Chapter 35: Headaches – Acute & Preventive Pharmacotherapy

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Welcome back to the Deep Dive.

You know, headaches.

They're just about the most common thing people walk into primary care for.

We're talking something like one in seven Americans dealing with them.

That's right.

It's a massive number.

So if you, the listener, are looking to

really get up to speed quickly on managing the drugs, the different types from simple OTCs to

the really new stuff, well, this deep dive into the core headache chapter is, frankly, your essential shortcut.

And getting a handle on this, it really starts with the basics.

Classification.

The very first clinical step has to be figuring out if it's a primary headache,

no underlying disease like a migraine or tension type, or if it's secondary, meaning there is a specific cause we can point to.

Today, we're focusing mostly on managing those big primary ones pharmacologically, and especially the challenges that come with pain that just keeps coming back.

Yeah, that recurrence aspect is so crucial because that's where one of the biggest pitfalls comes in, right?

Medication overuse headache.

So our mission today is really to cut through all that, cover attention type headaches, migraines, touch on cluster headaches, focusing on how the drugs work, the key classes, and critically, those absolute no -go contra indications for advanced practice.

Okay, let's unpack it starting with the super common tension type headache or TTH.

Right, TTH, often described as, you know, bilateral pressing tightening pain,

usually mild to moderate.

Kind of like that classic band around the head feeling people mention.

Precisely.

But clinically, what's really striking is just how prevalent it is a lifetime rate of up to 78%.

That's huge.

Wow.

And what's interesting, I think, is the shift in understanding.

It used to be sort of dismissed as maybe psychological, but now we know it's got clear neurobiologic roots.

It involves central and peripheral pain processing pathways.

But like you said, the immediate clinical hurdle isn't always the pain itself.

It's the risk that comes with treating it frequently.

The risk of medication overuse headache, MOH.

We know this is a major, issue.

So when you're talking to a TTH patient, how do you navigate that conversation, especially if they're reaching for Advil or Tylenol almost daily?

Yeah, that's a tough conversation, but you absolutely have to be crystal clear about the limits.

MOH is specifically a recurrent headache triggered by overusing acute treatments.

Okay.

And for over -the -counter stuff, your standard analgesics, the threshold is treating more than two headaches per week.

That's the line.

Only two.

That seems low compared to how people often use them.

It does.

But crossing that line really risks shifting the patient into a chronic daily headache pattern.

And it gets even riskier if things like caffeine or botalbutyl are in the mix.

Right.

So the initial treatment for MOH often means just stopping.

Often, yes.

Abruptly stopping the OTC analgesics.

Now, if it's something like a barbiturate, like botalbutyl, you have to taper that carefully to avoid withdrawal.

But for standard OTCs, often cold turkey.

Okay.

So if we want to avoid MOH, we need effective acute treatments that people don't overuse.

What are our go -to first -line options for mild to moderate TTH?

We generally rely on acetaminophen APEP or NSAIDs, non -steroidal anti -inflammatory drugs.

Got it.

APE is good for pain and fever and analgesic and antipyretic.

But importantly, it doesn't have anti -inflammatory action.

It works, but you must respect the dosing limits.

Hepatotoxicity liver damage is a real risk.

And those limits are?

Maximum single OTC dose is 650 milligrams.

And the absolute maximum daily dose is 3 ,250 milligrams.

Especially crucial if the patient drinks heavily.

That 3 ,250 daily max is so important, isn't it?

Because combination cold meds and things can push you over without realizing it.

Oh, absolutely.

You have to look at all sources.

Now, NSAIDs like ibuprofen or naproxen, they're often preferred because they actually tackle inflammation by inhibiting prostaglandin synthesis through COX2.

So they address a potential underlying mechanism better.

In many cases, yes.

Studies suggest NSAIDs often do work better than APAPIC or aspirin for moderate DT.

Here's a useful clinical pearl, too.

If one NSAID doesn't work for a patient for two headaches in a row,

try a different one in the same class.

Response can be really individual.

Okay, that makes sense.

But what if someone is hitting that two -day -a -week limit for acute meds?

When do we say, okay, we need to shift gears to prevention, to prophylaxis?

Prophylaxis is definitely indicated when a patient has more than two significant TT8 episodes per week.

Or if the headaches they do get are particularly severe or disabling.

And what's the first choice there?

The gold standard first -line agent is still amitriptyline.

It's a tricyclic antidepressant ATCA.

We use it at low doses, though.

Why low doses?

Because its effectiveness for headache isn't really about the antidepressant effect.

It's about its ananosusceptive properties, basically, dampening pain signals.

And that works at lower doses than needed for depression.

Okay.

And if amitriptyline doesn't work out, maybe side effects are an issue.

Then second -line options include the SNRI's selective serotonin or repnephrine reuptake inhibitors, like venlafaxine or maybe mirtazapine.

What about SSRI's, like Prozac?

That's a key point.

SSRI's, like fluoxetine, generally are not effective for headache prophylaxis.

It's an important distinction.

Good to know.

And you have to counsel the patient on timing.

Prophylactic meds aren't a quick fix.

They need a good four to eight weeks to really show their full effect.

It takes patience.

Right.

Managing expectations is key there.

Okay.

Let's pivot from TTH to migraine.

This feels like a whole different beast.

It really is.

Migraine isn't just a headache.

It's a full -blown neurologic syndrome.

You've got the throbbing pain, often severe nausea, that intense sensitivity to light and sound photophobia and phonophobia, often completely disabling.

And the underlying mechanism is different too, right?

More complex.

Much more complex.

It involves the trigeminovascular system.

Essentially, there's a release of these vasoactive neuropeptides, especially one called CGRP, calcitonin gene -related peptide.

CGRP.

Okay.

That's a term we'll come back to.

Definitely.

That release leads to vasodilation, blood vessels widening, and neurogenic inflammation.

That's the core pathophysiology we target.

So targeting that system, that brings us to the migraine -specific drugs, the tryptans.

Exactly.

Tryptans are 5 -HT1BD receptor agonists.

They hit two targets.

Binding to 5 -HT1B causes cerebral vasoconstriction tightening those dilated blood vessels.

Okay.

Vasoconstriction.

That sounds like a potential problem area.

It absolutely is.

We'll get back to that.

The other target is 5 -HT1D receptors on the trigeminal nerves.

Binding there blocks the release of those problematic neuropeptides like CGRP.

So it tackles both the vessel dilation and the inflammatory signal.

Precisely.

But that vasoconstriction you flagged, that's where the major risks and contraindications come in.

This is critical for practitioners.

Okay.

Let's spell it out.

Who absolutely cannot take a tryptan?

Because they constrict blood vessels.

Tryptans are an absolute no -go for any patient with known cardiovascular disease.

That's CAD, coronary artery disease, also cerebrovascular disease, like a history of stroke or TIA, severe peripheral vascular disease, PVD.

And they're also contraindicated in specific rarer migraine types like basilar, hemiplegic, or retinal migraines.

This isn't a suggestion.

It's a hard stop.

Non -negotiable.

And what about overuse?

Same MOH risk as with OTCs.

Yes, definitely.

The rule for tryptans is no more than nine days of use per month to avoid medication overuse headache.

Nine days.

Okay.

So given these restrictions and the fact there are, what, seven different tryptans available, how do we choose the right one for the right patient or situation?

Can we kind of mentally summarize their differences?

We can, yeah.

Think about it mainly in terms of speed of onset and how long they last, their half -life.

Sumatryptan is sort of the original, the benchmark.

Okay.

It's the fastest acting, especially the Soketenes injection that can work in as little as 10 minutes.

But the flip side is it has the shortest half -life, only about two hours.

So quick relief, but maybe the headache comes back.

It can, yeah.

But that fast action combined with its different forms, the injection,

a nasal spray, an orally dissolving tablet makes it really valuable for people who get severe nausea and vomiting early on and can't keep a pill down.

Makes sense.

What about the other end?

Say someone has migraines that reliably drag on for two days, a short half -life sounds unhelpful there.

Exactly.

And that's where a drug like provitryptan really shines.

It has the longest half -life of all tryptans, around 25 hours.

Wow.

That's a big difference.

It is.

And that makes it great for those really long -lasting migraines.

It's also the preferred agent for what we call mini -prophylaxis for menstrual migraines, taking it for a few days around the period.

Interesting.

Any others worth highlighting?

Maybe one for people who get side effects from Sumatryptan, like that chest tightness and report?

Yeah, that's a common concern.

For patients who experience that, or maybe headache recurrence with the faster ones, narrow tryptan is often a good alternative.

Its side effect profile is actually pretty close to placebo in studies, so it tends to be better tolerated.

Good to know.

But that underlying issue remains the vasoconstriction.

It rules out a lot of patients.

So these newer classes, the ditans and the guppants, they offer alternatives for those patients, right?

Let's start with ditans.

Yes.

The ditans, like lasmititan, represent a really significant step forward.

They are serotonin receptor agonists, like tryptans, but they're more selective.

They preferentially bind to the 5 -HT1F receptor.

And why is that important?

Because that 5 -HT1F receptor isn't involved in vasoconstriction like the 5 -HT1B receptor is.

So ditans largely avoid that blood vessel tightening effect.

Making them safer for patients with cardiovascular risk factors.

Exactly.

It opens up a new option for them.

However, ditans come with their own significant warning.

They can cause substantial CNS depression,

drowsiness, dizziness.

Okay, how significant?

Significant enough that the patient absolutely must be told not to drive or operate heavy machinery for at least eight hours after taking a dose.

That's a major counseling point.

Eight hours.

Right.

Okay, what about the gay pants?

They work differently again, targeting that CGRP pathway we mentioned.

They do.

Ubreft Pant and Remedjapan are the acute treatment japanes.

They are CGRP receptor antagonists.

So they directly block either the CGRP receptor itself or the CGRP molecule, the ligand.

And the effect of blocking CGRP is?

It reduces that neurogenic inflammation and the vasodilation that CGRP causes.

But here's the key advantage.

They do this without causing active vasoconstriction.

No vasoconstriction at all.

None.

Which makes them a highly attractive option, especially for patients with cardiac issues who couldn't take triptans.

It's really expanded our toolkit safely.

That sounds like a game -changer for certain patients.

Before we move on to prevention, though, we really need to underline the warnings about some older agents.

Opioids and those botalbitol -containing meds, like Furacet or Furinil.

Oh, absolutely.

Let's be very clear.

Opioids and botalbitol compounds are strongly discouraged as first -line or even second -line treatment for recurrent headaches like migraine.

Why so strongly discouraged?

They are controlled substances, C3 or CIV, and they carry extremely high risks.

Yeah.

Risk of dependency, risk of difficult withdrawal syndromes, and a very high risk of causing medication -overuse headache.

So they can actually make the headaches worse in the long run.

Precisely.

They should really only be considered very sparingly as a last -ditch rescue medication if and only if the migraine -specific treatments like triptans or gatans have completely failed.

The American Headache Society has even flagged their overuse as a major practice problem.

Got it.

Reserve for truly refractory cases used extremely cautiously.

Okay, let's shift now to preventing migraines.

You mentioned CGRP earlier, but first, who actually needs preventative therapy?

Prophylaxis is often, unfortunately, really underutilized.

Studies show maybe only 3 % to 13 % of people who could benefit actually receive it.

Wow.

That low.

Who should be getting it?

It's indicated for patients who have frequent attacks.

The general guideline is four or more migraine headache days per month, or if they're consistently overusing their acute medications, even if the frequency is slightly lower.

And the goal isn't necessarily zero headaches, right?

No.

The realistic goal we aim for is usually about a 50 % reduction in either the frequency or the severity of the attacks.

That's considered a successful outcome.

Okay.

So what are the established well -proven oral options for prevention?

We have several with solid level A evidence.

First, there are the anticonvulsants.

Devalprox sodium or Velprod is effective.

But there's always a but with anticonvulsants, it seems.

Right.

Big buts, contraindicated in liver disease,

and absolutely positively contraindicated in pregnancy due to a high risk of serious fetal toxicity.

Major birth defects.

Okay.

Huge warning there.

What other anticonvulsants?

Deporamate is another mainstay, also effective.

But it comes with its own set of potential adverse effects, particularly cognitive issues, problems with memory, word finding, concentration, sometimes called the dopamax effect.

Yeah, I've heard that term.

That can really impact someone's willingness to stick with it.

Definitely.

Adherence can be a big problem if those side effects are prominent.

Are there better tolerated first line options?

Often, yes.

Beta blockers are frequently used

propranolol, metoprolol, timolol.

They have good evidence, often achieve that 50 % reduction goal, and tend to be tolerated reasonably well by many patients.

And amitriptyline, the TCA we talked about for TTA prophylaxis, it's also considered a probably effective option for migraine prevention, too.

Again, at those lower doses.

Got it.

Now, let's talk about the really cutting edge stuff.

Those injectable CGRP monoclonal antibodies, the MABs, how do they fit in?

These are a major advance in prevention.

They are biologics monoclonal antibodies designed specifically to target the CGRP pathway.

Some target the CGRP receptor itself.

That's aranumab.

Others target the CGRP ligand, the molecule floating around that includes framinizumab, galcanizumab, and eptinizumab.

And what's the big advantage of these compared to the older oral meds?

A few things.

One is often a rapid onset of action.

Another huge plus is the dosing.

They're usually given as a subcutaneous injection either once a month or sometimes even once every three months.

Eptinizumab is an IV infusion every three months.

So no daily pills, no slow buildup needed.

Exactly.

No slow titration like with toparamate or amitriptyline.

You get to the therapeutic dose quickly.

The main side effect to watch for is with aranumab, which has a specific warning about potentially serious constipation.

Okay.

And what about Botox?

We hear about Botox for migraines.

Is that related to CGRP?

No, Botox, on a botulinum toxin A, works differently.

It's specifically FDA approved only for chronic migraine.

That's defined as 15 or more headache days per month with at least eight having migraine features.

15 or more days.

Wow.

Yeah.

It's a high burden.

Botox involves multiple small injections into specific muscles around the head and neck every 12 weeks.

Because it's a neurotoxin though, it carries a boxed warning about the potential for the toxin effect to spread away from the injection site.

Which could cause?

In rare cases, serious problems like difficulty swallowing or breathing.

So thorough patient education is absolutely critical.

Understood.

Okay.

Before we wrap up with special populations, we need to quickly touch on cluster headaches.

These sound particularly brutal.

They are often described as one of the most painful conditions known.

Excruciating, severe unilateral pain, usually centered in or around one eye.

Often described as burning, boring, or stabbing.

And they come in clusters, hence the name.

Exactly.

Periods of frequent attacks, then periods of remission.

For treating the acute attack, which is incredibly intense, the level A recommended options are injectable Sumitriptan.

Like for migraine.

Yes.

Subcutaneous Sumitriptan, also Zolmitriptan nasal spray.

And unique to cluster headache, inhaling 100 % oxygen via a non -rebreather mask is highly effective.

Oxygen.

Interesting.

What about preventing the clusters?

Prophylaxis is key.

Options include things like suboccipital steroid injections.

The calcium channel blocker for apomel, often used at higher doses than for cardiac conditions.

And one of the CGRP mabs, Galcanazumab, is also improved for episodic cluster headache prevention.

Okay.

Good overview.

Now let's bring it all together by thinking about specific patient groups.

Clinical practice isn't one size fits all.

How do these treatments change in, say, pregnancy?

Pregnancy is a really challenging area.

The good news is migraines often actually improve, especially in the second and third trimesters.

That is good news because treatment options are limited.

Very limited.

Triptans and the older ergot derivatives are strongly contraindicated due to risks to the fetus and uterus.

Acetaminophen, APP, is generally considered the safest pain reliever, but honestly, it's often not very effective for migraine -level pain.

Right.

What about NSAIDs, like ibuprofen?

Ibuprofen can be used, but sparingly, and only in the first and second trimesters.

It needs to be avoided in the third trimester due to risks to the fetal cardiovascular system.

And for prevention,

absolutely no valproic acid because of the severe fetal risks we mentioned.

A very restricted toolkit then.

Now you mentioned migraine is much more common in women, something like 3 to 1.

How does that impact treatment, especially around menstruation?

That hormonal link is clear for many women.

Menstrual migraine is a distinct entity, and this is where provitriptan with its super long half -life.

Ah yes, the 25 -hour one.

Exactly.

It becomes particularly useful.

It can be used as that mini -prophylaxis, taking it for maybe 2 days before the expected migraine onset and continuing for 5 -6 days total around the cycle.

It's quite effective for preventing those predictable attacks.

Makes sense.

What about at the other end of the lifespan, older adults?

In older adults, a couple of key things change.

First, any new onset headache, or a significant change in headache pattern, really requires a high degree of suspicion for an underlying organic cause.

Don't just assume it's primary headache.

Rule out secondary causes first.

Absolutely.

Second, regarding treatment, triptans are generally off the table.

Why?

Because cardiovascular and peripheral vascular disease risk factors are just so common in this age group, making vasoconstrictors unsafe.

Right, the contraindications become much more relevant.

Exactly.

And of course, you always need to consider age -related changes in liver and kidney function when dosing any medication, potentially starting lower and going slower.

Okay.

And finally, pediatric patients.

Kids get migraines too.

They do.

Migraine is actually the most common recurrent headache type in kids.

For acute treatment, we usually start simple.

APP, or ibuprofen, maybe with an anti -emetic if nausea is bad.

That's often first line.

What about prevention?

Are the options different?

Very different, especially regarding FDA approval.

For migraine prophylaxis in adolescents age 12 and over, topiramate is the only medication that currently has specific FDA approval.

Only topiramate.

That seems limiting.

It is.

Amitriptyline is often used off -label and can be effective.

But again, you have to be extremely cautious with valproic acid in any adolescent female who could potentially become pregnant due to the teratogenicity risk.

Okay, that brings us through the major groups.

Thinking about this whole landscape, it's complex.

It really is.

Managing headaches pharmacologically demands first getting the diagnosis right.

Then it's this constant balancing act, finding what works, minimizing side effects, and always being vigilant about the risk of medication overuse headache.

We've seen this evolution, haven't we?

From just general pain relievers to the targeted tryptans and now these even more specific agents like the Dayton's and especially the vasoconstricting kapans, it really offers new hope, particularly for those patients who had limited options due to heart health concerns.

So to really boil down the key takeaways for everyone listening, definitely watch out for MOH.

Remember those limits no more than two days a week for OTCs and TTs.

No more than nine days a month for tryptans and migraine.

Usual numbers.

Know those serious vascular contraindications for tryptans, CAD, stroke history, PVD.

They are absolute.

Non -negotiable.

And remember these newer agents, the Dayton's and Kapans, are really changing the game by expanding safe, effective, acute treatment options.

We have tools now we just didn't have even five years ago.

Absolutely.

Which brings up a final thought, perhaps.

Given how common MOH still is and how underused preventative therapies often are, it makes you wonder, how can we as advanced practitioners get better at integrating the non -drug approaches?

Things like cognitive behavioral therapy, biofeedback, weaving those into routine care alongside the medications.

Could that improve long -term outcomes and maybe reduce reliance on acute meds?

That's a really important question.

How to build that truly integrated approach for long -term success.

Definitely something for all of us managing patients with headache to think about.

Thank you for diving deep with us today into headache pharmacotherapy.

We'll catch you next time.