Transcript Pain - Palliative Care

Palliative care + PAIN
And the Emergency Physician
Dr. Mike O’Neil, MD, CCFP(EM ), FCFP
Clinical Asst. Prof. DEM , UBC
LGH EMERGENCY
Hospitalist, Pall care
What ?
Palliative care
• Aren’t they opposites
• NO
Emergency Medicine
• ? Oxymoron
• NOT
Palliative Care patients
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Often the sickest pts in hosp outside of ICU
SICK UNTO DEATH (Dr. Peter Edmunds)
But often get there in fits + starts
Often over days – weeks- months – years
Mostly DNR -2B – medical Rx
Some FULL CODE
Medical conditions in PCU ?
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Pain
Severe pain
Excruciating pain
Severe excruciating pain
on a bucket of meds
• Adjuvants
• Procedures
• Anesthesia
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Narcs
Equivalents
Routes of admin
Toxicities
Side effects
• Infusions, ketamine
- midazolam
Medical conditions in PCU ?
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Delerium
Depression
Anger
Denial
Confusion
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Seizures
Myoclonus
TIA’s
CVA’s
Spinal cord compression
acute
subacute
chronic
Medical conditions in PCU ?
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Febrile neutropenia
Sepsis
Pneumonia
Cellulitis
UTI’s
SBP
Menigiits
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Nausea
Vomintg
Diarrhea
Constipation
Dysphagia
hiccups
Anorexia
Tube feeds
Medical conditions in PCU ?
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Pleural effusions
Recurrent pl effusion
Ascites
Paracentesis
Edema
Anasarca
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CHF
ASTHMA
COPD
ACS
PE
Arrhythmias
Medical conditions in PCU ?
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IDDM
NIDDM
Hypo- hyper glycemia
Hypo – hyper K+
Hypo- hyper Na+
Hypo- hyper Ca++
Hypo-hyper Mag++
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Clotting abn
Epistaxis
Hemoptysis
Exsanguinating bleeds
• Falls
• #’s- path #’s
• Lacrtns
Medical conditions in PCU ?
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Bowel obstruciton
Ischemic bowel
Perf viscus
Urine retention
incontinence
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Family issues
Social issues
Psych issues
Religious issues
Cultural issues
Grief
Bereavement
Dealing with all this?
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Emergency physicians.
Good background and training and experience
To do palliative care
In ER and on a PCU
‘Ten commandments of Emergency Medicine’
1991 Wrenn and Slovis
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Secure the ABCs.
Consider or give naloxone, glucose and thiamine.
Get a pregnancy test.
Assume the worst: rule out serious disease.
Do not send unstable patients to radiology.
Look for the common red flags.
Trust no one, believe nothing (not even yourself ): check lab
results and rethink clinical decisions.
• Learn from your mistakes.
• Do unto others as you would your family (and that includes
coworkers).
• When in doubt, err on the side of the patient.
Do’s and don’ts of emergency medicine:
a primer for residents
• Eric Letovsky, MD
• CJEM / Volume 5 / Issue 02 / March 2003, pp
130 - 132
• Copyright © Canadian Association of Emergency
Physicians 2003
• http://dx.doi.org/10.1017/S1481803500008320
(About DOI),
• Published online: 21 May 2015
A few of 24 Do’s / Don;ts
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1. Don’t ignore abnormal vital signs.
2. Don’t take shortcuts on the physical exam.
3. Don’t wait to give antibiotics to sick patients.
4. Don’t be the health care police.
5. Don’t use “pink ladies” to rule out MI
6. Don’t be afraid to wake up a consultant.
• 7. Do pay special attentN to the very young and very old.
• 15. Do consider the worst possible disease for
every complaint.
Pain
Pain rx
Pain
Pain
• "Pain is an unpleasant sensory and emotional
experience
• associated with actual or potential tissue
damage,
• or described in terms of such damage."
Background basic physiology
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Quick review
May be all intuitive to some
Establish terminology seen in literature
Will elaborate on particular points
Classification
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Duration
Nociceptive
Neuropathic
Phantom
Psychogenic
Breakthrough pain
Incident pain
Pain asymbolia and insensitivity
Nociceptive
• Nociceptive pain is caused by stimulation of
peripheral nerve fibers that respond only to
stimuli approaching or exceeding harmful
intensity (nociceptors),
• Think of these as noxious receptors
• think of nocioceptive as noxious-sensation
Nociceptive
• may be classified according to the mode of
noxious stimulation.
The most common categories being
• "thermal" (e.g. heat or cold),
• "mechanical" (crushing, tearing, shearing,
• "chemical" (e.g. iodine in a cut, chili powder in
the eyes
Neuropathic pain
• Neuropathic pain is caused by damage or
disease affecting any part of the nervous
system involved in bodily feelings
• (the somatosensory system)
• Peripheral neuropathic pain is often described
as "burning", "tingling", "electrical",
"stabbing", or "pins and needles“
• Bumping the "funny bone" elicits acute
peripheral neuropathic pain
Pain asymbolia and insensitivity
• The ability to experience pain is essential for
protection from injury, and recognition of the
presence of injury.
• Episodic analgesia may occur under special
circumstances, such as in the excitement of
sport or war:
• a soldier on the battlefield may feel no pain
for many hours from a traumatic amputation
or other severe injury.
Insensitivity to pain may also result from abnormalities
in the nervous system
• This is usually the result of acquired damage to
the nerves, such as
• spinal cord injury,
• diabetes mellitus (diabetic neuropathy),
• leprosy (in countries where this is prevalent)
• These individuals are at risk of tissue damage
due to undiscovered injury
• People with diabetes-related nerve damage, for
instance, sustain poorly healing foot ulcers as a
result of decreased sensation
congenital insensitivity to pain
• A much smaller number of people are
insensitive to pain due to an inborn
abnormality of the nervous system, known as
congenital insensitivity to pain
Pain Rx
• How do we treat pain
• Tell it to go away
Pain Rx
Pain-Rx Description from HI-TECH
PHARMACEUTICALS
-Revolutionary "Quick Acting" Cox-2 Inhibitor
Ingredient
Amo
unt
Proprietary Blend with 600m
Explotab Technology
g
-Paullinia Tomestosa
Extract
-Chiococca Alba
Extract
-Mimosa Pudica
-Phellodendron
Amurense
-Lactuna Virosa Extract
-White Willow
-Turmeric Extract
-Valerian Extract
-Boswellia Extract
-Naringen
-6-7
Dihydroxybergamottin
-Yerba Mate
% Daily
Value**
Examples of nonprescription pain
medications
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Acetaminophen (Tylenol)
Aspirin
Ibuprofen (Advil, Motrin IB)
Naproxen (Aleve
Nonsteroidal anti-inflammatory drugs
(NSAIDs) Rx
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Diclofenac (Voltaren)
Diflunisal (Dolobid)
Etodolac (Lodine)
Fenoprofen (Nalfon)
Flurbiprofen (Ansaid)
Ibuprofen (Motrin)
Indomethacin (Indocin)
Ketorolac (Toradol)
Mefenamic acid (Ponstel)
Nabumetone (Relafen)
Naproxen (Naprosyn, Anaprox)
Oxaprozin (Daypro)
Piroxicam (Feldene)
Sulindac (Clinoril)
Tolmetin (Tolectin)
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Cox-2 Inhibitor
Celecoxib (Celebrex)
Meloxicam (Mobic)
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Rofecoxib (Vioxx) – gone
Opioid Analgesics
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Acetaminophen with codeine (Tylenol #2, #3, #4)
Fentanyl transdermal patches (Duragesic)
Hydrocodone with acetaminophen (Lortab Elixir, Vicodin)
Hydrocodone with ibuprofen (Vicoprofen)
Meperidine (Demerol, Merpergan)
Methadone (Dolophine)
Morphine and morphine sustained release (MS-Contin)
Oxycodone sustained release (OxyContin)
Oxycodone with acetaminophen (Percocet)
Oxycodone with aspirin (Percodan)
Oxycodone with ibuprofen (Combunox)
Oxymorphone (Opana)
Pentazocine (Talwin)
Propoxyphene with aspirin, propoxyphene with acetaminophen (Darvon,
Darvocet)
Tramadol, tramadol with acetaminophen (Ultram, Ultracet
Antidepressants
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Amitriptyline (Elavil)
Bupropion (Wellbutrin)
Desipramine (Norpramin)
Duloxetine (Cymbalta)
Imipramine (Tofranil)
Venlafaxine (Effexor
Anticonvulsants
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Carbamazepine (Tegretol)
Clonazepam (Klonopin)
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Pregabalin (Lyrica)
Tiagabine (Gabitril)
Topiramate (Topamax
Anxiolytics
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Alprazolam (Xanax)
Diazepam (Valium)
Lorazepam (Ativan)
Triazolam (Halcion
Muscle Relaxants
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Baclofen (Lioresal)
Carisoprodol (Soma)
Chlorzoxazone (Parafon Forte, DSC)
Cyclobenzaprine (Flexeril)
Dantrolene (Dantrium)
Metaxalone (Skelaxin)
Methocarbamol (Robaxin)
Orphenadrine (Norflex)
Tizanidine (Zanaflex
Corticosteroids
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Cortisone
Prednisone
Prednisolone
Dexamethasone
Methylprednisolone (Medrol, A-Methapred,
Depo Medrol, Solu Medrol)
• Triamcinolone (Allernaze, Aristospan 5mg,
Aristospan Injection 20mg, Kenalog 10 Injection,
Nasacort AQ)
Pain rx
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Pain meds work on receptors
Opioid receptors
Neurotransmitter receptors
Prostaglandin
NMDA receptors
Receptors
• Paul Ehrlich - 1899
• Specialized areas of cells to which drugs get
bound
• They are regulatory protein macro molecules
drugs should selectivity to a receptor
• Receptor should have ligand specificity to illicit
action
opioid
• An opioid is any psychoactive chemical that
resembles morphine or other opiates in its
pharmacological effects.
• Opioids work by binding to opioid receptors,
• which are found principally in the central and
peripheral nervous system and the
gastrointestinal tract.
• The receptors in these organ systems mediate
both the beneficial effects and the side effects of
opioids
opiate
• Although the term opiate is often used as a
synonym for opioid,
• the term opiate is properly limited to the
natural alkaloids found in the resin of the
opium poppy (Papaver somniferum),
• while opioid refers to both opiates and
synthetic substances, as well as to opioid
peptides
Opioids
• Opioids are among the
world's oldest known
drugs;
• the therapeutic use of
the opium poppy
predates recorded
history
• Cultivation of opium poppies for food,
anaesthesia, and ritual purposes dates back to
at least the Neolithic Age (new stone age).
• The Sumerian, Assyrian, Egyptian, Indian,
Minoan, Greek, Roman, Persian and Arab
Empires all made widespread use of opium,
• which was the most potent form of pain relief
then available, allowing ancient surgeons to
perform prolonged surgical procedures.
• Opium is mentioned in the most important
medical texts of the ancient world,
• including the Ebers Papyrus and the writings of
Dioscorides, Galen, and Avicenna.
• Widespread medical use of unprocessed opium
continued through the American Civil War
• before giving way to morphine and its successors,
which could be injected at a precisely controlled
dosage
Morphine
• Morphine was discovered as the first active
alkaloid extracted from the opium poppy plant
in December 1804 in Germany,
• The drug was first marketed to the general
public in 1817 as an analgesic,
• and also as a treatment for opium and alcohol
addiction.
Morphine
• Commercial production began in Germany in
1827
• by the pharmacy that became the
pharmaceutical company Merck,
• with morphine sales being a large part of their
early growth
Opiod recptors
• Opioid receptors are a group of G proteincoupled receptors with opioids as ligands
• The endogenous opioids are dynorphins,
enkephalins, endorphins, endomorphins and
nociceptin
• Opiate receptors are distributed widely in the
brain, and are found in the spinal cord and
digestive tract.
ligand
• In biochemistry and pharmacology, a ligand
(from the Latin ligandum, binding) is a
substance (usually a small molecule), that
forms a complex with a biomolecule to serve a
biological purpose
• Think ligature
• The docking (association) is usually reversible
(dissociation)
neurotransmitter receptors
The mechanism of action of heroin at
the delta (δ) and kappa (κ) opiate
receptors
• Heroin modifies the action of dopamine in the nucleus accumbens
and the ventral tegmental area of the brain – these areas form part
of the brain’s ‘reward pathway’. Once crossing the blood-brain
barrier, heroin is converted to morphine, which acts as a weak
agonist at the delta and kappa opioid receptors subtypes. This
binding inhibits the release of GABA from the nerve terminal,
reducing the inhibitory effect of GABA on dopaminergic neurones.
The increased activation of dopaminergic neurones and the release
of dopamine into the synaptic cleft results in activation of the postsynaptic membrane. Continued activation of the dopaminergic
reward pathway leads to the feelings of euphoria and the ‘high’
associated with heroin use. Morphine is a powerful agonist at the
opioid mu receptor subtype and activation of these receptors has a
strong activating effect on the dopaminergic reward pathway
The mechanism of action of heroin at the mu
(m) opiate receptors
• Heroin modifies the action of dopamine in the nucleus accumbens
and the ventral tegmental area of the brain – these areas form part
of the brain’s ‘reward pathway’. Once crossing the blood-brain
barrier, heroin is converted to morphine, which acts as a powerful
agonist at the mu opioid receptors subtype. This binding inhibits
the release of GABA from the nerve terminal, reducing the
inhibitory effect of GABA on dopaminergic neurones. The increased
activation of dopaminergic neurones and the release of dopamine
into the synaptic results in sustained activation of the post-synaptic
membrane. Continued activation of the dopaminergic reward
pathway leads to the feelings of euphoria and the ‘high’ associated
with heroin use. Morphine is a weak agonist at the opioid kappa
and delta receptor subtypes and activation of these receptors has a
weak activating effect on the dopaminergic reward pathway
Opiod recptors
• Opioid receptors are a group of G proteincoupled receptors with opioids as ligands
• The endogenous opioids are dynorphins,
enkephalins, endorphins, endomorphins and
nociceptin
• Opiate receptors are distributed widely in the
brain, and are found in the spinal cord and
digestive tract.
Opiod recptors
NMDA receptors
• The N-methyl-D-aspartate receptor
• (also known as the NMDA receptor or NMDAR),
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a glutamate receptor, is the predominant
molecular device for controlling synaptic
plasticity and memory function
Common NMDA receptor antagonists
include
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Amantadine[24]
Ketamine
Methoxetamine
Phencyclidine (PCP)
Nitrous oxide (laughing gas)
Dextromethorphan
Memantine
Ethanol
Dual opioid and NMDA receptor
antagonists
• Methadone
• Dextropropoxyphene
• Tramadol
NMDA Receptor Antagonists
• NMDA is a receptor for the excitatory
neurotransmitter glutamate,
• which is released with noxious peripheral
stimuli.7,9
• The activation of NMDA receptors has been
associated with hyperalgesia, neuropathic
pain, and reduced functionality of opioid
receptors.
NMDA Receptor Antagonists
• Hyperalgesia and neuropathic pain are a
result of increased spinal neuron sensitization,
leading to a heightened level of pain
• The reduced function of opioid receptors is
caused by a decrease in the opioid receptor’s
sensitivity
NMDA Receptor Antagonists
• This decreased sensitivity, in turn, translates
to opioid tolerance
• patients will require higher doses of opioids to
achieve the same therapeutic effects.
• Therefore, NMDA antagonists may have a role
in these areas of pain management.
Opioid Pharmacology: How to
choose and how to use
Romayne Gallagher MD, CCFP
Division of Palliative
Providence Health Care
Rules of thumb in chronic pain
• Not all pains are the same
• Not all patients have the same pain sensitivities
• Not all patients have the same pain relief from opioids
• Not all patients have the same side effects of opioids
• Not all opioids are the same
– Mercadante 2001, Pasternak 2001
Opioid Receptors
• Mu, Delta, Kappa
• All pure agonists act at Mu receptor
• Opioid receptors act on
– CNS: cortex, thalamus, periaquaductal gray, spinal
cord
– Peripheral neurons
– Inflammed tissue
– Immune cells
– Respiratory and GI tract
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Hydromorphone
Oxycodone
All animals received same mg/kg dose
Distinguishing Characteristics
• Pharmacokinetics
– Half life
– Metabolism
• Pharmacodynamics
– Potency
– Most have one or two peculiarities
Codeine
• Not an analgesic unless metabolized to
morphine
• Up to 10% of population are poor
metabolizers – little or no analgesia from
codeine
• Rapid metabolizers also may have little
analgesia
• Ceiling dose: 360mg/day
Codeine Pregnancy Warnings
• Codeine has been assigned to pregnancy
category C by the FDA.
• Codeine is the only narcotic analgesic which
has shown a statistically significant association
with teratogenicity
• (involving respiratory tract malformations)
Codeine Breastfeeding Warnings
• Codeine is excreted in human milk in small amounts.
• The FDA issued a Public Health Advisory about a very
rare, but serious, side effect in nursing infants
• whose mothers are taking codeine and are ultra-rapid
metabolizers of codeine.
• Several small series suggest that codeine may be
causative in episodes of apnea, bradycardia, and
cyanosis in the first week of life.
• Codeine is nevertheless considered compatible with
breast-feeding by the American Academy of Pediatrics
Morphine
• “natural opioid”
• Widely available in multiple forms: oral pill
and liquid, pills, parenteral
• Used to be considered “gold standard”
• Hydrophilic
Hydromorphone
• Synthetic “sister” of morphine
• Potency is 5X morphine
• Widely available in multiple forms: oral pill
and liquid, pills, parenteral
• More rapid onset and shorter half life
• ?less histamine release than morphine
• hydrophilic
Codeine, morphine, hydromorphone
metabolism
Glucuronidation
10% of codeine becomes morphine
Morphine and hydromorphone are
both glucuronated to active
metabolites.
Morphine and Hydromorphone
• Metabolized to 3-glucuronide metabolites
– No analgesic properties
– CSF doses often exceed doses of parent compound (rats)
– Cause neuroexcitation
• Smith MT Clin. Exper. Pharmacology Physiology 2000
• 6-glucuronide has analgesic properties
• Hydromorphone usually tolerated (low doses) as has
shorter half-life than morphine?
Opioid Induced Neurotoxicity
• Definition
– Neuroexcitability manifested by agitation, confusion, myoclonus,
hallucinations and rarely seizures
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High opioid doses
Prolonged opioid use
Recent rapid dose escalation
Dehydration
Renal failure
Advanced age
Other psychoactive drugs
*Daeninck PJ, Bruera E. Acta Anaesthesiol Scand. 1999
Management of OIN
• Rehydration
• Treat concurrent causes of delirium e.g. UTI,
pneumonia
• Reduce dose if pain controlled
• Switch to a different opioid
Oxycodone
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Synthetic “cousin” to morphine
Potency is 1.5-2X morphine
Targets mu receptor and kappa receptors
No clinically significant active metabolites
Not available in parenteral form in Canada
Fentanyl
• Targets mu and delta receptors
• 80-100X potency of morphine
• Rapid onset and very short half-life – needs to
be delivered as parenteral infusion or
transdermal patch for constant analgesia
• No active metabolites
• Highly lipophilic – useful in renal dialysis
Notes about the Fentanyl patch
• Takes 12 hours for onset of analgesia
• Need adequate subcutaneous tissue for
absorption
• Takes 24 hours to reach maximum effect
• Change patch every 72 hours
• Dosage change after six days on patch
• Suitable for stable pain only
Tramadol
• Structurally tramadol is not an opiate, but it
exhibits some opioid properties
• Weak opioid – mu receptor agonist
• Also inhibits reuptake of serotonin and
noradrenalin
• Requires metabolism to become analgesic
• Maximal dose 400-600 mg day
• ?? Useful for moderate pain – ISSUES
Tramadol Adverse Reactions
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Seizure risk
Suicide risk
Serotonin syndrome
Anaphylactoid and allergic reaction
Respiratory depression
Withdrawal symptoms
DEMEROL
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Synthetic opioid w multiple drug class effects
Mu narcitic
anticholinergic,
Serintonergic
• Norpethidine- -- toxic metabolite
Demerol side effects
• Seizures
• Serotonin syndrome
• Usual narco stuff
Libby Zion
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Admitted to NYC hosp
On MAOI
Called hysterical
Given Demerol
Died
MAOI reaction vs. serotonin syndrome
Buprenorphine
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Partial agonist of mu receptor
Requires metabolism to become analgesic
Slow onset, highly bound to receptor
Ceiling effect – consider as a weak opioid
Comes in patch that lasts 7 days
Useful for moderate pain ??
What opioid to choose?
• Age – renal clearance is lower, higher fat to
muscle ratio
• Renal Function
• What have they tried before and what was
their experience?
Opioids of choice
in frail elderly and renal failure
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Hydromorphone
Oxycodone
Fentanyl
Methadone
What route to use?
• GI tract and level of consciousness
• How rapidly you need to get pain under
control
• Cmax
– po ~ 1 hour
– sc ~ 30 minutes
– IV ~ 5-10 minutes
• This indicates how frequently you can give
breakthrough doses
Respiratory Depression
• In those who do not have pain or respiratory
symptoms it is an ongoing risk
• For those who are opioid naïve and receive
more drug than needed for pain it is a risk – i.e.
post operative
• Not an issue when opioids used appropriately
to treat pain and dyspnea even in patients with
cardiopulmonary disease
Respiratory Depression
• Best measure is
• the rise in peripheral pCO2
• and peripheral Po2 monitor
Morphine for dyspnea
• Study of patients with moderate to severe
dyspnea due to advanced cancer, ALS
• Patients administered short acting opioid for
dyspnea and parameters measured before, 30,
60, 90, 120 mins after opioid
Respiratory Depression
• Visual analogue scale shows significant reduction in
dyspnea p<.001
• Significant reduction in respiratory rate p<.002
• No significant rise in pCO2 or fall in pO2 during any
measurement p = 0.203 to p= 0.686
• Opioids work through reduction of respiratory rate
and workload
• Clemens et al J. Palliative Medicine 2008
Opioid Side Effects
• Nausea
– Metoclopramide 10mg qid
– If doesn’t resolve in a week switch opioid
• Itch
– Histamine release – not allergy
– Antihistamine until it subsides
Constipation
• Interindividual variation
• Need osmotic laxative or stimulant
• Some evidence that fentanyl patch may result
in less constipation
• PEG 3350 (Laxaday) – RCT: more effective,
better tolerated than lactulose
• No evidence to support use of docusate
Principles of opioid rotation
• Calculate the equianalgesic dose
• Reduce the dose of the new opioid by 25-50%
- potential greater sensitivity to new opioid
• Prescribe new opioid with adequate
breakthrough dose
• Reassess and titrate to target dose
Equianalgesic conversion
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Morphine
Tylenol #3
Codeine
Hydromorphone
Oxycodone
Methadone
» variable ratio
10mg
2 tablets
60mg
2mg
5-7.5mg
1mg (not q4hr)
Fentanyl patch
• Equi dosing – Canada
Fentanyl patch
• Equi dosing – Germany
OD’s
• Surrey RCMP issued a similar warning on July
15 after eight suspected heroin overdoses
were reported in a single day,
• likely due to drugs laced with fentanyl
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methylfentanyl
Methylfentanyl
• Following α-methylfentanyl on the market, ten
new analogs of fentanyl have been reported,
• para-fluorofentanyl,
• α-methylacetylfentanyl,
• 3-methylfentanyl,
• β-hydroxyfentanyl,
• ohmefentanyl,
• β-hydroxythiofentanyl
• β-hydroxy-4-methylfentanyl
Breakthrough Dose Guidelines
1. For each breakthrough dose, offer 5% to 15% of the 24-hour dose.
2. Codeine, hydrocodone, morphine, oxycodone, and hydromorphone
all behave similarly.
--therefore, an extra breakthrough dose can be offered:
--ONCE EVERY 1 HOUR if administered ORALLY,
or possibly less frequently for frail patients,
-- EVERY 30 MINUTES if administered -SC or IM
-- EVERY 10 TO 15 MINUTES if administered IV
Longer intervals between breakthrough doses only prolong a patient’s
pain unnecessarily.
Incident pain
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Sufentanil – Fentanyl
both absorbed thru buccal mucosa
Fentanyl – intranasal admin
Both onset 5-10 min
Peak 15- 30 min
Duration 30-40 min
Sufent 5-10 x more potent vs fent
Methadone
• AUTHORIZATION TO PRESCRIBE METHADONE
• “Full Authorization”
– Actually not full – Rx for analgesic purposes
– Not authorized for Rx for opioid dependency
• Temporary Authorization
• Hospitalist Authorization
Patient assesment
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Full hx
med/ surg/ psych / family
Px
Lab / imaging
Methadone •
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Beware –
Elderly
liver disease
Opiod naïve
Drug interactions
QT’s
Methadone
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Methadone is highly lipophilic
rapid absorption in the upper GI tract
onset of action within approx 30 min.
Half life – primary distribution ~14 hrs (+/-6)
Secondary elimination 54 -+/- 28 hrs.
Half up to 190hrs in some
Methadone
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It has a large initial volume of distribution
followed by slow tissue release
Steady state takes 2-10 days
Analgesic half life = 8-12 hrs
• Occ 6 hrs or longer than 12
Methadone
• Has a high bioavailability of around 80%
• Methadone has no active metabolites
• Biotransformation is not required for analgesic
effect.
Methadone
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Although available for many years,
it has gained renewed interest
due to its low cost
and particular activity in neuropathic pain
syndromes.
Methadone
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Methadone is unique
3 mechanisms of action
Opioid receptors, mu, kappa,delta
NMDA receptor antagonist
SNRI – Monoamines- RI
Methadone
• is available as methadone Hcl in Canada,
• a racemic mix of the l+d -isomers
• I+d Methadone isomers are different in
potentency @ mu (μ) opioid receptor agonist
and NMDA receptor antagonist..
Methadone
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The NMDA mechanism is thought to
play an important role
in the prevention of opioid tolerance,
potentiation of analgesic effects
and possibly efficacy for neuropathic pain
syndromes.
Methadone
• Metabolized by p450 cytochrome enzymes
• P450 system has 12 families
• Each family has up to 30 subtypes
• Mainly—CYP3A4 and,
• to a lesser extent, 1A2 and 2D6.
cytochrome P450 / Methadone
• cytochrome P450 (CYP) system — CYP3A4
• Patients have a 30 fold variability in activity
of this enzyme
Methadone
• Drugs which interact with methadone
generally involve inducers or inhibitors of the
• cytochrome P450 (CYP) system —
• mainly CYP3A4 and,
• to a lesser extent, 1A2 and 2D6.
Inducers of P450 3A4
• These drugs will reduce methadone levels —
for example,
• rifampin/rifampicin,
• phenytoin (Dilantin),
• phenobarbital,
• carbamazepine (Tegretol).
Inhibitors of P450 3A4
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These drugs will raise methadone levels
— for example,
ketoconazole, fluconazole,
fluvoxamine (Luvox), fluoxetine (Prozac),
cimetidine,
Ciprofloxacin
• careful observation is required
• the methadone dose may need to be reduced.
Substrates
• These drugs compete for metabolism with
methadone — for example
• imipramine - nortriptyline -alprazolam
• They may or may not also inhibit
• or induce the enzyme,
QT
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It is recommended that patients who have
cardiac disease,
other medications
or metabolic concerns known to cause QT
interval prolongation
• should have an ECG prior to starting on
methadone
Mind your QT;s
Mind your manners
• Please and thanQ
QT
• A list of drugs associated with QT interval
prolongation can be found …………
• Williscroft knows the list by heart
DRUGS that prolong QT
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MOST OF THE ANTI NAUSEANTS
Gravol
Ondansetron
Haldol
• Maxeran
• ? Dexamethasone
Dex – QT - Summary Statistics
• Reports of DEXAMETHASONE to FDA
• causing LONG QT SYNDROME: 6
• Reports of any side effect of DEX : 40801
• Percentage of DEXAMETHASONE patients
where LONG QT SYNDROME is a reported side
effect: 0.0147%
SWITCHING OPIOIDS
• opioids differ in their effects on receptors
• individuals vary in their ability to metabolize
the different drugs
• Often - differences are genetically based.
• At present, it is not possible to determine
which opioid will best suit an individual
---- other than by trial and error.
SWITCHING OPIOIDS
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An opioid may be most effective for one pain
and another for a different pain.
When initiating a trial of opioid therapy,
it is important to be prepared to try more than
one opioid.
SWITCHING OPIOIDS
• and get comfortable switching from one
opioid to another
• until satisfactory analgesia is achieved
• or the trial is abandoned
Indications for Switching Opioids
• 1. Inadequate pain control with dose‐limiting
side effects
• 2. Confusion, hallucinations or delirium
• 3. Non‐compliance
• 4. Problems with the route of administration
• 5. Cost
1 -Inadequate pain control with dose‐limiting
side effects
• This may occur especially with neuropathic
pain.
• Consider adjuvant analgesics
• and other treatments.
2. Confusion, hallucinations or delirium
• Although these are often attributable to
opioid toxicity,
• there are many potential causes for delirium
in patients
• Esp. with advanced cancer
• A clinical assessment and investigation
----- is imperative
METHODS FOR SWITCHING TO
METHADONE
• “Start Low, Go Slow”
• 1/3 Slow‐Switch Method:
33 % Steps at Three‐Day Intervals
• Rapid‐Switch Method
Start Low, Go Slow”
• This method is appropriate for patients who
are extremely intolerant of other opioids
• or are at high risk for adverse effects
--( previous anaphylaxis to morphine)
-- (or COPD patients with a CO2 retention)
• It is also the preferred method for
opioid‐naive patients.
Start Low, Go Slow”
• Start methadone at 1 mg every 8 hours.
• If delayed metabolite elimination
- such as with elderly patients
- those with impaired liver function)
- extreme sensitivity to opioids,
• even lower doses such as 0.5 mg q12h
Start Low, Go Slow”
• Increase the dose by 1 mg every 3 days
- until either satisfactory analgesia
- or the development of side effects.
• If more than 10 mg per dose is required
--increase by 2 mg increments.
• If more than 20 mg is required,
--increase the dose by 5 mg increments,
• but no more frequently than every 3 days
- allow the methadone level to stabilize.
Slow‐Switch Method: 33 Per Cent Steps at
Three‐Day Intervals
• This method is suitable for patients who may
benefit from switching to methadone,
• but do not urgently need to switch opioids
and are outpatients.
• A short‐acting form of the previous opioid
should be available for breakthrough pain or
for rescue dosing
Slow‐Switch Method: 33 Per Cent
Steps at Three‐Day Intervals
• To calculate the starting dose of methadone,
• use table to determine the patient’s current
oral morphine equivalent dose per 24 hours.
• Divide this number by the ratio appropriate
for that dose range
• Divide the total daily dose by 3 to give the q8h
dose.
Conversion table from morphine to methadone
(most commonly used in the USA
• 24 hour total dose of oral morphine Conversion ratio
(oral morphine: oral methadone)
• <30mg
2:1 (2mg morphine to 1mg methadone)
• 31-99mg
4:1
• 100-299mg
8:1
• 300-499mg
12:1
• 500-999mg
15:1
• 1000-1200mg
20:1
• >1200mg Consider consult with palliative care or pain
specialist
Slow‐Switch Method: 33 Per Cent
Steps at Three‐Day Intervals
• 120 mg morph/24 hrs, a 5:1 conversion ratio
→ 24 mg methadone/24 hours
= 8 mg methadone/8 hours
• 600 mg morph/24 hrs, a 10:1 conversion ratio
→ 60 mg methadone/24 hours
= 20 mg methadone/8 hours
3 day inc 1/3 -- 1/3
• Day 1 Calculate the starting dose of methadone
- but give only a third of that dose
-reducing the dose of previous opioid by a third.
• Day 4 Increase the methadone dose to two thirds
reduce the prev. opioid to a third prev. dose
• Day 7 Increase the methadone to the full dose
-and discontinue previous opioid.
Slow‐Switch Method: 33 Per Cent
Steps at Three‐Day Intervals
• Day 10 onward -- Adjust the dose of
methadone by increments of ~ 20 %
-every 3 to 5 days
- until an optimal balance
- between analgesia and side effects.
Slow‐Switch Method: 33 Per Cent
Steps at Three‐Day Intervals
• Methadone dosage should not be increased to
control short‐lived pain episodes
---- Incident pain
• Use a short acting opioid for these episodes
Rapid‐Switch Method
• This method is appropriate only for patients
with severe side effects from previous opioids
and uncontrolled pain.
• Stable dosing may be achieved in 3 to 5 days.
• Inpatient supervision is recommended.
Rapid‐Switch Method
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Calculate the methadone starting dose
Divide daily dose by 3- give the q8h methadone
Halve the dose of the previous opioid
And convert it to q4h short‐acting prep.
Give this with methadone for the first 24 hours.
Rapid‐Switch Method
• If switching from fentanyl patches,
-use the equianalgesic dose short‐acting morph
oxy or HM -instead of that for fentanyl.
• minimize the possibility of overdosage,
• the fentanyl level may not decrease for 18 hrs
after the patch is removed.
Rapid‐Switch Method -Example:
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300 mg L/A morphine BID
= 100 mg morphine every 4 hours
DIVIDE BY 2
50 mg i/r morphine/4 hours regularly
• Also methadone 20 mg every 8 hours
• Plus PRN b/t
Rapid‐Switch Method
• short‐acting opioid for breakthrough
• The usual b/t dose is the same as the q4h dose
• allow for more frequent dosing if necessary.
• e.g. - the b/t dose would be 50 mg q1h PRN.
Rapid‐Switch Method -Day 2
Reassess
• Prn -increase the dose of methadone
by 20 to 25 %
• Watch for side effects.
• If poss., wait before increasing the methadone
• Change the oral short acting to prn only
Rapid‐Switch Method -Day 3 reassess
• Assess and adjust methadone accordingly.
• Accumulation of methadone is most likely to
occur at this time.
• If the patient is excessively sedated,
-decrease the dose of methadone
• If pain control is inadequate and a short‐acting
opioid is still required,
• increase methadone by 20 to 25 per cent.
• If in doubt, wait another day.
Rapid‐Switch Method
• Thereafter,
• assess daily until stable analgesia is achieved,
• usually after 4 to 5 days.
Constipation
• All pts. W opioid Rx
• Need a bowel protocol
• He who neglects to prescribe this
- does the manual dis-impaction
Key findings Intranasal ketamine
Intranasal ketamine
• at dose of about 1 mg/kg
• was moderately effective
in providing pain relief as
a single agent
• to adult patients
• presenting to the ED
• With severe pain from
various presenting
complaints.
• Patients who did not
respond to initial dosing
of intranasal ketamine
• did not gain any
additional benefit from
an additional dose
Intranasal ketamine
• When using intranasal K as
an analgesic agent,
• other agents, such as
opioids,
• should be added in
patients who do not
respond to initial ketamine
dosing.
• Further research
regarding the role of
intranasal ketamine as
an analgesic in the ED
would be useful.
• Particularly, its role in
analgesic regimens with
opiod regimes
bs_bs_banner
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Emergency Medicine Australasia
(2014) ••, ••–•• doi:
10.1111/1742-6723.12173
© 2014
Intranasal Ketamine for Analgesia
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ORIGINAL RESEARCH CONTRIBUTION
Intranasal Ketamine for Analgesia in the
Emergency Department: A Prospective
Observational Series
Gary Andolfatto, MD, Elaine Willman, MD, Daniel Joo, MD, Philip
Miller, MD, Wai-Ben Wong, MD,
Martha Koehn, MD, Raea Dobson, Eric Angus, MD, and Susanne
Moadebi, PharmD
From the Department of Emergency Medicine (GA, DJ, PM, WW,
MK, EA), the Department of Pathology (EW), and the Department
of Pharmaceutical Sciences (RD, SM), University of British Columbia;
and the Lions Gate Hospital Emergency Department
(GA, DJ, PM, WW, MK, EA, SM), North Vancouver, BC, Canada.
The Ketamine Brain Continuum
• December 25th, 2013
• by reuben in PSA & analgesia
Ketamine -- NMDA antagonism
• In high doses, NMDA antagonism leads to
dissociation,
• a cataplectic state
• where the patient maintains airway reflexes
and cardiorespiratory function
• but cannot perceive any external stimuli nor
interact with the world in any way
Ketamine Analgesic dose
• Analgesic dose (0.1-0.3 mg/kg) ketamine has
minimal effect on perception or emotion but is
a powerful analgesic
• use analgesic dose ketamine as a second line
agent when opiates aren’t working or are
poorly tolerated,
• Or in cases when I don’t want to use opiates,
for example the patient with concerning
hypotension
ketamine
• In a normal sized adult, a 10 mg bolus will
usually have minimal psychiatric effect but
• may not have an adequate analgesic effect;
• a 20 mg bolus will usually produce terrific
analgesia
• but many patients will slide into recreational
dose and get loopy
ketamine Recreational dose
• Recreational dose (0.2-0.5 mg/kg) ketamine will deliver
excellent analgesia but also make your patient high.
• Pts. will have distortions of perception that most will like
• others will dislike,
• but at recreational dose, patients know what’s going on,
they know where they are, they know who they are.
• Patients can converse with you and follow commands, but
they are hallucinating and stoned.
• A few patients will require intervention for psychiatric
discomfort
• and many will be disappointed that the effect is wearing
off.
• An agitated patient will often become sedated in this range,
but the effect on level of arousal is variable.
ketamine Partially dissociated
• Partially dissociated dose (0.4-0.8 mg/kg)
• patients have some awareness and can make some
purposeful actions but not enough to allow patients
to be connected to the outside world, their bodies,
or reality.
• Many will be unable see or hear, talk or move;
these capabilities may fade in and out.
• Although most will tolerate this well, some will find
it terrifying–partially dissociated is where you want
your patients not to be.
Dissociative dose (>0.7 mg/kg)
ketamine
• Dissociative dose (>0.7 mg/kg) ketamine renders the patient isolated
from all external stimuli,
• which is the desired state in most cases where ketamine is used to
facilitate a procedure or endotracheal intubation.
• A dissociated patient perceives no sights, sounds or pain and cannot
interact.
• Though nystagmus, random and reflexive movements are common,
• dissociated patients are incapable of volitional action.
• Unlike conventional sedatives, the brain is on and patients area wake,
• cardiorespiratory function is preserved or stimulated,
• but the dissociated brain is unaware and does not build memories;
• patients generally do not recall this period.
• Dissociated is awake but unconscious.
The four stages
• The four stages of the ketamine brain continuum have
overlapping dose ranges that are highly variable among
patients.
• At small analgesic dose (<0.1 mg/kg) or large dissociative
dose (>2 mg/kg), effects are consistent;
• anything in between is unpredictable.
• A feature of ketamine’s dose-response that accounts for its
remarkable margin of safety is the dissociation threshold,
• above which higher doses do not produce any further effect:
• a dissociated patient does not become more dissociated
with more ketamine,
• higher doses only prolong duration of action.
Managing psychiatric distress
• Managing psychiatric distress caused by ketamine is straightforward
and much less dangerous than managing the cardiorespiratory
adverse events seen routinely with conventional sedatives.
• If the patient develops distress shortly after an initial dose,
• the patient is not fully dissociated and the best maneuver is usually to
give more ketamine.
• More commonly, the patient develops distress on emergence, after
the procedure is over;
• the mind is activated but disconnected.
• You can’t reconnect the mind,
• but you can deactivate the mind with a sedative such as midazolam
or propofol while it metabolizes through partial dissociation
Morphine and Ketamine Is Superior to
Morphine Alone
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Morphine and Ketamine Is Superior to Morphine Alone
for Out-of-Hospital Trauma Analgesia: A Randomized
Controlled Trial
Paul A. Jennings, PhD, BN, MClinEpi, Peter Cameron, MD,
MBBS, Stephen Bernard, MD, MBBS,
Tony Walker, ASM, MEd, BParamedStud, Damien Jolley,
MSc(Epidemiology), MSc, Mark Fitzgerald, MBBS, FACEM,
Kevin Masci, GradDipBus, ADipMICAStud
From Ambulance Victoria, Melbourne, Victoria, Australia
(Jennings, Bernard, Walker, Fitzgerald, Masci); Monash
University, Department of Epidemiology and
Preventive Medicine, Melbourne, Victoria, Australia
(Jennings, Cameron, Bernard, Jolley);
analgesic effects of ketamine
• Correspondence
• American Journal of Emergency Medicine
• journal homepage:
www.elsevier.com/locate/ajem
• Evaluation of analgesic effects of ketamine
through sub-dissociative dosing in the ED
Sum
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All pts are different
Know various opioids
Know equivalents
-be aware of conversion tables
Side effects
Drug interactions
Methadone
Ketamine
Adjuncts -- pharmacological and non pharm