Opioids
Definitions
 Opium: Dried latex from the opium poppy Papaver
Somniferum
 Opioid: Natural or synthetic pharmaceutical which has
an affinity to the opioid receptor
 Opiate: natural alkaloid product of opium
 Morphine, Codeine, Papaverine
 Narcotic: traditionally referred to opioids but more of
a legal term for drugs of addiction/abuse
Background
 Opium used by humans since the stone age
 Opos: Greek for “juice”
 Mentioned in many ancient texts for various
medicinal uses
 Beneficial (analgesia, hypnotic) and harmful (resp
depression, addiction) well known for centuries
Brief Opioid History
Opium poppies sprung from
the tears of Aphrodite
when she mourned for
her beloved Adonis.
Brief Opioid History
Opium is obtained from the
exudate of seed pods of
the poppy Papaver
somniferum
Brief Opioid History
Opioids used for the
treatment of pain for
thousands of years
Brief Opioid History
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3rd century BC
1527
1806
1817
mid 1800’s
1869
 1939
 1960
 1974-1976
 1991
- 1st reference of poppy juice (opium)
-Paracelsus formulated Laudanum
- Sertuener isolated ‘soporific principle’ in opium (opium alkaloid)
- isolated alkaloid named morphine
- medical use of pure alkaloids began to spread,
- morphine widely used to treat wounded soldiers during the
American Civil War
- meperidine (phenylpiperidine derivative) was the 1st totally
synthetic opioid produced
- fentanyl synthesized (4-anilinopiperidine derivative; derivative of
normeperidine)
- development of more potent opioid sufentanil and then alfentanil
- first descriptions of remifentanil
Mechanism of Action
 Opioids produce affects by activating opioid
receptors
 Opioid receptors highly concentrated in CNS:
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Tractus solitarius
Peri-aqueductal gray midbrain
Cerebral cortex
Substantia Gelantinosa spinal cord
 Also found in
 Peripheral nerves
Opioid receptors
 Coupled with inhibitory G-Proteins
 Agonism leads to:
 Closing voltage sensitive Ca++ channels
 Stimulation K+ influx (hyperpolarization)
 Reduced cyclic AMP
 Reduced neuronal cell excitation and transmission
Mechanism of Action
 Directly inhibit ascending transmission of nociceptive
information in spinal cord dorsal horn (Substantia
Gelantinosa)
 Mechanism of euphoria unclear but thought to
involve dopaminergic pathways in nucleus accumbens
Opioid Receptors and Effects
 MOP (mu)
 mu 1: analgesia, physical dependence
 mu 2: resp Depression, miosis, euphoria, dependence,
reduced GI motility
 mu 3: vasodilation
 KOP (kappa)
 analgesia, sedation, miosis, dysphoria
 DOP (delta)
 analgesia, antidepressant, convulsant, dependence
 NOP (nociceptan)
 anxiety, depression, tolerance
Opioid Effects - CNS
 Analgesia
 Best for visceral pain
 Less effective for somatic pain
 Poorly effective for neuropathic pain
 Sedation
 Mental cloudiness
 Can induce sleep, possibly because of relief of pain
 Not amnestic
Opioid Effects - CNS
 Euphoria and Dysphoria
 In absence of pain may cause dysphoria
 Hallucination
 More common with kappa agonists
 Tolerance and Dependence
 May be due to down regulation of receptors
 Withdrawal phenomenon:
 Restlessness, irritability, salivation, N/V, diarrhea, muscle
cramps, sweating
 Not fatal but may be dangerous for cardiac patients due to
sympathetic stress
Opioid Effects - CNS
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Mild decreases in Cerebral Metabolic Rate
Mild decrease in ICP
Little or no effect on Cerebral Blood Flow
Muscle Rigidity
 More common with high dose / potent opioids
 Prevented / attenuated with muscle relaxants
Opioid Effects - Cardiovascular
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Less effects on CVS than other anesthetic drugs
More stable at high doses
Mild bradycardia
Peripheral vasodilation due to histamine release
Decrease pre-load
Used at high doses in “cardiac anesthesia”
Opioid Effects - Respiratory
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Respiratory Depression (mu receptor)
Resp. rate decreases more than Tidal Volume
Decreased brainstem sensitivity to CO2
Exacerbated with addition of other anesthestics
Suppression of cough reflex
Blunt response to intubation
Opioid Effects – GI tract
 Stimulation of Chemoreceptor trigger zone
 Nausea and Vomiting
 Use of opioids as risk for Post-op N/V
 Increases pressure in biliary tract (exception:
meperidine)
 Decreased GI tract motility
 Constipation
Opioid Effects - Other
 Endocrine:
 Blunt stress response (decrease cortisol, ACTH)
 Ocular:
 Miosis
 Obstetric
 All opioids cross the placenta
 Chronic use by mother can result in neonatal withdrawal
 No known teratogenic effects
Balanced Anesthesia
 Balance of agents and techniques to produce
different components of anesthesia
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Analgesia
Amnesia
Muscle Relaxation
Abolition of Autonomic responses
Homeostasis
Balanced Anesthesia
 Use of Opioids in a balanced anesthetic:
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Reduces post-op pain
Reduces post-op anxiety
Decrease autonomic and somatic responses
Hemodynamic stability
Decrease requirements for volatile agents
Decrease requirements for IV anesthetics (propofol)
Pharmacokinetics
 Opioids are weak bases
 In plasma they dissociate into ionized and unionized
fractions depending on pKa
 Unionized fracture is more freely diffusable
 Poorly absorbed from acidic stomach (ionized +++)
 Readily absorbed from small intestine
Pharmacokinetics
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Lipid solubility
Protein binding
First pass metabolism
pKa and ionized/unionized fraction
Metabolism
 Mainly metabolized by the Liver
 Active and inactive metabolites
 Morphine
 Meperidine
 Kidneys involved in conjugation of Morphine
Commonly used Opioids
 Pure Agonists
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Morphine
Codeine
Hydromorphone
Fentanyl
Meperidine
Remifentanil
Alfentanil
Sufentanil
Methadone
 Agonist/Antagonists
 Pentazocine
 Buprenorphine
 Antagonists
 Naloxone
 Naltrexone
Morphine
 Gold standard opioid / Natural product
 MOP receptors
 Usual doses
 0.1-0.2mg/kg IM
 1-5mg IV
 Hydrophilic
 Slower peak onset, extended duration of action
 Long duration of action intrathecal/epidural 12-24hrs
 Peak onset
 IM : 30-60 mins
 IV : 10 minutes
 Use caution in renal impairment as Morphine-6-Glucuronide
accumulates
Codeine
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Natural opioid
Is a pro-drug, requires metabolism to morphine
Commonly used PO but can be given IM
Unpredictable conversion
 1% over metabolize
 10% under metabolize
 This has resulted in deaths
 Certain drugs affect enzymatic conversion
 Decrease: paroxetine, fluoxetine, bupropion benadryl.
 Increase: dexamethasone, rifampacin
 Not commonly used in Anesthesia, falling out of favour in pain
management
Fentanyl
 Synthetic, 100x more potent than morphine
 IV, IM, transbuccal, transdermal, neuraxial
 Peak onset 2-3 minutes IV
 Used as induction agent 2-3mcg/kg
 IV Boluses 0.5-2 mcg/kg
 Spinal 10-25 mcg Epidural 50-100 mcg
 Highly lipid soluble / large Vd
 Short duration after bolus due to redistribution
 Long context sensitive half-time with infusion
 Improves onset and quality of block in Spinal and Epidural
Hydromorphone (Dilaudid)
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Semi-synthetic mu agonist
5X as potent as morphine
PO, IV, IM, SC, Intrathecal, Epidural
More lipid soluble than morphine
More water soluble than fentanyl
Safer in renal impairment
Meperidine (Demerol - Pethidine)
 First synthetic opioid, approx 1/5 potency of morphine
 Mu and kappa action
 Local anesthetic properties
 Can be used as a single agent for spinal anesthesia
 Unique properties
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Decrease spasm in sphincter of oddi
Blocks sodium channels (local anesthetic action)
Results in tachycardia due to muscarinic blockade
Useful to stop shivering response
 Downsides:
 Metabolites have a long half-life and can cause seizures and accumulate in
renal failure
 Less commonly used now than in the past
Remifentanil
 Ultra-short acting, synthetic, highly potent opioid
 200X potent than morphine
 Independently metabolized by Plasma esterases due to ester linkage
 Useful as an infusion when deep opioid effects required but rapid recovery
desired
 Used for sedation, GA, TIVA
 Usual dose 0.025-1.0 mcg/kg/min
 Context sensitive half-time 6 minutes
 Bradycardia, hypotension, muscle rigidity more common
 Can be used as a co-induction agent “Rem-tubation”
 Can result in opioid induced hyperalgesia
 No residual effects thus need another opioid post-op
Pentazocine
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Partial antagonist/agonist
Approx ¼ potency of morphine
IM, SC (less often) IV and PO
Mostly action on kappa receptors
 More likely to cause nausea, bizarre dreams
 Less respiratory depression
 May provoke withdrawal in opioid dependent patients
 Less effective for severe pain
Naloxone
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Pure antagonist at all opioid receptors
Reverses respiratory depression
Resuscitation doses 0.2-.0.4mg
In peri-operative patient these doses may result in
severe pain crisis
 Small titration doses 0.04-0.08mg
 Effective antagonism 30 minutes
 May need re-dosing for longer acting drugs
Opioids in the OR
 Important part of a balanced anesthetic
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Decrease MAC
Patient comfort
Blunt stress response – better outcomes
Stable Hemodynamics
 The trick is to have an appropriate levels to correspond to
the varying stimulation levels of the surgery
 Need to anticipate pain control post-op
 Want patient to “wake up” comfortably but also want him to
“wake up” in a timely manner
Opioids in the OR
 Opioids have many downsides
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Constipation
Delay bowel recovery
Nausea & vomiting
Hallucination
 Co-analgesics and regional anesthetic techniques
spare their use
Opioids in the OR
 Often given at induction for intubation
 PRN Bolus therapy
 Need to anticipate stimulating parts of surgery and “top
up” as required
 Keep in mind peak onset
 Morphine 10 minutes
 Fentanyl 2-3 minutes
 Background infusions useful
 Fentanyl, sufentanil, hydromorphone, morphine
Opioids in the OR
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Unreliable as a single agent
Not amnestic
Used in conjunction with other agents
Dose dependent decrease in MAC for volatile agents
Blunt stress/sympathetic responses to pain and
intubation
Opioids in the OR
 Can be given a loading dose with intermittent boluses
 Continuous infusion
 Pay attention to Context sensitive half-time
 Post-op analgesia
 Part of a “Balanced Anesthetic”
 Smooth out extubation
Context Sensitive Half-time
 Time for blood levels to decrease by half after a
continuous infusion is discontinued
 “Context” is the duration of the infusion
 Very high for drugs with a large Vd due to
accumulation and redistribution
 Fentanyl, Sodium-thiopental
Opioids in Acute Pain
 Main ingredient in multi-modal analgesia
 Traditional approach of IM/SC boluses less effective
than IV PCA
 Avoid peaks/troughs
What is the “Best Way” to manage
acute post-operative/trauma pain?
 FIRST, DO NO HARM
Therefore, the “best way” is a BALANCE
Patient
Safety
Effective
Analgesic
Modalities
KEY POINTS
 “Emphasis is placed on the utilization of a multimodal
analgesic approach to maximize analgesia while
minimizing side-effects.”
 Transduction
 Transmission
 Modulation
 Perception
 There is as of yet no single silver bullet!!
Acute Pain Management Modalities
 Cyclo-oxygenase inhibitors
 Non-specific COX inhibitors(classical NSAIDs)
 Selective COX-2 inhibitors, the “coxibs”
 Acetaminophen is probably COX-3
 Opioids
 Local Anesthetics
 NMDA antagonists
 Ketamine, dextromethorphan
Analgesia with Opioids alone
 The harder we “push” with single mode analgesia, the
greater the degree of side-effects
Side-effects
Analgesia
Multi-modal Analgesia
 “With the multimodal analgesic approach there is
additive or even synergistic analgesia, while the sideeffects profiles are different and of small degree.”
Side-effects
Analgesia
The rationale for COX-Inhibitors in acute
pain management
 The problem with the “Little Pain – Little Gun, Big
Pain – Big Gun Approach”
 With opioids, analgesic efficacy is limited by side-effects
 “Optimal” analgesia is often difficult to titrate
 >10 – fold variability in opioid dose:response for analgesia in
opioid naïve patients!
 factors add to the difficulty
 Opioid tolerance, anxiety, obstructive sleep apnea, sleep
deprivation, concomitantly administered sedative drugs
The rationale for COX-Inhibitors in acute
pain management
 The problem with the “Little Pain – Little
Big Pain – Big Gun Approach”
Gun,
 Patient Safety!! If the “Big Gun” is failing due to
dose limiting sedation/respiratory depression, the
addition at that time of the “Little Gun” may kill the
patient.
Opioids
Pharmacokinetic + Pharmacodynamic
patient to patient variability results in1000 %
variability in opioid dose requirements
Concept # 1
 opioid dosage must be individualized
 therefore, if parenteral therapy indicated, IV PCA much
better suited to individual patient needs than IM/SC
Patient Controlled Analgesia with
Intravenous Opioids
 IV PCA:
 morphine
 golden standard, pruritus a common problem
 meperidine
 a little faster onset than morphine
 normeperidine a toxic metabolite is a problem for patients
with decreased renal function or using large dosages for
more than a few days
 hydromorphone
 less confusion in elderly patients?
Opioids
Issue
With parenteral opioids the patient may experience intolerable side
effects before adequate analgesia is attained
Opioids
CONCEPT # 2
Targeted regional
administration of opioid
results in enhancement of
the therapeutic index (ratio
of analgesia/side effects)
The proper use of oral opioids
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The limitations of combination drugs
Codeine is a “pro-drug”
Potent oral opioids are under-utilized
Offer “around the clock” not “prn”
In stable situations long acting, slow release
formulations may be indicated
Opioids
*Cancer Pain Monograph (H&W, 1984)
CONCEPT # 3
Under utilization of high efficacy PO opioids
 PO opioid equivalence of 10 mg morphine IM/SC *
morphine 20 mg
hydromorphone 4 mg
oxycodone 10 mg
codeine 120 mg
meperidine 200 mg
Opioids
Dilaudid 1 – 4 mg PO/IM/IV Q4H prn
NOT!
This represents up to 30 fold range in peak effect in
any given patient
1 mg PO ---- 4 mg IV bolus
homeopathic dose ---- potentially lethal
Opioids: Rational multi-route
orders?
 Foundation of Acetaminophen/COX-inh.
 Morphine 5 - 10 mg PO Q4h prn
 Morphine 2.5 - 5 mg s.c. Q4h prn
 Morphine 1-2 mg IV bolus Q1h prn
 Hydromorphone 1 - 2 mg PO Q4h prn
 Hydromorphone 0.5 – 1 mg s.c Q4h prn
 Hydromorphone 0.25 – 0.5 mg IV Q1h prn
NMDA Receptor Antagonists To prevent or reverse “pathological” acute pain
 Ketamine, Dextromethorphan
 Ketamine is widely known as a dissociative “general
anesthetic” - 3 mg/Kg IV bolus
 Ketamine 0.15 - 0.3 mg/kg IV with induction of general
anesthesia has pre-emptive analgesic effects - less pain
and less opioid use post-op
 Ketamine 2.5 - 5.0 mg IV bolus for analgesia in postsurgery/ trauma patient  Ketamine as co-analgesic - combined 1:1 with morphine
IV PCA. Better analgesia, less S/E
 Dextromethorphan 45 mg PO Q12H
The New Challenges in Managing Acute
Pain after Surgery and Trauma
 The Opioid Tolerant Patient
 The greatest change in pain management
practice/attitudes in the last 10 years is the now
wide spread acceptance of the use of opioids
for CHRONIC NON-MALIGNANT PAIN
 Renders the “usual” standard “box” orders
totally inadequate in these patients
Opioid
Fentanyl
Half-life
IV: 2 – 4h
Patch: 17h
Hydromorphone 2 – 3h
(Dilaudid)
Onset
Duration of
analgesic effect
IV: within minutes
Patch: 12-24h
IV: 0.5 – 1h
Patch: 72h
IV: 5 - 15 min
PO: 30 min
3 – 5h
Methadone**
8 – 59h
30 – 60 min
4 – 8h
Morphine
2 – 4h
IV:5 - 10 min
PO (IR): 30 - 60
min
IR: 3 – 6h
SR: 8 – 12h
Meperidine
(Demerol)
3 - 5h
(15-30h for
metabolite)
10 – 45 min
2 – 4h
Codeine
3 – 4h
30 – 60 min
4 – 6h
Oxycodone
IR: 2 – 5h
SR: 5h
15 – 60 min
IR: 3 – 6h
SR: 12h
Hydrocodone
3 – 4h
10 – 60 min
4 – 8h
59
Opioid
Usual Starting Dose
Comments
Fentanyl*
25 – 100 mcg IV q1h, then
1 – 2 mcg/kg/h
Patch: NOT for acute pain & NOT
for opioid-naïve pts; do not cut
patch in half
Hydromorphone
(Dilaudid)
0.5 – 1 mg q4h IV
1 – 2 mg q4h PO
Very potent; preferred in pts with
renal impairment
Methadone
5 mg q8-12h PO
Monitor for QT prolongation &
drug interactions
Morphine
2 – 5 mg q4h IV
5 – 10 mg q4h PO (IR)
15 – 30 mg q8 or 12h (SR)
MSContin: NOT for acute pain;
do not split/crush tablets
Meperidine
(Demerol)
50 mg q3-4h PO/IV
NOT recommended for chronic
use
Codeine
30 – 60 mg q4h PO
Has more side effects than
morphine
Oxycodone
5 mg q4h PO (IR)
10 – 20 mg q12h (SR)
OxyContin: NOT for acute pain;
do not split/crush tablets
Hydrocodone
5 – 10 mg q4h PO
always combined with APAP or
ibuprofen – which limits its
dosing
60
Case Problem: Inadequate Analgesia with
IV PCA after Open Cholecystectomy
 45 yr. female c/o severe pain at rest and difficulty
breathing due to incisional pain- 4 hrs. post-op
 IV PCA morphine: 1mg bolus, 5 min. lock-out
 150 demands : 28 good
 has stopped using PCA because, “it is making me sick(N/V) and
it’s not working”
 received 25 mg gravol X 2 one hour ago which helped just a little
with the N/V, but did make her quite groggy
 Solution?
 “Between a rock and a hard place!” as far as the use of
opioids goes.
Case Problem: Inadequate Analgesia with IV
PCA after Open Cholecystectomy
 Problem: Patient unable to attain required morphine
blood level due to intolerable side-effects (N/V, sedation)
 Solution:
 Administer COX-inhibitor
 Toradol IV/IM or Naproxen 500 mg PR Q12H, this may be
changed to 250 mg PO TID with meals once eating
 Control N/V
 Stemetil, Ondansetron, Decadron
 May need to consider changing opioid i.e. Demerol
 Local Anesthetics: intercostals, paravertebral, epidural
Case #2
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53 Year old male
Post-op Open Right Hemicolectomy x 45 minutes
Previously healthy except for Colon Cancer
Called by PACU for decreased level of consciousness
What do you do?
Case #2
 Apply standard monitors/IV access/Oxygen
 What are you next options?
 Treat and investigate concurrently
 Call for airway equipment/assistance
Case #2
 History
 Review anesthetic and PACU record
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 Given injection of morphine 15 minutes prior
Previously healthy
No allergies
Uneventful GA
Reversal given, patient awake and comfortable and transferred to PACU
 Get vital signs
 HR 64 BP 110/70 RR 5 SPO2 88% T35.8C
 Physical Exam
 GCS 8 Pinpoint Pupils Wound dry/OK
Decreased LOC in PACU
& Delayed Emergence
H’s
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Hypovolemia
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Vitals, Wound check, HGB
Hypothermia
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Vitals
Hypo/Hyper glycemia
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Glucometer
Hypoxia
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SPO2, ABG
Hyper/Hypo Kalemia
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ECG, ABG
Hydrogen Ion
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ABG
T’s
 Tablets/Toxins
 Opioids- Vital, Pupils
 Ketamine
 Muscle Relaxants - TOF
 Thrombosis
 PE
 Stroke
 Tamponade
 Tension PTX
 Trauma
Actions to take:
 Take control of the situation, call for help
 Oxygen, IV, Monitor
 ABCs
 A: Jaw thrust, OPA, LMA, ETT
 B: PPV if necessary
 C: Fluid bolus if necessary, pressor
 Discontinue Anesthetic infusions
 DON’T
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D: Dextrose
O: Oxygen
N: Naloxone , Neostigmine, Flumazinil
T: Thiamine
Drug Antidotes
 Naloxone
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Antidote for Opioid intoxication
Rapid onset (within minutes)
In post-op patients avoid large doses
Pain crisis may occur with limited ability to treat
1 Vial (0.4mg) diluted to 10cc
Give 0.04mg-0.08mg (1-2cc) increments
 Flumazinil
 Antidote for benzodiazepine
 Give in 0.2mg increments
 Caution: may provoke seizures
Case 2 Continued
 Give Naloxone 0.4mg IV
 Patient awakes and begins to complain of severe
severe pain
 Vitals:
 160/80 HR 110 SpO2 98% GCS 15
 Begins to develop chest pain
 What do you do now?
ECG Shows
Next steps?
 Oxygen, IV, Monitors
 Analgesic
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Naloxone will block effects of morphine
ASA
Ketamine
Acetominophen
Ketorolac
 Block stress response
 B Blocker
 Decrease Pre-load
 NTG Sublingual/IV
Patient Loses Consciousness
Questions?