1

Objectives

• Understand the pharmacodynamics of opioids and how they reach target receptors in the body.

• Learn about the different opioids that are the greatest concern to EMS.

• Examine special patient populations affected by opioid use, including palliative care patients,

geriatric, neonate, and those in drug rehabilitation.

• Debunk some of the myths regarding opioid use.

• Explore treatment options specifically tied to opiate overdose.

Completion of this continuing education for credit requires reading this

educational material and successfully passing the quiz offered through our

QuestBase portal at http://www.questbase.com/a/umcems. The quiz includes a

course evaluation, which is required under our continuing education license with

the Texas Department of State Health Services and also helps us to improve the

quality of our education.

Potent Poppies

Opioids in the prehospital setting

Continuing Education for EMS:

1 hour for Preparatory (Texas) or 1 hour for Medical: Toxicological Emergencies – Opioids (NREMT)

Texas DSHS EMS Continuing Education Provider License #100648

2

Table of Contents

Objectives ...................................................................................................................................................................... 1

Just summon the great “Fentanyl Fairy” for everyone, right? ...................................................................................... 3

Definition review ........................................................................................................................................................... 3

Quick history of opioids ................................................................................................................................................. 4

Pharmacokinetics: Opioid movement in the body ........................................................................................................ 4

A look at morphine: The best-known example of an opiate. .................................................................................... 4

How drugs reach their target cells, and why some drag their feet. .......................................................................... 6

Back to why some opiates last longer than others and onset times. ........................................................................ 8

Three main classes of opioid receptors ......................................................................................................................... 8

How opioid receptors work ........................................................................................................................................... 9

The adverse effects of opioids ..................................................................................................................................... 10

Respiratory Depression ........................................................................................................................................... 10

Constipation ............................................................................................................................................................ 11

Itching ...................................................................................................................................................................... 11

Cardiovascular Effects ............................................................................................................................................. 11

Nausea and Vomiting .............................................................................................................................................. 12

Increased intracranial pressure ............................................................................................................................... 12

The more common prehospital opiate medications ................................................................................................... 12

Morphine: ................................................................................................................................................................ 12

Fentanyl: .................................................................................................................................................................. 13

Morphine versus fentanyl debate: Which is better? ............................................................................................... 14

Opioid addiction treatment ......................................................................................................................................... 14

Buprenorphine with naloxone (Suboxone) ............................................................................................................. 15

Methadone: ............................................................................................................................................................. 15

Opioid antagonists: Naloxone (Narcan) ....................................................................................................................... 16

Debunking a few myths about opioids ........................................................................................................................ 16

“Don’t give me that… I’ll get addicted!” .................................................................................................................. 16

“Don’t give morphine… it causes a big histamine release!” .................................................................................... 17

“If diluted in a 10 mL saline flush, there’s no need for a slow IV push.” ................................................................. 17

“EMS gives too many narcotics. Adults only need 25 mcg of fentanyl.” ................................................................ 17

References ................................................................................................................................................................... 18

3

Just summon the great “Fentanyl Fairy” for everyone, right?

Acute pain is the most common reason people request EMS. For most patients,

appropriate pain management, reassessment, supportive care, and transport to the hospital makes up the

bulk of the call. Other situations are not as easy. Consider:

• A patient diagnosed with terminal cancer and

already taking heavy doses of oral morphine,

but is now experiencing severe breakthrough

pain. Do you give more morphine and snow

her, hold off and let the ED decide, or try

something different for analgesia?

• A heroin abuser who was given intranasal

naloxone (Narcan) before EMS arrival

becomes responsive, and now adamantly

refuses transport. Is it safe to allow her to

refuse?

• A patient who goes to the methadone clinic every day for his “pill” but missed today… and it’s closed

now. He pleas for a dose of morphine just to help him get through today, but aren’t opioid drugs

what got him into the methadone treatment in the first place? And, what is methadone, exactly?

• An elderly victim of a major vehicle collision refuses your offer for fentanyl or morphine because, “I

don’t want to get addicted to that stuff!”. However, you’re in pain just looking at her deformed,

twisted knee. Does her fear hold any real merit?

Every scenario has occurred and for some crews, even frequently. How should you handle these situations?

What really happens when you give a dose of fentanyl or morphine in the back of the ambulance, and is one

drug better than the other? How do you professionally address the physician who insists that every adult

patient only needs a total of 25 micrograms of fentanyl instead of our usual prehospital dose?

Definition review

• Agonists. Drugs that activate specific receptors on the cell membrane.

• Antagonists. Drugs that block specific receptors on the cell membrane.

• Enteral. An oral or other gastrointestinal route of medication administration.

• Equianalgesic charts. A reference chart that compares the pain relieving effectiveness of a selected

analgesic to morphine on a drug-dose basis. For example, 100 mcg of fentanyl should be as effective

Fentanyl for

Everyone?

4

as 10 mg of morphine by parental routes. However, 30 mg of oral morphine is only equivalent to 10

mg of intravenous or intramuscular morphine due to first-pass metabolism.

• Half-life. The half-life is the amount of time it takes for 50% of the drug to be removed from the

body. For some drugs, it’s just minutes. Others, such as amiodarone, are on the order of weeks.

• Minimum Effective Concentration (MEC). This is the blood plasma concentration of a drug that

starts producing a therapeutic effect. A concentration below the MEC does not provide any benefit

to the patient at all.

• Octanol-water partition coefficient. A laboratory-measured property of a substance that suggests

whether it dissolves better in a lipid environment or water (i.e: Its hydrophilic/lipophilic balance).

• Opiate. A more specific term than opioid that usually refers to drugs with natural opium in them

(example: morphine or codeine)

• Opioid. A general term used for natural or synthetic drugs with actions similar to morphine (binds to

opioid receptors, etc.).

• Parenteral. A non-oral route of medication administration that avoids first-pass metabolism by the

gastrointestinal (GI) tract and/or liver. Examples: Intravenous, intraosseous, and intramuscular.

Quick history of opioids

Morphine is the prototype for opioid medications, and is derived from the opium latex of the unripened

poppy seedpod (Papaver somniferum). Codeine, a popular prescription cough-suppressant, anti-diarrheal,

and pain reliever, is extracted from opium as well.

The pain-relieving and sedative properties of morphine have been

exploited for centuries, dating as far back as a record on a Sumerian

clay tablet around 2100 BC.1 It wasn’t until about 200 years ago where

morphine itself was isolated from opium, hypodermic needles and

syringes existed, and injectable morphine was finally made available as

a reliable post-surgical pain medication.2

Pharmacokinetics: Opioid movement in the body

A look at morphine: The best-known example of an opiate. Morphine is not

only a well-known example, but it is also considered as the prototype for all opioids --- natural or synthetic.

Equianalgesic dosing charts usually use morphine as the control or reference point. Morphine is one of the

oldest drugs known by man, can be administered through various routes, and is common medication used for

both acute and severe chronic pain (example: patients with cancer).

5

When given in appropriate doses, morphine and its synthetic

cousin fentanyl do not adversely affect the senses. Clarity of

sight, hearing, touch, and smell are all preserved, although

“brain fog”, drowsiness, respiratory depression, urinary

retention, and constipation are common adverse effects.3

Oral drugs versus injected. Hospice and oncology

(cancer) patients may be prescribed oral morphine drops or pills

in higher daily doses than we even carry on our ambulance. But,

this higher dose is needed to overcome the decreased

effectiveness of the drug through the oral route. For morphine,

first-pass metabolism begins within the intestinal wall,

continues for the most part in the liver, and will metabolize the

medication to such a degree that the oral dose can lose 60% or

more of its effectiveness!

4

Other factors may also affect how well the drug is absorbed

through the intestinal tract. For example, a patient with

diarrhea may absorb a lot less of the oral tablet since it would be

rapidly transported away from the vessel-rich intestinal tract.

There may be not enough endothelial “contact time” with the

drug to absorb a therapeutic amount of it.

First pass metabolism may not affect other oral analgesics as

strongly as it does with morphine. But, despite this reduced

potency, oral analgesics --- including opioids --- still remain as

the preferred choice for most oncology patients. Pills and liquid

oral analgesics avoid accessing implanted medication ports,

central venous catheters, or PICC lines frequently, which would

otherwise increase the risk for bloodborne infection and emboli

in these already immune-compromised patients.

Injected drugs avoid first-pass metabolism. Intravenous, intraosseous, intramuscular, subcutaneous, and

other parenteral (non-oral/GI tract) routes of opiate

administration avoid first-pass metabolism in the intestinal wall

and liver, so their effectiveness is not reduced by these organs.

Instead, the medication enters the bloodstream directly.

However, keep in mind that drug clearance through urine or

feces is still delayed in those with renal or hepatic compromise,

no matter the drug route used.

What is first-pass metabolism?

Most medications absorbed through the

gastrointestinal tract are delivered to the liver

(via the portal vein) before they even hit the

general circulation. A fraction of the drug is

then broken down and metabolized within the

liver before it reaches the systemic circulation.

Some drugs are metabolized to a greater degree

than others… morphine being one of them. This

reduces the oral bioavailability and in turn, the

effectiveness of the drug. Liver disease and

other conditions can affect the degree of

metabolism. For example, a person with

cirrhosis of the liver may not be able to

metabolize the drug as well as a someone with a

healthy liver. In this case, oral morphine would

be more potent for a person with cirrhosis.

Renal disease also extends the drug elimination

time, effectively delaying the medication’s

removal from the body through urine. This is

something to consider no matter the route of

drug administration. Titrating an analgesic to

effect may be the safest option for these

patients.

We also need to be careful in dosing for

geriatric patients, since both renal and hepatic

functionality declines with age. Other

susceptible populations include neonates and

infants, as they have an immature hepatic and

renal system for the first year of life.3

6

How drugs reach their target cells, and why some drag their feet.

All opioids differ in their duration of action, or how long the pain relief should last. The reasons can be

complex and not always predictable just by looking at their minimum effective concentrations (MEC) and

half-lives. For example, a dose of morphine usually lasts a lot longer compared to fentanyl, yet the half-life

for morphine (1.5 to 4.5 hours)4 is also within the range for fentanyl. This doesn’t make sense. The reason:

Morphine has a low lipid

solubility, which prolongs its

duration of action compared to

more lipid-soluble fentanyl.

No good deed goes unpunished

for morphine though. The low

lipid solubility also means that

morphine takes longer to reach

its analgesic peak. Not a great

option for someone screaming

in severe pain. To compare:

Fentanyl has a high lipid

solubility (octanol-water

partition coefficient is 9550).

Morphine’s octanol-water partition coefficient is just a mere six.

How do drugs reach their intended destination? Drugs must cross cell membranes to leave the

capillaries, travel through other cell membranes to reach target cells, and pass through cell membranes once

again to eventually be eliminated from the body. That’s a lot of physical barriers to overcome. Some are

easier than others, depending on the size of the drug molecule, the electrical charge it maintains, and the

degree of lipid solubility. All drugs are water and lipid soluble to some degree. But, the percent of each

(water versus lipid) differs and will affect the drug’s characteristics.

Most capillaries in the body are formed by a layer of cells with some space between them, so drugs can

usually exit the vessel simply by slipping between the capillary cells. This is illustrated below:

Time

Fentanyl’s

peak effect

Morphine’s

peak effect

Fentanyl’s

effect declines

Drug given

here: T=0

Fentanyl:

Morphine: A Generalized Drug Response Curve

(not to scale)

Capillary cutaway

Drug

Cell

Pain relief

7

However, within the “blood brain barrier” and other protective CNS capillaries, the vessels are formed by a

closely-packed arrangement of cells

with very little space in between them.

This helps prevent bacteria and other

large molecules from infiltrating the

brain and CNS. Within these

capillaries, drugs need to pass through

cells rather than between them to

navigate into the brain and other

neural tissues. Cell membranes in

general are not the easiest barriers to

cross since they have a thick wall consisting of a layer of carbohydrates and proteins on the top, followed by

two layers of phospholipids (lipids or fats with a phosphate atom attached to them) and even more proteins.

Despite all of these barriers though, there are three ways drugs can enter the cell:3

• Pass through very small channels or pores. This mechanism is usually reserved for very small ions

such as sodium and potassium, as most drugs are too large for this route.

• Use of a transport system. Cells can

have specialized proteins integrated into

the cell membrane that allows certain

drugs to bind to them. Once bound, the

carrier can bring a specific drug molecule

across the cell membrane and into the

cell. This works like a turnstile. The catch

is that this process is slow and requires

energy to operate. This system is also

used to help eliminate the drug from the

cell as well, and is vitally important for

drug transport into bile and urine.

• Forced entry into the cell. This is the

route used by most drugs that are too

large for channels/pores, and cells that

don’t have specific carrier proteins on

their membrane to help with transport. However, the drug needs to be lipid-soluble (lipophilic) to

some degree to allow it to enter the lipid-rich environment of the cell membrane. In this case, like

follows like. Just as water doesn’t dissolve in oil, a hydrophilic (water-soluble) or lipophobic (lipid-

fearing) drug does not use this route well.

The blood-brain barrier is formed by a tight arrangement of cells.

Since the drug molecule cannot slip between the cells here, they

now need to able to pass directly through cells to cross the barrier.

One example of a transport system. The molecules bind to specific

receptor sites on the carrier protein and then are pulled into the cell’s

cytoplasm.

Table sugar dissolves in water easily… it’s hydrophilic. But mix sugar into

butter (a lipid), and you’ll probably notice those grainy crystals every time you

bite into a biscuit slathered with it. As far as the lipid-rich cell membranes are

concerned, morphine is more like sugar compared to greasy fentanyl.

8

Back to why some opiates last longer than others and onset times.

Opioid medications attach to the opioid receptors sitting on the cell membrane. A receptor is much like a

standard light switch: It’s either on or off. There is no in-between. When an opioid medication binds to an

opioid receptor, it functions as an agonist and activates (turns on) the receptor so it

can control the intended physiological task: Reduce pain transmission. The more

opioid receptors that are activated, the greater the rate of physiological activity.

Drugs cannot change the cell’s function or abilities; they can only support/enhance

the receptor’s actions (switch is “on”) or block them (switch is “off”).

Opioids can affect more than one body system though. For example, opioid

receptors not only manage pain, but they are also found in the gastrointestinal tract

and brainstem areas. Administering morphine will address pain, but because this

drug binds to several classes of opioid receptors, it can adversely affect intestinal

motility, blood pressure, induce nausea, and depress respiratory effort.

As a review: Morphine has a low lipid-soluble profile, while opposite of that, fentanyl has a high degree of

lipid solubility. So, while morphine will eventually push through the cellular barrier, fentanyl can pass

through cell membranes faster and easier. This is one reason why the onset of action for fentanyl is so much

faster compared to morphine. But unfortunately for fentanyl, passing through a cell membrane this easily

works both ways and it can be eliminated just as quickly as well. Morphine has a longer duration of action

since it’s more difficult to push this drug out of the cellular barrier once it gets there.

Three main classes of opioid receptors

There isn’t just one class of opioid receptor, but three major ones and a few subtypes. All fall under the

umbrella of an opioid receptor, but how they react to receptor activation can vary. The chart below

describes the differences for the major three.3

Opioid Receptor Type

Mu Kappa Delta

Analgesia (pain relief) ✓ ✓ ✓

Respiratory depression ✓

Sedation ✓ ✓

Euphoria ✓ ✓

Decreased GI motility ✓ ✓

Mostly found in/at:

Brain Peripheral sensory neurons

Spinal cord Gastrointestinal tract

Brain Peripheral sensory neurons

Spinal cord

Brain Peripheral sensory neurons

9

Mu receptors are the most important ones to us, since these are the primary target for our opioid

medications. Kappa receptors are not affected very strongly by our prehospital opioid medications, and

delta receptors are all but ignored. However, while opioid drugs have a preference towards mu receptors,

naturally-produced endorphins and other opioid agonists produced by our body target all three receptor

classes, including the delta receptors.

How opioid receptors work

Activating opioid receptors (the “on” switch) with an opioid agonist causes the following to happen:

• Closes voltage-sensitive calcium channels, which may be affected more by kappa receptor

activation.5 This helps to decrease neuron excitability/contractility.

• Stimulates potassium removal from the cell,

leading to a state of hyperpolarization. Mu and

delta receptors are more likely to play a role

compared to kappa receptors.5

As shown in the graph on the right, -55 mV

represents the threshold where the cell could

start depolarizing and for our interests, send

those unwanted pain signals to neighboring

neurons. We try to delay that using opioid

medications… less frequent signal transmission

results in less pain felt by the patient.

When the opioid receptor is activated by a drug

such as morphine, the potassium ion channels in the neuron’s cell membrane stay open longer than

usual. This allows more potassium ions to leave the cell while repolarizing. Hyperpolarization

represents the point in time where maybe a little too much potassium has left the cell (an

overshoot). But, it normally doesn’t take long before the potassium channels close, membrane

potential recovers, and it all reaches the resting potential at – 70 mV again, ready to start the cycle

that leads to depolarization again.

When an opioid receptor is activated though, it allows the hyperpolarization state to last longer,

delaying the return to the resting potential. It acts like a prolonged refractory period. This delays

cell depolarization and in turn, reduces the transmission of pain impulses. Pain lessens.

• Problem is, both actions also blunt other organ functions as well, such as coordinated GI tract

motility and brain responses needed for respiratory control. They depend on a normal signal

transmission rate to function as expected, yet activating opioid receptors slows them down too.

10

The adverse effects of opioids

Respiratory Depression

Respiratory depression offers the highest risk for death from opioid administration, which is why

oxygen supplementation is required by our protocols and waveform capnography is recommended

to monitor the respiratory response. Waveform capnography provides an instantaneous look at

your patient’s respiratory status (respiratory rate and carbon dioxide concentration), while pulse

oximetry alone may not suggest a problem until the patient has already desaturated.

Since supplemental oxygen can affect carbon dioxide

concentration in blood, the chemoreceptors that

normally stimulate a breath can be affected in opioid-

naïve patients. Titrating oxygen flow to effect and

frequent re-assessment of your patient is a best

practice. As our EMS has evolved over the last

decade, we’ve finally accepted that not everyone

requires a non-rebreather mask when oxygen is

indicated. A nasal cannula will suffice for most of our

patients’ needs.

Timing. Respiratory depression usually peaks about 7 minutes after IV/IO administration of

morphine and 30 minutes after intramuscular administration, but this is an individualized response.4

Respiratory depression can last 4 to 5 hours though, regardless of the route.4 Those with cancer and

taking high-dose oral morphine usually develop a tolerance to this effect over a long period of time.

Unless their dose is changed, they normally do not experience respiratory depression from their

usual opioid medication and dose.3 However, observe them if you decide to administer parenteral

opioids for breakthrough pain.

Increased risk populations. Risk for respiratory depression increases with the very young, the

elderly, and those with a history of respiratory disease such as asthma or COPD. Concurrent use with

a benzodiazepine or other CNS depressant, or

even combined with alcohol will also increase

respiratory depression.

Patients who consumed alcohol can still feel

severe pain. If an opioid is given to them or any

other high-risk patient, it’s recommended to

split your doses and titrate to effect while

frequently reassessing for signs of any adverse

effects. Was beer involved? Even so, he may still feel severe pain.

11

Constipation

Something we all take for granted, but when taking an opioid for even a couple of days, the risk for

constipation increases. Continuously activating the opioid receptors in the gut can decrease

coordinated peristaltic (wave-like) movements in the gastrointestinal tract, reduce the amount of

fluid excreted into the bowel, and even increase anal sphincter tone.3 This combination can result in

constipation, but is usually avoided if the patient remains hydrated and takes a stool softener (not a

harsh laxative) daily as soon as they learn opioids will be used to manage their pain for a while.

Itching

Itching is an occasional symptom reported after opiate administration, and seems to be more

prevalent with natural opioids, such as morphine or codeine, versus purely synthetic ones such as

fentanyl. The cause is still under debate. Some suggest activating the mu receptors themselves may

trigger itching, while others believe more centralized receptors may be activated with opioids, such

as the MOR1D receptors. Histamine release was traditionally blamed, but recent studies suggest

that therapeutic doses of opioids are inadequate to induce mast cell degranulation, which causes

itching. 6,7 Again, the real cause is still unknown.

Cardiovascular Effects

Morphine and other opioids can blunt the baroreceptor

reflex that helps regulate blood pressure. Morphine may

also dilate peripheral arterioles and veins, which further

lowers pressure. Since morphine and other opioids also

effect the brainstem, sympathetic drive, and sinoatrial

node of the heart, respiratory and heart rate may also

decline. Orthostatic hypotension is one of the adverse

effects encountered with opioid use3… these are the

patients who should not be asked to stand up (if at all

possible) during prehospital care.

Constipated?

Get a quick cure here.

12

Nausea and Vomiting

There are opioid receptors on the medulla’s chemoreceptor zone that initiate the feeling of nausea

and can trigger vomiting. Movement seems to increase the sensation, which is pretty much

unavoidable in a moving ambulance. But, the nausea can be safely treated with a non-CNS

depressant antiemetic such as ondansetron (Zofran).

Increased intracranial pressure

This is a preventable adverse effect. Carbon dioxide

concentrations in blood may increase if the opioid

medication reduces respiratory drive. This elevation can

affect cerebral vessel dilation, causing intracranial

pressure to rise.

Maintaining normal levels by monitoring with

capnography and titrating supplemental oxygen can

prevent this harmful rise in patients with head injury, a

suspected stroke, or other conditions, such as a clogged

ventriculoperitoneal shunt used to drain cerebral spinal

fluid from the brain. In most cases, the goal is to maintain

normal capnography (35 to 45 mmHg), not overtreat it

with hyperventilation or inappropriate use of high flow

oxygen.

The more common prehospital opiate medications

Morphine:

Morphine is a potent analgesic with good sedative and anxiolytic (anxiety-reducing) properties. The

time to peak effect by IV or IO averages 20 minutes and duration of action ranges from 3 to 5 hours,

but can extend up to 7 hours.3,4 Intravenous administration should be titrated to effect, usually in 2

mg boluses for adults and administered over at least a minute to avoid pronounced adverse effects.

In children, consider administering 25% to 33% of the total recommended weight-based dose at a

time to titrate to effect.8

13

Morphine remains the “go to” drug for severe pain

associated with cancer. These patients may take morphine

tablets or oral drops at home several times a day to relieve

pain and decrease anxiety.

One concern EMS providers may face is caring for a patient

with a terminal illness who appears to be in severe pain.

Family members are usually the ones administering morphine

if the patient remains at home. Did the patient receive her

medications today? Sometimes, the family members are

confused about the prescription itself and may need help

understanding how much to give and how often. They may

even be scared to give the large prescribed dose.

On the other hand, is there a rare chance that one of the

family members or another healthcare provider is

consuming or selling her medications instead? If you have a sound basis for this suspicion, it should

be reported to Adult Protective Services and the receiving hospital staff to prevent continued

suffering.

Fentanyl:

Fentanyl is 100 times more potent than morphine on a weight basis. This is why it’s administered in

microgram amounts, not milligrams like morphine. Equianalgesic charts report that 100 micrograms

of fentanyl is equivalent to 10 milligrams of morphine or 75 milligrams of meperidine (Demerol) by

parenteral routes. As mentioned earlier though, it’s very lipid-soluble so while it’s half-life of about 3

to 4 hours is close to morphine, the duration of action is very short. When given in doses of 1 to 2

micrograms per kilogram IV/IO or intranasally (IN), it has a very rapid onset and a short duration of

action (30 to 60 minutes).8

In the smaller doses, it has little sedative effect unless

combined with other CNS depressants. Higher doses are

used by anesthesiologists to blunt the sympathetic

response to laryngoscopy and intubation. Fentanyl is

also available as transdermal patch for chronic pain

conditions and as a lollipop to premedicate children.

For intramuscular use, fentanyl lasts longer (1 to 2

hours) but takes about 7 to 8 minutes before reaching

peak effect.8

Morphine: Extended release tablets from one

pharmaceutical company. However, other

brands may not have the “M” on the tablet.

One type of a fentanyl lollipop.

14

Even though fentanyl is 500 times more lipid-soluble than morphine and more rapidly and

extensively distributed in the body, it shares many properties with morphine. It produces respiratory

depression in dose-dependent manner. Extremely large doses have been infused during cardiac

surgery to blunt the metabolic stress response. At such high doses, sedation is usually unavoidable

and unconsciousness may occur. Muscular rigidity of the chest wall may affect ventilation either by a

high dose or by administering the lower prehospital dose too fast.

Morphine versus fentanyl debate: Which is better?

Morphine: 4,7,9 Fentanyl: 7-9

Onset of action: Slower Faster

Reaches analgesic peak: About 20 minutes by IV/IO 1 to 4 minutes by IV/IO

Duration of analgesia: 3 to 5 hours, but up to 7 hours 30 to 60 minutes

Histamine release potential: None None

Hypotension potential: Equal Equal

Respiratory depression potential: Equal – dose dependent Equal – dose dependent

Safer for liver disease patients: About equal; cautious use About equal; cautious use

Safer for kidney disease patients: Not as safe as fentanyl Safer than morphine

Opioid addiction treatment

This education won’t cover the wide range of opioid partial agonists available to treat moderate pain or

opioids intended for addiction or drug abuse treatment. However, there are two that are commonly used in

this area: Buprenorphine with naloxone and methadone. Both may be used for chronic pain that’s not

responsive to other analgesics. In more well-known situations though, both drugs are used to rehabilitate

patients who are addicted to or are abusing opioids.

So, why are physicians prescribing opioid and heroin addicts more opioids? Aren’t they just fueling their

habit? There are two main reasons:

1. For those who can be weaned off their opioid medications, these drugs can provide a one-dose-a-

day option to help with treatment and avoid the symptoms of opioid withdrawal. Usually, these

patients have a physical dependence on the opioid, but do not abuse it.

2. For those with a history of abusing heroin or other injectable drugs, it can provide a safer option as

an opioid source but without the risk of sharing needles, buying contaminated drugs, and other

potentially-fatal decisions. Ideally, the patient would be enrolled in a treatment plan to get them

back on the right track. Drug abuse can be defined as drug use that is inconsistent with medical or

social norms.3 For example, a person is abusing an opioid if not used for severe pain, but instead to

gain the euphoric feeling that usually accompanies a bolus of an opioid.3

15

When used for drug rehabilitation, methadone in particular requires the person to receive their medication

each day and his or her use of it is monitored by a healthcare professional under physician’s orders. The drug

itself is only one part of a comprehensive treatment plan; Counseling, social services support, and other

services should be integrated into the treatment plan for successful rehabilitation.

Won’t they abuse these drugs too? Buprenorphine with naloxone and methadone don’t produce a

euphoric "high" in those who already have physical dependence or addiction to opioids, but instead minimize

withdrawal symptoms and cravings. This makes it possible for the patient to function normally, attend school

or work, and participate in other forms of treatment or recovery support services to help them become free

of their addiction over time.

Buprenorphine with naloxone (Suboxone)

Buprenorphine with naloxone (Suboxone) is a long-lasting opioid that can prevent withdrawal

symptoms for 24 hours. So why mix an opioid (buprenophrine) with Narcan (naloxone)? Doesn’t

that seem counter-productive?

This formulation is designed to deter diversion and misuse.

The naloxone portion has no effect on the individual as

long as the drug is taken orally, as intended. The naloxone

is ineffective. But, if the medication is crushed, dissolved,

and injected by IV for a euphoric opioid rush, the naloxone

blocks the effect of the buprenorphine in blood and can

induce really unpleasant withdrawal symptoms.

You may find chronic pain patients --- particularly the

elderly or others requiring family care --- also taking this

medication. It may be that in this case, it’s not because

they are physically-dependent on the opioid, but the physician has a concern that the medication

may be crushed and used or sold by one of the family members instead. Sadly, this happens.

Methadone:

Methadone is another long-lasting, monitored opioid with an extensive history of opioid use disorder

treatment… since 1947. It is a potent opioid analgesic that is both well-absorbed and with a good

oral bioavailability (75%) profile. Its mainly used as an opioid substitute to reduce the incidence of

withdrawal symptoms, and lasts about 22 to 24 hours. Its use is monitored at a regulated clinic as

mentioned before, but can help reduce the criminal activity and hazardous injection practices that

occur with heroin or other opioid drug abuse.

Suboxone tablets.

16

Opioid antagonists: Naloxone (Narcan)

Naloxone and its longer-acting derivative naltrexone occupy

opioid receptors, but as antagonists, they simply compete for

receptor sites to prevent opioids from activating them. They

are basically the squatters of the opioid receptors. While low

to moderate doses of naloxone given to someone who has

not used opioids generally has no effect on them, giving

multiple doses can antagonize their naturally-produced

endorphins.3

Also, if you administer naloxone and then a short while later,

fentanyl or morphine for pain, the opioid may not work as intended. This can occur during cardiac arrest if

naloxone was given “just because” and then pulses return. Any effort to provide pain relief from chest

compressions, intubation, and other painful interventions with fentanyl may be futile.

Naloxone is a pure opioid antagonist and will reverse opioid effects at the mu, kappa, and delta receptors,

although its affinity is highest at the mu receptors. It is the drug of choice for the treatment of opioid-

induced respiratory depression or failure. In our treatment protocols, it’s not indicated for “waking him up”

if there’s no respiratory compromise involved.

Naloxone’s effective duration of action is about 30 minutes, but if the patient used more opioid than a single

dose of naloxone can cover, additional doses may be needed just a few minutes after the first.3 For those

patients with a physical dependence to opioids, be cautious about giving naloxone as it may cause an acute

withdrawal state with hypertension, pulmonary edema, and cardiac arrhythmias.

Debunking a few myths about opioids

“Don’t give me that… I’ll get addicted!”

Short term use of opioid medications will not cause addiction or physical dependence, and this is

particularly true in the prehospital setting.

It’s been estimated that 8% of the population is prone to drug abuse of some form.3 These 8% may

already have a history of abusing drugs inside or outside of the hospital setting,3 and it’s still in

debate to whether this is a genetically-based cause, socially-driven, or otherwise a learned behavior

for a variety of reasons. For the remaining 92% of the population, physical dependence may occur

with long term use of an opioid, but this will not be caused by one or a few doses of fentanyl in the

back of the ambulance.

Looks like we

have a squatter.

17

“Don’t give morphine… it causes a big histamine release!”

In the early 80s, a study suggested that morphine triggered a histamine release, which would explain

the hypotension and reduced cardiac output that accompanied its use.10 Almost a decade later,

another study emerged using an improved and more accurate histamine assay and compared the

histamine response of patients receiving large cardiac-surgery doses of morphine or fentanyl. In this

newer randomized study, patients were either assigned to receive 1 mg/kg of morphine infused over

10 minutes, or 50 mcg/kg over 10 minutes; Both doses are much larger than we use prehospitally.

What they found was surprising: There was no significant difference in histamine released by the

patients receiving morphine compared to fentanyl. In addition, the amount of histamine that was

released remained within normal physiological limits.7

So what causes the lowered blood pressure? One hypothesis: A person in pain usually has an

increased sympathetic response (more circulating epinephrine, norepinephrine, and dopamine) that

increases heart rate and blood pressure. When you “fix” the pain, this response decreases and the

patient finally begins to relax. Heart rate lowers along with blood pressure. There is still an effect

from any opioid on the sinoatrial node of the heart and regulatory centers of the brain, so that also

plays a role in the response.

“If diluted in a 10 mL saline flush, there’s no need for a slow IV push.”

Why are most IV or IO medications given over one minute or

more? The entire blood volume within the body is circulated

about once every minute. If the medication is given over one

minute, it allows the opioid to be diluted in the maximum volume

of blood in the shortest time. This is much more than what 10 mL

of mixed saline can offer, although the diluted syringe helps

prevent vein irritation from a concentrated medication. And, a

10 mL syringe makes titrating doses a lot easier. Most

importantly though, giving the medication over a minute avoids

hitting body systems with a drug concentration that can be

dangerously high.

“EMS gives too many narcotics. Adults only need 25 mcg of fentanyl.”

Unfortunately, this very statement has been made by at least one emergency center physician in

Lubbock. Per its drug insert, the recommended dose for fentanyl is 1 to 2 mcg/kg;8 our maximum

dose is 100 mcg. These recommendations are usually based on the drug’s minimum effective

concentration (MEC), as described earlier. If the dose falls below this lower limit, the patient will not

benefit at all from the medication. However, opioid doses should be titrated to effect and the

patient not just given the maximum dose all at once. This is to prevent the adverse reactions

associated with opioids, particularly in those patients who are not accustomed to them.

When a drug is injected in the AC

(antecubital area of the arm), it

reaches the brain in about 15 seconds.

Please be sure to complete the quiz for CE credit. Any questions? Just contact a member of the UMC EMS training staff for assistance.

18

References

1. Norn S, Kruse PR, Kruse E. History of opium poppy and morphine. Dan Medicinhist Arbog.

2005;33:171-184.

2. Hamilton GR, Baskett TF. In the arms of Morpheus the development of morphine for postoperative

pain relief. Can J Anaesth. 2000 Apr;47(4):367-374.

3. Lehne, Richard A. Pharmacology for Nursing Care. 8th ed. St. Louis, MO: Elsevier/Saunders, 2013.

Print.

4. Monograph for morphine sulfate. Available at: https://www.drugs.com/monograph/morphine-

sulfate.html

5. North RA. Opioid receptor types and membrane ion channels. Trends Neuro. 1986;9:114-117.

6. Wong LS, Wu T, Lee CH. Inflammatory and Noninflammatory Itch: Implications in Pathophysiology-

Directed Treatments. Int J Mol Sci. 2017 Jul 10;18(7). pii: E1485. doi: 10.3390/ijms18071485.

7. Warner MA, Hosking MP, Gray JR, et al. Narcotic-induced histamine release: a comparison of

morphine, oxymorphone, and fentanyl infusions. J Cardiothorac Vasc Anesth. 1991 Oct;5(5):481-484.

8. Monograph for fentanyl citrate. Available at:

http://www.acphd.org/media/330951/fentanyl%20citrate%20package%20insert.pdf

9. Gelot S and Nakhla E. Opioid Dosing in Renal and Hepatic Impairment. US Pharm. 2014;39(8):34-38.

Available at: https://www.uspharmacist.com/article/opioid-dosing-in-renal-and-hepatic-impairment

10. Rosow CE, Moss J, Philbin DM, et al. Histamine release during morphine and fentanyl anesthesia.

Anesthesiology. 1982;56:93-96.

Image credit: Page 7 – Carrier transport system illustration. Blausen.com staff (2014). "Medical gallery of

Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436. - Own

work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=28781688