Chapter 24: Opioid Analgesics, Opioid Antagonists, and Nonopioid Centrally Acting Analgesics

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You know, usually when we think about fixing a problem in medicine, there's this expectation of structural repair.

Right, like engineering.

Yeah, exactly, like engineering.

You have a patient with a fractured radius.

The x -ray shows that jagged white line.

The provider sets the bone, puts on a cast and says, you know, there it is, we fixed the hardware.

Right, it's very localized.

Very mechanical.

But then you step into the world of severe pain management and suddenly you aren't just fixing the hardware anymore.

You are actively hacking the nervous system's software

to, well, to basically alter its fundamental perception of reality.

And the tools we use to execute that hack are incredibly powerful.

But, I mean, they're also incredibly dangerous.

It's a profound responsibility.

It really is.

So welcome to your special deep dive.

If you are listening to this, you are likely an advanced practice nursing or physician assistant student.

So consider this your one -on -one tutoring session.

Yeah, we are stepping entirely away from the dry, crowded lecture halls today.

Oh, for sure.

Our mission today is to master Chapter 24 of Lane's Pharmacotherapeutics.

We are going to thoroughly understand opioid analgesics, opioid antagonists and non -opioid centrally acting analgesics.

It's a vital mission.

I mean, we are talking about the most potent pain relievers available to modern medicine.

Right.

But their sheer power requires rigorous, flawless clinical reasoning from you as a future prescriber.

So we're going to walk through this material exactly as it appears in your text.

We're building a logical organic flow from the underlying pathophysiology all the way to safe patient outcomes.

So I want to clear up a terminology issue right out of the gate.

Yeah.

Because I hear the words opioid and opiate thrown around interchangeably on the floor all the time.

Are we talking about the same thing?

Clinically, yeah.

People get sloppy with the terms.

But pharmacologically, your text draws a strict boundary.

OK.

And opioid is any drug, natural or synthetic, that has actions similar to morphine.

But the term opiate is much more specific.

So opiate is just the natural stuff.

Exactly.

It applies only to compounds actually present in natural opium.

So we're talking strictly about morphine and codeine.

OK.

So opioids are the broader umbrella.

And our bodies actually make our own endogenous versions of these, right?

They do.

Yeah.

Because, I mean, we wouldn't have receptors for these drugs if our bodies weren't naturally geared to process something similar.

That's the evolutionary key right there.

We produce endogenous opioid peptides like enkephalins, endorphins and dynorphins.

And they act as neurotransmitters and neuromodulators.

Right.

Now, we don't fully understand their precise physiological roles yet.

But what we absolutely do know is how our exogenous medications interact with the body's hardware.

There are three main classes of opioid receptors.

Mu, kappa and delta.

OK, let's unpack this.

Looking at the text, the delta receptor barely gets a mention regarding our medications.

It seems like the Mu receptor is considered the absolute VIP of this group from a pharmacological perspective.

Why is that?

What's fascinating here is a specific study detailed in your text involving genetically engineered mice.

Oh, the knockout mice.

Researchers bred a line of mice that entirely lacked the gene for Mu receptors.

When researchers gave these mice morphine, the drug did absolutely nothing.

Zero pain relief.

No physical dependence.

No behavioral changes.

Wow.

Nothing at all.

Nothing.

It proved that translating heavily to human pharmacology, of course, Mu receptors are both necessary and sufficient to mediate the major actions of opioid drugs.

So activating that Mu receptor is the master switch.

It gives us the desired therapeutic effect.

But I'm guessing it's also responsible for the dangerous side effects.

Oh, it's totally a package deal.

Activating Mu receptors causes profound analgesia, but it also causes respiratory depression, euphoria, sedation and physical dependence.

Right.

And what about the kappa receptors?

Well, activating the kappa receptor also produces analgesia and sedation, but it comes with its own unique baggage.

Kappa activation can cause psychotomimetic effects.

Meaning it can trigger strange thoughts, nightmares or hallucinations.

Right.

So based on how our drugs interact with these specific receptors, your textbook classifies them into three groups.

Pure opioid agonists, agonist antagonist opioids and pure opioid antagonists.

Which brings us to the trototype drug for the pure opioid agonists.

Morphine.

The big one.

Yeah, this is the gold standard.

It's the yardstick we use to measure all of their opioids.

Its primary therapeutic use is relieving moderate to severe pain.

But the DEX notes a really interesting distinction.

About the type of pain.

Yeah.

It's actually more effective against dull, constant pain than sharp, intermittent pain.

Though, obviously, if you push the dose high enough, it can dull the sharp pain, too.

Part of its effectiveness is psychological, actually.

It causes mental clouding and decreases anxiety.

So they just care less about the pain.

Basically, it doesn't just block the ascending pain signal in the spinal cord.

It literally changes the patient's emotional response to the pain.

They might still feel the sensation, but they simply don't care about it anymore.

But that level of central nervous system alteration comes with a heavy burden of adverse effects.

As a prescriber, your safety, well, patient safety has to be your absolute priority.

Absolutely.

And respiratory depression is the most serious threat on the board.

I've always wondered about the clinical timing here.

If I give a patient an oral dose of morphine and they look totally fine 30 minutes later, am I in the clear to move on to my next patient?

That is a massive clinical trap.

Wait, really?

Oh, yeah.

The time course for respiratory depression does not peak instantly with oral doses.

It begins up to 90 minutes after oral ingestion.

Wow.

An hour and a half later.

Right.

You might give a pill, check on the patient half an hour later, see they are breathing at 16 breaths per minute and wrongly assume they are safe.

You have to monitor them much longer, especially your opioid naive patients.

And it's not just the lungs we have to worry about.

The gut is heavily impacted.

Constipation isn't just an annoyance here.

It's a profound complication.

Think about the mechanism.

By activating those same receptors located in the gut,

morphine suppresses propulsive intestinal contractions and it actively increases the tone of the anal sphincter.

So it essentially paralyzes the bowel.

Pretty much.

It also causes orthostatic hypertension by blunting the baroreceptor reflex and triggering the release of histamine.

So when your patient stands up, their peripheral blood vessels are dilated.

Their blood pressure bottoms out and they fall.

Let's paint a picture of another trap.

Imagine giving a patient morphine for a broken leg.

And 12 hours later, they are in absolute agony.

Not from the leg, but because their bladder is completely paralyzed and distended.

Urinary retention is a severe issue.

Morphine increases tone in the bladder sphincter.

Add to that the direct stimulation of the chemoreceptor trigger zone in the medulla.

Which causes the emesis or vomiting.

Exactly.

As a prescriber, you have to anticipate all of this.

Looking at table 24 .3 on drug interactions, it seems like a clinician's job is really about managing compounding effects.

It is.

If your patient takes CNS depressants like alcohol or benzodiazepines alongside morphine, you exponentially increase the risk of fatal respiratory depression.

Makes sense.

And if they are on anti -cholinergic drugs like certain antihistamines or tricyclic antidepressants, you will severely exacerbate the constipation and urinary retention.

You're just stacking the side effects.

And if that stacking goes wrong or a patient mismanages their dose, we're looking at opioid toxicity.

The text lays out a very clear, classic triad of opioid overdose that every clinician needs memorized.

Right.

The triad, coma, profound respiratory depression, sometimes dropping down to just two to four shallow breaths per minute and pinpoint pupils.

Pinpoint pupils is a big red flag.

It is.

Now, a caveat here.

As hypoxia eventually sets in from the lack of oxygen, the pupils might actually dilate later.

That's followed by a severe drop in blood pressure and shock.

Treatment requires immediate ventilatory support and an opioid antagonist like naloxone.

If morphine is the gold standard, why do we need other options?

What happens when we need something fundamentally stronger?

That moves us into the realm of.

Other strong opioid agonists like fentanyl.

Now, these aren't necessarily better than morphine and how they work, but they have unique properties.

Yeah, they carry the exact same mechanism and risks.

Respiratory depression, sedation, constipation.

But fentanyl is defined by its sheer high milligram potency.

It's roughly a hundred times more potent than morphine.

Right.

Yes, a hundred times.

And the black box warnings for fentanyl really reflect that power.

It comes in transdermal patches and transmucosal forms like lozenges and sprays.

How should a provider safely navigate those specific formulations?

The clinical reasoning behind those warnings is literally life or death.

I mean, transmucosal fentanyl is strictly approved only for breakthrough cancer pain.

And that's in patients who are already opioid tolerant.

Right.

Never for acute pain.

Exactly.

Never for a post -op headache or something.

And the transdermal patch must never be used in opioid naive patients either.

It is completely contraindicated in children under two years old or anyone under 18 who weighs less than 110 pounds.

The pharmacokinetics of the patch seem incredibly tricky.

You slap it on, but it takes 24 hours to reach effective blood levels.

Which means you can't use it for acute fluctuating pain.

It's for steady state.

And here is the major danger.

If respiratory depression develops, simply ripping the patch off your patient doesn't fix the problem instantly.

Because the drugs are already in their system.

Worse, because there is a residual depot of the drug remaining in the subcutaneous fat of the skin.

It continues to absorb into the bloodstream for hours after removal.

Furthermore, fentanyl is heavily metabolized by the CYP3A4 liver enzyme.

If a patient takes a CYP3A4 inhibitor like certain antifungals or HIV medications, fentanyl levels can suddenly spike in the blood, causing fatal toxicity.

Here's where it gets really interesting.

Methadone.

It's used for severe pain and opioid addiction treatment, but prescribing it is famously difficult.

Why is it such a pharmacological minefield?

Two major reasons.

First, it has a very long half life, meaning with repeated doses, the drug accumulates in the body.

So it builds up.

Right.

It's dangerously easy to accidentally overdose a patient over a period of several days because the drug is stacking up faster than they can clear it.

Second, it carries a severe black box warning for QT interval prolongation on an electrocardiogram, which leads to dysrhythmias.

Yeah, it can lead to a fatal dysrhythmia called torsades de pointes.

The strict clinical rule here is that patients must have an ECG before starting treatment again at 30 days and annually thereafter.

Before we step down to strength, we should mention hydromorphone and oxymorphone.

They are also in this strong agonist class, and they carry their own strict black box warnings regarding high abuse, potential and fatal respiratory depression, especially if combined with alcohol.

So moving to situations that aren't quite as severe, we look at moderate to strong opioid agonists.

These drugs produce less analgesia and less respiratory depression than morphine.

But the underlying cellular mechanisms and the associated risks are virtually identical.

Coding is the classic example here.

It's used for mild to moderate pain and cough suppression.

But there's a massive safety alert regarding coding and the CYP2D6 enzyme.

The text explains that coding is actually a prodrug.

Can you explain what that means clinically?

A prodrug means the pill you swallow doesn't actually do the heavy lifting.

Coding itself is very weak.

But once it hits the liver, about 10 percent of the dose is converted directly into morphine by the CYP2D6 enzyme.

Oh, I see.

Yeah, that newly synthesized morphine is what actually provides the pain relief.

So what happens if a patient is an ultra rapid macabalizer, like someone who genetically has multiple copies of this CYP2D6 gene?

It creates a highly dangerous, unpredictable situation.

Their liver converts coding into morphine incredibly fast, leading to sudden, dangerously high spikes of morphine in the blood.

That sounds awful.

It is.

This mechanism has caused actual fatalities in children taking coding post surgery.

It's also caused severe, even fatal toxicity in breastfed infants, whose mothers were ultra rapid metabolizers taking coding for postpartum pain.

Because the morphine gets into the breast milk.

Exactly.

That massive dose of morphine easily passes into the breast milk.

That is a terrifying clinical scenario.

Then we have oxycodone and hydrocodone.

Hydrocodone is often combined with acetaminophen like in Vicodin.

I imagine that brings its own distinct organ risks.

It does.

It brings a severe black box warning for hepatotoxicity liver damage caused by the acetaminophen component.

Oh, right.

The Tylenol part.

Exactly.

Both oxycodone and hydrocodone also have black box warnings, emphasizing their abuse potential and the risk of fatal respiratory depression, particularly when prescribers use their extended release formulations inappropriately.

Rounding out this moderate section is tapentolo.

How does it differentiate itself from the rest of the pack?

Tapentadol is unique because it employs a dual mechanism of action.

It activates mu receptors, just like the others, but also blocks the reuptake of norepinephrine in the central nervous system.

OK, so it does two things at once.

Right.

Because it relies slightly less on the mu receptor for its full analgesic effect, it tends to cause less constipation than traditional pure opioids.

So we have these pure agonists.

But what if we want to get clever and only activate some of the system?

That brings us to agonist antagonist opioids like pentazocine and buprenorphine.

A very interesting class.

The text notes they have a lower potential for abuse and produce less respiratory depression.

But I'm looking at table twenty four point nine of the scene, and I'm a bit confused.

It says it acts as an agonist at the Kappa receptors, but an antagonist at the mu receptors.

How can a drug be both a gas pedal and a break?

It's all about receptor affinity and intrinsic activity.

Pentazocine binds to Kappa receptors and turns them on, producing analgesia and sedation.

But when it encounters a mu receptor, it binds to it and does absolutely nothing.

It just sits there.

Yeah.

Acting like a physical blockade, preventing other drugs from activating it.

So if it acts as a break on mu receptors,

what happens if you administer this to a patient who is already physically dependent on a pure opioid agonist like morphine?

Because the morphine needs that mu receptor to keep the patient out of withdrawal.

It triggers an immediate, severe, precipitated withdrawal reaction.

By blocking the mu receptor, pentazocine instantly kicks the morphine off the receptor.

Oh, wow.

Throwing the patient into acute, explosive withdrawal.

Clinicians must always safely and slowly withdraw the patient from the pure agonist first before ever introducing an agonist antagonist.

Buprenorphine is another major player in this class, often used for treating opioid addiction.

Yes, but its receptor activity is flipped.

Buprenorphine is a partial agonist at the mu receptor and an antagonist at the Kappa receptor.

OK, so the opposite of pentazocine.

Basically, it's a vital tool, but it prolongs the QT interval.

Posing those same dysrhythmia risks we saw with methadone.

Crucially, it binds so tightly to the mu receptors that if a patient overdoses on buprenorphine, our standard rescue drug, naloxone, cannot readily displace it to reverse the toxicity.

Speaking of rescue drugs, what happens when it all goes wrong and we need to hit the emergency brake?

That brings us to the pure opioid antagonists, the antidotes.

The prototype is naloxone.

Naloxone is a structural analog of morphine.

But it acts strictly as a competitive antagonist at opioid receptors.

If there are no opioids in the patient's system, giving them naloxone does nothing.

Nothing at all.

Zero effect.

But if opioids are present, it aggressively outcompetes them for the receptor space, instantly reversing respiratory depression, coma and analgesia.

If we connect this to the bigger picture, treating an overdose isn't just a one and done shot, is it?

I imagine you can't just administer naloxone, see the patient wake up and discharge them.

If we connect this to the bigger picture, you have to closely analyze the pharmacokinetics.

Naloxone's half life is about two hours.

That is significantly shorter than the half life of most opioids.

So the naloxone wears off first.

Precisely.

A patient might wake up, look perfectly fine.

And then two hours later, the naloxone wears off.

The opioid is still circulating in their system and they slip right back into a fatal coma.

The clinician's reasoning must constantly involve the anticipation of repeated dosing.

That makes total sense.

Also, you have to titrate it incredibly carefully.

If you push too much naloxone too fast to an addict, you instantly throw them into severe acute withdrawal.

The goal is to give just enough to restore their respiratory drive without erasing their baseline dependence all at once.

We also have peripheral opioid antagonists listed like methylnultrexone, naloxol and naldemedine.

I like to think of them like bouncers that only work in the gut.

They stand at the velvet rope of the blood brain barrier saying no entry.

That's the perfect way to visualize it.

They are selective mu -opioid antagonists that structurally cannot cross into the central nervous system.

So they stay put.

Right.

They stay in the gastrointestinal tract, block the mu receptors there and effectively treat severe opioid induced constipation.

But because they can't reach the brain, they don't ruin the pain relief and they don't cause systemic withdrawal.

The text also mentions nultrexone, which is used for both opioid and alcohol abuse to block euphoria.

But it requires the patient to be completely opioid free before starting.

And it carries a risk of hepatocellular injury or liver damage.

Moving slightly away from traditional opioids, we have non -opioid centrally acting analgesics, specifically tramadol.

Tramadol is an analog of codeine.

It has very weak mu agonist activity.

But its primary mechanism for relieving pain is actually blocking the neuronal uptake of norepinephrine and serotonin.

Which enhances the spinal inhibition of pain signals.

Exactly.

It's widely prescribed.

But what are the clinical dangers we need to watch for?

Because it seems like it flies under the radar compared to, say, oxycodone.

It does, which makes it dangerous.

Two major clinical alerts here.

First, tramadol lowers the seizure threshold.

Oh, so watch out for epilepsy.

Yes, it should be strictly avoided in patients with epilepsy or other underlying neurologic disorders.

Second, because it blocks the uptake of serotonin and norepinephrine, combining it with a monoamine oxidase inhibitor or MAOI can cause a fatal hypertensive crisis.

And what about SSRIs?

Combining it with SSRIs or SNRIs can trigger a lethal serotonin syndrome.

So what does this all mean for us today?

We are taking in all this heavy pharmacology, but we are practicing in the shadow of a massive societal opioid epidemic.

We are, and it's vital context.

In the 1990s, there was a radical shift in medicine to treat pain as the fifth vital sign.

Hospital reimbursements literally became tied to patient pain satisfaction scores.

Which is wild to think about now.

It really is.

This led to a tenfold increase in opioid prescriptions, which directly fueled the current crisis.

To put it in perspective, in 2022 alone, there were over 105 ,400 overdose deaths in the U .S.

And the pharmaceutical industry and FDA have tried to mandate efforts to decrease misuse, as seen in Table 24 .11, like reformulating Oxycontin.

Yes, the development of abuse deterrent formulations.

New Oxycontin pills are engineered so that if someone tries to crush them, to snort them, they are physically too hard to break down.

And if they try to dissolve them in water, it turns into a thick, unusable gel.

There's also the Riems Program Risk Evaluation and Mitigation Strategy, which mandates comprehensive education for prescribers on safe patient selection and rigorous monitoring.

Which leads right into the CDC guidelines for safe prescribing, outlined in Box 24 .1.

How should a clinician reason through these guidelines when a patient is actually sitting in front of them?

The guidelines demand a highly conservative, methodical approach.

Non -pharmacologic and non -OQA therapies must be exhausted first.

You have to establish realistic goals for pain and function.

Meaning zero pain isn't the goal.

Right.

Making sure the patient understands that zero pain is rarely a realistic outcome for chronic conditions.

You should prescribe immediate release opioids instead of extended release when starting.

Use the absolute lowest effective dose.

And for acute pain?

For acute pain, like a post -surgical sprain,

three days or less of medication is usually sufficient.

And you must aggressively avoid prescribing opioids concurrently with benzodiazepines.

Practically speaking,

how does a clinician assess a patient's risk when prescribing?

Because you can't just go off a gut feeling.

No, it requires objective data gathering.

You use validated screening tools like the Nadiya Modified Assist to evaluate substance use risk before writing the first script.

You absolutely must check your state's PDMP.

The Prescription Drug Monitoring Program.

Exactly.

This database shows you every controlled substance prescribed to that patient across the state.

Ensuring they aren't doctor shopping or getting dangerous combinations of drugs from multiple unaware providers.

And you perform baseline and at least annual urine drug tests.

Just to confirm they're taking the med safely.

Yes, to confirm they are taking the prescribed medication and not taking illicit drugs.

And if we need to take a patient off opioids, we don't just stop cold turkey.

We taper them over three days or seven to 10 days for highly dependent patients to avoid the abstinence syndrome.

Now, all these strict rules, they change entirely when we talk about cancer pain, don't they?

Completely.

For cancer related pain or terminal illness, the objective shifts entirely to maximizing comfort.

Psychological and physical dependence are no longer the primary clinical concerns.

Which is a huge mental shift.

It is.

The mandate is clear.

No patient should suffer severe pain because of a prescriber's fear of using adequate doses.

You give what is needed to relieve the suffering, period.

Finally, let's dive deeply into the lifespan considerations for opioids.

Because the physiology of a newborn is vastly different from an 85 year old.

And prescribing requires true person centered care.

Absolutely.

Let's start with infants.

The core issue here is that their blood brain barrier is poorly developed.

Drugs cross into their central nervous system much more readily, making them exquisitely sensitive to respiratory depression.

And what about during pregnancy?

Regular opioid use during pregnancy will cause physical dependence in the fetus, leading to severe withdrawal symptoms after delivery.

Plus well documented risks of congenital defects.

For children, we obviously assess pain carefully.

But the text specifically warns against using aspirin as an adjuvant painkiller.

Why is that?

Because in children, especially those with viral illnesses,

aspirin carries the risk of triggering Ray syndrome, a rare but often fatal condition causing swelling in the liver and brain.

Oh, wow.

Good to know.

Yes.

For breastfeeding individuals, we must constantly monitor the infant for drowsiness.

As small but clinically significant amounts of opioids pass directly into the milk.

And for older adults,

it seems they are incredibly vulnerable to being mismanaged.

Persistent pain is often severely undertreated in the frail older adult population.

Clinicians get scared.

Older adults metabolize and excrete drugs much slower, which means drugs accumulate faster.

So start low and go slow.

Exactly.

The guidelines suggest a trial of acetaminophen first.

But, and this is critical, if they have moderate to severe uncontrolled pain, you must not withhold opiates simply out of a generalized fear of age.

You use them carefully with rigorous monitoring to restore their baseline function and comfort.

It's an incredible balancing act.

We started this deep dive talking about hacking the nervous system software, about using these immensely powerful tools that alter a human being's fundamental perception of reality.

This raises an important question for all of us stepping into clinical practice.

We talked earlier about codeine and the CYP2D6 enzyme and how ultra rapid metabolizers can overdose on a standard dose, which leaves us with a provocative thought.

If genetic testing continues to become cheaper and more instant, will we soon see a day where prescribing a standard dose of codeine or morphine without testing is considered malpractice?

That's a fascinating point.

Will every opioid prescription eventually be uniquely engineered to a patient's individual genotype?

It's the ultimate future of safe prescribing.

That is the tightrope you will walk as a prescriber, balancing standardized guidelines with the unique physiology of the patient sitting right in front of you.

Thank you for joining us for this rigorous study session.

You've got the knowledge, now it's about applying the reasoning.

Concluding with a warm thank you from the Last Minute Lecture Team, we'll see you next time.