Palliative care + PAIN And the Emergency Physician

Dr. Mike O’Neil, MD, CCFP(EM ), FCFP Clinical Asst. Prof. DEM , UBC

LGH EMERGENCYHospitalist, Pall care

What ?

Palliative care • Aren’t they opposites • NO

Emergency Medicine • ? Oxymoron • NOT

Palliative Care patients

• 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 ?

• Pain • Severe pain• Excruciating pain • Severe excruciating pain on a bucket of meds• Adjuvants • Procedures• Anesthesia

• Narcs • Equivalents• Routes of admin • Toxicities• Side effects

• Infusions, ketamine- midazolam

Medical conditions in PCU ?

• Delerium • Depression • Anger• Denial • Confusion

• Seizures• Myoclonus• TIA’s • CVA’s• Spinal cord compression

acutesubacute chronic

Medical conditions in PCU ?

• Febrile neutropenia • Sepsis • Pneumonia • Cellulitis • UTI’s • SBP• Menigiits •

• Nausea • Vomintg • Diarrhea• Constipation • Dysphagia• hiccups• Anorexia • Tube feeds

Medical conditions in PCU ?

• Pleural effusions• Recurrent pl effusion • Ascites • Paracentesis• Edema • Anasarca

• CHF• ASTHMA • COPD• ACS• PE• Arrhythmias

Medical conditions in PCU ?

• IDDM • NIDDM• Hypo- hyper glycemia• Hypo – hyper K+• Hypo- hyper Na+• Hypo- hyper Ca++ • Hypo-hyper Mag++

• Clotting abn • Epistaxis • Hemoptysis • Exsanguinating bleeds

• Falls • #’s- path #’s • Lacrtns

Medical conditions in PCU ?

• Bowel obstruciton • Ischemic bowel• Perf viscus• Urine retention • incontinence

• Family issues• Social issues• Psych issues • Religious issues• Cultural issues• Grief • Bereavement

Dealing with all this?

• 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

• 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

• 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

• Quick review • May be all intuitive to some • Establish terminology seen in literature • Will elaborate on particular points

Classification

• 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 InhibitorIngredient Amo

unt% Daily

Value**

Proprietary Blend with Explotab Technology

600mg

-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

Examples of nonprescription pain medications

• Acetaminophen (Tylenol)• Aspirin• Ibuprofen (Advil, Motrin IB)• Naproxen (Aleve

Nonsteroidal anti-inflammatory drugs (NSAIDs) Rx

• 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)

• Cox-2 Inhibitor• Celecoxib (Celebrex)• Meloxicam (Mobic)

• Rofecoxib (Vioxx) – gone

Opioid Analgesics

• 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

• Amitriptyline (Elavil)• Bupropion (Wellbutrin)• Desipramine (Norpramin)• Duloxetine (Cymbalta)• Imipramine (Tofranil)• Venlafaxine (Effexor

Anticonvulsants

• Carbamazepine (Tegretol)• Clonazepam (Klonopin)• Gabapentin (Neurontin)• Lamotrigine (Lamictal)• Pregabalin (Lyrica)• Tiagabine (Gabitril)• Topiramate (Topamax

Anxiolytics

• Alprazolam (Xanax)• Diazepam (Valium)• Lorazepam (Ativan)• Triazolam (Halcion

Muscle Relaxants

• Baclofen (Lioresal)• Carisoprodol (Soma)• Chlorzoxazone (Parafon Forte, DSC)• Cyclobenzaprine (Flexeril)• Dantrolene (Dantrium)• Metaxalone (Skelaxin)• Methocarbamol (Robaxin)• Orphenadrine (Norflex)• Tizanidine (Zanaflex

Corticosteroids

• 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

• 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 protein-coupled 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 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 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 protein-coupled 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),

• a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function

Common NMDA receptor antagonists include

• 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, CCFPDivision 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

Oxycodone

• Hydromorphone

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

• Predisposing Factors:– 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

• 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

• Seizure risk• Suicide risk• Serotonin syndrome • Anaphylactoid and allergic reaction• Respiratory depression• Withdrawal symptoms

DEMEROL

• 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

• Admitted to NYC hosp • On MAOI • Called hysterical • Given Demerol • Died • MAOI reaction vs. serotonin syndrome

Buprenorphine

• 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

• 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

• Morphine 10mg• Tylenol #3 2 tablets• Codeine 60mg• Hydromorphone 2mg• Oxycodone 5-7.5mg• Methadone 1mg (not q4hr)

» variable ratio

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

• ---• 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

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’spain unnecessarily.

Breakthrough Dose Guidelines

Incident pain

• 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

• Full hx • med/ surg/ psych / family • Px • Lab / imaging

Methadone -

• Beware –• Elderly • liver disease• Opiod naïve • Drug interactions • QT’s

Methadone

• 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

• 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

• Although available for many years,• it has gained renewed interest • due to its low cost • and particular activity in neuropathic pain

syndromes.

Methadone

• 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

• 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

• 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

• 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

• 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

• 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 TOMETHADONE

• “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‐

• 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:

• 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

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• Emergency Medicine Australasia (2014) ••, ••–•• doi: 10.1111/1742-6723.12173

• © 2014

Intranasal Ketamine for Analgesia• 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

• 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

• 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