do not impact QTc as signficantly as SSRIs. Venlafaxine is the only SNRI listed on the CredibleMeds list of drugs that is associated with reports of QTc prolongation.12 Rare QT prolongation has been described with venlafaxine at therapeutic doses and overdoses. Additionally, venlafaxine appears to possess the highest risk for QT prolongation among the newer non-SSRI antidepressants.29

One study reviewed the effects of high-dose venlafaxine (mean 346.15 mg) on various cardiovascular parameters.30 Among the 37 patients in the study, only 1 had mildly prolonged QTc (476 ms). The QTc range was 321 ms to 476 ms, with a mean of 400.19 ms. Unfortunately, baseline ECGs were not done prior to the initiation of this study, limiting the clinical usefulness of this data.

It is more difficult to assess the remaining SNRIs with respect to QT prolongation. One clinical trial comparing the safety and tolerability of duloxetine to placebo in elderly patients with MDD randomized 207 patients to either duloxetine 60 mg once daily or placebo for 8 weeks. The median age of the patients was 72 years. QTc intervals between the 2 groups were found to be statistically similar.31 Another trial studied the electrophysiologic effects of duloxetine at supratherapeutic doses. Healthy female subjects aged 19 to 74 were enrolled in this randomized, double-blind, placebo-controlled, crossover study in which duloxetine dosages were escalated from 60 mg twice daily to 200 mg twice daily. Interestingly, the mean QTc change from baseline actually decreased with duloxetine 200 mg twice-daily dosing.32

Although no published studies were identified addressing desvenlafaxine’s effect on the QT interval, data from registration studies included in the prescribing information indicated that no clinically relevant differences in QT interval were noted between desvenlafaxine (Prestiq, others) and placebo.33 However, prolongation of the QT interval was reported as a postmarketing AE with venlafaxine, and desvenlafaxine is its major metabolite.34

Limited evidence was found to support a relationship between milnacipran or levomilnacipran (Fetzima) and QT prolongation. In a double blind, placebo-controlled study of supratherapeutic doses of milnacipran, cardiac repolarization was evaluated in a group of healthy volunteers. Clinically relevant QT prolongation was not observed at therapeutic and supratherapeutic doses.35 Additionally, a 48-week extension study found no meaningful change in mean QT interval with levomilnacipran.36

Milnacipran’s product labeling refers to an unpublished, double-blind, placebo-controlled parallel study in 88 healthy subjects in which patients experienced a mean QTc change of 8 ms, although the dose used in these patients (600 mg/d) was 3 to 6 times the recommended therapeutic dose for fibromyalgia. This change was not considered to be clinically significant, even with the significantly elevated dose. The package insert makes no mention of any other ECG-related AEs, including TdP.37 Levomilnacipran’s product labeling notes that it does not prolong QTc to any clinically relevant extent, even at supratherapeutic doses.38

Most documented cases of ECG changes with SNRIs involved patients who took supratherapeutic doses, in combination with other medications known to extend the QT interval, or who had predisposing risk factors for QT prolongation. As a result, it most likely is unnecessary to monitor the ECG of patients initiated on an SNRI solely for this reason. However, it may be beneficial to do so in those concomitantly taking a medication known or suspected to prolong the QT interval, those with known risk factors for prolonged QT, or those presenting with symptoms of prolonged QT, including palpitations, seizures, or syncope. As with the SSRIs, risk versus benefit should be carefully evaluated on a patient by patient basis.

Conclusion

Starting a patient on an SSRI or SNRI requires careful consideration of pre-existing cardiac conditions, drug interactions with co-existing medications, and modifiable risk factors for arrhythmia. While risks for QT prolongation and TdP with commonly prescribed doses of these medications have been documented, these cases generally constitute rare circumstances and are most commonly associated with drug interactions or pre-existing cardiac conditions, including congenital LQTS.

Based on available evidence, the medications with the highest risk for ECG changes are citalopram and escitalopram. However, the potential for QT interval prolongation and TdP cannot be ruled out definitively for other SSRIs based on individual case documentation and AE reporting. Therefore, it is reasonable to monitor the ECG of any patient initiated on an SSRI at baseline and once post-initiation at a time interval deemed appropriate by the prescribing practitioner based on the half-life of the individual agent employed.

More importantly for pain practitioners, among the SNRIs, evidence suggests that the medication with the highest risk for ECG alterations is venlafaxine. However, the level of evidence associated with this medication is not nearly as strong as with citalopram or escitalopram. Limited literature exists to assess the potential for QT prolongation with the remaining SNRIs.

Last updated on: March 16, 2017
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