6.5. Challenges in POTS Management

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Prognosis and Future Outlook]] → -------- ##### Summary >[!Summary] >- patients pose a particular challenge in management, which reflects the pathophysiologic heterogeneity of orthostatic intolerance, the presence of multiple comorbidities not directly related to orthostatic stress[[#^1]] >- lack of patient education (or, worse, patient misinformation) about the disorder[[#^2]] >- unrealistic expectations about the beneficial effects of treatment aimed to correct the postural tachycardia and secondary frustration and symptom amplification[[#^2]] >- failure to recognize the heterogeneous pathophysiologic basis of orthostatic tachycardia in POTS[[#^3]] >- drug treatment may need to be individualized, depending on whether impaired peripheral vasoconstriction and venous pooling, hyperadrenergic state, or hypovolemia is thought to be the most prominent trigger[[#^3]] >- complicating factor is that the doses of fludrocortisone, midodrine, -blockers, or pyridostigmine used for treatment of other conditions such as neurogenic orthostatic hypotension or inappropriate sinus tachycardia may not be tolerated by many patients with POTS[[#^3]] >- Drugs used to treat POTS comorbidities may also exacerbate orthostatic tachycardia; these include amphetaminelike psychostimulants used to treat chronic fatigue and antidepressants such as amitriptyline used to treat insomnia, migraine, fibromyalgia, or visceral pain[[#^3]] >- reason for symptom persistence is the failure to address physical deconditioning with a gradual exercise program. patients may initially exercise too vigorously, leading to worsening of symptoms[[#^3]] >- fundamental role of somatic hypervigilance, behavioral arousal, and emotional conditioning in the maintenance of the patient’s orthostatic, as well as nonorthostatic, symptoms[[#^3]] >- heterogeneity and wide spectrum of POTS-related symptoms create a great challenge for clinicians and affected patients[[#^4]] >- poorly explored pathophysiology of POTS makes it literally impossibly to treat the roots of disease and the management of POTS is usually focused on symptom alleviation[[#^4]] >- long-term prognosis of POTS is not well explored[[#^4]] > >**Wrong Medication** >- POTS patients might have less “tachycardia reserve” and be more susceptible to exaggerated tachycardia with many antidepressant and attention deficit medications (can recreate an orthostatic tachycardia phenotype even in susceptible healthy volunteer subjects)[[#^5]] >- norepinephrine transporter (NET) inhibitors, or serotonin norepinephrine reuptake inhibitors (SNRIs), can exacerbate tachycardia in POTS[[#^6]] >- tricyclic antidepressants, such as amitriptyline and nortriptyline, should be used with caution in POTS since they can increase drowsiness and cognitive impairment[[#^8]] >- selective norepinephrine reuptake inhibitors (SNRIs) are not recommended for POTS (one randomized, placebo-controlled trial found that an acute 40 mg oral dose of the SNRI atomoxetine increased orthostatic tachycardia and worsened symptoms in POTS patients). SNRIs also have numerous side effects including nausea, dry mouth, dizziness, headache, fatigue, and insomnia. According to the HRS Expert Consensus Statement, in most cases, SNRIs should be avoided in POTS[[#^9]] >- β-antagonists, SSRIs, and SNRIs were felt to have made brain fog worse. Effects of SNRIs on brain fog could be due to high levels of synaptic norepinephrine in the hyperadrenergic POTS variant[[#^10]] -------- >_“These patients pose a particular challenge in management, which reflects the pathophysiologic heterogeneity of orthostatic intolerance, the presence of multiple comorbidities not directly related to orthostatic stress, and the lack of recognition that patients with POTS frequently require exercise training and behavioral-cognitive approaches to obtain longterm control of their symptoms.”_ ([[Benarroch-2012]], [p. 1](zotero://open-pdf/library/items/WEZLT9QC?page=1&annotation=IJBF9KDP))^1 >_“Several factors contribute to the difficulties in the management of patients with POTS. First is the lack of patient education (or, worse, patient misinformation) about the disorder. This leads to unrealistic expectations about the beneficial effects of treatment aimed to correct the postural tachycardia and secondary frustration and symptom amplification.”_ ([[Benarroch-2012]], [p. 8](zotero://open-pdf/library/items/WEZLT9QC?page=8&annotation=5XQT2T99))^2 >_“A second factor is the failure to recognize the heterogeneous pathophysiologic basis of orthostatic tachycardia in POTS. Drug treatment may need to be individualized, depending on whether impaired peripheral vasoconstriction and venous pooling, hyperadrenergic state, or hypovolemia is thought to be the most prominent trigger. A complicating factor is that the doses of fludrocortisone, midodrine, -blockers, or pyridostigmine used for treatment of other conditions such as neurogenic orthostatic hypotension or inappropriate sinus tachycardia may not be tolerated by many patients with POTS, particularly those with physical deconditioning and ([p. 8](zotero://open-pdf/library/items/WEZLT9QC?page=8&annotation=F8PGH36R)) comorbid conditions. Drugs used to treat POTS comorbidities may also exacerbate orthostatic tachycardia; these include amphetaminelike psychostimulants used to treat chronic fatigue and antidepressants such as amitriptyline used to treat insomnia, migraine, fibromyalgia, or visceral pain. Another reason for symptom persistence is the failure to address physical deconditioning with a gradual exercise program. Although many patients are motivated to exercise, they may initially exercise too vigorously, leading to worsening of symptoms. Finally and perhaps most importantly is the fundamental role of somatic hypervigilance, behavioral arousal, and emotional conditioning in the maintenance of the patient’s orthostatic, as well as nonorthostatic, symptoms.”_ ([[Benarroch-2012]], [p. 9](zotero://open-pdf/library/items/WEZLT9QC?page=9&annotation=L8R7UXX5))^3 >*“The heterogeneity and wide spectrum of POTS-related symptoms create a great challenge for clinicians and affected patients. Moreover, poorly *([p. 8](zotero://open-pdf/library/items/BZ35QDLR?page=8&annotation=Q2FABPU3))* explored pathophysiology of POTS makes it literally impossibly to treat the roots of disease and the management of POTS is usually focused on symptom alleviation [63, 64]. The long-term prognosis of POTS is not well explored.” *([[Fedorowski-2019]], [p. 9](zotero://open-pdf/library/items/BZ35QDLR?page=9&annotation=IZG4LNB8))^4 ## Wrong Medication >*“many antidepressant and attention deficit medications work at least in part through inhibition of NET. This includes traditional drugs such as tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine, or milnacipran), or purer NET inhibitors (e.g., atomoxetine or reboxetine). Pharmacological NET inhibition can recreate an orthostatic tachycardia phenotype in susceptible healthy volunteer subjects 12. POTS patients might have less “tachycardia reserve” and be more susceptible to exaggerated tachycardia with these medications.” *([[Raj-2013]], [p. 4](zotero://open-pdf/library/items/CCJLQKRB?page=4&annotation=MVPVKC3J))^5 >*“Norepinephrine transporter (NET) inhibitors, or serotonin norepinephrine reuptake inhibitors (SNRIs), can exacerbate tachycardia in POTS [73]. The HRS cautions against their use in POTS” *([[Garland-2015]], [p. 10](zotero://open-pdf/library/items/CAWTWYLR?page=10&annotation=93YQMCVW))^6 >*“Selective serotonin reuptake inhibitors (SSRIs) have a mild vasoconstrictor effect however, they are mostly used in POTS for the psychotropic effects. No studies to date have assessed the effectiveness in of SSRIs in POTS.”* ([[Miller-2018]], [p. 6](zotero://open-pdf/library/items/A3CIPE3G?page=6&annotation=5H3Q93Q2))^7 >*“Tricyclic antidepressants, such as amitriptyline and nortriptyline, should be used with caution in POTS since they can increase drowsiness and cognitive impairment.”* ([[Miller-2018]], [p. 6](zotero://open-pdf/library/items/A3CIPE3G?page=6&annotation=EYMWTVL8))^8 >*“Conversely, selective norepinephrine reuptake inhibitors (SNRIs) are not recommended for POTS. SNRIs have been suggested as a potential treatment for POTS because they can also increase blood pressure by increasing plasma levels of norepinephrine (the “N” in “SNRI”). Several SNRI drugs, such as duloxetine and venlafaxine, have been advocated for the treatment of neuropathic pain in related disorders such as fibromyalgia (Hauser et al., 2013). However, there have been very few trials of this drug in POTS. One randomized, placebo-controlled trial found that an acute 40 mg oral dose of the SNRI atomoxetine increased orthostatic tachycardia and worsened symptoms in POTS patients (Green et al., 2013). SNRIs also have numerous side effects including nausea, dry mouth, dizziness, headache, fatigue, and insomnia. The HRS Expert Consensus Statement made this a class 3 recommendation, meaning that in most cases SNRIs should be avoided in POTS (Sheldon et al., 2015).”* ([[Miller-2018]], [p. 6](zotero://open-pdf/library/items/A3CIPE3G?page=6&annotation=9EJ7E6VQ))^9 >*“some treatments commonly used to treat POTS, such as β-antagonists, SSRIs, and SNRIs were felt to have made brain fog worse ([p. 5](zotero://open-pdf/library/items/5NBCV5L2?page=5&annotation=GGBGBY8G)) [...] The negative effects of SNRIs on brain fog could be due to high levels of synaptic norepinephrine in the hyperadrenergic POTS variant”* ([[Ross-2013]], [p. 5](zotero://open-pdf/library/items/5NBCV5L2?page=5&annotation=KNUSFNT5))^10