It's always weird to me that acetaminophen has such a low therapeutic index, like in order to get enough for it to do anything, you're also on the verge of liver failure (especially if you also drink alcohol). Also it just doesn't work super well in my personal experience --- I hardly feel anything when I take it. And yet it's one of the most commonly taken medicines worldwide.
I'm a big fan of it in terms of efficacy; does wonders for headaches as well as joint aches.
My concern is about the relatively recent findings about potential Alzheimer risk [1]:
> During a median follow-up of 12.3 years, 6407 (3.0%) participants developed new-onset all-cause dementia. Participants who regularly used paracetamol had a significantly higher risk of new-onset all-cause dementia (adjusted HR, 1.18; 95%CI: 1.10-1.26), compared with non-users. However, there was no significant association between regular use of ibuprofen and new-onset all-cause dementia (users vs. non-users; adjusted HR, 1.06; 95%CI: 0.97-1.16).
I don't follow the research closely enough to know if this is reliable evidence, but there are other studies showing the same thing.
Paracetamol also well known as mood-altering, apparently inhibiting empathy [2], which may be part of why it has an analgesic effect. That isn't as scary on a personal level, but imagine a society full of millions of people on paracetamol whose ability to feel empathy has been blunted.
I'm pretty sure ibuprofens risks are significantly higher than a 10-20% increased risk of dementia, it gives significantly increased risk of strokes iirc
"Therapeutic index" is a strange number to worry about. Those index scores are the balance between efficacy and toxicity.
Acetaminophen is an effective analgesic, just toxic in large doses. It's perfect for lower intensity pain. It's non-addictive, doesn't have long term issues like NSAIDs. It's popular for a reason.
My family always had boxes of it around the place when I was growing up. Never really had much use for pain killers. But when I was in my early 20s, no money, not looking at myself, I cracked a tooth in half and it took a few days to see the dentist. It was excruciating. First thing I did, take paracetamol (our name for acetaminophen). It did absolutely nothing. The pain was like a lightning bolt from tooth to brain. After another 30 minutes, I couldn't handle it any more, went to the pharmacy and got aspirin. That worked within 20 minutes.
I have never taken acetaminophen since then. If it's a low intensity pain, then I can handle it myself. If I need actual pain relief I'll use an NSAID.
Finding out later that paracetamol dosage is super close to overdose, and how it actually kills you... That put the tin hat on it.
The effectiveness varies a lot. For me it works great, several other people I know get no effects at all from taking safe doses and of course excess doses are potentially extremely dangerous, extremely fast - about 2.5x the usual maximum dose causes liver failure in some people, that's barely more than "Oops, I already took that and I forgot" from a nasty death.
If it was discovered tomorrow rather than last century, it would never get OTC approval, because while for some people (like me) it's useful, the dangers are too high, so they'd definitely make it prescription-only. I'd probably still come back from any surgery with a bag of paracetamol because it's cheap and the surgeons can prescribe it to somebody it works on without worrying (it's not like an opioid, nobody is going to get unnecessary surgery so as to secure more paracetamol) but it would not be in cold & flu meds if they hadn't found it last century when they were more lax about safety.
It’s unfortunate that it doesn’t work for you. Personally, I’ve never experienced a pharmaceutical that worked so reliably and predictably. It would bring a fever down in my kids when they were young without fail in about 25 minutes.
To be fair though I really haven’t been involved with more than a handful of medications. I’m sure there’s many that work very crisply.
Similar to you it is incredible at bringing down fever in my kid. I've seen my kid go from whimpering looking like death, to be crawling about playing happily again in half an hour. With the behaviour change tracking with her temperature coming down.
As an adult using it as a pain killer it has been ineffective.
Calpol in the UK, paracetamol for children in liquid form (which is British name for acetaminophen) works wonders for kids with a fever. I'm not exaggerating when I say that every doctor I've seen with my kids has said not to withhold it as it really helps with fever.
Two tablets work great for me for headaches but results do vary. The danger zone for liver damage is roughly 14 tablets taken all at once. (Less if you've been drinking.) From what I'm told, acetaminophen overdose is quite an unpleasant way to die.
You die from liver failure. Which is a horrible way to die. You’re bleeding and clotting at the same time. Your abdomen swells with fluid. Then your legs and your whole body. Your skin turns yellow and you’re itching constantly. You become increasingly confused and violent. Infections start brewing in that pool of fluid in your abdomen.
Well, it doesn't work for high fever (> 39-40 Celsius). For that, I alternate Ibuprofen and sodium metamizole every 4 hours.
For pain release, paracetamol it's very modest. Some effect for light head pain, zero for strong pain. Zero effect for strong back pain. Ibuprofen works better in all these cases but comes with stomach damage if taken for long.
“56,000 emergency department visits and 2600 hospitalizations, acetaminophen poisoning causes 500 deaths annually in the United States” -Acetaminophen Toxicity
Suneil Agrawal; Brian P. Murray; Babak Khazaeni. https://www.ncbi.nlm.nih.gov/books/NBK441917/
Would that not make it a very effective pain killer? /s
But seriously - you are not supposed to "feel" a drug. Opiates work on a much different mechanism, and you do "feel" them, but that is also the same mechanism that make them so addictive. What you want is a drug that helps you manage pain and not be addictive.
The same website is also for the excellent Science News print magazine, which will ship you top notch science reporting right to your door. My father was a subscriber since, well, whenever blue LEDs were invented, because I recall reading about them in Science News.
Science News is a big part of my childhood. My stepdad's dad was a subscriber and every issue was handed down to us gently used. I have thousands of back issues.
I'm impressed beyond words by these kids, though I think I'd give her the top prize. Watching my grandfather's final days taken away from him by the effects of morphine has always made me wish so much that we had much more effective non-narcotic painkillers
They aren't doing it on their own. Most of these kids are working with established researchers who give them the shape of the project, as well as the tools and the expertise to accomplish it.
More recently the US scientific funding bodies have had summer programs for kids who wouldn't otherwise get that kind of access, but it's still the exception. It takes more than a summer to do this kind of work.
Edit: quick search for the father's name brings up this professor of biochemistry at UT Tyler:
I don't mean to take anything away from the kid or suggest that they don't work hard, are smart, etc., but these kinds of science fairs are fundamentally about access.
Morphine, like all neurotransmitter drugs, affects the autonomic nervous system which can yield a cornucopia of unwanted and seemingly unrelated side effects. It’s a complex system that’s best treated with care.
Nurses in palliative care and hospice are well-known to generously administer morphine in increasing doses, because it eventually takes away all the pain and suffering (of the families and nurses).
at least according to these people [0], you can overdose on morphine, same as any opiate or opioid. not sure their credentials but it makes sense; it's an opioid/opiate and those can cause respiratory depression.
Fentanyl is pretty much better than morphine in every way. Less toxic, cheaper, and works better with less side-effects. Especially less histamine response, which is the body itching people get.
Unfortunately, it's tainted by illicit use. Damned to only be used in dire circumstances. It's a shame, really.
I’m not going to shit on it, nothing wrong with going into the family business - but it isn’t a complete coincidence that her dad is a PhD biochemist at UT Tyler.
Yeah, it's great to have kids excited about science, but at 17 it's extremely unlikely that she taught herself enough chemistry, organic chemistry and biochemistry to come up with this. She needs years more of college-level coursework. Essentially impossible without a biochemist in the family to guide her.
Seeing articles like this is almost hard to read. My kids are very smart but this girl is 1000 times what they are doing. This girl is 1000 times what I am doing.
Maybe it is just imposter syndrome but sometimes I read articles like this and think I fell short in life. But I am also top of my peers at work and I am a health care provider and my clients all request me so I know I am doing good. Sometimes I just wonder what mark I will leave on this world.
My experience is that stuff like this isn't because someone is wildly smarter than everyone but because there are connections, support, and resources of some form.
it's just a four step synthesis. with the help of a phd chemist you could probably learn the steps in three months, and if you put your mind to it you could learn the ochem in a year. this project is the culmination of at least a year-maybe even up to three-of work.
whats surprising is that parents let their kids do ochem at 17!! thats some toxic shit :). safety is why chemistry is not a super popular field at high school level science fairs.
I think the idea that one has to leave a mark on the world before one dies is overrated and not super useful.
First, what would such a mark be like for you? Is it something you could plausibly achieve with all the resources within your reach? Is it well-defined or is it nebulous? Is it likely to remain stable over the time you would require to achieve it, or is it more defined by the whims and fancies of the world which seemingly change every other week now?
Then, even if you did achieve it, how long would it continue to matter to you? Would you remain satisfied with it or could you become habituated to the achievement in a week, month or year and replace it another mark that would then become the one task you must complete before you die? Even if you did remain satisfied with your great achievement, would it really matter to you at the end of your life, or would you completely forget about it in the physical and mental anguish that many people seem to experience at the end of their lives?
And after you are dead, how long would that achievement be remembered before being supplanted in the public eye by something bigger?
And would it really make a difference to you at that point? Whether it remains a grand success for a thousand years or is forgotten in a day, you won't be there to know the difference anyway. It really only matters to you for the brief periods of time in which you're thinking about it right now. During times that you're distracted, tired, enjoying and appreciating something else or are simply asleep, it's hard to believe it matters at all.
If you're happy, healthy, not harming others, making a decent and honourable living, raising kids, I think you're already winning.
If the idea of having to leave a mark is making you unhappy, maybe it's better to just drop the idea.
apart from that: the word "mark" comes from a root for "boundary" or "border", and really it doesn't need to be about that; we're all in this together.
The key synthetic step using Ir was published after I graduated (and left Chemistry...) way to make me feel old :)
I'm very impressed by the level of chemistry demonstrated by a 17 year old. During my time as a chemistry student this level of project and synthesis probably could have been included as a chunk of a master's thesis. Did she perform all the synthesis herself? That takes a decent amount of experimental skill and more importantly what lab did she do all of this in?
Any uni ought to be delighted to get a precocious talent like this!
impressive for a high schooler but this just adds a protecting group onto tylenol. am i missing something?
edit: oh i see. its really blurry but the silyl modified tylenol is predicted to have good trpv1 binding computationally. afaict no in vitro or in vivo studies were done. could be cool. not sure if diethylethynylphenylsilyl group has good Lipinski properties though (i suspect not)
[Very good comment! I'd use the opportunity to add more questions.]
How expensive are the steps? They look like advanced steps that can be done in a lab to prepare a few micrograms, but I'm not sure if they can be scaled to industrial production.
Why silicon instead of just a carbon? Is it better blocking the docking? Is it better moving the orbital energy levels? Is it as safe as the poster claim?
I'm not an expert in pharmaceutical chemistry, but this looks like a series of relatively complex and low yield reactions. Would it be likely that this would push the price of this product beyond what is reasonable for a general use drug?
The starting point is ~free (like 2 or 4 cents retail per dose for generic in the US). Given my relatively light usage of pain drugs, I would certainly pay 10x that for reduced toxicity.
And then it isn't necessarily the case that the identified reactions are the most cost effective available.
If you have light usage, do you need reduced toxicity?
Acetaminophen's effective dose is pretty close to the dangerous dose, but I would take light use to mean you take something maybe once a month max and only a single dose (or maybe even just one pill when the dose is two pills). At that level of use, I don't think you're at risk of anything.
Otoh, if the title is accurate and it can be more effective at pain release and less damaging to the liver, that would be great for people who experience pain frequently.
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.
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.
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)
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)
Readit News
My concern is about the relatively recent findings about potential Alzheimer risk [1]:
> During a median follow-up of 12.3 years, 6407 (3.0%) participants developed new-onset all-cause dementia. Participants who regularly used paracetamol had a significantly higher risk of new-onset all-cause dementia (adjusted HR, 1.18; 95%CI: 1.10-1.26), compared with non-users. However, there was no significant association between regular use of ibuprofen and new-onset all-cause dementia (users vs. non-users; adjusted HR, 1.06; 95%CI: 0.97-1.16).
I don't follow the research closely enough to know if this is reliable evidence, but there are other studies showing the same thing.
Paracetamol also well known as mood-altering, apparently inhibiting empathy [2], which may be part of why it has an analgesic effect. That isn't as scary on a personal level, but imagine a society full of millions of people on paracetamol whose ability to feel empathy has been blunted.
[1] https://pubmed.ncbi.nlm.nih.gov/37633120/
[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC6455058/
Acetaminophen is an effective analgesic, just toxic in large doses. It's perfect for lower intensity pain. It's non-addictive, doesn't have long term issues like NSAIDs. It's popular for a reason.
I have never taken acetaminophen since then. If it's a low intensity pain, then I can handle it myself. If I need actual pain relief I'll use an NSAID.
Finding out later that paracetamol dosage is super close to overdose, and how it actually kills you... That put the tin hat on it.
If it was discovered tomorrow rather than last century, it would never get OTC approval, because while for some people (like me) it's useful, the dangers are too high, so they'd definitely make it prescription-only. I'd probably still come back from any surgery with a bag of paracetamol because it's cheap and the surgeons can prescribe it to somebody it works on without worrying (it's not like an opioid, nobody is going to get unnecessary surgery so as to secure more paracetamol) but it would not be in cold & flu meds if they hadn't found it last century when they were more lax about safety.
[Edited to insert crucial omitted "not"]
To be fair though I really haven’t been involved with more than a handful of medications. I’m sure there’s many that work very crisply.
As an adult using it as a pain killer it has been ineffective.
Any more and it's liver damage.
For pain release, paracetamol it's very modest. Some effect for light head pain, zero for strong pain. Zero effect for strong back pain. Ibuprofen works better in all these cases but comes with stomach damage if taken for long.
Would that not make it a very effective pain killer? /s
But seriously - you are not supposed to "feel" a drug. Opiates work on a much different mechanism, and you do "feel" them, but that is also the same mechanism that make them so addictive. What you want is a drug that helps you manage pain and not be addictive.
Strong recommendation for any science-lover.
I'm impressed beyond words by these kids, though I think I'd give her the top prize. Watching my grandfather's final days taken away from him by the effects of morphine has always made me wish so much that we had much more effective non-narcotic painkillers
She's in top 4, awarded $600? I dunno this is a confusing layout/structure for how the program is conducted seeing as how the headline is $9m awarded.
More recently the US scientific funding bodies have had summer programs for kids who wouldn't otherwise get that kind of access, but it's still the exception. It takes more than a summer to do this kind of work.
Edit: quick search for the father's name brings up this professor of biochemistry at UT Tyler:
https://www.uttyler.edu/directory/chemistry/lee-jiyong.php
and mom's name brings up this professor of pharmaceutical science:
https://www.unthsc.edu/college-of-pharmacy/eul-hyun-suh
I don't mean to take anything away from the kid or suggest that they don't work hard, are smart, etc., but these kinds of science fairs are fundamentally about access.
Deleted Comment
Those were not prbly his final days. he was artifically kept alive by modern medicine. Those final days are not natural part of dying.
[0]https://www.addictiongroup.org/drugs/opioids/morphine/overdo...
Fentanyl, my brother claims to be the best. It, too, can work wonders under a controlled environment.
Unfortunately, it's tainted by illicit use. Damned to only be used in dire circumstances. It's a shame, really.
Something tells me he didn't launch the satellite.
whats surprising is that parents let their kids do ochem at 17!! thats some toxic shit :). safety is why chemistry is not a super popular field at high school level science fairs.
First, what would such a mark be like for you? Is it something you could plausibly achieve with all the resources within your reach? Is it well-defined or is it nebulous? Is it likely to remain stable over the time you would require to achieve it, or is it more defined by the whims and fancies of the world which seemingly change every other week now?
Then, even if you did achieve it, how long would it continue to matter to you? Would you remain satisfied with it or could you become habituated to the achievement in a week, month or year and replace it another mark that would then become the one task you must complete before you die? Even if you did remain satisfied with your great achievement, would it really matter to you at the end of your life, or would you completely forget about it in the physical and mental anguish that many people seem to experience at the end of their lives?
And after you are dead, how long would that achievement be remembered before being supplanted in the public eye by something bigger?
And would it really make a difference to you at that point? Whether it remains a grand success for a thousand years or is forgotten in a day, you won't be there to know the difference anyway. It really only matters to you for the brief periods of time in which you're thinking about it right now. During times that you're distracted, tired, enjoying and appreciating something else or are simply asleep, it's hard to believe it matters at all.
If you're happy, healthy, not harming others, making a decent and honourable living, raising kids, I think you're already winning.
If the idea of having to leave a mark is making you unhappy, maybe it's better to just drop the idea.
apart from that: the word "mark" comes from a root for "boundary" or "border", and really it doesn't need to be about that; we're all in this together.
I'm very impressed by the level of chemistry demonstrated by a 17 year old. During my time as a chemistry student this level of project and synthesis probably could have been included as a chunk of a master's thesis. Did she perform all the synthesis herself? That takes a decent amount of experimental skill and more importantly what lab did she do all of this in?
Any uni ought to be delighted to get a precocious talent like this!
edit: oh i see. its really blurry but the silyl modified tylenol is predicted to have good trpv1 binding computationally. afaict no in vitro or in vivo studies were done. could be cool. not sure if diethylethynylphenylsilyl group has good Lipinski properties though (i suspect not)
edit: s/aspirin/Tylenol
How expensive are the steps? They look like advanced steps that can be done in a lab to prepare a few micrograms, but I'm not sure if they can be scaled to industrial production.
Why silicon instead of just a carbon? Is it better blocking the docking? Is it better moving the orbital energy levels? Is it as safe as the poster claim?
https://www.science.org/content/blog-post/silicon-drug-molec...
that molecule almost certainly fails the ClogP not greater than five lipinski rule (it's too greasy)
And then it isn't necessarily the case that the identified reactions are the most cost effective available.
Acetaminophen's effective dose is pretty close to the dangerous dose, but I would take light use to mean you take something maybe once a month max and only a single dose (or maybe even just one pill when the dose is two pills). At that level of use, I don't think you're at risk of anything.
Otoh, if the title is accurate and it can be more effective at pain release and less damaging to the liver, that would be great for people who experience pain frequently.
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.
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)