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Management of headache and chronic pain in POTS

  • Glen A. Cook Jr
    Correspondence
    Corresponding author at: Department of Neurology, Naval Medical Center, Portsmouth, VA, United States of America.
    Affiliations
    Department of Neurology, Naval Medical Center, Portsmouth, VA, United States of America

    Uniformed Services University F. Edward Hebert School of Medicine, Bethesda, MD, United States of America
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  • Paola Sandroni
    Affiliations
    Department of Neurology, Mayo Clinic, Rochester, MN, United States of America
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      Abstract

      Primary headache syndromes and chronic pain syndromes are common in patients with postural tachycardia syndrome (POTS). There is overlap in potential mechanisms for migraine, chronic pain, and POTS symptomatology. Management of chronic pain and headaches in POTS requires a judicious use of pharmacotherapies that takes into account patient comorbidities and co-existing symptoms. Patient-centric, non-pharmacologic modalities include physical exercise, cognitive behavioral therapies, and treatment of sleep disorders.

      Keywords

      1. Introduction

      Chronic pain and headache are prevalent conditions in the general population and a frequent cause for seeking medical care in both primary and specialty care settings. About 1 in 5 adults in the United States reports daily pain (
      • Nahin R.L.
      Estimates of pain prevalence and severity in adults: United States, 2012.
      ) and about 10% of adults have neuropathic pain (
      • Yawn B.P.
      • Wollan P.C.
      • Weingarten T.N.
      • Watson J.C.
      • Hooten W.M.
      • Melton L.J.
      The prevalence of neuropathic pain: clinical evaluation compared with screening tools in a community population.
      ). Migraine, responsible for the majority of disability and medical cost related to headache (
      • Younger D.S.
      Epidemiology of migraine.
      ), occurs in 18% of people across their lifetime and at a rate of 13% of all people in any given year (
      • Abu-Arafeh I.
      • Razak S.
      • Sivaraman B.
      • Graham C.
      Prevalence of headache and migraine in children and adolescents: a systematic review of population-based studies.
      ).
      There are no studies of pharmacologic or non-pharmacologic management of headache or chronic pain specific to POTS. Therefore, the clinician must consider other symptoms and comorbidities of POTS patients when selecting treatment approaches. Mechanisms of action and common side effects of treatments must be weighed against other symptoms the patient with POTS may have.

      2. Headache epidemiology

      Data regarding the prevalence of pain and headache disorders in persons with postural tachycardia syndrome (POTS) are limited.
      • Deb A.
      • Morgenshtern K.
      • Culbertson C.J.
      • Wang L.B.
      • Hohler A.D.
      A survey-based analysis of symptoms in patients with postural orthostatic tachycardia syndrome.
      reported on a cohort of 39 patients diagnosed in their center with POTS. Eighty-seven percent of these patients reported headaches.
      • Ojha A.
      • Chelimsky T.C.
      • Chelimsky G.
      Comorbidities in pediatric patients with postural orthostatic tachycardia syndrome.
      reported a headache rate of 46% in adolescents and 61% in adults with POTS.
      • Khurana R.K.
      • Eisenberg L.
      Orthostatic and non-orthostatic headache in postural tachycardia syndrome.
      reported that 96% of their cohort of 24 POTS patients met criteria for migraine or probable migraine. In a survey of 3030 patients diagnosed by a physician with POTS,
      • Raj S.R.
      • Stiles L.E.
      • Shaw B.
      • Green E.A.
      • Dorminy C.A.
      • Shibao C.A.
      • et al.
      The face of postural tachycardia syndrome: a cross-sectional community-based survey.
      reported migraines in 41% of people with POTS.

      2.1 Headache classification and pathogenesis

      Headaches are classified in a hierarchical fashion according to criteria delineated in the International Classification of Headache Disorders (ICHD), now in its third version (). As noted above, migraines and other primary headaches are highly prevalent in POTS populations. Key diagnostic features of common primary headache disorders are summarized in Table 1.
      Table 1Key diagnostic features of common and selected primary headache disorders ().
      Primary headache classificationHeadache typeDescription and comments
      MigraineMigraine without auraHeadache has at least two of the following four characteristics:

      • Unilateral location
      • Pulsating quality
      • Moderate or severe pain intensity
      • Aggravation by or causing avoidance of routine physical activity
      And at least one of the following:

      • Nausea and/or vomiting
      • Photophobia and phonophobia
      Migraine with typical auraAura consisting of visual, sensory and/or speech/language symptoms, each fully reversible, but no motor, brainstem or retinal symptoms

      At least two of the following four characteristics:

      • At least one aura symptom spreads gradually over ≥5 min, and/or two or more symptoms occur in succession
      • Each individual aura symptom lasts 5–60 min
      • At least one aura symptom is unilateral
      • The aura is accompanied or followed within 60 min by headache
      Aura may occur without headache
      Migraine with brainstem auraAs with migraine with typical aura, but with at least two of the following brainstem symptoms:

      • Dysarthria
      • Vertigo
      • Tinnitus
      • Hypoacusis
      • Diplopia
      • Ataxia
      • Decreased level of consciousness
      Hemiplegic migraineSimilar to migraine with typical aura, but aura consisting of both of the following:

      • Fully reversible motor weakness
      • Fully reversible visual, sensory and/or speech/language symptoms
      May be sporadic or familial
      Chronic migraineHeadache occurring on 15 or more days per month for more than three months, which, on at least 8 days per month, has the features of migraine headache
      Tension-type headacheHeadache is typically bilateral, pressing or tightening in quality and of mild to moderate intensity, lasting minutes to days. The pain does not worsen with routine physical activity and is not associated with nausea, but photophobia or phonophobia may be present.

      May be classified as infrequent episodic, frequent episodic, or chronic.

      May be associated with pericranial tenderness.
      Trigeminal autonomic cephalalgias (TACs)Hemicrania continua, cluster headache, paroxysmal hemicranias, and short-lasting neuralgiform headache attacksThe TACs exist along a spectrum (
      • Newman L.C.
      Trigeminal autonomic cephalalgias.
      ) and are associated with symptoms of craniofacial autonomic alterations ipsilateral to the pain, such as lacrimation, ptosis, pupillary changes, tear production, conjunctival injection, rhinorrhea, or sweating.

      Magnetic resonance imaging and pituitary testing should be performed to exclude pituitary tumors, which can rarely cause TAC-like pain.

      Hemicrania continua and paroxysmal hemicrania are typically responsive to indomethacin
      OtherPrimary stabbing headacheTransient and localized stabs of pain in the head that occur spontaneously in the absence of organic disease of underlying structures or of the cranial nerves. No accompanying cranial autonomic symptoms
      Other migraineEpisodic and other syndromes that may be associated with migraineRecurrent gastrointestinal disturbance (cyclical vomiting syndrome and abdominal migraine)

      Benign paroxysmal vertigo/chronic persistent perceptual dizziness
      Auras may occur in the absence of headache (). Typical aura without headache (previously referred to as acephalgic migraine) and other migraine equivalents, including chronic persistent perceptual dizziness (
      • Holle D.
      • Schulte-Steinberg B.
      • Wurthmann S.
      • Naegel S.
      • Ayzenberg I.
      • Diener H.C.
      • et al.
      Persistent postural-perceptual dizziness: a matter of higher, central dysfunction?.
      ;
      • Baker B.J.
      • Curtis A.
      • Trueblood P.
      • Vangsnes E.
      Vestibular functioning and migraine: comparing those with and without vertigo to a normal population.
      ), may contribute to the symptomatology in POTS (
      • Heyer G.L.
      • Fedak E.M.
      • Legros A.L.
      Symptoms predictive of postural tachycardia syndrome (POTS) in the adolescent headache patient.
      ).
      Migraine is more common in women than in men, with prevalence of 17.3–20.2% in females compared to 5.7–9.4% in males (
      • Buse D.C.
      • Loder E.W.
      • Gorman J.A.
      • Stewart W.F.
      • Reed M.L.
      • Fanning K.M.
      • et al.
      Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study.
      ;
      • Burch R.C.
      • Loder S.
      • Loder E.
      • Smitherman T.A.
      The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies.
      ). Fluctuations in estrogen levels are largely, but not solely, responsible for this gender difference (
      • Lay C.L.
      • Broner S.W.
      Migraine in women.
      ). As the population of patients with POTS is predominantly female, this accounts for some of the higher rate of migraine in the POTS population generally. However, the 46% to 96% prevalence in POTS patients (cited above) is much greater than that seen in the female population generally.
      Migraine involves the release of neuropeptides near sensory fibers innervating the meninges and meningeal arteries. These peptides lead to both pain and vasodilation (
      • Shevel E.
      The extracranial vascular theory of migraine—a great story confirmed by the facts.
      ). Migraine can be associated with vestibular and autonomic symptoms, possibly originating in the brainstem. Whether the vascular, vestibular, and autonomic phenomena of migraine and POTS share similar mechanisms is still undetermined.
      While migraine is seen most commonly, patients with POTS can present with varied headache types, and a single patient may have more than one type of headache.

      2.2 Approaches to the treatment of primary headache syndromes

      Two specific considerations must be made in the POTS patient with headaches: First, headache types or mechanisms that occur at increased rates in the POTS population. Second, symptoms and comorbidities common in POTS patients may affect the usefulness of specific treatments.

      2.2.1 Behavioral headache management

      Non-pharmacologic treatment of primary headache syndromes requires proper attention to headache triggers, physical exercise, cognitive behavioral therapies, and sufficient sleep.
      Patients should be asked about potential migraine triggers. Emotional stress, changes in weather, menstruation, visual stimuli, nitrates, wine, fasting, sleep disturbances, and aspartame may trigger migraines in susceptible individuals (
      • Martin V.T.
      • Behbehani M.M.
      Toward a rational understanding of migraine trigger factors.
      ). Once identified, such triggers may be avoided.
      Sleep disturbance can exacerbate migraine (
      • Kelman L.
      The triggers or precipitants of the acute migraine attack.
      ;
      • Walters A.B.
      • Hamer J.D.
      • Smitherman T.A.
      Sleep disturbance and affective comorbidity among episodic migraineurs.
      ) and tension-type headache (
      • Rains J.C.
      • Davis R.E.
      • Smitherman T.A.
      Tension-type headache and sleep.
      ). Sleep disorders are common in people with migraine (
      • Yang C.P.
      • Wang S.J.
      Sleep in patients with chronic migraine.
      ), and should be screened for in all patients with POTS and migraine. Headaches occurring upon waking may be secondary to sleep apnea, and polysomnography should be considered for individuals with prominent waking headaches. Insomnia should be treated with sleep hygiene, stimulus control, and relaxation therapies. Cognitive behavioral therapies are effective for treating insomnia (
      • Trauer J.M.
      • Qian M.Y.
      • Doyle J.S.
      • Rajaratnam S.M.
      • Cunnington D.
      Cognitive behavioral therapy for chronic insomnia: a systematic review and meta-analysis.
      ). Pharmacologic treatment of insomnia may be appropriate in some patients, and has been reviewed elsewhere (
      • Sateia M.J.
      • Buysse D.J.
      • Krystal A.D.
      • Neubauer D.N.
      • Heald J.L.
      Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American academy of sleep medicine clinical practice guideline.
      ). Both pharmacologic and non-pharmacologic approaches to treating sleep disturbance prevent chronification of migraine and reduce headache frequency (
      • Yang C.P.
      • Wang S.J.
      Sleep in patients with chronic migraine.
      ;
      • Ruff R.L.
      • Ruff S.S.
      • Wang X.F.
      Improving sleep: initial headache treatment in OIF/OEF veterans with blast-induced mild traumatic brain injury.
      ;
      • Johnson K.G.
      • Ziemba A.M.
      • Garb J.L.
      Improvement in headaches with continuous positive airway pressure for obstructive sleep apnea: a retrospective analysis.
      ;
      • Bruni O.
      • Galli F.
      • Guidetti V.
      Sleep hygiene and migraine in children and adolescents.
      ;
      • Guidetti V.
      • Dosi C.
      • Bruni O.
      The relationship between sleep and headache in children: implications for treatment.
      ).
      Aerobic exercise appears to be particularly beneficial for the prevention of migraine in the general population (
      • Daenen L.
      • Varkey E.
      • Kellmann M.
      • Nijs J.
      Exercise, not to exercise, or how to exercise in patients with chronic pain? Applying science to practice.
      ). Exercise for patients with POTS is addressed elsewhere in this issue (

      Fu Q, Levine B. Article in this issue. 2018.

      ).
      Biofeedback training, relaxation training, and cognitive behavioral therapies have all shown high levels of evidence for their benefit in treating migraine and tension-type headaches (
      • Pistoia F.
      • Sacco S.
      • Carolei A.
      Behavioral therapy for chronic migraine.
      ;
      • Holroyd K.A.
      • Drew J.B.
      Behavioral approaches to the treatment of migraine.
      ). The delivery methods and formats of these treatments have been reviewed in detail by Holroyd and Drew (
      • Holroyd K.A.
      • Drew J.B.
      Behavioral approaches to the treatment of migraine.
      ). These treatments are administered by trained mental health professionals using direct inter-personal interaction. Similar to work with physical therapists, patients are typically given techniques and exercises to perform on their own after or between treatment encounters.
      Transcutaneous nerve stimulation has also been demonstrated to be effect for prevention of migraine (
      • Schoenen J.
      • Vandersmissen B.
      • Jeangette S.
      • Herroelen L.
      • Vandenheede M.
      • Gerard P.
      • et al.
      Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial.
      ), and has been reviewed elsewhere (
      • Robbins M.S.
      • Lipton R.B.
      Transcutaneous and percutaneous neurostimulation for headache disorders.
      ).

      2.2.2 Pharmacologic management of migraine

      Acute migraine treatment in the outpatient setting does not appear to differ between patients with POTS and the general population. Acute migraine treatments have been reviewed elsewhere (
      • Becker W.J.
      Acute migraine treatment.
      ).
      In contrast to acute treatment for migraines, many of the medicines used for migraine prevention do raise particular considerations in the POTS population (see Table 2). For example, while TCAs are commonly used effectively for migraine preventive therapy, they may often worsen the dry mouth, constipation, and fatigue that are often seen in POTS patients. Nortriptyline, as a secondary amine, often has fewer anticholinergic side effects than tertiary amines, including amitriptyline (which is more widely studied in migraine prevention). Venlafaxine, a combined serotonin-norepinephrine reuptake inhibitor (SNRI), has level B evidence of its effectiveness in migraine prevention (similar to the TCA amitriptyline) (
      • Silberstein S.D.
      Preventive migraine treatment.
      ). Some patients with bothersome tachycardia or palpitations may find these symptoms worsened when taking an SNRI.
      Table 2Diagnostic criteria for headache attributed to low cerebrospinal fluid (CSF) pressure ().
      • Any headache that develops in temporal relation to low cerebrospinal fluid (CSF) pressure or CSF leakage, or leading to its discovery
      • With either or both of the following:
        1. Low CSF pressure (<60 mm CSF)
        2. Evidence of CSF leakage on imaging (brain imaging showing sagging or pachymeningeal enhancement, or spine imaging showing extradural CSF)
      • Not better accounted for by another ICHD-3 diagnosis
      Topiramate, also commonly used for migraine prevention, has level A evidence for benefit in migraine prevention. Its use has been associated with restricted fetal growth (
      • Hernandez-Diaz S.
      • Mittendorf R.
      • Smith C.R.
      • Hauser W.A.
      • Yerby M.
      • Holmes L.B.
      Association between topiramate and zonisamide use during pregnancy and low birth weight.
      ;
      • Veiby G.
      • Daltveit A.K.
      • Engelsen B.A.
      • Gilhus N.E.
      Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy.
      ), microcephaly (
      • Veiby G.
      • Daltveit A.K.
      • Engelsen B.A.
      • Gilhus N.E.
      Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy.
      ), and cleft lip and other fetal anomalies (
      • Castilla-Puentes R.
      • Ford L.
      • Manera L.
      • Kwarta Jr., R.F.
      • Ascher S.
      • Li Q.
      Topiramate monotherapy use in women with and without epilepsy: pregnancy and neonatal outcomes.
      ). At higher doses, topiramate increases the clearance of oral hormonal contraceptives. Women of childbearing potential must be counselled clearly about these considerations in its use. The cognitive slowing often reported with use of topiramate may be particularly bothersome for POTS patients already dealing with “brain fog”.
      The beta-blockers metoprolol, propranolol, timolol, atenolol, and nadolol all have level A or B evidence for their effectiveness in migraine prevention (
      • Silberstein S.D.
      Preventive migraine treatment.
      ). However, many POTS patients cannot tolerate the higher doses typically used for migraine prevention (
      • Raj S.R.
      • Black B.K.
      • Biaggioni I.
      • Paranjape S.Y.
      • Ramirez M.
      • Dupont W.D.
      • et al.
      Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: less is more.
      ). When used at lower doses, beta blockers, and perhaps propranolol in particular due to its pleiotropic effects (
      • Wang D.W.
      • Mistry A.M.
      • Kahlig K.M.
      • Kearney J.A.
      • Xiang J.
      • George Jr., A.L.
      Propranolol blocks cardiac and neuronal voltage-gated sodium channels.
      ), may be a particularly good choice for POTS patients with bothersome tachycardia and migraines.
      Cyproheptadine, while only of level C evidence in terms of its effectiveness for migraine prevention in adults (
      • Silberstein S.D.
      Preventive migraine treatment.
      ), may be particularly helpful in augmenting appetite in those with anorexia.
      While the results of studies using magnesium supplementation for migraine prevention are mixed (
      • Tepper S.J.
      Nutraceutical and other modalities for the treatment of headache.
      ), the treatment is often well tolerated in POTS patients. We will often use it as an adjunct to other treatments. Common side effects include diarrhea, and this makes the medication a good choice for patients with constipation. Paradoxically, occasional patients may have worsened constipation with magnesium. Magnesium citrate 600 mg daily has been most consistently effective in studies of migraine prevention. Though a study of magnesium oxide for migraine prevention in children was equivocal (
      • Wang F.
      • Van Den Eeden S.K.
      • Ackerson L.M.
      • Salk S.E.
      • Reince R.H.
      • Elin R.J.
      Oral magnesium oxide prophylaxis of frequent migrainous headache in children: a randomized, double-blind, placebo-controlled trial.
      ), we often use magnesium oxide dosed at 400–800 mg daily (for adults) due to its more widespread availability in tablet form in some pharmacies.
      Riboflavin (vitamin B2) 400 mg (alone or in combination) has shown evidence of reducing migraine frequency in adults (
      • Schoenen J.
      • Jacquy J.
      • Lenaerts M.
      Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial.
      ;
      • Maizels M.
      • Blumenfeld A.
      • Burchette R.
      A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial.
      ). Two studies in the pediatric population using lower doses did not show a significant difference compared to placebo (
      • MacLennan S.C.
      • Wade F.M.
      • Forrest K.M.
      • Ratanayake P.D.
      • Fagan E.
      • Antony J.
      High-dose riboflavin for migraine prophylaxis in children: a double-blind, randomized, placebo-controlled trial.
      ;
      • Bruijn J.
      • Duivenvoorden H.
      • Passchier J.
      • Locher H.
      • Dijkstra N.
      • Arts W.F.
      Medium-dose riboflavin as a prophylactic agent in children with migraine: a preliminary placebo-controlled, randomised, double-blind, cross-over trial.
      ). This supplement is well tolerated. Diarrhea and polyuria rarely occur. It does typically cause bright yellow urine.
      Feverfew (Tanacetum parthenium) is rated as having Level B evidence for migraine prevention (
      • Holland S.
      • Silberstein S.D.
      • Freitag F.
      • Dodick D.W.
      • Argoff C.
      • Ashman E.
      Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society.
      ). However, the variable concentration of proposed active chemicals in commercially available preparations, and the lack of long-term safety data challenge its widespread use in clinical practice.
      Onabotulinum toxin A (Botox) injection has been shown to be effective for treatment of chronic migraine (see Table 1). While its use has not specifically been studied for migraine in patients with POTS, we have often found it useful in managing chronic migraine in POTS when response to first-line agents is not sufficient or not tolerated due to side effects. Common side effects of botulinum toxin injection include local pain or provocation of a headache. In our experience, side effects do not appear more commonly in POTS patients treated with botulinum toxin injection than the general population.
      For women with prominent menstrual migraine, short term prophylaxis with either naproxen or a long-acting triptan (frovatriptan, naratriptan, or zolmitriptan) can be particularly helpful. Long acting triptan doses are “bridged” for a 6 to 7 day course across start of the menstrual period (see (
      • MacGregor E.A.
      Migraine management during menstruation and menopause.
      for dosing regimens).
      With any given patient, a consideration must be given to the patient's overall symptoms and how they relate to the side effect profile of the medication and dose being considered. Some medications, like those affecting serotonin and dopamine pathways, may have a synergistic effect by preventing migraines directly while also improving sleep quality, adding additional benefit for migraine prevention in those with sleep disturbance.

      2.2.3 Treatment of other primary headache disorders

      While the frequency of other primary headache disorders in POTS has not been explored separately from that of migraine, other primary headaches do occur in POTS patients. Most frequent among these is tension headache. Tricyclics, venlafaxine, and mirtazapine have all shown efficacy in preventive treatment of tension-type headache (
      • Barbanti P.
      • Egeo G.
      • Aurilia C.
      • Fofi L.
      Treatment of tension-type headache: from old myths to modern concepts.
      ). Considerations regarding TCA and SNRI use are discussed above. Mirtazapine may be helpful in underweight patients or those with insomnia, as it promotes, appetite, reduces nausea, promotes sleep and has been used in chronic pain syndromes (
      • Ansari A.
      The efficacy of newer antidepressants in the treatment of chronic pain: a review of current literature.
      ).
      Frequency of trigeminal autonomic cephalalgias has not been studied in POTS patients. While their occurrence is much less common than that of migraine and tension-type headache, recognition of the TACs is important (see Table 1) as the various TACs tend to respond to particular medication types or classes (
      • Newman L.C.
      Trigeminal autonomic cephalalgias.
      ).

      2.2.4 Starting preventive headache therapies

      Like all other aspects of treatment, the decision to start preventive headache therapies must be individualized. As a general guide for migraine, if a patient is having two or more migraine days per week, it is often reasonable to start preventive pharmacotherapy. Other considerations in this decision include the degree to which the migraine impacts the patient's socioeconomic function and how well they respond to abortive therapies.
      It is important that patients understand the expected timeframe and magnitude of benefit from a preventive headache therapy. Establishing expectations a priori seems to lead to better patient outcomes. Most preventive therapies do not have full effect until two or more months or regular use. Further, it is not expected that most headaches will entirely disappear with preventive therapy. With most preventive therapies, reduction of headache frequency of 50% is typically considered successful. Other markers of successful response to preventive therapies are decreased migraine duration or improved responsiveness to abortive medications. A headache log or diary is often very useful in gauging headache frequency, associated symptoms, duration, and response to medications. Such logs may be maintained in written form or electronically, and there are even applications for mobile devices for tracking headache-related data.

      2.3 Secondary headache syndromes in POTS

      Secondary headaches of particular concern in patients with POTS include 1) pain from insufficient orthostatic blood flow to head and neck structures and 2) pain related to spontaneous intracranial hypotension.
      Orthostatic headache without orthostatic hypotension can occur in POTS and is at least partially responsive to volume expansion (
      • Mokri B.
      • Low P.A.
      Orthostatic headaches without CSF leak in postural tachycardia syndrome.
      ). The mechanism of these headaches is not known, but may be similar to the “coat-hanger”-type pain sometimes seen in people with orthostatic hypotension.
      As discussed elsewhere in this issue, there is an overlap between POTS and hypermobility spectrum disorders (

      Francomano C RP. Article in this issue. 2018.

      ), and individuals with hypermobility spectrum disorders are at increased risk of spontaneous intracranial hypotension (sICH). All patients with POTS should be asked about orthostatic headaches. Headaches from spontaneous sICH arise from intracranial hypotension and often come on within 15 min of standing, but may take up to 2 h to manifest (
      • Mea E.
      • Chiapparini L.
      • Savoiardo M.
      • Franzini A.
      • Grimaldi D.
      • Bussone G.
      • et al.
      Application of IHS criteria to headache attributed to spontaneous intracranial hypotension in a large population.
      ). The headache typically goes away within minutes of lying down and is typically symmetric and described as dull or throbbing (
      • Mokri B.
      Spontaneous low pressure, low CSF volume headaches: spontaneous CSF leaks.
      ). About half of patients with sICH have symptoms besides headache, the most common being neck pain or stiffness, nausea, and vomiting (
      • Schievink W.I.
      Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension.
      ) (Table 3). Other less common side effect attributable to distortion or compression of structures of the base of the brain or the brainstem may also occur (
      • Schievink W.I.
      Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension.
      ;
      • Mokri B.
      Spontaneous CSF leaks: low CSF volume syndromes.
      ). The ICHD-3 emphasizes the exclusion of POTS in the diagnosis of headache attributed to low CSF pressure. While sICH should be suspected in any case of orthostatic headache, POTS may present with orthostatic headaches without sICH (
      • Leep Hunderfund A.N.
      • Mokri B.
      Orthostatic headache without CSF leak.
      ).
      Table 3Migraine preventive medications with high-level evidence of efficacy, with other selected preventive medications - dosing and considerations related to postural tachycardia syndrome. Evidence levels: A – Medications with established efficacy (≥2 class I trials); B – Medications with probable efficacy (1 class I or 2 class II studies).
      Medication ClassMedicationEvidence level (
      • Silberstein S.D.
      Preventive migraine treatment.
      )
      Typical daily doseComorbidities that may be worsenedComorbidities that may be improvedOther considerations
      Anti-seizure drugsDivalproe × sodium, sodium valproateA500–2000 mgFatigue; dizziness; nausea; anorexia; abdominal pain; main worsen headache in some individualsMood disordersTeratogenicity severely restricts use in women of childbearing potential



      Start at 250 to 500 mg daily
      TopiramateA50–200 mgAnhidrosis/heat intolerance; cognition (“brain fog”); weight lossMay promote weight lossStart 25 mg at bedtime, then increase 25 mg per week to 75–100 mg.
      Beta-blockersMetoprololA100–200 mg dailyFatigue, orthostatic intolerance, sexualPalpitations/tachycardia
      PropranololA40–240 mgThe short-acting form dosed at 20 mg 2 or 3 times per day is often better tolerated.
      AtenololB50–200 mg
      NadololB20–160 mg
      TricyclicsAmitriptylineB10–200 mgDry mouth, constipation, fatigueInsomnia, chronic pain, depressionStart 10–25 mg at bedtime, increase weekly to 75–100 mg
      NortriptylineAnecdotal10–150 mgInsomniaInsomnia, chronic pain, depressionStart 10–25 mg at bedtime, increase weekly to 75–100 mg.

      If insomnia occurs, take in the morning.
      SNRIVenlafaxineB75–225 mgTachycardia, insomniaChronic pain
      Natural supplementsFeverfewB50–300 mgLack of long-term safety data; varied potency of commercially-available preparations
      Riboflavin (vitamin B2)B400 mgMaximal clinical effect starting at about two months
      Magnesium citrateB400–600 mgConstipationEffectiveness of oral magnesium oxide (9 mg/kg/day) was equivocal, but magnesium oxide is often used at the same dose due to availability.



      May paradoxically worsen constipation in some individuals.
      Magnetic resonance imaging (MRI) of the brain with gadolinium in considered the initial study for confirming the presence of sICH. The mnemonic SEEPS has been proposed to help recall the prominent MRI features of intracranial hypotension: subdural fluid collections, enhancement of the pachymeninges, engorgement of venous structures, pituitary hyperemia, and sagging of the brain (
      • Schievink W.I.
      Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension.
      ). MRI does not detect all sICH and does not demonstrate the location of a CSF leak.
      Lumbar puncture with a low CSF opening pressure (<60 mmH2O) is a confirmatory finding, but intracranial pressure can be normal in patients with sICH. Therefore, many experts defer lumbar puncture in the workup of sICH. While computed tomographic (CT) myelography is considered the best test to detect dural defects causing CSF leak (
      • Mokri B.
      Spontaneous intracranial hypotension.
      ), dynamic CT myelography may better detect rapid CSF leaks (
      • Luetmer P.H.
      • Mokri B.
      Dynamic CT myelography: a technique for localizing high-flow spinal cerebrospinal fluid leaks.
      ). Magnetic resonance myelography and digital subtraction myelography may localize fluid leaks when in some CT-negative cases. In a comparison of imaging modalities in 19 patients with spontaneous intracranial hypotension, the sensitivity of MR and CT myelography were equivalent (
      • Wang Y.F.
      • Lirng J.F.
      • Fuh J.L.
      • Hseu S.S.
      • Wang S.J.
      Heavily T2-weighted MR myelography vs CT myelography in spontaneous intracranial hypotension.
      ).
      Acute (<2 weeks), uncomplicated sICH in people without joint hypermobility can be managed conservatively, with bedrest and 200 to 300 mg caffeine given two to three times daily (
      • Mokri B.
      Spontaneous low pressure, low CSF volume headaches: spontaneous CSF leaks.
      ). Epidural blood patch (EBP) is considered first-line therapy in people with connective tissue disease or joint hypermobility, CSF leak secondary to non-penetrating trauma, severe headache or disabling symptoms, or symptomatic headache for over two weeks (
      • Mokri B.
      Spontaneous low pressure, low CSF volume headaches: spontaneous CSF leaks.
      ;
      • Amoozegar F.
      • Guglielmin D.
      • Hu W.
      • Chan D.
      • Becker W.J.
      Spontaneous intracranial hypotension: recommendations for management.
      ). A retrospective study of 56 patients showed that targeted blood patch at the effected level was more effective than “blind” lumbar injection (
      • Cho K.I.
      • Moon H.S.
      • Jeon H.J.
      • Park K.
      • Kong D.S.
      Spontaneous intracranial hypotension: efficacy of radiologic targeting vs blind blood patch.
      ). However, lumbar injections often are effective even with more cranially-located defects. About half of patients with sICH will require more than one EBP (
      • Sencakova D.
      • Mokri B.
      • Mcclelland R.L.
      The efficacy of epidural blood patch in spontaneous CSF leaks.
      ;
      • Berroir S.
      • Loisel B.
      • Ducros A.
      • Boukobza M.
      • Tzourio C.
      • Valade D.
      • et al.
      Early epidural blood patch in spontaneous intracranial hypotension.
      ). Directed EPBs, fibrin sealant, or surgical closure may be needed in refractory cases.

      3. Pain epidemiology in POTS

      A percentage of patients with POTS experience visceral symptoms referred to the upper or lower gastrointestinal tract, bladder, and other abdominal and pelvic organs. In a large series of adult patients with POTS (
      • Thieben M.J.
      • Sandroni P.
      • Sletten D.M.
      • Benrud-Larson L.M.
      • Fealey R.D.
      • Vernino S.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ), nausea was present in 39%, bloating in 24%, diarrhea in 18%, constipation in 15%, abdominal pain in 15%, and bladder symptoms in 9% of cases. These symptoms are similar to those typically reported by patients with functional motility disorders such as functional dyspepsia, irritable bowel syndrome, and interstitial cystitis, among others. Symptoms mimicking those of subjects with gastrointestinal motility disorders (such as gastroparesis) are also common, despite lack of objective evidence of true abnormalities on transit studies. Sixty-eight percent of a small cohort of women with POTS met criteria for a diagnosis of overactive urinary bladder (
      • Kaufman M.R.
      • Chang-Kit L.
      • Raj S.R.
      • Black B.K.
      • Milam D.F.
      • Reynolds W.S.
      • et al.
      Overactive bladder and autonomic dysfunction: lower urinary tract symptoms in females with postural tachycardia syndrome.
      ). The underlying pathophysiology of these disorders includes variable mucosal inflammation, visceral hypersensitivity, and secondary visceromotor dysfunction. Behavioral amplification may also play a significant role. Gastrointestinal disorders and dysmotility are addressed more specifically elsewhere in this issue (

      Chelimsky G. Article in this issue. 2018.

      ).
      Chronic fatigue (
      • Okamoto L.E.
      • Raj S.R.
      • Peltier A.
      • Gamboa A.
      • Shibao C.
      • Diedrich A.
      • et al.
      Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes.
      ;
      • Ocon A.J.
      • Messer Z.R.
      • Medow M.S.
      • Stewart J.M.
      Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome.
      ) and fibromyalgia (
      • Staud R.
      Autonomic dysfunction in fibromyalgia syndrome: postural orthostatic tachycardia.
      ) have been frequently associated with POTS. In the large survey referred to above, 21% of respondents reported having fibromyalgia. Eighty-five percent of
      • Ojha A.
      • Chelimsky T.C.
      • Chelimsky G.
      Comorbidities in pediatric patients with postural orthostatic tachycardia syndrome.
      pediatric POTS patients reported chronic pain other than headache. In the other large series of adult patients with POTS (
      • Thieben M.J.
      • Sandroni P.
      • Sletten D.M.
      • Benrud-Larson L.M.
      • Fealey R.D.
      • Vernino S.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ), many reported chronic fatigue (48%), sleep disturbance (32%), and myofascial pain (16%). There is a well-known overlap between chronic fatigue syndrome and POTS. Poor sleep, pain, and deconditioning all contribute to the cluster of such manifestations. Non-restorative sleep and pain can further amplify the already present sympathetic over-activity, thus worsening POTS symptoms.

      3.1 Mechanisms of chronic pain

      Multiple mechanisms may lead to chronic or maladaptive pain, including central sensitization (
      • Kuner R.
      Central mechanisms of pathological pain.
      ;
      • Phillips K.
      • Clauw D.J.
      Central pain mechanisms in chronic pain states—maybe it is all in their head.
      ;
      • Kuner R.
      Spinal excitatory mechanisms of pathological pain.
      ), peripheral sensitization (
      • Mickle A.D.
      • Shepherd A.J.
      • Mohapatra D.P.
      Nociceptive TRP channels: sensory detectors and transducers in multiple pain pathologies.
      ;
      • Berta T.
      • Qadri Y.
      • Tan P.H.
      • Ji R.R.
      Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain.
      ), neuronal hyperexcitability (
      • Berta T.
      • Qadri Y.
      • Tan P.H.
      • Ji R.R.
      Targeting dorsal root ganglia and primary sensory neurons for the treatment of chronic pain.
      ;
      • Ratte S.
      • Prescott S.A.
      Afferent hyperexcitability in neuropathic pain and the inconvenient truth about its degeneracy.
      ), phenotypic switch of sensory neurons (
      • Ueda H.
      Molecular mechanisms of neuropathic pain-phenotypic switch and initiation mechanisms.
      ;
      • Wang T.
      • Molliver D.C.
      • Jing X.
      • Schwartz E.S.
      • Yang F.C.
      • Samad O.A.
      • et al.
      Phenotypic switching of nonpeptidergic cutaneous sensory neurons following peripheral nerve injury.
      ), alterations of inhibitory pathways (
      • Kuner R.
      Spinal excitatory mechanisms of pathological pain.
      ;
      • Prescott S.A.
      Synaptic inhibition and disinhibition in the spinal dorsal horn.
      ), and alterations in sensory gating as a result of afferent denervation (
      • Woolf C.J.
      Pain: moving from symptom control toward mechanism-specific pharmacologic management.
      ). These mechanisms are not mutually exclusive of one another. Such pain is labelled maladaptive as the pain no longer serves any protective factor. Despite the higher rates of occurrence, there is no evidence that mechanisms of chronic, non-nociceptive pain differ in POTS patients compared to the general population.
      Higher rates of hypermobility spectrum disorders are seen in patients with POTS and may contribute to increased pain from joint dislocation and subluxation. However, pediatric POTS patients with joint hypermobility did not differ from those without joint hypermobility in their rates of migraine, functional abdominal pain, or fibromyalgia-like pain (
      • Chelimsky G.
      • Kovacic K.
      • Simpson P.
      • Nugent M.
      • Basel D.
      • Banda J.
      • et al.
      Benign joint hypermobility minimally impacts autonomic abnormalities in pediatric subjects with chronic functional pain disorders.
      ).
      As detailed above, functional pain syndromes, such as fibromyalgia, irritable bowel syndrome, functional abdominal pain, interstitial cystitis, and temporomandibular disorders seem to be more common in POTS patients, and share the common unifying factor of central sensitization. Alterations in brain activity related to autonomic nervous system function, immune and neuroendocrine activities, and genetic predispositions may be involved in the amplification of pain perception (
      • Furquim B.A.
      • Flamengui L.
      • Conti P.C.R.
      TMD and chronic pain: a current view.
      ).
      Peripheral mechanisms may contribute to higher rates of pain disorders in POTS. Roughly a third to a half of all POTS patients has evidence of small fiber peripheral neuropathy (
      • Thieben M.J.
      • Sandroni P.
      • Sletten D.M.
      • Benrud-Larson L.M.
      • Fealey R.D.
      • Vernino S.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ;
      • Garland E.M.
      • Celedonio J.E.
      • Raj S.R.
      Postural tachycardia syndrome: beyond orthostatic intolerance.
      ;
      • Gibbons C.H.
      • Bonyhay I.
      • Benson A.
      • Wang N.
      • Freeman R.
      Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome.
      ). While in some cases, the neuropathy may be related to the small fiber autonomic fibers, overlapping pathology with small fiber sensory fibers appears to occur in many cases. This corresponds with consistent evidence pointing to a peripheral neuropathic mechanism for about one-third of patients with fibromyalgia (
      • Oaklander A.L.
      • Herzog Z.D.
      • Downs H.M.
      • Klein M.M.
      Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia.
      ;
      • Oaklander A.L.
      • Klein M.M.
      Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes.
      ;
      • Giannoccaro M.P.
      • Donadio V.
      • Incensi A.
      • Avoni P.
      • Liguori R.
      Small nerve fiber involvement in patients referred for fibromyalgia.
      ;
      • Doppler K.
      • Rittner H.L.
      • Deckart M.
      • Sommer C.
      Reduced dermal nerve fiber diameter in skin biopsies of patients with fibromyalgia.
      ).

      3.2 Approaches to treating chronic pain

      As with other patients with chronic pain, a multi-disciplinary and multi-modal approach to treating pain is most likely to be successful in the patient with POTS. Pain in people with POTS may be broadly categorized into four categories: neuropathic pain, pain due to central sensitization (including fibromyalgia), nociceptive pain due to joint hypermobility, and pain secondary to consequences of autonomic dysfunction (i.e., abdominal pain secondary to severe constipation).
      Non-pharmacologic treatments are essential in managing chronic pain related to POTS. Physical exercise activates endogenous opioid pathways and increases pain-inhibiting serotonergic pathways in the central nervous system. There is concern that endogenous analgesic pathways are deficient in some individuals with chronic pain disorders and that physical exercise may provoke symptom flares secondary to inappropriate or excessive physical exercise (
      • Daenen L.
      • Varkey E.
      • Kellmann M.
      • Nijs J.
      Exercise, not to exercise, or how to exercise in patients with chronic pain? Applying science to practice.
      ). Thus, an individually-tailored approach to exercise is necessary. Again, physical exercise for POTS patients is addressed elsewhere in this issue (

      Fu Q, Levine B. Article in this issue. 2018.

      ).
      Cognitive behavioral therapy (CBT) has shown effectiveness in improving symptoms across a wide spectrum of chronic pain syndromes, populations, and delivery formats (
      • Ehde D.M.
      • Dillworth T.M.
      • Turner J.A.
      Cognitive-behavioral therapy for individuals with chronic pain: efficacy, innovations, and directions for research.
      ). Resting-state functional MRI has demonstrated alterations in functional connectivity corresponding with improvement in chronic pain after CBT, providing evidence of an “unlearning” of chronic pain (
      • Shpaner M.
      • Kelly C.
      • Lieberman G.
      • Perelman H.
      • Davis M.
      • Keefe F.J.
      • et al.
      Unlearning chronic pain: a randomized controlled trial to investigate changes in intrinsic brain connectivity following cognitive behavioral therapy.
      ).
      There is consistent evidence that insufficient sleep results in decreased pain thresholds acutely and the development of chronic pain syndromes over the long term (
      • Finan P.H.
      • Goodin B.R.
      • Smith M.T.
      The association of sleep and pain: an update and a path forward.
      ). While pain can negatively affect sleep, the evidence indicates that sleep disturbance is a stronger predictor of future pain (rather than the other way around) (
      • Finan P.H.
      • Goodin B.R.
      • Smith M.T.
      The association of sleep and pain: an update and a path forward.
      ). It is not clear whether or not improving sleep using pharmacologic therapy improves pain (
      • Denucci D.J.
      • Sobiski C.
      • Dionne R.A.
      Triazolam improves sleep but fails to alter pain in TMD patients.
      ;
      • Smith M.T.
      • Haythornthwaite J.A.
      How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature.
      ). The efficacy of pharmacologic options for treating insomnia has been reviewed elsewhere (
      • Sateia M.J.
      • Buysse D.J.
      • Krystal A.D.
      • Neubauer D.N.
      • Heald J.L.
      Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American academy of sleep medicine clinical practice guideline.
      ). While cognitive behavioral therapies appear to improve sleep in chronic pain, the resulting effect on pain has been inconsistent (
      • Tang N.K.
      Cognitive-behavioral therapy for sleep abnormalities of chronic pain patients.
      ), though measures of day-to-day function do improve (
      • Finan P.H.
      • Buenaver L.F.
      • Coryell V.T.
      • Smith M.T.
      Cognitive-behavioral therapy for comorbid insomnia and chronic pain.
      ). A focus on teaching and ensuring appropriate sleep hygiene, with judicious use of pharmacologic and cognitive behavioral interventions when needed, is probably the most beneficial approach.
      There are currently no data to suggest that treatment responses to pharmacologic interventions for pain are any different in people with POTS compared to the general population. Some medicines, however, are likely to worsen other symptoms commonly seen in POTS, while others may have a synergistic or poly-modal effects (see Table 4). Pharmacologic approaches to treating non-nociceptive, non-inflammatory pain may be broadly categorized by their central or peripheral targets: 1) decreasing central excitation, 2) increasing endogenous central inhibitory pathways 3) decreasing peripheral excitation, and 4) directly stimulating receptors involved in increasing pain thresholds (i.e., cannabinoid receptor agonists).
      Table 4Medications commonly used to treat neuropathic pain and fibromyalgia with side effect considerations and possible synergistic uses specific to postural tachycardia syndrome.
      Medication or medication classComorbidities that may be worsenedComorbidities that may be improved
      Tricyclic antidepressantsDry mouth, constipation, fatigue, orthostatic intoleranceSleep disturbance; migraine; depression (may require higher doses); bladder pain
      Serotonin reuptake inhibitorsInsomnia, headache, dizziness, fatigue, nausea, sexual dysfunctionSleep disturbance
      CyclobenzaprineFatigue, dry mouthSleep disturbance
      Alpha-2-delta calcium channel agonists (gabapentin, pregabalin)Fatigue, weight gainSleep disturbance.

      May promote weight gain
      Serotonin and norepinephrine reuptake inhibitors (duloxetine, venlafaxine, desvenlafaxine, milnacipran)Headache; nausea; palpitations; dry mouth (in adults); abdominal pain (in children and adolescents); weight loss (in children and adolescents)Depression
      Approaches to decrease central excitation include use of n‑methyl‑d‑aspartate receptor antagonists (such as ketamine), alpha-2-delta calcium channel subunit antagonists (gabapentin and pregabalin), and other anti-epileptic drugs. Both gabapentin and pregabalin are considered first-line treatments for neuropathic pain (
      • Dworkin R.H.
      • O'Connor A.B.
      • Backonja M.
      • Farrar J.T.
      • Finnerup N.B.
      • Jensen T.S.
      • et al.
      Pharmacologic management of neuropathic pain: evidence-based recommendations.
      ). Gabapentin dosing is typically initiated at a low dose – 900 mg or less per day in three divided doses – and increased gradually until effectiveness or intolerable side effects are reached. Up to 3600 mg per day in three doses may be used. Pregabalin is typically started at 75 mg per day and increased to 150 mg daily after a week. Pregabalin may provide analgesia more quickly than gabapentin, and this is likely at least in part due to the ability to titrate more rapidly to an effective dose (
      • Stacey B.R.
      • Barrett J.A.
      • Whalen E.
      • Phillips K.F.
      • Rowbotham M.C.
      Pregabalin for postherpetic neuralgia: placebo-controlled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief.
      ).
      Central inhibitory pathways, which are primarily serotonergic, may be augmented with tricyclics (TCAs), serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors (SNRIs). While TCAs are often beneficial in the general population with chronic pains of various origins, including neuropathic pain (
      • Dworkin R.H.
      • O'Connor A.B.
      • Backonja M.
      • Farrar J.T.
      • Finnerup N.B.
      • Jensen T.S.
      • et al.
      Pharmacologic management of neuropathic pain: evidence-based recommendations.
      ), their prominent anticholinergic effects may exacerbate many of the symptoms commonly seen in POTS.
      Of the SNRIs, venlafaxine and duloxetine have demonstrated efficacy in treating neuropathic pain (
      • Aiyer R.
      • Barkin R.L.
      • Bhatia A.
      Treatment of neuropathic pain with venlafaxine: a systematic review.
      ;
      • Gao Y.
      • Guo X.
      • Han P.
      • Li Q.
      • Yang G.
      • Qu S.
      • et al.
      Treatment of patients with diabetic peripheral neuropathic pain in China: a double-blind randomised trial of duloxetine vs. placebo.
      ). Duloxetine and milnalcipran have both shown benefit in treating fibromyalgia (
      ;
      • Cording M.
      • Derry S.
      • Phillips T.
      • Moore R.A.
      • Wiffen P.J.
      Milnacipran for pain in fibromyalgia in adults.
      ). Duloxetine is also approved for the treatment of chronic musculoskeletal pain and chronic low back pain (
      • Pergolizzi Jr., J.V.
      • Raffa R.B.
      • Taylor Jr., R.
      • Rodriguez G.
      • Nalamachu S.
      • Langley P.
      A review of duloxetine 60 mg once-daily dosing for the management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic osteoarthritis pain and low back pain.
      ). Duloxetine is typically dosed at 60 mg per day. If SNRIs are to be discontinued, a very gradual taper is recommended in order to avoid withdrawal symptoms.
      Peripheral nerve excitation may be targeted using medications that decrease voltage-gated sodium channel activation. Carbamazepine has shown moderate effectiveness for chronic neuropathic pain in short-term trials (
      • Wiffen P.J.
      • Derry S.
      • Moore R.A.
      • HJ McQuay
      Carbamazepine for acute and chronic pain in adults.
      ). However, these medications are less frequently used because of the better side effect profiles of the SNRIs and gabapentinoids.
      While opioid medications do effectively treat many types of pain, any benefit has to be weighed against the potential risks of tachyphylaxis, dependence, overdose, and perhaps even potentiation of non-nociceptive pain (
      • Heinl C.
      • Drdla-Schutting R.
      • Xanthos D.N.
      • Sandkuhler J.
      Distinct mechanisms underlying pronociceptive effects of opioids.
      ;
      • Roeckel L.A.
      • Le Coz G.M.
      • Gaveriaux-Ruff C.
      • Simonin F.
      Opioid-induced hyperalgesia: cellular and molecular mechanisms.
      ). The U.S. Centers for Disease Control and Prevention have published detailed guidelines regarding opioid prescription for chronic pain (
      • Dowell D.
      • Haegerich T.M.
      • Chou R.
      CDC guideline for prescribing opioids for chronic pain - United States, 2016.
      ).
      Low dose naltrexone has emerged as a potential treatment of chronic pain. It is thought that the low-level opioid receptor blockade results in rebound production of endogenous opioids. While further studies are needed, this may be a well-tolerated and inexpensive treatment for chronic pain (
      • Metyas S.K.
      • Yeter K.
      • Solyman J.
      • Arkfeld D.
      Low dose naltrexone in the treatment of fibromyalgia.
      ;
      • Patten D.K.
      • Schultz B.G.
      • Berlau D.J.
      The safety and efficacy of low-dose naltrexone in the management of chronic pain and inflammation in multiple sclerosis, fibromyalgia, Crohn's disease, and other chronic pain disorders.
      ).
      The use of cannabis and cannabinoids in the treatment of chronic pain remains controversial. A recent meta-analysis of the use of cannabinoids in chronic non-cancer pain concluded that limited evidence suggests a potential benefit in relieving chronic neuropathic pain. However, there is insufficient evidence for any benefit toward other types of chronic pain (
      • Nugent S.M.
      • Morasco B.J.
      • O'Neil M.E.
      • Freeman M.
      • Low A.
      • Kondo K.
      • et al.
      The effects of cannabis among adults with chronic pain and an overview of general harms: a systematic review.
      ).
      Topical medications, including anesthetics such as lidocaine or capsaicin-containing creams, may be helpful for some individuals with neuropathic pain, especially when that pain is localized.

      4. Conclusion

      Headache syndromes, particularly migraine, and chronic pain are common in the POTS population. While there is no data regarding different responses to treatments for migraine and chronic pain among people with or without POTS, co-existing conditions and symptoms must be considered when tailoring therapies for the POTS patient. In addition to the judicious use of pharmacologic therapies, non-pharmacologic therapies including exercise, treating sleep disorders and cognitive behavioral therapies are important for treating chronic pain and the most common primary headache syndromes in patients with POTS.

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