Headaches & long COVID – how we treat ongoing symptoms.

In my last blog, I covered in great detail the complex mechanisms that in many long hauler COVID patients can cause a number of neurological issues, including headaches.

We know that headaches especially for some individuals (e.g. migraine sufferers) can be extremely debilitating, even when experienced on an occasional basis. And with long COVID, and regardless of the relative mildness or severity of an original infection, these headaches can be daily and feel almost never ending.
 
Our practice is working with more and more patients in recent months and providing several therapeutic measures to address both the symptoms and root cause of what starts as inflammation and left unchecked may indeed spiral into more problems. 
 
Treatment Strategies 
 
Our practice is working with more and more patients in recent months and providing several therapeutic measures to address both the symptoms and root cause of what starts as inflammation and left unchecked may indeed spiral into more problems. 
 
An approach to improving headache symptoms in long COVID may include, as appropriate to each patient’s condition:

• Reduce inflammation: one of the first steps, as we recommend with many immune-mediated diagnoses, is to address and reduce systemic inflammation. We wrote about this extensively in another blog in this series, which you can review at: https://www.suzannegazdamd.com/blog---long-covid/a-protocol-for-treatment-starts-with-tamping-down-inflammation

 

• Eat a healthy diet, preferably organic if accessible: Results published in The British Medical Journal (BMJ) and noted in MedPage Today presented promising evidence that a diet higher in two specific omega-3, fatty acids (EPA and DHA) “reduced headache frequency and intensity and lowered levels of pain-related lipids in migraine patients.”1


• Heal your gut: previous studies have already found an association between gastrointestinal disorders and migraines because of the gut-brain connection.

 

• Lower oxidative stress (Vitamin C, NAD, Melatonin, Resveratrol, Quercetin, Curcumin, Luteolin are a few supplements that help reduce oxidative stress).

 

• Avoid exposure to more spike protein. 

 

• Lower stress: Exercise if possible, meditate, try deep breathing techniques, and try to limit use of electronic devices. For more recommendations, see: https://www.suzannegazdamd.com/blog/stress-glucocorticoids-and-the-effects-on-our-brain

 

• Get quality sleep, ideally seven to eight hours nightly. If you have problems with sleep apnea or similar disordered breathing issues, consult a doctor for appropriate sleep evaluation and specialized therapies.   

 

• Address potential dehydration: Drinking enough water every day is critical to our healthy; strive for eight, 8-ounce glasses daily and reduce consumption of things like caffeine and alcohol that can exacerbate dehydration.

 

• Reduce migraine triggers: Patients should avoid factors that can precipitate a migraine attack (e.g., lack of sleep, fatigue, stress, certain foods, use of vasodilators). Use a daily diary to document the headaches as an effective and inexpensive tool to follow the course of the disease and track headache episodes.

 

• Avoid wearing a mask: Some studies have shown a correlation between extended use of personal protective equipment (PPE) and migraine incidence among frontline workers during the pandemic. Address depression anxiety and other neuropsychiatric symptoms.

 

• Check blood pressure periodically at your physician’s office or using a quality blood pressure monitoring device.

Target treatment to type of headache.
 
1. Migraine severe unilateral/throbbing worsens with movement and associated with either nausea and/or vomiting or light or sound sensitivity. Some migraines are preceded by an aura, which may include visual disturbances or sensations such as flashing lights or zigzag lines.

2. Migraine with aura: may include at least one of the following, but with no motor weakness:
 
• Fully reversible dysphasic speech disturbance where speech is temporarily disrupted.

• Sensory symptoms that are fully reversible, including positive features (e.g., pins and needles) and/or negative features (e.g., numbness).

• Visual symptoms that are fully reversible, including positive features (e.g., flickering lights, spots, lines) and/or negative features (e.g., loss of vision)

3. Tension headache: mild to moderate, bilateral, pressure-like, not aggravated by movement and should not be associated with light/sound sensitivity and nausea. 
​
• For prevention we use Amitriptyline 25-75mg hs , Nortriptyline 25-75mg hs , Protriptyline 20-30mg given in the a.m. for it is activating, or Effexor 150mg.

Acute migraines.
 
There are a number of approaches to treating migraine headaches:
 
--First-line agents: NSAIDS or combination analgesics such as Excedrin (aspirin + acetaminophen + caffeine) Also Triptans, Diclofenac 
--Second line:  Celebrex, Relafen, and Mobic with prochloperazine 10 mg, three times daily, or every night at bedtime for three days, or Promethazine 25-50 mg 
--Migraine-specific agents: If the headaches don’t respond to first-line agents, try one of these:
Triptans:  

• Almotriptan (Axert)
• Eletriptan (Relpax)
• Frovatriptan (Frova)
• Lasmiditan (Reyvow)
• Naratriptan (Amerge)
• Rizatriptan (Maxalt)
• Sumatriptan (Imitrex, Onzetra Xsail, Sumavel DosePro, Zembrace)
• Zolmitriptan (Zomig)

 
The best results occur when triptans are taken early in an attack. For migraine with aura, evidence suggests that the best results are achieved by taking the triptan early in an attack, at the onset of pain rather than the onset of aura; however, taking a triptan during a typical aura also appears to be safe. Triptans are generally well tolerated. A 2016 meta-analysis found no significantly increased risk of serious adverse effects.2  
 
Commonly experienced side effects of triptans can include: 

• warm sensations 
• tightness 
• tingling 
• flushing 
• feelings of heaviness in the face, limbs or chest 

 
Some people may also experience a generalized feeling of being sick, dry mouth, and drowsiness. All triptans should be limited to no more than 10 days of use per month to avoid medication overuse headache. Based on limited evidence, it is still recommended that triptans be avoided in patients with peripheral vascular disease, hemiplegic migraine, basilar migraine, ischemic stroke, ischemic heart disease, Prinzmetal's angina, uncontrolled hypertension, ischemic bowel disease, cerebrovascular syndromes, and in those who are pregnant.3

They mimic the activity of the neurotransmitter serotonin (5-HT) and are effective in the early stages of an attack. At 5-HT1B receptors, they reduce pain by causing cranial blood vessels to constrict. At 5-HT1D receptors, they block the release of neuropeptides that trigger inflammation.

Almotripta
Almotriptan (Axert) 6.25-12.5mg as single dose  No more than 25 mg in 24 hours 
 
Eletriptan (Relpax)  20- and 40-mg tablets - Least cardiovascular risk

Frovatriptan (Frova) 2.5 mg  - Recommended for menstrual migraine

Naratriptan (Amerge) 1 and 2.5 mg 

Rizatriptan (Maxalt) 5 and 10 mg tablet and also orally disintegrating tab 

Sumatriptan (Imitrex) 25, 50, 100 mg 
6 mg injection 
5 or 20 mg nasal spray 
Oral and intranasal formulations, and subcutaneous injection

Zolmitriptan (Zomig) 2.5 or 5 mg tab and orally disintegrating tablets and 5 mg nasal spray 
 
Sumatriptan/naproxen  85/500mg (Treximet)  Take at onset of headache. May repeat in 2 hours  No more than 2 tablets in 24 hours 

Naratriptan and frovatriptan have the slowest onset of action among the triptans and may have the lowest propensity to cause side effects.
Combination with monoamine oxidase inhibitors is relatively contraindicated with triptans because of the risk of serotonin syndrome. Triptans should not be used within 24 hours of the use of ergotamine preparations or a different triptan medication as serotonin syndrome is a concern.4 
 
The drug eletriptan is primarily metabolized by cytochrome P-450 enzyme CYP3A4. Therefore, eletriptan should not be used within at least 72 hours of treatment with other drugs that are potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir. The dose of rizatriptan must be reduced to 5 mg in patients taking propranolol. 

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For more information regarding these and other prescribed medications for the treatment of migraine, you can read more at: 
https://www.webmd.com/migraines-headaches/migraine-treatments
https://www.rxlist.com/migraine_medications/drugs-condition.htm
https://www.healthline.com/health/migraine-drugs#triptans

What other options are there?
 
In the event that triptans have not helped or there is a contraindication for use, gepants may be employed. Note: in most instances, a patient has to have failed triptans or be unable to take this class of medication in order to obtain insurance coverage for a gepant prescription. 
 
Gepants are small molecule calcitonin gene-related peptide (CGRP) receptor antagonists. Calcitonin gene-related peptide (CGRP) is a protein that carries pain signals along nerves that are involved in generating the headache pain associated with migraine. Gepants work to block CGRP from attaching to its receptor and initiating those pain signals; they do not cause vasoconstriction per se.5
 
The drugs are available in two forms - small molecules called gepants (Nurtec, Ubrelvy, and Qulipta) and large molecule monoclonal antibodies (Aimovig, Ajovy, Emgality, and Vyepti). Both forms disrupt CGRP action by preventing it from binding to and activating its receptor, and therefore, the migraine chain reaction is thwarted.
 
Learn more about the action of CGRP at: https://www.suzannegazdamd.com/blog/migraines-the-science-causes-and-treatment-options

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Rimegepant (Nurtec ODT): The maximum dosage of rimegepant is a single 75 mg dose as needed per 24 hour treatment; rimegepant does not appear to be associated with medication-overuse headache.
 
Ubrogepant: Recommended 50-100 mg for acute migraine and, if needed, patients may take second dose at least 2 hours after initial dose, with a maximum dose of 200 mg/day.
Note:  There are many potential drug interactions with this class of medications.  Be sure and check with your doctor or pharmacist 
 
Additional options: ditans 
 
Ditans are a class of “abortive” medications for the treatment of migraines, which selectively bind to the 5-HT1F receptor subtype. 
 
Lasmidtitan (Reyvow): This drug is a serotonin 5-HT1F receptor agonists. Ditans do not elicit a vasoconstrictive effect, whereas triptans cause vasoconstriction via agonistic action at 5-HT1B/1D receptors.5 It has better two-hour pain results, but the side effects are dizziness and sedation so patients cannot drive for at least eight (8) hours. It is a schedule 5 drug; dose for adults is 50 mg, 100 mg, or 200 mg per day as needed. Patients should not take more than one dose within a 24-hour period.
 
Additionally, ergotamine (nasal spray) may be helpful. Ergotamine is an ergot alkaloid medicine that is used to treat or prevent a vascular headache (such as a migraine or cluster headache). It is not intended for daily use and will not treat headache pain.
 
As needed, anti-nausea medications (antiemetics) such as Zofran, Phenergan, or Compazine and their generic formularies also may be prescribed for associated symptoms.
 
Migraine Preventative Therapies.
    
These medications are appropriate for a patient experiencing more than two migraines a week, with the understanding that prophylactic medication won’t prevent all headaches. At best, medication alone can be expected to cut the number of headaches in half.

• Topiramate, 50-200 mg/day (side effects include weight loss, anorexia, fatigue, memory problems, and paresthesia’s)
• Propranolol, 80 mg/day (note that beta blockers have anti-inflammatory properties and act in Modulation of central neurotransmitters).
• Metoprolol, 50-200 mg/day
• Amitriptyline, 10-100 mg/day (modulates central nervous system neurotransmitters) 
• Cymbalta 60-120 mg (studies show it is not that helpful) 
• Venlafaxine (Effexor) 12.5 -150 mg / day (while rare, one side effect may decrease platelets)
• Valproic Acid (Depakote) (enhancing gamma-aminobutyric acidergic (GABAergic) inhibition) 250-500mg bidi or can use Depakote ER 500-1000 mg/day. Note that in this study, researchers found that valproic acid downregulates ACE-2 expression and inhibits the expression of inflammatory cytokines.
• Calcitonin gene-related peptide (CGRP) inhibitors: In our prior blog, we discussed the study that proposes that spike protein and the CGRP receptor share molecular mimicry and therefore high levels of CGRP may be driving at least part of the severe headaches in long COVID.

 
Learn more about why long COVID occurs at: https://www.suzannegazdamd.com/blog---long-covid/why-does-long-covid-happen
 
Note: For insurers to approve a CGRP inhibitor:

1. Individual must be 18 years of age or older
2. Individual has four or more migraine headache days per month (prior to initiating a migraine- preventative medication).
3. Documentation of ONE of the following (i or ii): 
4. Individual has had an inadequate response following a minimum 3-month trial of TWO different prescription migraine prevention therapies from different classes of migraine prophylaxis medications or patient has a contraindication to any of these.

 
How do CGRP inhibitors work?
The pathophysiology of migraine is understood to develop from a cascade of events within the nervous system and vasculature (blood vessels) of the brain, with calcitonin gene-related peptide (CGRP) being one player in a large cast. Initial depolarization of central nervous system neurons (nerve cells) spreads and triggers trigeminal nerve fibers, resulting in pain. The trigeminal nerve network releases CGRP, among other proteins that mediate inflammation and vascular tone. CGRP is active in pain signal transmission, vasodilator effects (blood vessel dilation), and brain inflammation, all of which amplify the headache pain. 
​
Blocking CGRP can interrupt the sequence of migraine mechanisms and thereby provide relief from an attack or prevention when used regularly. Anti-CGRP agents work by either binding to CGRP itself or to the CGRP receptor site. 

An overview of some anti migraine drugs that directly block CGRP or its receptor. Since CGRP plays an important role in the pathophysiology of migraine, in the last few decades new anti migraine drugs have been developed for migraine treatment. These drugs include (i) gepants, which act by directly blocking the CGRP receptor (i.e. rmiegepant and atogepant); and (ii) monoclonal antibodies, which directly block CGRP (i.e.eptinezumab, fremanezumab and galcanezumab or its receptor (i.e. erenumab).  CLR, calcitonin receptor-like receptor; RA<P1, receptor activity-modifying protein 1.

• Erenumab  Aimovig: subcutaneous (SQ) dose monthly 70 and 140 mg; side effects include constipation and risk of hypertension
• Fremanyzumab Ajovy  SQ dose monthly or quarterly/225 mg auto-inject monthly or 675 mg quarterly (must be given as 3 separate injections) 
• Galcanezeumab Emgality  SQ injection given monthly with a loading dose of 240 mg, then 120 mg/month
• Eptinizumab Vyepti  is given intravenously (IV) quarterly  at doses of  100 or 300 mg IV every 3 months  
• Atogepant (Qulipta) QULIPTA™ (atogepant) is the first and only oral calcitonin gene-related peptide (CGRP) receptor antagonist (gepant) specifically developed for the preventive treatment of episodic migraine. CGRP and its receptors are expressed in regions of the nervous system associated with migraine pathophysiology, and studies have shown that CGRP levels are elevated during migraine attacks. QULIPTA blocks CGRP through a once-daily dose and is available in three strengths – 10 mg, 30 mg and 60 mg.
• Unknown Long Term Data  Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones, or attenuate wound healing. The biggest unknown is the long-term safety and efficacy of the drug, as no long-term data currently exists. CGRP is involved and affects many different physiologic systems including the cardiovascular system, gastrointestinal system, pituitary system, and the immune system. The short-term safety data has shown predominantly mild and low adverse effects, but there is limited data on how long-term effects of interfering with CGRP will affect the many different physiologic systems in which CGRP is involved. Some potential long-term adverse effects could be increased risk of heart attacks and stroke from the loss of the protective cardiovascular role CGRP has on the cardiovascular system, decreased wound-healing abilities, and increased risk for ulcers and inflammatory bowel disease from the thinning of the mucosal lining of the gut.
• Botox injections   Botox is injected around pain fibers that are involved in headaches. Botox enters the nerve endings around where it is injected and blocks the release of chemicals involved in pain transmission. This prevents activation of pain networks in the brain. A subcutaneous (SQ) injection with 30-40 shots is given every 12 weeks. The patient must have failed at least three preventive treatments and been appropriately managed for medication overuse headache to be considered a candidate for treatment.

Complementary therapies in addition to prescribed medications may include:

• Riboflavin and Magnesium supplementation
• Melatonin
• Coenzyme Q10  
• Butterbur
• Body work, such as chiropractic, massage, and craniosacral therapy 
• Other nutritional and herbal supplements as appropriate for each patient.
• Yoga 
• Acupressure and acupuncture
• Biofeedback

Additional drug therapies to consider:

• Memantine 10 mg/day acts by blocking the brain’s N-methyl-D-aspartate (NDMA) receptor in the brain, therefore attenuating the effects of glutamate.
• Mirtazapine 15 mg-45  at bedtime (may cause low white blood cell count and low platelets)
• Indomethacin 25-50 mg, twice daily

 
Indomethacin for refractory COVID headache: After treatment with indomethacin, 36 patients reported greater than 50% headache relief from the third day and 5 patients became asymptomatic on the fifth day.6  In addition to the inhibition of cyclooxygenase, preventing the production of prostaglandins from arachidonic acid, indomethacin has a unique action that is not yet clarified. It may interfere with iontophoresed glutamate-activated dural-responsive second order neurons in the Trigeminal Nucleus Caudalis. Moreover, indomethacin may modulate nitric oxide (NO) signaling pathways. Nitric oxide is known to induce headache and delayed migraine in patients.
 
In some cases, indomethacin therapy caused persistent inhibition of platelet function. Patients suffering from classic migraine showed a high incidence of platelet activation (>90%) in comparison with common migraine patients.
 
For patients whose individual health condition may preclude use of some of these other or newer pharmaceutical options, there are studies that point to relief using:
• Fluvoxamine  In one study compared to the tricyclic antidepressant amitriptyline, fluvoxamine showed better migraine reduction and less drowsy side effects7; additionally, selective serotonin reuptake inhibitors (SSRIs) like fluvoxamine inhibit mast cell activation.8  https://www.jimmunol.org/content/202/1_Supplement/54.11
• Ibuprofen (Advil, Motrin)  The non-steroidal anti-inflammatory agent, ibuprofen, also has been implicated in raising ACE2 levels. In a study of rats with type 1 diabetes, ibuprofen raised cardiac ACE2 protein levels, or more correctly, attenuated the diabetes-induced reduction in ACE2 levels.9
Qiao W, Wang C, Chen B, et al. Ibuprofen attenuates cardiac fibrosis in streptozotocin-induced diabetic rats. Cardiology. 2015;131(2):97–106. [Crossref],
 
Devices for migraine treatment.
While costly, there are a number of devices may be preferred by people who want to avoid medication side effects:
https://www.goodrx.com/conditions/migraine/consumer-devices-for-migraine-treatment-and-prevention

In summary, we know that there are many treatment options for headaches. And as we continue to see more instances of headaches in our long COVID patients, we must keep in mind the mechanisms driving these symptoms, including high levels of systemic and brain inflammation as well the propensity for thrombosis generated by spike protein. Addressing this inflammation, much like we do with all neurological autoimmune disease, is key to achieving more successful outcomes. In our practice, we are utilizing a comprehensive long hauler recovery protocol designed to treat headaches as well as numerous other symptoms in order to ultimately help heal the whole patient. There is no single therapeutic protocol with efficacy for all patients, so it is imperative to consult a clinician with experience in treating long-haulers syndrome. Please continue to check back for additional articles in our long COVID series and don’t hesitate to reach out to our offices if we can help or if you’d like to schedule a visit. 
 
In hope and health,
Dr. Suzanne Gazda
 
Reference 

1 George, J. Migraine Frequency, Severity Drop Substantially With Diet Interventions. MedPage Today. July 2021. https://www.medpagetoday.com/neurology/migraines/93375
See also: BMJ 2021;374:n1535;  https://www.bmj.com/content/374/bmj.n1535
 
2 Mayans, L., Walling, A. Acute Migraine Headache: Treatment Strategies. Am Fam Physician. 2018;97(4):243-251.https://www.aafp.org/pubs/afp/issues/2018/0215/p243.html#afp20180215p243-b27
 
3 Jamieson DG. The safety of triptans in the treatment of patients with migraine. Am J Med. 2002 Feb 1;112(2):135-40. doi: 10.1016/s0002-9343(01)01064-6. PMID: 11835952.
 
4 Gillman PK. Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review. Headache. 2010;50(2):264-272. doi:10.1111/j.1526-4610.2009.01575.x
 
5 Edvinsson L. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. Br J Clin Pharmacol. 2015;80(2):193-199. doi:10.1111/bcp.12618
 
6 Krymchantowski AV, Silva-Néto RP, Jevoux C, Krymchantowski AG. Indomethacin for refractory COVID or post-COVID headache: a retrospective study. Acta Neurol Belg. 2022;122(2):465-469. doi:10.1007/s13760-021-01790-3
 
7 Bánk J. A comparative study of amitriptyline and fluvoxamine in migraine prophylaxis. Headache. 1994;34(8):476-478. doi:10.1111/j.1526-4610.1994.hed3408476.x
 
8 Selective Serotonin Reuptake Inhibitors Suppress Mast Cell Function
Haque, T., Ryan, J. Selective Serotonin Reuptake Inhibitors Suppress Mast Cell Function.
The Journal of Immunology, May 1, 2019, 202 (1 Supplement) 54.11; https://www.jimmunol.org/content/202/1_Supplement/54.11
 
9 Saghir Akhtar, Ibrahim F. Benter, Mohammed I. Danjuma, Suhail A. R. Doi, Syed S. Hasan & Abdella M. Habib (2020) Pharmacotherapy in COVID-19 patients: a review of ACE2-raising drugs and their clinical safety, Journal of Drug Targeting, 28:7-8, 683-699, DOI: 10.1080/1061186X.2020.1797754
 
Additional reading:
 
Acute migraine treatment
https://www.uptodate.com/contents/acute-treatment-of-migraine-in-adults/abstract/79
See also: https://www.aafp.org/pubs/afp/issues/2018/0215/p243.html#afp20180215p243-b12
 
Migraine treatments
https://www.webmd.com/migraines-headaches/migraine-treatments
 
The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice
https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.14153
 
CGRP inhibitors for migraine prophylaxis: a safety review
https://www.tandfonline.com/doi/pdf/10.1080/14740338.2020.1811229
 
The efficacy and safety of venlafaxine in the prophylaxis of migraine
https://pubmed.ncbi.nlm.nih.gov/15705120/
 
A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis
https://n.neurology.org/content/58/11/1652