[foxwolf]

All my life, I've suffered from frequent (as in daily) headaches. I even have a photo of myself from my 10th birthday (or thereabouts), where you can visibly tell from how I'm holding my head that I had a headache. The nature and intensity of my headaches has changed over time.

In my 20's I discovered Excedrin (acetaminophen + caffeine) and, surprisingly, it not only worked, but worked very well. One tablet would kill most of headaches I was having at that time of my life in about 15 minutes.

Unfortunately, it stopped working for me by the time I was 30. It no longer has any noticeable effect.

Aspirin, Naproxen, Ibuprofin, and Tylenol 3 have no effect, either.

[mancerayder]

Have you ruled out head/neck muscle tightness due to jaw clenching? Have you tried muscle Botox injections? or seen a migraine specialist?

[djmips]

That is a tragedy. Sounds like you could use some precision medicine but it feels like that revolution is not happening fast though.

[uselesswords]

disclaimer: Not medical advice. Just an exercise in theory. See a real doctor/neurologist or migrane specialist.

I would be very suspect of a Medication Overuse Headache (MOH) due what appears to be acute/abortive use of painkiller medication as compared to a prophylactic usage of other drugs. I'll do this exercise mostly ignoring the #1 concern because presumably your doctors would be hyperaware of that.

# Pathways

0. Excedrin is combination of aspirin, acetaminophen, & caffeine.

1. Aspirin --> COX-1 (/2) inhibition --> Reduces Prostacyclin/Prostaglandin/Thromboxane Synthesis --> Decreased inflammation, nociceptor sensitization, pain signaling

2. Acetaminophen --> Central COX Inhibition, possible COX-3 inhibition (splice variant of COX-1) --> Reduces Prostacyclin/Prostaglandin/Thromboxane Synthesis --> Decreased inflammation, nociceptor sensitization, pain signaling

3.a. Acetaminophen --> Metabolized to N-Arachidonoylphenolamine (AM404) --> Inhibition of reuptake of Anadamide (endogenous cannabinoid) --> Increased activation of CB1 receptors

3.b. Acetaminophen --> Metabolized to N-Arachidonoylphenolamine (AM404) --> Transient Receptor Potential Vanilloid (TRPV1) agonist --> active? at periaqueductal (central) gray --> opioid receptors that send descending axons to modulate pain at the level of the dorsal horn of the spinal cord

4. Acetaminophen --> Enhancement of serotonergic descending inhibition (5-HT pathways)

5. Caffeine --> Adenosine anatagonist (nonselective A1, A2A, A2B) --> Inhibition of vasodilation --> Cerebral vasoconstriction

6. Caffeine --> Analgesic Adjuvant --> Enhances availability of aspirin and acetaminophen.

# Thoughts

1. Selective: -COX, +CB1, +TRPV1, +Opioid, -Serotenergic, -Adenosine, -Inflammation, +Vasoconstriction/-Vasodilation

2. Aspirin doesn't work in isolation.

3. Tylenol-3 (acetaminophen) doesn't work in isolation (surprising!!!).

4. Headaches probably not -COX mechanisms

5. Caffeine is likely needed for -adenosine, vasculature effect implicating cerebral vasodilation

6. Densensitization strongly implicates +CB1/+TRPV1 as well as -adenosine, +Sero, +Opioid.

# Concluding Thoughts

0. Need to address MOH, this should be a conversatio with your real doctor.

1. Then for the headache, normal first-line would probably be a TCA prophylaxis such as amitriptyline with bonus target +sero/+opioid. Assuming you've tried this.

2. The failure of your other drugs means you should probably try CGRP Inhibitors to target vascular and pain-signaling effects. Maybe even gepants (acute)

3. Botox could be a consideration in a complex CDH case.

4. Zebras: Ditan/Lasmiditan. I assumed +vasoconstriction, but could be -vasoconstriction which is why non-combination drugs failed. Target 5-HT1F and avoid vasoconstriction for symptomatic relief, but doesn't treat underlying. Probably avoid due to MOH.

# Clarifying questions for your doctor, not me

1. Is your headache pulsatile/throbbing (migrane) or dull, tight, & persistent (tension-type)?

2. Onset characterized by stress (tension-type)?

3. Is it unilateral (migrane) or bilateral (tension-type)?

# What I would do next

1. Make an appointment with a neurologist

2. Before the appointment, make a detailed headache diary (when your headaches start/end, intensity of the pain, location and quality of the pain, associated symptoms (nausea, light senstivity), any potential triggers, what you did to try to relieve the headache and if it worked)