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Nov.14.2019

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

Summary

  • Serotonin norepinephrine reuptake inhibitors (SNRIs) differ from selective serotonin reuptake inhibitors (SSRIs) in that they also inhibit the reuptake of norepinephrine, as the class name indicates, but their potency with regard to serotonin reuptake inhibition is comparable to that of the SSRIs.
  • SNRIs are used for the treatment of numerous psychiatric disorders, including major depression and anxiety disorders.[49961][58403][58404][50550][50542]
  • Despite the expectation that dual receptor activity might provide greater clinical efficacy, SNRIs as a class appear to provide similar response rates to SSRIs in the treatment of major depression in adults.[50533][50534]
  • Determinants of which SNRI to choose include indication, drug interactions, drug-specific precautions (e.g., renal disease, hepatic disease), and response history of the patient.
  • Drug interactions may occur with duloxetine, desvenlafaxine, and venlafaxine due to metabolism by CYP isoenzymes. Milnacipran and levomilnacipran have minimal CYP450 metabolism, and clinically relevant interactions related to CYP metabolism are not expected.
  • Duloxetine should not be used in patients with hepatic impairment or risk factors for hepatic impairment (e.g., alcoholism). Milnacipran, levomilnacipran, venlafaxine, and desvenlafaxine can be used in patients with hepatic impairment; however, dosage adjustments for venlafaxine and desvenlafaxine are required.
  • Drug-specific dosage adjustments are required for desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine in the presence of renal dysfunction and are based upon the severity of the renal impairment.
  • Milnacipran is the only SNRI not approved in the U.S. for the treatment of major depressive disorder (MDD), but the drug is effective for MDD and is approved in some other countries for this indication.[50546]
  • Like tricyclic antidepressants (TCAs), the noradrenergic effects of the SNRIs may explain the effectiveness of some of these agents in the treatment of various pain syndromes. For example, milnacipran and duloxetine are used for fibromyalgia, and duloxetine is effective for diabetic neuropathy.

Pharmacology/Mechanism of Action

SNRIs inhibit the reuptake of both serotonin and norepinephrine. Although this reuptake blockade is thought to contribute to the therapeutic effects of SNRIs in depression and anxiety, the exact mechanism is not known. The members of the class differ in their relative potency at serotonin and norepinephrine auto-receptors; duloxetine and desvenlafaxine demonstrate a 10-fold higher selectivity for serotonin reuptake inhibition than norepinephrine reuptake inhibition and venlafaxine has a 30-fold higher affinity for the reuptake inhibition of serotonin compared to norepinephrine. Conversely, levomilnacipran and milnacipran demonstrate a 2-fold and 3-fold greater potency for norepinephrine reuptake inhibition than serotonin reuptake inhibition, respectively. Norepinephrine receptor blockade is considered important in the treatment of pain, as SSRIs have not been proven efficacious for pain disorders. Thus, some SNRIs, including milnacipran and duloxetine, have FDA-approved indications in the treatment of some pain disorders. All SNRIs inhibit serotonin uptake in human platelets, which has been associated with an increased risk of bleeding adverse events. SNRIs do not have a significant affinity for histaminergic, muscarinic, alpha1-adrenergic, postsynaptic serotonin or dopamine, GABA, or glutamate receptors in vitro, nor do they inhibit monoamine oxidase (MAO). Duloxetine and venlafaxine at high doses weakly inhibit the reuptake of dopamine, which may contribute to effects on blood pressure.[44281][50533][50534][50535][50536][50537][50540][64700]

Therapeutic Use

Major depressive disorder

  • Given the absence of differences in efficacy or tolerability between drug classes, the SNRIs are not preferentially recommended over SSRIs in the treatment of major depressive disorder (MDD).[50533][50534][50541]
  • Choice of antidepressant for each patient is based on several factors such as tolerability, drug interactions, prior history of response, and efficacy in the selected indication.[49961][50534][50541]
  • SNRIs have not been approved for use in pediatric populations for the treatment of depression; however, guidelines from the American Academy of Child and Adolescent Psychiatry (AACAP) recommend the use of antidepressants when nonpharmacologic treatment is insufficient or illness severity is high. Data specific to SNRIs in the treatment of pediatric depression are limited. Therefore, SNRIs are generally reserved for use in pediatric patients with documented antidepressant treatment failure or intolerability to an SSRI.[49959][50551]
  • According to the manufacturer of duloxetine, efficacy was not established in two 10-week controlled trials with 800 pediatric patients 7 years and older with major depressive disorder.[29934]

Anxiety

  • Due to their efficacy and safety profile, venlafaxine and duloxetine are considered first-line treatment options for generalized anxiety disorder (GAD) in adults.[50550]
  • Duloxetine is approved for GAD in pediatric patients 7 years and older.[29934]

Fibromyalgia

  • Duloxetine and milnacipran have proven efficacy and safety in the treatment of fibromyalgia in adults. Duloxetine is the only SNRI approved for the treatment of fibromyalgia in adolescents 13 years and older.[29934][23431]
  • In adults, the overall benefit is modest (i.e., benefit for pain, sleep, fatigue, depression, and health-related quality of life in randomized controlled trials was significant, but the effect size was small for pain and not substantial for the other efficacy parameters).[50536]
  • Duloxetine and milnacipran are similar in efficacy to pregabalin, an anticonvulsant with FDA approval for the treatment of fibromyalgia; however, pregabalin is superior to milnacipran for sleep outcomes.[50552]

Other uses

  • Duloxetine has shown effectiveness in treating pain associated with diabetic peripheral neuropathy (DPN), and was the first drug specifically approved for DPN in adults.[29934]
  • Duloxetine is beneficial for treating chronic musculoskeletal pain in adults. Efficacy was established in patients with chronic low back pain and chronic pain due to osteoarthritis.[29934]
  • Duloxetine is recommended for the off-label treatment of stress urinary incontinence in women because it increases detrusor muscle tone.[50543]
  • Venlafaxine and desvenlafaxine are used off-label in the treatment of vasomotor symptoms (hot flushes) associated with menopause or breast cancer; these drugs are effective alternatives for women who cannot use, or do not wish to use, hormonal therapy for vasomotor symptom control.[59154][50675][62040]

Comparative Efficacy

Meta-Analysis of SNRIs vs. SSRIs for Depression[50533]

 Venlafaxine vs FluoxetineDuloxetine vs EscitalopramMilnacipran vs Fluoxetine
SNRI, Respondersa (n)/total treatedb (N) (%)679/1116 (61)260/562 (46)156/336 (46)
SSRI, respondersa (n)/total treatedb (N) (%)607/1126 (54)286/558 (51)106/224 (47)
Odds ratio SNRI to SSRI (95% CI)1.36 (1.14-1.62)c0.77 (0.52-1.13)0.87 (0.54-1.39)
Efficacy conclusionVenlafaxine had a significantly higher response rate than fluoxetineNo significant difference in efficacy between duloxetine and escitalopramNo significant difference in efficacy between milnacipran and fluoxetine
SNRI, All-cause withdrawal (n)/total randomizedd (N) (%)302/1220 (25)131/411 (32)138/336 (41)

SSRI, all-cause withdrawal (n)/total randomizedd (N) (%)

 

290/1226 (24)87/414 (21)83/224 (37)
Odds ratio SNRI to SSRI (95% CI)1.07 (0.88-1.29)1.93 (0.99-3.77)1.02 (0.71-1.46)
Acceptability conclusionNo significant difference in acceptability between venlafaxine and fluoxetineNo significant difference in acceptability between duloxetine and escitalopramNo significant difference in acceptability between milnacipran and fluoxetine

aResponse = a reduction of at least 50% from the baseline score on the Hamilton Depression Rating Scale (HAM-D) or Montgomery-Asberg depression rating scale (MADRS), or a score of "much improved" or "very much improved" on the Clinical Global Impression scale (CGI) at 8 weeks (intention to treat; last observation carried forward [ITT-LOCF]); bITT population; cstatistically significant (lower limit of 95% confidence interval [CI] 1 or greater); dsafety population

 

SNRIs Comparative Efficacy Trials

Citation/Study NameDesign/RegimenResultsConclusion
Perahia DG, et al. J Psychiatr Res. 2008;42:22-34 [50544]

Data pooled from 2 similarly designed, double-blind, parallel group studies; patients with major depressive disorder were randomized to duloxetine (n=330) or venlafaxine XR (n=337) x 12-weeks

 

The primary outcome measure was Global Benefit-Risk (GBR). In the GBR analysis, benefit was defined as remission at end point (17-item HAM-D score of 7 or less). Risk was defined by 4 categories: i) patients having no adverse events (AEs); ii) AEs with no severity rating greater than moderate; iii) AEs with at least 1 severity rating of severe; and iv) having discontinued with a reason of self-reported AE. GBR scores ranged from +5 (remission and no AEs) to -5 (no remission and discontinued due to AE)

GBR at 12 weeks (LOCF, linear score, mean [SE]): duloxetine vs venlafaxine, -0.35 (0.21) vs -0.12 (0.20), p=0.44

 

Completion rates: 74.5% for venlafaxine XR vs 64.8% for duloxetine, p < 0.01

 

Remission rates at 12 weeks: duloxetine, 48.1% vs venlafaxine, 50.3%

 

Common AEs: nausea (43.6% vs 35.0%, p=0.02) and dizziness (16.1% vs 10.4%, p=0.03) were more frequent in duloxetine group

 

Discontinuation due to AEs: occurred more frequently in the duloxetine group at 12 weeks (14.5% vs 9.2%; p=0.03)

Both drugs had negative GBR scores at 12 weeks, suggesting that this outcome measure may have been too strict. About one-half of patients taking either drug achieved remission at 12 weeks. Venlafaxine was slightly but significantly better tolerated as evidenced by fewer discontinuations due to AEs and higher study completion rates. The study was sponsored by Lilly, the maker of duloxetine
Cunningham LA. Ann Clin Psychiatry. 1997;9:157-164 [50545]

Double-blind, placebo-controlled comparison of the efficacy and safety of venlafaxine XR and venlafaxine immediate-release (IR) x 12 weeks.

 

Primary efficacy variables were the 21-item HAM-D Rating Scale total score and depressed mood item, the MADRS total scores, and the CGI severity scale. Safety/tolerability were assessed by AEs, physical exam, sentinel events, vital signs, electrocardiogram, and lab tests

Efficacy at week 12: HAM-D: XR, 9.4; IR, 12.3; placebo, 15.8 (p < 0.05 favoring XR vs IR) MADRS: XR, 10.6; IR, 13.3; placebo, 18.3 (p < 0.05 favoring XR vs IR) CGI: XR, 2.08; IR, 2.67; placebo, 3.18 (p < 0.05 favoring XR vs IR) Both XR and IR were superior to placebo at weeks 6 and 12

 

Completion rates: XR group had a higher rate (71%) than IR (60%) or placebo (59%) (p=NS)

 

AEs: Nausea most common in XR and IR (45% each); sexual dysfunction in men highest in XR (27%) vs IR (6%) and placebo (0%)

Venlafaxine XR exhibited superiority over venlafaxine IR at week 12 for all efficacy variables. The most common AE was nausea, regardless of formulation. The results indicate that venlafaxine XR is safe, effective, and well-tolerated. Sexual dysfunction in men was higher in the XR group
Tourian KA, et al. Clin Ther. 2009;31(Pt 1):1405-1423 [44282]

Double-blind, duloxetine-referenced, placebo-controlled, parallel-group, 8-week study comparing desvenlafaxine (50 or 100 mg/day) to duloxetine (60 mg/day) in 615 adults with major depressive disorder (HAMD-17 score of 20 or more).

 

Primary outcome measure was HAMD-17 total score at final evaluation. Additional measures included the CGI-I, MADRS, and CGI-S. Tolerability assessments included discontinuation rates, AEs, vital signs, and lab tests. Post hoc pooled analysis was performed using data from the current study and 2 previous similar studies that compared the efficacy and tolerability of desvenlafaxine with placebo for major depressive disorder

HAMD-17: desvenlafaxine 100 mg/day (-10.5, p=0.03) and duloxetine 60 mg/day (-10.3, p < 0.05) groups compared with placebo (-8.7). Desvenlafaxine 50 mg did not differ from placebo.

 

CGI-I, MADRS, and CGI-S: desvenlafaxine 100 mg/day and duloxetine 60 mg/day had significantly better scores compared with placebo; desvenlafaxine 50 mg was not superior to placebo.

 

Discontinuation rates due to AEs: 5%, 7%, 13%, and 6% for the desvenlafaxine 50 mg/day, desvenlafaxine 100 mg/day, duloxetine 60 mg/day, and placebo groups, respectively.

 

Post hoc pooled HAM-D(17) (N=1388): desvenlafaxine 50 mg/day (-11.5, p < 0.001), desvenlafaxine 100 mg/day (-11.8, p < 0.001) were superior to placebo (-9.6)

The pooled analysis showed that desvenlafaxine 50 mg and 100 mg daily were similarly significantly more efficacious than placebo on the primary outcome measure. In the duloxetine-referenced trial, only the 100 mg dose was superior to placebo and equivalent in efficacy to duloxetine. Both doses of desvenlafaxine had placebo-like tolerability profiles
Sechter D, et al. J Affect Disord. 2004;83(2-3):233-236 [50546]A 6-week double-blind, randomized, parallel group study compared milnacipran (100 mg/day) with paroxetine (20 mg/day) in 300 outpatients with major depression. Efficacy (ITT-LOCF) was evaluated using HAMD17, MADRS, and CGI. Safety and tolerability were assessed in standard fashion

HAMD17, MADRS, and CGI: No significant differences were noted on any outcome measure between groups

 

Safety/tolerability: No major safety issues were noted; tolerability was similar

Both milnacipran and paroxetine were effective and well-tolerated by outpatients with major depression treated for 6 weeks. After treatment discontinuation milnacipran was associated with fewer emergent symptoms

Adverse Reactions/Toxicities

Gastrointestinal adverse reactions

Gastrointestinal (GI) side effects are the most common adverse reactions in patients receiving SNRI treatment. Nausea is the most common adverse reaction with any SNRI. It is most often transient and of mild to moderate intensity. Other less frequently reported GI effects include dry mouth (xerostomia), constipation, and vomiting. One review noted that venlafaxine, one of the SNRIs, was associated with a higher risk for nausea when compared to agents in the SSRI class.[50534][23430][23431][28275][33715][34940][55469]

Central nervous system adverse reactions

Headache, dizziness, drowsiness, and insomnia are the most common centrally-mediated adverse reactions, but are rarely severe and usually do not lead to treatment discontinuation.[23430][23431][28275][33715][34940][55469]

Bleeding

Impaired platelet aggregation may occur during treatment with SNRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. A postmarketing study showed a higher incidence of postpartum hemorrhage in mothers taking duloxetine. Other bleeding events related to SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Concomitant use of antiplatelet drugs (e.g., aspirin), non-steroidal antiinflammatory drugs (NSAIDs), or anticoagulant medications may add to this risk.[23430][23431][28275][33715][34940][55469]

Blood pressure changes

All SNRIs have been associated with sustained elevation of blood pressure, most notably venlafaxine. Blood pressure should be monitored closely when initiating therapy or increasing SNRI dosages, and routinely thereafter. Orthostatic hypotension has also been reported, particularly in the elderly.[50534][23430][23431][28275][33715][34940][55469]

Hyponatremia

SNRIs may cause hyponatremia as a result of the syndrome of inappropriate antidiuretic hormone secretion; serum sodium levels less than 110 mmol/L have been reported. Elderly patients, those receiving diuretics or prone to dehydration, and those who are otherwise volume-depleted (e.g., hypovolemia) appear to be at greatest risk. The syndrome is reversible upon discontinuation of the causative SNRI.[23430][23431][28275][33715][34940][55469]

Dermatologic and hypersensitivity reactions

Hyperhidrosis (increased sweating) is the most common adverse dermatologic effect associated with SNRIs. Severe reactions, including anaphylactoid reactions, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, have been reported rarely with the various SNRIs. The SNRI should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other cause can be identified.[50534][23430][23431][28275][33715][34940][55469]

Sexual dysfunction

Sexual dysfunction is commonly reported with the use of serotonergic agents such as SNRIs and may result in treatment discontinuation in some patients. In men, these symptoms may include ejaculatory failure or delay, decreased libido, and/or erectile dysfunction. Women may experience decreased libido and delayed or absent orgasm. Clinicians should discuss sexual function with patients prior to initiating treatment and throughout treatment to identify any changes in sexual function and determine if they are medication-related or attributed to the underlying psychiatric disorder. Patients should also be provided with management strategies and treatment options for symptoms of sexual dysfunction.[50534][23430][23431][28275][33715][34940][55469]

Angle-closure glaucoma

Closed-angle glaucoma has occurred in patients with untreated anatomically narrow angles during treatment with antidepressants. Duloxetine is contraindicated in patients with uncontrolled angle-closure glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.[23430][23431][28275][33715][34940][55469]

Hepatotoxicity

Elevated liver function tests (LFTs) have been reported with all SNRIs and appear to be dose-related. Hepatitis and hepatic failure have occurred during administration of some SNRIs; fatalities have been reported. SNRIs with renal excretion as the major route of elimination (e.g., levomilnacipran) are an alternative to consider in patients with hepatic disease.[23430][23431][28275][33715][34940][55469]

Neonatal abstinence syndrome

Symptoms consistent with a neonatal discontinuation syndrome (e.g., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting) have been reported in infants exposed to SNRIs in utero, particularly during the third trimester. SNRIs should be used in pregnancy only where the benefit to the mother clearly outweighs any potential risk to the fetus. Consider the risks of untreated depression during pregnancy as well as the potential risks to the fetus from exposure to the drug. If clinically feasible, and taking the drug half-life into consideration, tapering of the antidepressant prior to delivery may be considered.[46229][62732][50547][23430][23431][28275][33715][34940][55469]

Drug Interactions

MAO inhibitors

SNRIs are contraindicated in patients receiving MAO inhibitors (MAOIs) or within 2 weeks of their discontinuation due to the risk of serotonin syndrome. Medications with MAOI activity, such as linezolid or intravenous methylene blue, are also contraindicated for use with SNRIs because of an increased risk of serotonin syndrome.[23430][23431][28275][29934][33715][34940][55469]

SSRIs, SNRIs and other serotonergic drugs

Any use of an SNRI with other serotonergic agents increases the likelihood of serotonergic adverse effects and should be monitored closely. Drugs that have serotonergic properties include opiates, triptans, most antidepressants, amphetamines, St. John's wort, tramadol, lithium, buspirone, and others.[23430][23431][28275][29934][33715][34940][55469]

Antithrombotic drugs

Anticoagulants, antiplatelet drugs (e.g., aspirin), and nonsteroidal anti-inflammatory drugs (NSAIDs) should be administered with caution to any patient taking an SNRI. Platelet aggregation may be impaired by SNRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.[23430][23431][28275][29934][33715][34940][55469]

Drugs that inhibit CYP2D6 or CYP1A2

Levomilnacipran and milnacipran are not metabolized to any significant extent by CYP450 isoenzymes and are not inducers or inhibitors of any of these isoenzymes. Venlafaxine is metabolized by CYP2D6, and CYP2D6 inhibitors may increase venlafaxine concentrations. A dose-related CYP2D6 inhibitory effect has been observed with desvenlafaxine; therefore, the dose of primary CYP2D6 substrates should be reduced by up to one-half if coadministered with desvenlafaxine 400 mg/day. Duloxetine is metabolized by CYP1A2 and CYP2D6; inhibitors of CYP1A2 and CYP2D6 may increase duloxetine concentrations.[23430][23431][28275][29934][33715][34940][55469]

Safety Issues

Hypersensitivity and cross-sensitivity issues

Allergic reactions may occur with the use of any SNRI. Because some SNRIs are available as both a racemic compound (e.g., milnacipran) and a single enantiomer of the racemic compound (e.g., levomilnacipran), cross-sensitivity should be expected. Similarly, cross-sensitivity is possible between desvenlafaxine and venlafaxine, since venlafaxine is the parent compound of desvenlafaxine. Levomilnacipran and milnacipran are contraindicated in patients exhibiting hypersensitivity to the related drug; desvenlafaxine and venlafaxine are contraindicated in patients who have demonstrated a hypersensitivity to the related drug.[23430][23431][28275][33715][34940][55469]

Increased risk of suicide

The approved labeling for all antidepressants carries a boxed warning of an increased risk of suicidal thoughts and behavior in children and young adults, particularly during the first few months of therapy. Experts state that the apparent increase in suicidality reflected by a greater number of spontaneously reported events is mitigated by the lack of any completed suicides, the decline in overall suicidality on rating scales, and the greater number of patients who benefit from antidepressants than who experience these serious adverse effects. Careful assessment and monitoring of suicidality are warranted in all patients initiating treatment with an SNRI.[50534][62891][23430][23431][28275][33715][34940][55469]

Bipolar disorder

The use of antidepressants has been associated with the precipitation of mania or hypomania in susceptible individuals. If a patient develops manic symptoms, the antidepressant should be withheld, and appropriate therapy initiated to treat the manic symptoms. Depression may also be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.[23430][23431][28275][33715][34940][55469]

Hepatic impairment

SNRI use has been associated with elevated hepatic enzymes. Duloxetine is not recommended in patients with any degree of hepatic impairment. Avoidance of duloxetine is recommended in patients with substantial alcohol use, alcoholism, hepatic necrosis, and/or chronic liver disease. Dosage adjustments of venlafaxine and desvenlafaxine are recommended in patients with hepatic impairment. Milnacipran can be used cautiously in patients with hepatic impairment. SNRIs with renal excretion as the major route of elimination (e.g., levomilnacipran) are an alternative option in patients with hepatic disease.[23430][23431][28275][33715][34940][55469]

Pregnancy

Treatment with all selective serotonin reuptake inhibitors (SSRIs) during pregnancy should be individualized. The American Psychiatric Association guidelines state that treatment of depression during early pregnancy requires careful risk-benefit assessment, in collaboration with the patient and potentially a neonatal specialist. Use of serotonergic antidepressants, including SNRIs, during the third trimester has been associated with neonatal complications, including prolonged hospitalization, respiratory support, and tube feeding. In addition, exposure to SNRIs in mid to late pregnancy may increase the risk of eclampsia. Exposure near delivery may increase the risk for postpartum hemorrhage. The benefits of treatment should clearly outweigh risks to justify treatment during pregnancy.[23430][23431][28275][33715][34940][55469][49961][62732]

Breast-feeding

Small concentrations of SNRIs have been measured in breast milk, with uncertain consequences for the infant. The benefits of drug treatment to the mother need to be weighed against the potential risk of infant drug exposure. There are reports of agitation, irritability, poor feeding, and poor weight gain following exposure to serotonergic antidepressants through breast milk. Any infant exposed to an SNRI through breast-feeding should be monitored for these adverse effects.[46229][61269][62732]

Abrupt discontinuation

Similar to other antidepressants, a discontinuation syndrome can occur when SNRIs are abruptly halted. This syndrome is characterized by dizziness, weakness, nausea, headache, lethargy, insomnia, anxiety, poor concentration, paresthesias (tactile sensations), and increased gastrointestinal motility. Symptoms occur most frequently and severely with shorter-acting agents (e.g., immediate-release venlafaxine). A slow, individualized taper is advisable, particularly after chronic use, to minimize discontinuation symptoms.[42869][64743]

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