Hi, I'm Dr. Jacob Strand. I'm the

chair of the Enterprise Center for

Palliative Medicine at the Mayo

Clinic. I do a lot of work with

patients with complex

cancer-associated pain, pain

in elderly patient populations,

and today we're going to talk about

opioid pharmacology and why it

matters in the clinical practice.

As we think about opioid

pharmacology, it's really easy to

get kind of taken away by the

science of it, but it really matters

as we think about the care for our

patients and how

that care impacts those around them,

their caregivers, their loved ones,

their work and their physical

function.

So in thinking about why it matters.

I'll just talk to you about a case

of a patient of mine.

Sixty three year old advanced,

oxygen dependent, chronic

obstructive pulmonary disease,

had stage four chronic kidney

disease and an unfortunate history

of osteoporotic vertebral

compression fractures and

unfortunately came back into the

hospital with really severe back

pain from further fracturing

of the lumbar spine.

And as is pretty common, we see in

a lot of our systems, patient got

intravenous morphine in the

emergency department, then got

another dose on the floor, got a

couple of doses of IV fentanyl,

again in low doses, and

unfortunately was still in really

severe nine out of ten pain.

And there was a lot of concern about

how to manage this patient because

of the medical complexity.

And so this is,

I think, a great case for us to sort

of jump off on.

You know, opioids in this setting or

in settings like it, are really

effective tools in certain

clinical cases.

We know that there is an opioid

epidemic, and we have to be very

cautious about how we use opioids.

But in cases like acute severe

pain for a patient in the hospital,

patients with cancer-associated

pain, and even in some chronic

pain states, meaning certain

clinical conditions, they are really

effective tools in the setting of

a multi-modal analgesic

approach.

And although, again, while we're

moving away from opioids in the case

of minor pain,

even minor acute pain and chronic,

most chronic pain settings, when we

can use it effectively, we can

help improve analgesia as part

of that multimodal approach, as well

as improve function and quality of

life. But for the patient, there's a

really wide variability in terms of

how well they tolerate these

medications, the side effects,

the risk profile.

They're willing to associate

themselves with the cost and

the route of administration, all

which really impact how someone

is going to tolerate these

medicines.

And for the clinician, there's a

whole wide variety of things to

consider as we try to provide

the best care for our patients.

And that might be the potency of the

medication we're selecting, the

side effects of the opioids and how

those change from opioid to opioid,

the metabolic pathway and the

metabolites generated that will and

should influence our choice of

medication. We also have to think

about drug-drug interactions, the

conversion factors that all make

this very complicated.

But I think that when we do it well,

the goal is that if we can find that

right drug for the right patient in

the right clinical setting, we

really do improve the overall

efficacy, reduce the side effect

and the risk profile for our

patients.

So what about our patient with this

compression fracture?

Well, I think for this patient, it's

really important to acknowledge that

this is someone who is admitted to a

hospital with severe acute

pain. And so most likely

we're going to be using IV

medications, particularly for

somebody whose pain is in a severity

of nine or 10 out of 10 with

significantly impaired function.

And the reason to choose an IV form

is that we can get a quicker time

to onset of action for

this medication and for most opioids

given in an IV form that time to

onset of action is between three and

30 minutes, depending on the

medication chosen for the patient.

And we're going to get maybe 30

minutes to two or even three hours

for some of these medications in

terms of efficacy and duration.

So that's going to give us some time

to be able to judge response,

potentially even need to redose,

and make sure that the side effects

are tolerable.

An important piece of this, too, is

that even when a patient doesn't

have an IV form, say, outside

of a hospital but still in an acute

setting, in hospice patients

or for patients for whom we've lost

IV access and we're still trying to

gain the right route of

administration, subcutaneous dosing

can be really effective.

There is a slower uptake to those

medications. And so we kind of

think, if maybe we think about a 10

minute time to onset for a dose of

IV morphine or hydromorphone,

maybe we're looking more like 20

minutes for a dose of subcutaneous

morphine or hydromorphone.

And for acute pain in

where it's maybe more moderate in

severity or when we're in an

outpatient setting where we need to

use oral medications, those can work

very effectively. But it's really

important to make sure our patients

are aware that that time to onset,

that time to peak analgesia, is

going to be much longer.

That time to onset, may be more like

30 or 45 or 60 minutes,

depending on the medication.

And so when a patient comes to me

and says, you know, Doc, I tried

this medicine, but it took like an

hour to work.

If it's an oral medication that

feels just about right, and it means

that I need to do a better job of

setting appropriate expectations for

these medications.

A couple of things that do come into

play are a couple of no-nos that we

just really have moved away from.

And that's the idea that

intramuscular dosing is really not

needed, particularly when we have

multiple routes, whether that's

IV, subcu,

liquid medications, oral

medications, or even rectal

administration.

IM administration or intramuscular

dosing is really erratic.

It's painful at the site, and it can

lead to some different side effects

that we may not expect.

And then the other thing is that for

patients who have an initial

treatment where we're starting to

treat acute pain, long acting forms

really aren't the most appropriate

option because we're going to get

stuck with a long acting form, even

though the patient's clinical

picture might be changing.

So for this patient that we're

talking about who's admitted to the

hospital and we're trying to control

their acute severe pain in the

setting of a compression fracture,

we are probably going to look to a

medication like parenteral

hydromorphone, for example, along

with other multimodal strategies,

both pharmacologic and non

pharmacologic.

And that's because really in this

patient, the other thing we need to

consider is how these medicines are

going to be metabolized.

So fentanyl they already got, and it

didn't last long enough.

Morphine, repeated doses of

morphine are going to be really

problematic in this patient with

severe chronic kidney disease

because of what's going to build up

over time.

And so in thinking about that, let's

just dive into some of these

different drugs we're talking about.

Morphine, as I mentioned, probably

not the right choice in this

patient, is still a very good

opioid. It's a prototypical opioid.

It's very cheap.

Lots of flexible dose options and

routes. Can be given IV,

in a concentrated liquid

sublingually.

Can be given subcu, as I mentioned,

rectally, and obviously in an oral

form as well.

It has long acting forms in addition

to the short acting forms.

And so it gives us a lot of dosing

options.

It is metabolized by the liver and

that can be both good and bad.

It's glucuronidated within the

liver. And so that leaves a couple

of clinically active metabolites;

morphine three and six glucuronide,

which are renally cleared.

So in this patient, this is a real

problem because that morphine six

glucuronide in particular is going

to build up and can lead to adverse

respiratory outcomes for this

patient.

It's also something where we see

that these metabolites can be

neuroactive, meaning that in

repeated administration for,

particularly for a very sick

patient, can cause delirium,

confusion, agitation, and

even seizures.

However, that glucuronidation

is something that's helpful for

patients who have other drugs that

might interact at the

P450 level that we may want, not

want to introduce another drug that

interacts at that level.

As we think about other medications,

so the choice that I gave for this

patient is hydromorphone, a really

common medication used orally and

IV, it's much more potent

compared to morphine, and

that allows us to be able to give

smaller doses and potentially

avoid some of those side effects,

even though it is like morphine

glucuronidated in the liver and

renally cleared it.

It also has those flexible dose

options: IV, sublingual,

subcutaneous, rectal administration,

and oral. And so it gives us those

options to be able to treat patients

in a whole variety of clinical

settings. So why not fentanyl?

And we talked about how this patient

received fentanyl in the emergency

department and on the floor.

Great option, because it's a potent

analgesic, one hundred times more

potent than morphine.

So, again, we can use lower doses,

get a good effect.

It has rapid onset, a short

duration of action, which is really

helpful in a number of clinical

scenarios.

We think about the patient in the

intensive care unit for where we're

using this medicine for analgesia

and even as part of a sedation

protocol.

We want to be able to adjust the

doses frequently and monitor

for side effects, patients with

hemodynamic instability or

just patients that we're not sure

which direction they're heading

clinically. And we want to make sure

that we're not overdosing for

the effect that we desire.

It also has a transdermal form which

can be used for long acting

analgesia in certain clinical

scenarios. It's a medicine we reach

for, for patients with chronic

cancer-associated pain, for patients

with other chronic severe

pain syndromes in a palliative care

setting who might have really

bad kidney function, bad liver

function.

But we do have some notes of

caution. And that, number one, as I

mentioned earlier, it's a short

duration of action.

So for somebody with continuous

pain, maybe not the best option.

It also has a lot of interactions

within that P450 system.

It's metabolized through the 3A4

pathway. And so we do see drug-drug

interactions with a number of

different medications.

It also is a serotonin potentiator.

And this is something that has

gotten a lot more recognition in

clinical settings over the past five

to 10 years.

In combination with really common

medicines like SSRIs,

5-HT3 antagonists used for treatment

of nausea, we can induce serotonin

syndrome with fentanyl products.

And so understanding that is really

important as we think about, again,

that right drug for the right

patient in the right clinical

scenario. Oxycodone is another

medicine that we could use in an

oral form in the US, really common

medication.

It has, again, numerous different

formulations, including short acting

and long acting.

And it's nice if we want to take

acetaminophen out of the combination

drug. So instead of giving somebody

a combination of hydrocodone

and acetaminophen or oxycodone

and acetaminophen, we can use the

oxycodone alone, get good clinical

efficacy and use the acetaminophen

differently.

It still has those drug-drug

interactions, however, a

CYP2D6 and 3A4 pathway.

And so, again, those drug-drug

interactions and different clinical

encounters based on the patient's

genetics.

And this is something that's gotten,

again, a lot more appropriate

attention as we realize there's a

wide variety of patients who

might be really rapidly metabolizing

these medicines, slowly metabolizing

these medications, all of which can

affect how the drug works and the

side effects that we see for those

patients. And that makes this job

that we have when we're managing

pain and dealing with opiate

pharmacology much more complicated.

For those drugs that are active

already in the system, people who

are rapid metabolizers, it's going

to rapidly inactivate that drug.

We're going to have to use much

higher doses potentially.

And so that's really important

clinically as we see a patient who

might be coming to us for, that

dose didn't work, that dose didn't

work. That may not be addiction.

That may not be aberrant behaviors.

That may be really somebody who

genetically isn't getting any

efficacy with that dose.

For other drugs that are pro drugs

these P450 interactions

can lead to increased or decreased

efficacy depending on the patient

scenario.

And so when we want to move some of

the genetic polymorphisms out of the

clinical decision making, opioids

like hydromorphone, morphine,

tapentadol are all potentially good

choices because they're not likely

to have any genetic polymorphisms

that affect the clinical outcome.

You know, codeine is another great

example. I would tell you that

the last time I used codeine was

probably 10 or 11 years ago,

because codeine is going to have a

variety of clinical efficacy

based on the patient's genetics.

And so understanding that allows us

to choose drugs that are more likely

to work consistently across

populations.

Another big issue besides the

genetics is just what's going on

with our organs. Is it somebody with

chronic kidney disease or liver

disease, or is it someone who is

aging. In elderly patients, for

example, you know, we see a lot of

elderly patients who come in to

clinic or the hospital on Tramadol

because I think clinicians are

thinking, well, maybe that's a

better drug, maybe is a little bit

less potent and maybe fewer side

effects.

And they're thinking about that

appropriately.

The problem is, is that we also know

that elderly patients have decreased

hepatic blood flow, leading to a

variety of clinical effects,

including medications like Tramadol

in terms of how they're metabolized. They

have reduced glomerular filtration

rate. So we're going to see

increased toxicity in some

of these medications like Tramadol

that are renally cleared.

And so we have to be thoughtful

about whether or not that's the

right drug. And in most cases,

it means that a medicine like

Tramadol in an elderly patient is

probably not a good idea.

Even though it's less potent, it has

serotonergic and noradrenergic

effects.

We can see again those variations

in genetic metabolism, and it's kind

of a dirty drug. So we see pretty

significant rates of dizziness

and nausea.

So even though some of these

medicines are marketed as

potentially being gentler or easier,

that patient specific factor

gets really important.

Another piece I just wanted to

share. We talked about the renal.

We don't talk as much about the

hepatic concerns with opioids.

And part of that is because it's

just potentially not as recognized

or because it has dual concerns.

So for patients with hepatic,

reduced hepatic blood flow or

reduced hepatic function,

we see that both those metabolic

pathways are decreased and the

metabolites aren't really cleared.

So we see drugs that have a much

longer half life and a varying

degree of analgesia leading to

dosing problems.

We also see that as a patient with

liver dysfunction has decreased

circulating protein, we're going

to see an increase in drugs that are

predominantly protein bound and an

increased generation of toxic

metabolites. So really thinking

about not just the patient's age,

age, their genetic, activity

potentially, but also that kidney

and liver function is really

important.

The last thing I'll talk about is

thinking about these different right

drug for the right patient, the

right scenario is, you know, some of

the side effects.

Won't go into too much of the side

effects because there's quite a few

of them. But thinking about how we

distinguish between some of the

expected effects, between

from actually how we treat a patient

with pain.

So the patient from the very

beginning of our discussion is

really somebody who's been in pain

for a significant amount of time,

is coming into the hospital, may not

have slept.

And when we give them medications,

their fatigue level or even

wanting to go to sleep may not be

actual sedation.

It may be something like exhaustion.

And we have to be careful because we

absolutely know that opioids can

cause sedation directly on the CNS

and put patients in danger,

particularly those who have

underlying respiratory conditions.

But figuring out what's sedation,

what's fatigue, what's exhaustion

and sleep deprivation for patients

with pain is really critical.

And it's particularly critical for

patients at the end of life for whom

pain may have been the primary

stimulant for them to be awake in

the first place, and treating pain

at the end of life that expected

outcome might be that they're

sedated.

And so it's important, again, to put

this all in that clinical context.

A few things just to mention,

because we didn't talk about

already, are medications like

methadone and buprenorphine.

Methadone is a really important

medication in the treatment of

complex cancer-associated pain

and the treatment of pain for

patients involved in specialty

palliative care.

And it's because it's a really

inexpensive medication that's quite

potent, both with potent

opiate agonism as well as NMDA

receptor antagonism, which we think

is involved in reducing opioid

tolerance.

And so it allows us to rotate

patients on to doses of methadone

that might provide lower side

effects and improved efficacy.

It's also a medication that you can

dose in numerous forms.

It's the only long acting medication

that we can give in a liquid form

and give through a gastrostomy

tube for patients who otherwise

wouldn't be able to tolerate

medicines like MS Contin

or OxyContin, because

those medications can't be crushed.

It is, however, a really complicated

medication from the pharmacology

perspective, has a biphasic

metabolism and can have

a half-life within the body

of anywhere between 24 to

150 hours. And so understanding

how to dose it, how to switch

another opiate over to methadone is

really, really, really critical.

And so methadone really should only

be used by a specialist in pain

medicine or specialist in hospice

and palliative medicine.

Another medication that we're seeing

more and more of, and I think all of

us are going to have to know more

about, is buprenorphine.

Buprenorphine is widely used in

opioid use disorder treatments and

is seeing more activity now in the

treatment of chronic pain because

its safety profile perhaps

is a little bit better than some

of our other opioid choices.

It's a partial mu opioid receptor

agonist, some weak kappa

activity, very high affinity

for that receptor, and long duration

in most forms, which again

can be really useful in some patient

cases, but very complicated

for patients with acute pain given

that significant receptor binding

affinity. And so, again, best

in terms of somebody who is a

specialist in this medication or

in someone who's had advanced

training in the use of buprenorphine.

I think importantly and just to

close out with all of this, is that

as we think about how to use opioids

and the role that pharmacology

plays, it's going to be affected by

the patient clinical case.

It's going to be affected by the

patients available routes of

administration, their prior history

with opioids and allergies,

their genetic polymorphisms,

underlying kidney function, and then

ultimately how we understand the

conversions between on one opioid

and another when we have to use

repeated doses.

And so, again, getting to the right

drug for the right patient with the

right clinical case is critical and

always knowing that you can reach

out for help when these cases become

more complex.

Thanks so much for for listening and

chatting a bit today about opioid

pharmacology.

Hopefully we can continue this

conversation with ongoing Mayo

Clinic CME courses and always feel

free to reach out by a direct

message or follow me at

@jakejstrand on Twitter.