potent poppies...• examine special patient populations affected by opioid use, including...
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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
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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
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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).
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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
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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
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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.
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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
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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.
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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.
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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.
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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
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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.
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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.
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“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.
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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
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