Chapter 43: Substance Use Disorders – Treatment Pharmacology

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Welcome to the Deep Dive.

Today we are cracking open a really critical and frankly complex area for advanced practice.

Pharmacotherapy for substance use disorders, SUDs for short.

Yeah, definitely complex.

Our main focus will be on alcohol use disorder, AUD, and opioid use disorder, OUD.

We really want to synthesize the, well, the huge amount of information out there.

It's absolutely necessary knowledge.

I mean, we're talking about a chronic public health crisis here, and SUD is defined as recurrent use that leads to clinically significant impairment.

So it's really disrupting someone's life in a major way.

Exactly.

And the severe end of that spectrum, addiction, we now understand is actually a chronic brain disease.

And the stats, they really paint a stark picture of why you, our listeners, need this info.

I mean, back in 2017, over 70 ,000 people died just from opioid overdoses.

Terrible numbers.

But here's the kicker, the real treatment gap.

In that same time frame, only about 7 .5 % of people who actually had an SUD got any kind of specialty treatment.

Just 7 .5%, it's staggering.

That leaves a huge population relying on generalist care, which is where many advanced practice clinicians are working.

Right.

So our mission today, our goal for this deep dive is to give you that clinical shortcut.

Yeah.

Unpack the mechanisms, the dosing nuances,

the critical things you need to know before prescribing for both acute withdrawal and the long -term maintenance side of things for AUD and medications.

We need a diagnosis.

How do we actually formalize an SUD diagnosis?

Well, we use the established criteria from the DSM -5.

There are 11 criteria in total.

11 criteria.

And it's a spectrum.

It is.

The severity depends entirely on how many of those criteria the patient meets.

So two or three criteria means it's a mild disorder.

Four or five, that's moderate.

And if it meets six or more, that indicates a severe SUD.

Okay, got it.

Now you mentioned addiction as a brain disease.

Let's unpack the brain science a bit.

Where does this actually happen in the brain?

It's really rooted in the mesolimbic pathway, often called the reward pathway.

The reward pathway.

This pathway runs from the ventral tegmental area, the VTA, to the nucleus accumbens, or NAC.

It's kind of the brain's engine for motivation and pleasure.

And how does it normally work?

Normally, the VTA is kept in check, tightly controlled by GABAergic neurons, inhibitory neurons.

But when someone uses a substance, that GABA control gets, well, lifted.

Ah, so the brakes come off.

Precisely.

And that leads to a flood of dopamine release in the nucleus accumbens.

That's the initial high, the pleasure response, and the pathway remembers that feeling.

Over time, this can lead to actual structural changes in the brain, driving that compulsive use we see in addiction.

And different drugs hijack this system in different ways, don't they?

They do.

It's quite interesting.

Take alcohol and benzodiazepines, for instance.

They work by enhancing the function of GABA itself.

The inhibitory neurotransmitter.

Exactly.

So they basically increase inhibition, quiet things down system -wide.

That's why they cause sedation, drowsiness.

You have the stimulants, like cocaine or amphetamines.

Completely different story.

Right.

Almost the opposite effect.

They dramatically increase the levels of monoamines, dopamine, norepinephrine, serotonin, either by blocking their reuptake, they hang around longer, or by forcing more release.

Which leads to that characteristic rush and hyperactivity.

Exactly.

But opioids, they play by slightly different rules again.

How so?

They have their own dedicated receptors, primarily the mu -opioid receptors.

These are heavily concentrated in the limbic system, especially the amygdala, which is involved in emotion.

And that interaction causes the pain relief and that really intense euphoria.

Precisely.

Understanding these different targets, GABA for alcohol, monoamines for stimulants, mu receptors for opioids.

It really lays the groundwork for why the specific pharmacotherapies work.

Makes sense.

But before jumping to treatment, how do we identify patients who need help?

That brings us to SBIRT, right?

Yes.

SBIRT, screening, brief intervention, and referral to treatment.

It's a really important public health strategy for catching these issues early, often in primary care settings.

What tools are we using for that screening part?

Are they just questionnaires?

Pretty much.

We use validated standardized questionnaires.

For alcohol, the go -to is often the adidide, the alcohol use disorder identification test.

For general drug use, there's the DES -10.

And specifically for patients on chronic opioid therapy, to monitor for misuse, we might use the COMEM, the current opioid misuse measure.

And the scores tell you what to do next.

Exactly.

They guide the intervention.

For example, with the adidide, a score between, say, 4 and 26 suggests moderate risk.

That indicates the need for a brief intervention, like some counseling and education.

But higher scores mean more intensive action.

Definitely.

A score of 27 or more on the adidide T -signals high risk, and that patient really needs an immediate referral to specialized treatment.

Okay, that makes sense.

Let's shift gears then to managing alcohol use disorder,

starting with the acute phase, withdrawal.

What makes alcohol withdrawal so particularly dangerous?

Alcohol withdrawal is uniquely dangerous among substance withdrawals because it absolutely can be life -threatening.

It's not just uncomfortable.

It's potentially fatal.

Right.

It progresses along a spectrum.

Mild symptoms might just be anxiety, some sweating, maybe trouble sleeping.

But it can escalate quickly to severe symptoms like hallucinations, seizures.

And the most feared complication.

Delirium tremens, DTs.

That's the big one we watch out for.

Tell us about DTs.

What characterizes that?

DTs involve a really rapid, dramatic onset of psychological confusion and neurological changes.

Think severe agitation, disorientation.

Plus, there's this intense sympathetic nervous system overdrive.

So heart racing, high blood pressure, fever.

Exactly.

And that massive physiological stress can lead to cardiovascular collapse.

The fatality rate for DTs is estimated between 5 % and even up to 25 % if not managed properly.

Wow.

And when does this typically happen?

Usually within about 24 to 72 hours after the person's last drink.

So any patient showing moderate to severe withdrawal symptoms needs immediate, close medical supervision.

No question.

So for managing this acute withdrawal crisis, what's the standard of care pharmacologically?

Benzodiazepines.

Beesies are the mainstay, the foundation of treatment for acute alcohol withdrawal.

And there are different types of benzos.

How do we choose?

I know the chapter mentions Table 43 .1 comparing them.

Right.

The key difference often comes down to half -life and metabolism.

You have the long half -life agents like Clodiazepoxide, Librium, and Diazepam, Valium.

What's the advantage there?

Their long duration means they essentially self -taper as they leave the system slowly.

So you often don't need a separate tapering schedule.

But there's a catch, right?

Especially concerning the liver.

Absolutely.

That's the critical point.

Because they are metabolized by the liver and have active metabolites, they can accumulate dangerously in patients with severe liver dysfunction like cirrhosis.

So if you have a patient with significant liver disease, those are probably not your first choice.

Definitely not.

In that situation, you immediately pivot to the shorter acting agents.

Lorazepam, Ativan,

and Oxazepam, Cerex.

Why are they safer?

They undergo glucuronidation, a different metabolic pathway that's less affected by and they don't have significant active metabolites.

So, much safer profile in hepatic impairment.

But the downside?

The downside is their shorter action means you must implement a gradual taper when discontinuing them to prevent rebound withdrawal symptoms.

You can't just stop them abruptly.

Okay, that's crucial for acute withdrawal.

Now once that crisis has passed, the focus shifts to long -term maintenance, helping the patient stay abstinent or reduce harm.

Let's start with Acamprosate.

Right, Acamprosate.

It's used for maintenance after withdrawal is complete.

Its mechanism isn't perfectly understood, but it seems to modulate GABA and glutamate transmission, maybe normalizing brain activity disrupted by chronic alcohol use.

And the dosing is quite specific.

It is.

The standard dose is 666 mg, taken three times a day, TID.

6666 TID.

Memorable.

What's a really critical check before starting Acamprosate, something easily missed?

Renal function.

Absolutely non -negotiable.

Acamprosate is primarily eliminated by the kidneys.

So kidney problems are a red flag.

A big one.

If your patient's creatinine clearance, the CRCL, is less than 30 mL per minute, it's contraindicated, period.

If it's between 30 and 50 mL, you need to reduce the dose.

Good clinical pearl.

Any major side effects to watch for?

Mostly gastrointestinal, like diarrhea.

Some patients report insomnia or anxiety, but generally it's fairly well tolerated compared to others.

Okay, next up for maintenance, Naltrexone.

We mentioned it acts on opioid receptors.

Yes, Naltrexone is an opioid antagonist.

It has a high affinity for the mu -opioid receptor.

The thinking is that by blocking these receptors, it reduces the rewarding effects of alcohol and decreases craving.

How is it given?

You have two main options.

Oral tablets, usually 50 to 100 mg daily, or a long -acting intramuscular injection,

380 mg given once a month.

The injection helps with adherence, I imagine.

Big time.

Adherence can be a real issue with oral Naltrexone.

What are the key contraindications for Naltrexone?

Well, because it's an opioid antagonist, you absolutely cannot give it to patients currently taking opioids.

It would precipitate immediate severe withdrawal.

Same goes for patients in active opioid withdrawal.

And interestingly, it's also generally not recommended if the patient is still actively drinking heavily, as efficacy seems lower then.

And you need to watch liver function.

Right, liver function again.

Yeah, significant liver issues can be a contraindication or require careful monitoring.

Okay.

And the third maintenance option is disulfiram, often known as anti -abuse.

This one works very differently.

Completely different.

Disulfiram is purely a deterrent therapy.

It works by irreversibly inhibiting an enzyme called aldehyde dehydrogenase.

What does that enzyme normally do?

It breaks down acetaldehyde, which is a toxic byproduct of alcohol metabolism.

So if you block that enzyme and the patient drinks alcohol, Acetaldehyde builds up.

Builds up rapidly to toxic levels.

This causes a really unpleasant, potentially dangerous reaction known as the disulfiram -like reaction.

Describe that reaction.

Intense facial flushing, a throbbing headache, difficulty breathing, nausea, vomiting.

It can even progress to cardiovascular collapse in severe cases.

It's designed to make drinking alcohol extremely aversive.

Sounds like patient education is paramount here.

Absolutely critical.

Patients must understand they have to avoid all sources of alcohol.

Obvious things like drinks, but also hidden sources, some cough syrups, mouthwashes, even certain sauces or vinegars cooked with alcohol.

And who should definitely not take disulfiram?

It's strictly contraindicated in patients with significant cardiovascular disease, like coronary artery disease or heart failure, because the reaction puts such a strain on the heart.

Also contraindicated in patients with psychosis.

So wrapping up AED maintenance.

We have naltrexone and acamprosate as first line.

How does an advanced practice clinician choose between them?

It really boils down to the patient's organ function primarily.

Both are considered good first line options.

So the tiebreaker is?

If your patient has severe liver dysfunction, you lean away from naltrexone.

If they have significant kidney dysfunction, that CRCL below 50, especially below 30, you avoid acamprosate.

Patient preference and potential side effects also play a role, of course.

And disulfiram.

Usually reserved for second line.

It requires a highly motivated patient who understands the risks and is committed to total abstinence given the severity of that potential reaction.

Okay, let's transition now to opioid use disorder, OUD.

A huge crisis, as we mentioned.

Often driven now by highly potent synthetic opioids like fentanyl.

The major immediate risk here is what?

Respiratory depression.

That's the killer with opioid overdose.

Fentanyl's potency makes that risk incredibly high, even with small amounts.

Now, opioid withdrawal,

how does it compare to alcohol withdrawal in terms of danger?

That's a key distinction.

Unlike alcohol withdrawal, opioid withdrawal is generally not considered life -threatening.

It's intensely unpleasant, miserable for the patient, but typically not medically dangerous in the same way DTs are.

What are the typical symptoms?

Think severe flu -like symptoms.

Lots of GI distress, nausea, vomiting, diarrhea, cramps, muscle aches and cramps.

And then that characteristic watery discharge, runny nose, tearing eyes, yawning, sweating, goosebumps, just profound discomfort.

When do these symptoms start?

Depends on the opioid used.

For short -acting ones like heroin or immediate release oxycodone, withdrawal usually starts within 8 to 24 hours after the last dose.

For long -acting opioids like methadone, it might be delayed, starting maybe 12 to 24 hours or even longer.

And we track the severity.

Yeah, often using a standardized scale like the SOWS, the Short Opioid Withdrawal Scale, to quantify how severe the symptoms are and guide treatment.

Before we get to long -term treatment, let's quickly cover the emergency intervention for overdose, naloxone.

Box 43 .6 of the text highlights this.

Right, naloxone.

Narcan is the common brand name.

It's a pure opioid antagonist.

It competitively blocks opioid receptors, specifically mo -receptors, reversing the effects of opioids.

Especially that life -threatening respiratory depression.

Exactly, its main job is to reverse the CNS and respiratory depression.

Onset is very fast within a couple of minutes if given IV, maybe up to 5 minutes if given IM, or intranasally.

But there's a crucial point about its duration.

Yes, this is critical.

Naloxone's duration of action is quite short, typically only 30 to 60 minutes.

So if the person overdosed on a long -acting opioid like methadone or even a large dose of fentanyl.

They can fall back into respiratory depression after the naloxone wears off.

The opioid outlasts the antidote.

Which means they need ongoing monitoring.

What's the typical dosing?

Initial dose is usually 0 .4 to 2 milligrams IV or IM, or there's a 4 milligram intranasal spray readily available now.

But because of that short duration, doses often need to be repeated every 2 to 3 minutes until breathing normalizes.

You might need up to 10 milligram total in some cases.

And continuous monitoring is essential.

Okay, very important.

Now for the long haul, managing OUD relies on medication -assisted treatment, or MAT.

There are three main FDA -approved options.

Let's start with the preferred first -line agent, especially in primary care settings, buprenorphine.

Right, buprenorphine is really interesting pharmacologically.

It's a mixed agonist antagonist.

What does that mean exactly?

It's a partial agonist at the mu -opioid receptor.

This means it binds to the receptor and activates it, but only partially enough to prevent withdrawal symptoms and reduce cravings, but not enough to produce the intense euphoria or high of full agonists like heroin or methadone.

But it has another key property.

Yes.

It also acts as an antagonist at the kappa -opioid receptor, and importantly, it exhibits a sealing effect for respiratory depression at the mu receptor.

A sealing effect, meaning?

Meaning that beyond a certain dose,

giving more buprenorphine doesn't produce significantly more mu receptor activation or respiratory depression.

This makes it much safer in terms of overdose risk compared to full agonists.

Now, there's a huge clinical pearl associated with starting buprenorphine, probably the most important thing to know about its induction.

Absolutely critical.

You cannot start buprenorphine too soon after the patient's last opioid use.

Why not?

Because buprenorphine has a high affinity for the mu receptor, but lower intrinsic activity than full agonists.

If you give it while there are still full agonists bound to those receptors, like heroin or oxycodone, the buprenorphine will kick them off and bind preferentially.

But because it activates the receptor less strongly, it actually triggers a sudden,

intense withdrawal state.

We call this precipitated withdrawal.

Precipitated withdrawal.

Sounds awful.

It is, often described as violent and extremely distressing for the patient.

So the gil is, the patient must be opioid free for a specific period, usually 12 to 24 hours for short acting opioids, and crucially, they must be showing clear objective signs of early to moderate withdrawal before you give that first dose.

You essentially have to wait for them to start feeling sick.

Wait for the suffering to start.

Got it.

What about its metabolism?

Important point.

Buprenorphine is primarily metabolized by the CYP3A4 enzyme system in the liver.

Ah, the big one involved in many drug interactions.

Exactly.

So you need to be really mindful of other medications the patient might be taking that could inhibit or induce CYP3A4, as that can significantly alter buprenorphine levels and increase risks.

Okay.

So buprenorphine first line, what's the second line option?

That would be methadone.

Unlike buprenorphine, methadone is a full -mupopioid agonist, similar pharmacologically to morphine or heroin.

Full agonist.

So no sealing effect for respiratory depression.

Correct.

No sealing effect.

This inherently makes it riskier in terms of overdose potential, especially during initiation or if doses are increased too quickly.

And there's a major regulatory constraint with methadone, right?

Yes, a very significant one.

In the US, for the treatment of OUD, methadone can generally only be dispensed through federally certified opioid treatment programs or OTPs.

Patients typically have to go to the clinic daily, at least initially, for observed dosing.

Which creates barriers related to access, travel stigma.

Absolutely.

Those logistical and social factors are major reasons why it's often considered second line, despite being very effective for some patients.

And it carries a specific warning.

It does.

Methadone has an FDA black box warning highlighting the risk of QT prolongations, serious arrhythmias, and of course respiratory depression, and its potential for abuse and dependence because it's a full agonist.

So buprenorphine first, methadone second.

What's the third line at action?

Injectable naltrexone.

We talked about naltrexone for alcohol, but the long -acting injectable formulation, often Vivitrol, is also approved for OUD prevention of relapse.

Why only the injectable form for OUD?

Primarily due to adherence issues with the oral form.

Studies showed poor outcomes with oral naltrexone for OUD, likely because patients would simply stop taking it if they wanted to use opioids again.

The monthly injection overcomes that daily adherence challenge.

Makes sense.

Does naltrexone also have a critical prerequisite before starting it for OUD?

Yes, very similar to the contraindication for AUD, but even more stringent for OUD initiation.

Because it's a potent opioid antagonist, the patient must be completely opioid -free for a significant period, typically 7 to 10 days before receiving the first injection.

7 to 10 days?

That's a long time to manage withdrawal without agonist support.

It is, and you absolutely must verify this abstinence, sometimes even using a naloxone challenge test, giving a small dose of naloxone to see if it precipitates withdrawal, before administering the injectable naltrexone.

Starting it too soon would cause severe precipitated withdrawal.

Okay, that's a major hurdle.

And finally, there's a newer agent mentioned, lefexidime.

What does that fit in?

Lefexidime is different.

It's not an opioid, and it's not for maintenance therapy.

It's indicated specifically for mitigating opioid withdrawal symptoms.

Just for getting through the withdrawal period.

Exactly.

It's an alpha -2 adrenergic agonist.

It works by decreasing the release of norepinephrine in the brain.

Opioid withdrawal involves a rebound surge in norepinephrine, causing many of those unpleasant autonomic symptoms like sweating, anxiety, and agitation.

Lefexidime helps calm that down.

So it treats the symptoms, but doesn't address the underlying cravings or opioid receptor issues long -term.

Correct.

It's purely for symptom management during withdrawal, often used for up to 14 days.

Okay, let's synthesize the OUD treatment strategy then.

What's the general approach?

Generally, Duprenorphine, often in combination with naloxone to deter misuse like suboxone, is the preferred first -line agent, especially for initiation in primary care or office -based settings because of its safety profile and accessibility.

And second line?

Methadone is typically second line, primarily due to the OTP requirements, the daily dosing burden, stigma, and its higher overdose risk profile compared to Duprenorphine.

However, it's highly effective for patients who can access and adhere to OTP treatment.

And injectable naltrexone.

That's usually considered third line.

It's a good option for highly motivated patients who desire a complete opioid blockade, can successfully achieve and maintain the required 7 -10 -day opioid -free period before starting, and are committed to monthly injections.

Right.

So lots of factors to weigh for each patient.

Absolutely.

Patient preference, treatment history, co -occurring conditions, social support, access to care, they all play a role.

Okay, bringing this all together then for the advanced practice to do the listening.

What are the absolute key takeaways from this deep dive into AUD and OUD pharmacotherapy?

I think there are three main buckets.

First, really understand the difference in managing withdrawal.

AUD withdrawal can be deadly, needing prompt benzodiazepine treatment, often guided by CIWA scores.

OUD withdrawal is miserable, but usually not life -threatening, managed symptomatically, or with buprenorphine induction or lefexidine.

Okay, withdrawal management is distinct.

What's second?

Second is maintenance therapy selection, especially for AUD.

Remember the organ function checks, naltrexone and liver function, acamprosate and kidney function.

That's often the deciding factor between those two first -line agents.

And third?

Third, for OUD tate, master those initiation prerequisites, knowing you must wait for withdrawal before starting buprenorphine to avoid precipitated withdrawal versus needing that verified 7 in 10 -day abstinence window before injectable naltrexone.

Getting that wrong has serious consequences.

Those are definitely the core clinical distinctions, but it's also crucial to remember that these medications, the pharmacotherapy, are just one piece of the puzzle.

Right.

They're tools, not the whole solution.

Exactly.

True recovery success, as Sam HSA, the Substance Abuse and Mental Health Services Administration defines it, is about more than just not using.

It's about improving overall health, living a self -directed life, and striving towards one's full potential.

And that requires ongoing support.

Immense ongoing support.

Pharmacotherapy stabilizes the patient, allowing them to engage in the essential psychosocial aspects of recovery.

This includes everything from counseling and therapy to self -help groups like Alcoholics Anonymous AA or Narcotics Anonymous NA, and increasingly, Recovery Community Centers, RCCs, that offer peer support and resources.

So the medication enables the deeper work of recovery.

Precisely.

It manages the neurobiological aspects so the person can rebuild their life.

Okay.

Let's leave our listeners with a final thought to chew on.

We know risk factors for developing SUDs often include things like childhood trauma or early adolescent substance exposure.

If we really embrace this view of SUD, particularly addiction, as a neurophysiologic brain disease, how does that perspective fundamentally shift our clinical approach?

Well, it moves us away from viewing addiction as a moral failing or a lack of willpower, which often leads to punitive approaches.

Instead, if we see it as a chronic, treatable brain condition like diabetes or hypertension, then the focus becomes maximizing long -term management strategies, right?

Using medications like buprenorphine or methadone, not just short -term, but potentially long -term, as essential tools to manage the chronic condition and support sustained recovery.

It changes the goal from cure to chronic disease management focused on function and well -being.

Exactly.

It reframes the entire conversation towards support, harm reduction, and sustained recovery resources rather than judgment.

A really important shift in thinking for all clinicians.

A critical perspective indeed.

Thank you so much for guiding us through this complex but vital topic.

And thank you, our listeners, for joining us for this deep dive into substance use disorder pharmacotherapy.

We genuinely hope you feel more confident and better equipped to help your patients navigate these challenging but highly treatable conditions.