In the wake of the prescription opioid crisis, many providers have sought to implement nonopioid therapies to employ safer medication options.

Nonetheless, like opioids, nonopioid options carry inherent risks, including drug–drug interactions that must be carefully considered when designing patient-specific polypharmacy regimens for pain and nonanalgesic purposes. One such class of medications is serotonin norepinephrine reuptake inhibitors (SNRIs), often used to treat neuropathic pain because of their norepinephrine reuptake inhibition.1 They also exert nonanalgesic activity by serotonin reuptake blockade. The sum effect results in increased extracellular neuroamines to postsynaptic receptors.1 The serotonin component of SNRIs offers particular interest when considering drug–drug interactions. Beyond effects on the neural synapse, inhibition of serotonin reuptake has larger systemic implications, as the effect also plays out in other areas of the body. Endogenous serotonin, located in platelets, is involved in the clotting cascadem, causing localized vasoconstriction, and is also involved in the conversion of fibrinogen to fibrin, promoting platelet aggregation.2 Specifically, serotonin reuptake inhibitors (SSRIs) have been shown to inhibit reuptake of serotonin in platelets, impairing platelet aggregation.A wide variety of studies have examined increased bleeding risk with the use of SSRIs alone or in combination with other agents, which increases risk.

Although fewer studies examining the effects of SNRIs on bleeding risk exist, it is logical to expect SNRIs to affect bleeding to some extent. The degree to which they do is unclear. One theory for the degree of effect is the serotonin-to-norepinephrine (NE) ratio, which is calculated by examining the Ki binding affinity to the receptor.1,4 Increasing norepinephrine activity of SNRIs correlates with diminished serotonin effects.As such, it seems plausible that SNRIs with greater NE activity and lower serotonin impact could offer a lesser impact to bleeding risk than those with lower NE ratios and SSRIs. A study by Renoux et al examined the association of SSRIs with spontaneous intracranial hemorrhage (ICH) and found an increased risk of ICH with antidepressants, and those that have an increased affinity for the serotonin transporter posed a higher risk.5 Sayadipour and colleagues examined blood loss in patients undergoing spinal surgery with concomitant antidepressant use including SSRI, SNRI, bupropion, serotonin antagonist, or tricyclic antidepressant as either monotherapy or a combination.6 The team found an increase in blood loss of 23% in those taking antidepressants compared with the control group.6

Regarding such bleeding risks, certain concomitant medications could potentiate bleeding. Commonly prescribed medications to watch for include anticoagulants, antiplatelet agents, and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). The data are limited on concomitant use of 1 or more of these agents with SNRIs and/or SSRIs. Of note, however, Perahia et al examined available safety data from studies of duloxetine over 7 years.7 On analysis of adverse events, they identified a significantly greater bleeding risk in patients treated with duloxetine alone compared with a placebo. Interestingly, the same analysis did not find a statistically significant increase in bleeding in patients taking concomitant duloxetine and an NSAID. However, it is difficult to draw a conclusion regarding bleeding risk with concomitant NSAIDs because NSAID stratification by dose and cyclooxy- genase selectivity varied across studies.7

A recent subanalysis of data from the ROCKET AF trial examined bleeding risk in patients anticoag- ulated and receiving a concomitant antidepressant.The authors concluded there was a “suggestion” for increased bleeding in patients anticoagulated with warfarin and taking an SSRI but did not find a significantly increased bleeding risk with the combination of anticoagulants and SSRIs in general.The authors were prudent to point out the need to consider these results within the clinical context, citing their own previous study, whose results concluded that SSRI use was associated with an increased risk of major hemorrhage in the setting of concomitant warfarin use.9

When considering this information within the clinical context, providers should note the potential bleeding risk posed by SNRIs/SSRIs within the context of additive factors. The clinical risk for a bleeding incident is likely to increase with the prescription of an SNRI/SSRI combined with anticoagulants, nonselective NSAIDs, and/or aspirin. An important interaction to consider is alcohol consumption, given the associated anticoagulant effects.10 Although comorbid clotting disorders, such as von Willebrand disease, would likely increase this risk with SNRI/SSRI use, another additive factor to consider is genetic polymorphism in the serotonin transporter gene, which is known to be associated with platelet dysfunction.3

As with the selection of any medication, providers should weigh the benefits against the risks and particularly consider potential additive factors. Although providers want to find alternatives to opioids, SNRIs can offer benefits. However, they have inherent risks that must be considered to ensure that polypharmacy remains rational.

 
Erica L. Wegrzyn, PharmD, is a clinical pharmacy specialist in pain management at Stratton VA Medical Center in Albany, New York, as well as a member of the adjunct faculty at Western New England University College of Pharmacy and Health Sciences in Springfield, Massachusetts, and the Albany College of Pharmacy and Health Sciences in New York.

Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB, is chief executive officer and chief medical officer of Remitigate LLC. In addition, he is the owner and managing editor of PainDr.com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences and an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences.



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