Opioids
Opioids
Opium: Dried latex from the opium poppy Papaver
SomniferumOpioid: Natural or synthetic pharmaceutical which has an
affinity to the opioid receptorOpiate: natural alkaloid product of
opiumMorphine, Codeine, PapaverineNarcotic: traditionally referred
to opioids but more of a legal term for drugs of
addiction/abuseDefinitionsOpium used by humans since the stone
ageOpos: Greek for juiceMentioned in many ancient texts for various
medicinal usesBeneficial (analgesia, hypnotic) and harmful (resp
depression, addiction) well known for centuries
Background
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 HistoryOpioids used for the treatment of pain for
thousands of years
3rd century BC- 1st reference of poppy juice
(opium)1527-Paracelsus formulated Laudanum 1806- Sertuener isolated
soporific principle in opium (opium alkaloid)1817- isolated
alkaloid named morphinemid 1800s- medical use of pure alkaloids
began to spread, 1869- morphine widely used to treat wounded
soldiers during the American Civil War1939- meperidine
(phenylpiperidine derivative) was the 1st totally synthetic opioid
produced1960- fentanyl synthesized (4-anilinopiperidine derivative;
derivative of normeperidine)1974-1976- development of more potent
opioid sufentanil and then alfentanil1991- first descriptions of
remifentanil
Brief Opioid HistoryOpioids produce affects by activating opioid
receptorsOpioid receptors highly concentrated in CNS:Tractus
solitariusPeri-aqueductal gray midbrainCerebral cortexSubstantia
Gelantinosa spinal cordAlso found in Peripheral nerves
Mechanism of ActionCoupled with inhibitory G-ProteinsAgonism
leads to:Closing voltage sensitive Ca++ channelsStimulation K+
influx (hyperpolarization)Reduced cyclic AMPReduced neuronal cell
excitation and transmission Opioid receptorsDirectly 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
Mechanism of ActionMOP (mu)mu 1: analgesia, physical dependencemu
2: resp Depression, miosis, euphoria, dependence, reduced GI
motilitymu 3: vasodilationKOP (kappa)analgesia, sedation, miosis,
dysphoriaDOP (delta)analgesia, antidepressant, convulsant,
dependenceNOP (nociceptan)anxiety, depression, toleranceOpioid
Receptors and EffectsAnalgesiaBest for visceral painLess effective
for somatic painPoorly effective for neuropathic painSedationMental
cloudinessCan induce sleep, possibly because of relief of painNot
amnesticOpioid Effects - CNSEuphoria and DysphoriaIn absence of
pain may cause dysphoriaHallucinationMore common with kappa
agonistsTolerance and DependenceMay be due to down regulation of
receptorsWithdrawal phenomenon:Restlessness, irritability,
salivation, N/V, diarrhea, muscle cramps, sweatingNot fatal but may
be dangerous for cardiac patients due to sympathetic stressOpioid
Effects - CNS
Mild decreases in Cerebral Metabolic RateMild decrease in
ICPLittle or no effect on Cerebral Blood FlowMuscle RigidityMore
common with high dose / potent opioidsPrevented / attenuated with
muscle relaxantsOpioid Effects - CNSLess effects on CVS than other
anesthetic drugsMore stable at high dosesMild bradycardiaPeripheral
vasodilation due to histamine releaseDecrease pre-loadUsed at high
doses in cardiac anesthesiaOpioid Effects - Cardiovascular
Respiratory Depression (mu receptor)Resp. rate decreases more
than Tidal VolumeDecreased brainstem sensitivity to CO2 Exacerbated
with addition of other anesthesticsSuppression of cough reflexBlunt
response to intubationOpioid Effects - Respiratory
Stimulation of Chemoreceptor trigger zoneNausea and VomitingUse
of opioids as risk for Post-op N/VIncreases pressure in biliary
tract (exception: meperidine)Decreased GI tract
motilityConstipationOpioid Effects GI tract
Endocrine:Blunt stress response (decrease cortisol,
ACTH)Ocular:MiosisObstetricAll opioids cross the placentaChronic
use by mother can result in neonatal withdrawalNo known teratogenic
effects
Opioid Effects - OtherBalance of agents and techniques to
produce different components of anesthesiaAnalgesiaAmnesiaMuscle
RelaxationAbolition of Autonomic responsesHomeostasisBalanced
AnesthesiaUse of Opioids in a balanced anesthetic:Reduces post-op
painReduces post-op anxietyDecrease autonomic and somatic
responsesHemodynamic stabilityDecrease requirements for volatile
agentsDecrease requirements for IV anesthetics (propofol)Balanced
AnesthesiaOpioids are weak basesIn plasma they dissociate into
ionized and unionized fractions depending on pKaUnionized fracture
is more freely diffusablePoorly absorbed from acidic stomach
(ionized +++)Readily absorbed from small
intestinePharmacokineticsLipid solubility Protein bindingFirst pass
metabolismpKa and ionized/unionized fractionPharmacokineticsMainly
metabolized by the LiverActive and inactive metabolitesMorphine
MeperidineKidneys involved in conjugation of MorphineMetabolism
Commonly used OpioidsPure AgonistsMorphineCodeineHydromorphone
FentanylMeperidineRemifentanilAlfentanilSufentanilMethadone
Agonist/AntagonistsPentazocineBuprenorphine
AntagonistsNaloxoneNaltrexoneGold standard opioid / Natural
productMOP receptorsUsual doses 0.1-0.2mg/kg IM1-5mg
IVHydrophilicSlower peak onset, extended duration of actionLong
duration of action intrathecal/epidural 12-24hrsPeak onsetIM :
30-60 minsIV : 10 minutesUse caution in renal impairment as
Morphine-6-Glucuronide accumulates
MorphineNatural opioidIs a pro-drug, requires metabolism to
morphine Commonly used PO but can be given IMUnpredictable
conversion 1% over metabolize10% under metabolizeThis has resulted
in deathsCertain drugs affect enzymatic conversionDecrease:
paroxetine, fluoxetine, bupropion benadryl.Increase: dexamethasone,
rifampacinNot commonly used in Anesthesia, falling out of favour in
pain management
Codeine
27In contrast to morphine, codeine is about 60% as effective
orally as parenterally. The greater oral efficacy is due to less
1st pass metabolism in the liver. However, Codeine has
exceptionally low affinity for opioid receptors and the analgesic
effect of codeine is due to its conversion to morphine
(O-demethylation, about 10% of codeine is O-demethylated to
morphine). The conversion of codeine to morphine is effected by the
cytochrome P450 enzyme CYP2D6. Well characterized genetic
polymorphisms in this enzyme lead to the inability of convert
codeine to morphine, thus making codeine in-effective as an
analgesic for about 10% of the Caucasian population(Eichelbaum and
Evert, 1996). Other polymorhisms can lead to enhanced metabolism
and enhanced effect. Ref(Goodman and Gilman 10th ed. 2001 pg
589Synthetic, 100x more potent than morphineIV, IM, transbuccal,
transdermal, neuraxialPeak onset 2-3 minutes IVUsed as induction
agent 2-3mcg/kgIV Boluses 0.5-2 mcg/kgSpinal 10-25 mcg Epidural
50-100 mcgHighly lipid soluble / large VdShort duration after bolus
due to redistribution Long context sensitive half-time with
infusion Improves onset and quality of block in Spinal and
Epidural
FentanylSemi-synthetic mu agonist5X as potent as morphinePO, IV,
IM, SC, Intrathecal, EpiduralMore lipid soluble than morphineMore
water soluble than fentanylSafer in renal impairment
Hydromorphone (Dilaudid)First synthetic opioid, approx 1/5
potency of morphine Mu and kappa actionLocal anesthetic
propertiesCan be used as a single agent for spinal anesthesiaUnique
propertiesDecrease spasm in sphincter of oddi Blocks sodium
channels (local anesthetic action)Results in tachycardia due to
muscarinic blockadeUseful to stop shivering
responseDownsides:Metabolites have a long half-life and can cause
seizures and accumulate in renal failureLess commonly used now than
in the past
Meperidine (Demerol - Pethidine)Ultra-short acting, synthetic,
highly potent opioid200X potent than morphineIndependently
metabolized by Plasma esterases due to ester linkage Useful as an
infusion when deep opioid effects required but rapid recovery
desiredUsed for sedation, GA, TIVAUsual dose 0.025-1.0
mcg/kg/minContext sensitive half-time 6 minutesBradycardia,
hypotension, muscle rigidity more commonCan be used as a
co-induction agent Rem-tubationCan result in opioid induced
hyperalgesia No residual effects thus need another opioid
post-op
RemifentanilPartial antagonist/agonistApprox potency of
morphineIM, SC (less often) IV and POMostly action on kappa
receptorsMore likely to cause nausea, bizarre dreamsLess
respiratory depressionMay provoke withdrawal in opioid dependent
patientsLess effective for severe painPentazocinePure antagonist at
all opioid receptorsReverses respiratory depressionResuscitation
doses 0.2-.0.4mgIn peri-operative patient these doses may result in
severe pain crisisSmall titration doses 0.04-0.08mgEffective
antagonism 30 minutesMay need re-dosing for longer acting
drugsNaloxoneImportant part of a balanced anestheticDecrease
MACPatient comfortBlunt stress response better outcomesStable
HemodynamicsThe trick is to have an appropriate levels to
correspond to the varying stimulation levels of the surgeryNeed to
anticipate pain control post-opWant patient to wake up comfortably
but also want him to wake up in a timely mannerOpioids in the
OROpioids have many downsidesConstipationDelay bowel recoveryNausea
& vomitingHallucinationCo-analgesics and regional anesthetic
techniques spare their useOpioids in the OROften given at induction
for intubationPRN Bolus therapyNeed to anticipate stimulating parts
of surgery and top up as requiredKeep in mind peak onsetMorphine 10
minutesFentanyl 2-3 minutesBackground infusions usefulFentanyl,
sufentanil, hydromorphone, morphine
Opioids in the ORUnreliable as a single agentNot amnesticUsed in
conjunction with other agentsDose dependent decrease in MAC for
volatile agentsBlunt stress/sympathetic responses to pain and
intubationOpioids in the ORCan be given a loading dose with
intermittent bolusesContinuous infusion Pay attention to Context
sensitive half-timePost-op analgesiaPart of a Balanced
AnestheticSmooth out extubationOpioids in the ORTime for blood
levels to decrease by half after a continuous infusion is
discontinuedContext is the duration of the infusionVery high for
drugs with a large Vd due to accumulation and
redistributionFentanyl, Sodium-thiopental
Context Sensitive Half-time
Main ingredient in multi-modal analgesiaTraditional approach of
IM/SC boluses less effective than IV PCAAvoid peaks/troughs
Opioids in Acute PainFIRST, DO NO HARMTherefore, the best way is
a BALANCE
What is the Best Way to manage acute post-operative/trauma
pain?
Patient SafetyEffective AnalgesicModalities
42Emphasis is placed on the utilization of a multimodal
analgesic approach to maximize analgesia while minimizing
side-effects. TransductionTransmissionModulationPerceptionThere is
as of yet no single silver bullet!!KEY POINTS
43Safety means avoid side-effects. Emphasis is placed on the
utilization of a multimodal analgesic approach to maximize
analgesia while minimizing side-effects. The 4 basic target areas
within the nervous system where various drug modalities may act to
diminish conversion of nociception to actual realized pain are:
transduction, transmission, modulation and perception.
Cyclo-oxygenase inhibitorsNon-specific COX inhibitors(classical
NSAIDs)Selective COX-2 inhibitors, the coxibsAcetaminophen is
probably COX-3
Opioids
Local Anesthetics
NMDA antagonistsKetamine, dextromethorphan Acute Pain Management
Modalities
44COX-inhibitors affect transduction and modulation. Opioids
modulation and perception. Local anesthetics affect transmission
and NMDA antagonists affect modulation.The harder we push with
single mode analgesia, the greater the degree of side-effects
Analgesia with Opioids alone
AnalgesiaSide-effects
45There is no single silver bullet that is able to provide
adequate analgesia in moderate to severe pain conditions in all
patients.With the multimodal analgesic approach there is additive
or even synergistic analgesia, while the side-effects profiles are
different and of small degree. Multi-modal Analgesia
AnalgesiaSide-effects
46There is no single silver bullet. The problem with the Little
Pain Little Gun, Big Pain Big Gun ApproachWith opioids, analgesic
efficacy is limited by side-effectsOptimal analgesia is often
difficult to titrate>10 fold variability in opioid dose:response
for analgesia in opioid nave patients! factors add to the
difficultyOpioid tolerance, anxiety, obstructive sleep apnea, sleep
deprivation, concomitantly administered sedative drugs
The rationale for COX-Inhibitors in acute pain management
47The problem we get into with going straight to opioid
analgesia for moderate-severe to severe or excruciating pain is
that we usually get into some nasty side-effects. Frequently we
cant even attain satisfactory analgesia on account of dose limiting
complications. The state of morphine-failure, when the patient is
oscillating between the state of over-sedation and writhing in
acute pain. However, the foundation of non-opioid analgesia
provided cox-inhibitors works in wonderful concert with the opioid
analgesics. Greater analgesia is attained with fewer opioid
side-effects ( the opioid sparing effect). This idea of adding a
cox-inhibitor to a patient already receiving and perhaps even
failing analgesic therapy with a powerful opioid, is quite
difficult for some patients and even doctors to grasp. Whats the
point of adding a little gun, if the big guns are not even
working?? Patients have to be educated that these drugs from
different classes work together, the analgesic result being greater
than the sum of the individual parts and with less side-effects
too! A useful analogy that patients and maybe even surgeon find
easy to understand is using the opening of a door as a model of
analgesic efficacy. Morphine can blow the door open but it cant
activate the door handle very well. The COX-inhibitor is adept at
activating the door handle but can only open the door partially.
Working together they can open the door wide open much more easily
and with less potential for collateral damage.
The problem with the Little Pain Little Gun, Big Pain Big Gun
Approach
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.
The rationale for COX-Inhibitors in acute pain management
Pharmacokinetic + Pharmacodynamic patient to patient variability
results in1000 % variability in opioid dose requirements
Concept # 1opioid dosage must be individualized
therefore, if parenteral therapy indicated, IV PCA much better
suited to individual patient needs than IM/SC
Opioids
49IV PCA:morphinegolden standard, pruritus a common
problemmeperidinea little faster onset than morphinenormeperidine a
toxic metabolite is a problem for patients with decreased renal
function or using large dosages for more than a few
dayshydromorphoneless confusion in elderly patients?Patient
Controlled Analgesia with Intravenous Opioids
50IssueWith parenteral opioids the patient may experience
intolerable side effects before adequate analgesia is attained
Opioids
51OpioidsCONCEPT # 2Targeted regionaladministration of
opioidresults in enhancement ofthe therapeutic index (ratioof
analgesia/side effects)
52Opioids can be administered directly into lumbar CSF or
epidurally for enhanced analgesic effects.The limitations of
combination drugsCodeine is a pro-drugPotent oral opioids are
under-utilizedOffer around the clock not prnIn stable situations
long acting, slow release formulations may be indicated
The proper use of oral opioids
53The principles to proper use of oral opioids require an
understanding of the above.CONCEPT # 3Under utilization of high
efficacy PO opioids
PO opioid equivalence of 10 mg morphine IM/SC *
morphine 20 mg codeine 120 mghydromorphone 4 mg meperidine 200
mg oxycodone 10 mg
Opioids *Cancer Pain Monograph (H&W, 1984)
54The three most frequently used potent PO opioids are morphine,
hydromorphone(Dilaudid) and oxycodone(active opioid in Percocet and
Oxycontin and Oxy-IR). Note listed amounts are equivalent to twice
opioid activity of two T#3. Meperidine PO equivalent is listed to
emphasize it lack of potency via the oral route. It is associated
with high rate of S/E due to toxic metabolites and is not
recommended.Dilaudid 1 4 mg PO/IM/IV Q4H prnNOT!This represents up
to 30 fold range in peak effect in any given patient
1 mg PO ---- 4 mg IV bolushomeopathic dose ---- potentially
lethalOpioids
55PO to IV conversions are based on total daily equivalents.
They do not take into account the more rapid onset of action via
the IV bolus route, leading to a greater peak effect. This is
especially true of the more lipophyllic drugs like HM and demerol
compared to morphine.Therefore 4 mg IV is equivalent to 4X4 = 16 PO
but the peak effect is at least double I.e. 32mg.Foundation of
Acetaminophen/COX-inh.
Morphine 5 - 10 mg PO Q4h prnMorphine 2.5 - 5 mg s.c. Q4h
prnMorphine 1-2 mg IV bolus Q1h prn
Hydromorphone 1 - 2 mg PO Q4h prnHydromorphone 0.5 1 mg s.c Q4h
prnHydromorphone 0.25 0.5 mg IV Q1h prn
Opioids: Rational multi-route orders?
Ketamine, DextromethorphanKetamine is widely known as a
dissociative general anesthetic - 3 mg/Kg IV bolusKetamine 0.15 -
0.3 mg/kg IV with induction of general anesthesia has pre-emptive
analgesic effects - less pain and less opioid use post-opKetamine
2.5 - 5.0 mg IV bolus for analgesia in post-surgery/ trauma patient
- Ketamine as co-analgesic - combined 1:1 with morphine IV PCA.
Better analgesia, less S/EDextromethorphan 45 mg PO Q12H NMDA
Receptor Antagonists -To prevent or reverse pathological acute
pain
57The Opioid Tolerant PatientThe 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 patientsThe New Challenges in Managing Acute Pain after
Surgery and Trauma
58Demerol 75 mg IM Q4H prn or Tylenol #3 just isnt going to cut
it!59OpioidHalf-lifeOnsetDuration of analgesic effectFentanylIV: 2
4hPatch: 17h IV: within minutesPatch: 12-24h IV: 0.5 1hPatch:
72hHydromorphone (Dilaudid)2 3hIV: 5 - 15 minPO: 30 min3 5h
Methadone**8 59h30 60 min4 8h Morphine2 4h IV:5 - 10 minPO (IR): 30
- 60 minIR: 3 6h SR: 8 12hMeperidine (Demerol)3 - 5h (15-30h for
metabolite)10 45 min2 4hCodeine3 4h30 60 min4 6hOxycodoneIR: 2 5h
SR: 5h 15 60 minIR: 3 6hSR: 12hHydrocodone3 4h10 60 min4 8hTable
compares some of the PKSAll have similar t1/2 and onset (except for
methadone)Duration of analgesic effect helps determine proper
dosing frequencyIV fentanylMethadone: long-acting
product**half-life can be long but analgesic effect lasts 4 8 h
5960OpioidUsual Starting DoseCommentsFentanyl*25 100 mcg IV q1h,
then 1 2 mcg/kg/hPatch: NOT for acute pain & NOT for
opioid-nave pts; do not cut patch in halfHydromorphone
(Dilaudid)0.5 1 mg q4h IV1 2 mg q4h POVery potent; preferred in pts
with renal impairmentMethadone5 mg q8-12h POMonitor for QT
prolongation & drug interactionsMorphine2 5 mg q4h IV5 10 mg
q4h PO (IR)15 30 mg q8 or 12h (SR)MSContin: NOT for acute pain; do
not split/crush tabletsMeperidine (Demerol)50 mg q3-4h PO/IVNOT
recommended for chronic useCodeine30 60 mg q4h POHas more side
effects than morphineOxycodone5 mg q4h PO (IR)10 20 mg q12h
(SR)OxyContin: NOT for acute pain; do not split/crush
tabletsHydrocodone5 10 mg q4h POalways combined with APAP or
ibuprofen which limits its dosing**fentanyl: different indications
(adjuvant for general anesthesia maintenance, minor & major
surgical procedures, control of post-op painFentanyl patch dose
will varyMSContin & OxyContin dose will vary depending upon
narcotic requirementMSContin can be dosed q8 to q12hCodeine has
more side effects than morphine more nausea and constipation6045
yr. female c/o severe pain at rest and difficulty breathing due to
incisional pain- 4 hrs. post-opIV PCA morphine: 1mg bolus, 5 min.
lock-out150 demands : 28 goodhas stopped using PCA because, it is
making me sick(N/V) and its not workingreceived 25 mg gravol X 2
one hour ago which helped just a little with the N/V, but did make
her quite groggySolution?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
61This case illustrates how most practitioners utilize the
cox-inhibitor group.Problem: Patient unable to attain required
morphine blood level due to intolerable side-effects (N/V,
sedation)Solution:Administer COX-inhibitorToradol IV/IM or Naproxen
500 mg PR Q12H, this may be changed to 250 mg PO TID with meals
once eatingControl N/VStemetil, Ondansetron, DecadronMay need to
consider changing opioid i.e. Demerol
Local Anesthetics: intercostals, paravertebral, epidural
Case Problem: Inadequate Analgesia with IV PCA after Open
Cholecystectomy
6253 Year old malePost-op Open Right Hemicolectomy x 45
minutesPreviously healthy except for Colon CancerCalled by PACU for
decreased level of consciousnessWhat do you do?
Case #2
Apply standard monitors/IV access/OxygenWhat are you next
options?Treat and investigate concurrentlyCall for airway
equipment/assistanceCase #2
HistoryReview anesthetic and PACU recordGiven injection of
morphine 15 minutes priorPreviously healthyNo allergiesUneventful
GA Reversal given, patient awake and comfortable and transferred to
PACUGet vital signsHR 64 BP 110/70 RR 5 SPO2 88% T35.8CPhysical
ExamGCS 8 Pinpoint Pupils Wound dry/OK
Case #2
Decreased LOC in PACU & Delayed
EmergenceHsHypovolemiaVitals, Wound check,
HGBHypothermiaVitalsHypo/Hyper glycemiaGlucometerHypoxiaSPO2,
ABGHyper/Hypo KalemiaECG, ABGHydrogen
IonABGTsTablets/ToxinsOpioids- Vital, PupilsKetamineMuscle
Relaxants - TOFThrombosisPEStrokeTamponadeTension PTXTrauma
Take control of the situation, call for helpOxygen, IV,
MonitorABCsA: Jaw thrust, OPA, LMA, ETTB: PPV if necessaryC: Fluid
bolus if necessary, pressorDiscontinue Anesthetic infusionsDONTD:
DextroseO: OxygenN: Naloxone , Neostigmine, FlumazinilT:
Thiamine
Actions to take:NaloxoneAntidote for Opioid intoxicationRapid
onset (within minutes)In post-op patients avoid large dosesPain
crisis may occur with limited ability to treat1 Vial (0.4mg)
diluted to 10ccGive 0.04mg-0.08mg (1-2cc) incrementsFlumazinil
Antidote for benzodiazepineGive in 0.2mg incrementsCaution: may
provoke seizures
Drug AntidotesGive Naloxone 0.4mg IVPatient 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?
Case 2 Continued
ECG ShowsOxygen, IV, MonitorsAnalgesicNaloxone will block
effects of morphineASAKetamineAcetominophenKetorolacBlock stress
responseB BlockerDecrease Pre-loadNTG Sublingual/IVNext steps?
Patient Loses Consciousness
Questions?
