Schedule 2 Education for APN Prescriptive...

OAAPN and FPB 10/25/2012

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Chris Winkelman, RN, PhD Associate Professor

Schedule 2 Education for APN Prescriptive Authority

Opioids

Conflict of InterestPersonal financial and relevant relationshipsI have received research funding from • NIH R21NR01078 PI: Chris Winkelman• NIH R01NR011186 PI: P. Morris • Clinical Research Units: MetroHealth GCRC M01RR00080 and University Hospitals Case Medical

Center Dahms CRU M01RR00080-2• American Association of Critical-Care Nurses• Hill-Rom• Ohio Nurses Foundation• Clinical Translation Center (University Hospitals)• Frances Payne Bolton School of Nursing• Sigma Theta Tau, Alpha Mu Chapter

I have received compensation from Elsevier for authoring chapters in Medical-Surgical Nursing: Critical Thinking for Collaborative Care (5-7th editions, 2006, 2009, 2012.). Ignatavicius DD & Workman ML (Eds.). Philadelphia: Saunders and Clinical Companion to Medical-Surgical Nursing: Critical Thinking for Collaborative Practice (7th ed.).

I am a full-time employee at Case Western Reserve and a part-time employee at MetroHealth Medical Center.

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Objectives and OverviewA) Describe pharmacodynamics, pharmacokinetics & indications of a broad spectrum of Schedule 2 controlled substances

1. Opioids2. Stimulants3. Depressants/Sedatives

B) Apply treatment guidelines for pain management, sedation, and hyperactivity disorders as they relate to safe prescribing and management of schedule II controlled substances

1. Pain Management2. Hyperactivity Management3. Depressant Sedative Use4. Indications and monitoring effectiveness

I will not be advocating off label use of drugs although this topic will occur.

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Objectives and Overview con’tC) Integrate fiscal and ethical implications of prescribing schedule 2 controlled substances to the pharmacotherapeutic decision making process

1. Costs of undertreated pain2. Costs of addiction and inappropriate prescribing3. Application of Ethical Principles related to prescribing and practice

D) Describe methods to prevent abuse and diversion of schedule 2 controlled substances

1. REMS: Risk Evaluation and Mitigation Strategy2. Surveillance with OARRS: Ohio Automatic RX Reporting System3. Types of assistance available for abuse and diversion4. Inappropriate Prescribing

I will not be advocating off label use of drugs although this topic will occur.

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OPIOID ANALGESICS AND ANTAGONISTS

Opiates: “natural,“ derived from opium/poppyExamples: morphine and codeine

Opioids: natural, semi‐synthetic, and synthetic derivativesExamples: semisynthetics are heroin, oxycodone, buprenorphine

fully synthetic is methadone (i.e., chemical structure is unrelated to opium)

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Opioid Analgesics • Opioid peptides released from nerve endings modulate transmission in the peripheral sensory (afferent) neurons, the spinal cord and the brain via their interactions with specific receptors.– Many pharmacologic actions of opioids are a result of interactions with endogenous opioid peptide receptors

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Acute Versus Chronic PainSimilarities

– Inflammation and sympathetic nervous system activity enhance sensitivity of pain receptors

– Transmission of sensation contributes to pain experience

– Perception of pain occurs in the brain• Influenced by modality (what receptors are activated), sensory transmission (how neurons communicate), genetic variation in pain perception, learned and inherited pain behaviors, potential for repeated noxious stimuli, psychosocial factors, context, and more!

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Aα and Aβ Aδ “nociceptors” C “nociceptors”

Large diameterMyelinated

Small diameterMyelinated

Small diameterUnmyelinated

Transmits position & light touch

Transmits sharp pain

Transmits temperature, itch & dull pain

Acute versus Chronic PainDifferencesAcute Pain

• Tissue injury, infection, &/or inflammation

• Often associated with activation of the sympathetic nervous system– Associated

symptoms: tachycardia, sweating

Chronic pain• Lasts > 3 months

– Despite treatment– Does not include pain associated with terminal,

progressive condition• May be present long after apparent healing of

tissue or resolution of acute pain source– Long‐term excessive input from C fibers can

promote excitatory mechanisms, increased sensitivity to pain stimuli, conversion of innocuous stimuli to nociceptive, and enhance nociceptive transmission. SNS not involved.

– Alterations in brain circuitry can change pain perception

• May occur despite a lack of casual evidence– For example, neuropathic pain can be the result of

ordinarily innocuous stimuli

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Pain Transmission

http://www.youtube.com/watch?v=6tLqh1qYvV4

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Classes of OpioidsVariable ways to categorize based on…• Major therapeutic use

– Analgesic, antitussive, and antidiarrheal• Relative strength/ability to relieve pain

– Strong, moderate, weak, and partial agonist• Ratio of Agonist to Antagonist effects

– Agonist, (full or partial), antagonists, or mixed agonist‐antagonist

• Chemical structure– Phenathrenes, benzomorphan, phenylpipiridines, diphenylheptanes

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Classes of OpioidsVariable ways to categorize based on…• Major therapeutic use

– Analgesic, antitussive, and antidiarrheal• Relative strength/ability to relieve pain

– Strong, moderate, weak, partial agonist/mixed agonist‐antagonist

• Ratio of Agonist to Antagonist effects– Agonist, (full or partial), antagonists, or mixed agonist‐antagonist

• Chemical structure– Phenathrenes, benzomorphan, phenylpipiridines, diphenylheptanes

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Strong Opioids• Phenanthremes

– Morphine, hydromorphone, oxymorphone• Phenylheptylamine

– Methdaone• Phenylpiperidines

– Fentanyl• Sufentianil, alfentanil, remifentamil

– Meperidine

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Pharmacokinetics

Absorption• Most opioids are well‐absorbed

– First pass effects reduce the bioavailability of many oral opioids

• So the oral dose of morphine, hydromorphone, oxymorphone, & fentanyl is much higher than the parenteral dose

• Codeine and oxycodone have reduced first pass effects– So oral, parenteral doses are similar

• Nasal insufflation, oral mucosa absorption via lozenges, and transdermal application avoid first pass metabolism

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PharmacokineticsDistribution

– The uptake of opioids by organs and tissues is affected by both physiologic and chemical factors

• Opioids rapidly leave the blood compartment • Opioids localize in highest concentrations in highly perfused tissues: brain, lungs, liver, kidneys, and spleen

– Muscles can serve as a reservoir but with relatively low perfusion, not a problem acutely. Can be problematic in chronic care , especially during periods of metabolism.

– Frequent, high dose administration or continuous infusions can allow opioids to accumulate in fatty tissue (especially fentanyl, highly lipophilic)

– Distribution is WIDE• Cross placenta, into breast milk.

– APNs cannot prescribe opioids for pregnant women10/25/2012 14

PharmacokineticsMetabolism

Opioids are broken down in the liver• Accumulation of active metabolites can occur in the presence of renal failure or with exceptionally high doses

– Morphine, meperidine metabolites can cause seizures, CNS effects– Codeine, oxycodone, and hydrocodone are metabolized by CYP2D6 resulting in metabolites of greater potency than the original formulation

» Genetic variation in CYP2D6 enzymes yields both ultra rapid and poor metabolizers

• Fentanyl has the most predictable kinetics – Fentanyl is converted to inactive metabolites—the only opioid with this characteristic!

• Methadone has particularly unpredictable kinetics

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Pharmacokinetics

Excretion– Polar metabolites are excreted mainly in the urine

• Small amounts of unchanged drug may also be excreted• Some bile excretion (small amounts of conjugated morphine)

– Metabolites, even if marginally active, accumulate in kidney injury and failure

• For example, morphine‐6‐gluronide doesn’t typically cross the blood brain barrier. But when it accumulates during kidney failure, it prolongs morphine sedation.

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Pharmacodynamics• Opioids bind to receptors• Opioid receptors are found in the CNS (i.e., cortex,

thalamus, brainstem [periaquaductal gray matter], and dorsal horn of spinal cord), in visceral and smooth vascular muscle, in musculoskeletal structures, and at the terminals of the peripheral sympathetic and sensory neurons.– Opioids modulate pain by blocking neuroexcitatory transmitters at these multiple sites and by decreasing neurotransmission/activity along the pain pathway.

10/25/2012 17Kappa receptor in poppy nih.gov

Opioid PharmacodynamicsReceptors

Activation of receptors inhibitssynaptic processes

• Opens K+ channels to cause membrane hyperpolarization post‐synapse neurons

• Close calcium ion channels to inhibit neurotransmitter release in pre‐synapse neurons

– Presynaptic actions result in inhibiting release of multiple neurotransmitters: acetylcholine, norepinephrine, serotonin, glutamate, and substance P.

Block Ca ++

Pain signal

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Opioid Pharmacodynamics

• μ– Also hyperpolarize second‐order

pain transmission by altering K+ conductance, evoking an inhibitory postsynaptic potential

– Endorphins have highest binding here

– μ‐ 1 receptors are responsible for supraspinal analgesia

– μ‐2 receptors are responsible for respiratory depression, bradycardia, and physical dependence.

• δ– Receptors in CNS only– Enkephalins have highest binding here– Delta receptors produce analgesia,

mood alterations, and emesis

• Κ– Receptors in CNS only– Dynorphins have highest binding here– Kappa receptors contribute to spinal

analgesia• ORL‐1

– Nociphen binds here– Central modulation of pain

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Receptors– All reduce excitatory transmitter release from presynaptic terminal of nociceptive

neurons– All are activated by endogenous peptides made in the soma of neurons, the

adrenal medulla, and neural plexus of the gut.

Generic Adverse Drug Effects for Opioids• Sedation: drowsiness and clouding of

mentation– Advise about driving and machine operation restrictions– Consider this when using additive agents (sedatives,

other sedating CNS agents)• Respiratory Depression

– Greatest risk in opioid naïve, so start with low dose• Most problematic with individuals with intracranial

hypertension, asthma, chronic obstructive pulmonary disease,, heart failure may suffer with hypercarbia

– Can be overcome with environmental stimuli• Cough Suppression

– May allow accumulations and thus lead to airway obstruction

• Bradycardia, Hypotension– Some opioids contribute to histamine release,

vasodilation, low SBP– Exception: meperidine’s antimuscarinic effect is

tachycardia– PURITIS: Histamine release also results in sweating and

itching• Endocrine

– Opioids stimulate the release of vasopressin, prolactin, and somatotropin and inhibit release of luteinizing hormone.

• Temperature– Regulation of body temperature is regulated by

endogenous opioids.– Mu agonist can produce hyperthermia– Kappa agonists can induce hypothermia

• Antidiruresis– Combined sodium reabsorption and decreased renal

blood flow– Increase sphincter tone can result in urinary/bladder

retention• Nausea and vomiting: activation of brainstem

chemoreceptor trigger zone.– May also be a vestibular component because walking

appears to increase Nausea and vomiting– Anti‐nausea drugs work well

• Constipation– Actions on the mu receptors in the GI tract result in

decreased motility and acid secretion but persistent increased tone

• The increase in smooth muscle tone can contribute to biliary colic

• Convulsions– Typically attributed to accumulation of metabolites,

so more problematic with impaired liver function and chronic use

• Immune effects– Chronic administration interfere with lymphocyte

proliferation, antibody production, and chemotaxis• Miosis

– Pupil constriction can contribute to visual disturbances and this effect does not alter even in highly tolerant addicts

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Katzung et al. 2012 Basic and Clinical Pharmacology. McGraw Hill

Adverse Drug Effects for Opioids con’t

• Drug‐drug interactions– Additive CNS depression with alcohol, sedative‐hypnotics, anesthetics,

antipsychotic drugs, tricyclic antidepressants, and antihistamines– Meperidine + monoamine oxidase inhibitors leads to higher incidence of

hyperpyrexic coma– Meperidine + serotonin reuptake inhibitors is associated with serotonin

syndrome

• Overdose– Triad of miosis, coma, and respiratory depression

• Respiratory depression leads to most fatalities• Diagnosis confirmed with IV injection of antagonist, naloxone.• Treatment: naloxone and support (Basic/Advanced life support)

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Specific Adverse Drug Effects con’t

• Truncal rigidity: an intensification of tone in large trunk muscles (spinal cord receptors)– fentanyl, sufentanil, alfentanil, remifentanil

• Illegal/Abuse events– Oxymorphone ER (Opana) is linked to thrombocytopenia puerpera (TTP; potentially fatal coagulopathy) when injected intravenously

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Rx for overdose: Opioid Antagonist(s)naloxone (IV)

nalmefene (IV), naltrexone (oral)methylnaltrexone, almivipan

• Mechanism of action– Bind to receptor, block agonist effects– Have greater affinity for μ receptors than δ or κ

• Therapeutic indication– Opioid overdose; use IV agents initially

• Naloxone: 1‐2 hour duration of action; multiple doses may be required• Nalmefene duration of action 8‐12h• Naltrexone (oral) blocks actins of strong agonists for up to 48h

– GI distress in chronic use: methylnaltrexone, almivipan• Do NOT cross blood brain barrier• Bind to receptors in periphery including GI tract, relieving GI distress

– Minimal effects on analgesia– Do not precipitate abstinence/withdrawal syndrome in those with physical dependence on

opioids

• Adverse Drug effects: generally none from these antagonists

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Pharmacodynamics of Strong OpioidsDrug Receptor Half‐life

eliminationOnset Duration

Morphine Mu agonistKappa agonist

1.5‐4.5h 15‐30 min oral


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Pharmacodynamics of Strong Opioids con’t

Drug Receptor Half‐life elimination

Onset Duration

Methadone Mu agonistBlocks NMDA receptors and monoaminergic reuptake transporters

8‐59 h .5‐1 h oral10‐20 min parenteral

4‐6 h but with repeatedadministration…2‐48 h

Fentanyl 1‐2 mcg/kg

Mu agonist 2‐4 h Immediate IV 7‐15 min IM

1‐1.5 h

Meperidine Mu agonist 3‐5 h Rapid (SC/IM/IV)

2‐4h (SC/IM)

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Dosing: Strong OpioidsOpioid Brand Formulation Strength Dose interval

Morphine MS Contin tablets 10, 15, 20, 3045, 50, 60, 75, 90, 100 mg and 200 mg

Every 4h

Morphine parenteral .5 mg/mL to 50 mg/mL

IV 2.5‐15/70 kg every 4hSC/IM 5‐20 mg/ 70 kg every 4 h

Morphine liquid 10 or 20 mg/mL Every 4 h

Morphine suppository 5, 10, 20 30 mg Every 4 h

Morphine Avinza, Kadian, oramorph SR, more

Controlled release capsule

Every 8‐12 h

Morphine Embeda Morphine/ naltrexone

20/.8, 30/1.2, 50/2, 60/2.4, 80/3.2, 100/4

Every 12 or 24 h

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Dosing: Strong Opioids con’tOpioid Brand Formulation Strength Dose interval

Hydro‐morphone

Dilaudid

Exalgo (extendedrelease)

TabletsOral solution

2, 4, 8 mgExtended release 8, 12, 16 mgOral solution 5 mg/5mL

Every 3‐6 h

Hydro‐morphone

parenteral 2‐10 mg/mL Every 2‐3 h; every 4‐6 if IM or SC

Hydro‐morphone

suppository 3 mg Every 6‐8 h

Oxycodone Roxicodone, OxyFASTOxyContin, OxyIR, Oxecta

Tablet (short‐acting)

Extended release

Oral solution

Immediate 5, 10, 15, 20, 30 mgER 10, 15, 20, 30 mg40, 60, 80 mg

Every 4‐6 h

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Dosing: Strong Opioids con’tOpioid Brand Formulation Strength Dose interval

Methadone Methadose, Dolpine

TabletSoluble tablet

oral solution

5, 10 mg tab40 mg soluble tablet1, 2, & 10 mg/mL

Every 4‐12 h

Methadone parenteral 10 mg/mL; 2.5‐10 mg IM/SC

Every 4‐12 h

Fentanyl Sublimaze Parenteral .05 mg/mL Every 30‐60 min

Meperidine Demerol Pethidine

TabletOral solution

50, 100 mg50 mg/5mL

Every 3‐4 h

Parenteral 25‐100 mg/mL Every 1‐4 h

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Pharmacodynamics: MODERATE OPIOID

• Absorption, distribution, metabolism, and excretion unremarkable• Most commonly formulated as extended release

• Manufacturers have tried various approaches since its 2008 debut to reduce abuse

• Safety not established in pediatric patients

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Drug Receptor Half‐life elimination Onset DurationOxycodone Moderate

Mu agonist2 ‐ 4 h* 3 ‐ 4.5h some sources

10‐15 min 3‐6 hours

Pharmacokinetics: MODERATE OPIOIDOXYCODONE

Dosing: Moderate OpioidOXYCODONE

Opioid Brand Formulation Strength Dose interval

oxycodone/ aspirin

Percodan, Endodan, Oxycodan

tablets 4.835 mg/325 mg Every 4‐6h

oxycodone/ acetaminophen(APAP)

Percocet, Tylox, Pimlev, Roxicet

tablets 2.5,5,7.5, & 10 mg/ 325 or 650 mg APAP

Every 4‐6h

oxycodone/ ibuprofen

Combunox tablets 5mg/400 mg Every 4‐6h

oxycodone Roxicodone,Oxycontin, Oxy IR, more

tablets 5, 10, 15, 20, 30 mg 5‐30 mg every 4‐6h*Every 3‐6h some sources

oxycodone Oral solution 20 mg/mL5 mg/mL

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Weak Opioids

• Schedule 3 and 4 drugs– Hydrocodone – Codeine

• Often prescribed in a fixed opioid + non‐opioid combination– Hydrocodone + acetaminophen: Hycet, Lorcet, Lortab, Vicodan, Xodol, Zydone– Hydrocodone + ibuprofen: Ibudone, Reprexain, Vicoprofen– Codeine + acetaminophen: Tylenol # 2, 3, or 4– Dyhyrocodeine + acetaminophen + caffeine: Panlor– Dyhydrocodeine + aspirin + caffeine: Synalog‐DC

• Remember– Acetaminophen has a ceiling dose of 4 grams/day (less with liver dx)

• A dose of 150‐200 mg/kg (children) or 7 g total (adults) is potentially toxic• Lortab 7.5/500mg means 500 mg of acetaminophen• Tylenol # 3 has 30 mg codeine and 300 mg of acetaminophen; Tylenol # 4 has 60 mg of

codeine and 300 mg of acetaminophen– Ibuprofen can interfere with anti‐platelet drugs treating cardiovascular

conditions

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Not new; prescriptive privileges granted 2000 with original

Ohio law

Pharmacokinetics: Hydrocodone & Codeine

• Hydrocodone is metabolized to hydromorphone via CYP 2D6; poor metabolizers may not get adequate analgesia

• Hydrocodone safety and efficacy not established in children

• 10% of codeine is metabolized to morphine by CYP2D6; poor metabolizers may not get adequate analgesia

• Risk of life‐threatening side effects in nursing babies if mother is an ultra rapid metabolizer of codeine

• Do not give codeine IV due to severe adverse reactions

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Pharmacodynamics: Weak OpioidsDrug Receptor Half‐life

eliminationOnset Duration

Hydrocodone (only available as combo)

Prodrug;Partial Mu receptor agonist

3.3‐ 4.4 h variable 4‐8 h

Codeine (schedule 2)

Prodrug; Mu receptoragonist

3‐4 h 30‐60 min oral10‐30 min IM

4‐6 h

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Dosing Weak Opioids: hydrocodone & codeine examples

Opioid Brand Formulation Strength Dose intervalCodeine+ acetaminophen

Tylenol #3 tablets 30 mg + 300 mg Every 4 hours

Codeine+ acetaminophen

Tylenol #4 tablets 60 mg + 300 mg Every 4 hours

Hydrocodone + acetaminophen

Lortab 2.5/500 Scoredtablets

2.5 mg + 500 mg 4‐6 hours


Lortab 5/500 Scoredtablets

5 mg + 500 mg 4‐6 hours


Lortab 7.5/500 Scored tablets 7.5 mg + 500 mg 4‐6 hours


Lortab 10/500 Scoredtablets

10 mg + 500 mg 4‐6 hours


Lortab elixir Liquid 7.5. mg + 500 mg per 15 mL

4‐6 hours

Hydrocodone + ibuprofen

Ibudone Tablets 5mg + 200 mg; 10 mg + 200 mg

4‐6 hours

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Additional Schedule 3 and 4 Drugs:Opioids with Mixed Receptor Actions

• Phenantrens– Nalbuphine (Nubain)– Buprenorphine (Buprenex)NOT FOR APNs!

• Subutex is a combo with naloxone for Rx opioid dependence

• Morphinan– Butorphanol (Stadol)

• Benzomorphan– Pentazocine (Talwin)

• All are analgesics• All can produce respiratory depression and sedation

• All may produce withdrawal in opioid dependent patients

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Pharmacodynamics: Opioids with Mixed Receptor Actions

Drug Receptor Half‐life elimination

Onset Duration

Nalbuphine Mu antagonistModerate Kappa agonist

5 h 15 min IM; IV 2‐3 min

3‐6 h

NOT for APNsBuprenorpine

Partial Mu agonist. High affinity but low intrinsic activityKappa and delta antagonist

2.2 h 15 min 4‐10h

Butorphanol Partial Mu agonistStrong Kappa agonist

4.6 h 5‐10 min IV/IM15 min nasal

3.4 h

Pentazocin Partial Mu agonistMild Kappa agonist

2‐3 h 20 min IM3 min IV

2h IM1 h IV

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Dosing Partial and Mixed AgonistsOpioid Brand Formulation Strength Dose intervalNalbuphine Nubain parenteral 10, 20 mg/mL 10‐20 mg/70 kg every

3‐6 hours Children > 1 yr: 1‐.2 mg/kg

Butorphanol Stadol Parenteral 1, 2 mg/mL .5‐2 mg every 3‐4hButorphanol Stadol Nasal spray 10 mg/mL 1 spray/1 nostril every

3‐4 hPentazocin Talwin/

Talacen (with acetaminophen)

tablets 25 mg/650 mg 1 tab every 4 h; do not exceed 6 tabs/day

Pentazocin Talwin Parenteral 30 mg/mL Every 3‐4h

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Equianalgesia• Recommendations for substituting one opioid for another vary

somewhat, depending on setting and patient condition– Substitution recommendations in the setting of procedural care, acute

care, and chronic care vary• Example: critical illness changes volume of distribution and elimination for many drugs

– Opioid doses may need to adjusted downward in patients with impaired kidney or liver disease

– Substitution recommendations in the setting of procedural care, acute care, and chronic care vary

• Assess both physiologic responses (level of sedation and respiratory status) and function (level of activity) with each adjustment– Opioid‐naïve patients with acute pain are more like to experience

respiratory depression than those on scheduled therapy for > 5 days• Sedation usually precedes respiratory depression• Be cautious of the additive effects of sedatives

– Remember sedatives like valium, midazolam, lorazepam, propofol, and others do NOT relieve pain BUT they do alter mental status, increase sedation, and depress respiratory status

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Examples of EquianalgesiaDrug Approximate Equivalence

SC/IV Oral/OtherMorphine 10 mg 30 mg

Hydromorphone 1.5 mg 7.5 mg

Fentanyl 0.1 mg * 100 microgram patch/2‐3days is equivalent to 200 mg morphine/24h

Methadone Marked patient variability Marked patient variability

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Sources: Katzung 2010. Index Medicus 2012

• Typically, equianalgesia conversions use morphine equivalents.• Consider developing population or institution guidelines for determining

acceptable substitutions. • Keep in mind that analgesic regimens need to be individualized.• There are “apps” for smart phones & tablets to assist with daily opioid

calculation & conversions (e.g., iMedical.com/eopioid‐app).


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Opioids: Therapeutic Indications• Analgesia. Moderate‐to‐severe pain

– Routes of administration: IV, (IM), (epidural), subcutaneous, oral, buccal, suppository, transdermal

– Strong Agonists• Acute setting• Life‐limiting conditions/end‐of‐life

– Moderate Agonists• Less severe and chronic pain

• Cough suppression– Weak agonists: codeine (schedule 2) and

dexamethorphan• Dexamethorphan: FDA warning about potential

for abuse; large doses can cause hallucinations, excitation, coma and decreased breathing

• Treatment of diarrhea– Weak agonists: diphenoxylate and loperamide

(schedule 3)

• Anesthesia (not for NPs, CNSs)

• Management of acute pulmonary edema

– Parenteral morphine for histamine‐mediated vasodilation

– Calming effects• Management of dyspnea at end‐

of‐life– Off‐label use

• Opioid Dependence NOT FOR APN– Methadone. Blocks the euphoria‐

inducing effects of shorter acting opioids. Permits a slow tapering of opioids to diminish abstinence syndrome

– Buprenorphine. Long duration of action makes it useful in withdrawal states/acute detoxification. Not for APNs

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Opioids: Acute Effects• Analgesia

– Relieve pain at both the sensory and emotional levels

• Sedation and euphoria– Dysphoria for some– Little/no amnesia– At high doses, stupor and coma

• Respiratory depression– Decreased response to carbon

dioxide challenge• Increased CO2 may lead to CV

dilation, increased cerebral blood flow and increased intracranial pressure

• Nausea and vomiting– Activation of the chemoreceptor

trigger zone• GI effects

– Constipation thru decreased peristalsis (antidiarrheal effects)

– Little or no tolerance

• Smooth muscle– Contraction of biliary tract smooth

muscle, ↑ ureteral and bladder sphincter tone, and ↓ uterine tone

• Miosis pupillary constriction– Little or no tolerance

• Antitussive– Unknown mechanism

• Miscellaneous– Flushing and pruritus through

histamine release• Especially morphine

– Release of vasopressin and prolactin

– Exaggerated responses to opioids can occur inpatients with adrenal insufficiency or hypothyroidism

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Opioids: Chronic Effects• Tolerance

– Marked reduction of acute effects (except miosis and constipation)

• Thought to be a result of “uncoupling”• There is some cross‐tolerance between different opioid agonists, but tolerance is not completely shared. This is the basis for “opioid rotation” to maintain analgesia in chronic, cancer pain

• Dependence– Anticipated and well‐documented physiologic response in chronic therapy, especially with strong agonists

• Dependence is revealed with abrupt discontinuation: “abstinence syndrome”

• Characterized by rhinorrhea, lacrimation, chills, gooseflesh, muscle aches, diarrhea, yawning, anxiety, and hostility

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More about Opioid Tolerance . . .• Tolerance is denoted by loss of effectiveness

– Persistent activation of receptors has a primary role in tolerance

• Current thought is that tolerance develops when receptors are not “recycled” via endocytosis. When endocytosis is impaired, there is an uncoupling of the receptor from the second messenger systems.

– Upregulation of cAMP also contributes to tolerance and dependence.

• This is the rationale for “switching” long term/long‐acting opioids in cancer/hospice care: “Recycle the receptors”

– Note the opioid effects of miosis, constipation and convulsions have no or minimal changes despite high, repeated dosing

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Consequences of Unrelieved Pain

Acute and surgical pain– Adversely affects patient's ability to participate in walking and physical therapy

• Immobility increases risk for venothromboembolism• Missed rehabilitation sessions can still be billed

– Compromise’s immune function• Delayed wound healing

– Interferes with rest and sleep– Increases anxiety– Contributes to lower quality of life– Reduces patient satisfaction– May contribute to unanticipated hospital re‐admissions

• When pain is poorly controlled at discharge

Pasero, C. 2011. J Perianesth NursPasero & McCaffery (eds.) 2011. Pain Assessment and Pharmacologic Management. St. Louis: Mosby

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• Disturbed sleep duration and quality• Impaired cognitive processes and brain

function ( up to 66% of patients report impaired memory and attention)

• Disordered mood/mental health (33‐46% of patients report anxiety, depression, suicidal ideation compared to 10% of overall population)

• Decreased cardiovascular health(hypertension and subsequent CV mortality)

• Impaired sexual function• Economic costs (both personal and societal)• Reduced overall quality of life

– Less social interactions– Inability to work

“Chronic pain has the capacity to become increasingly complex in its pathophysiology and potentially more difficult to treat over time” Fine, PG 2011. Long-term consequences of chronic pain. Pain Med, 12: 996-1004

Structural and functional alteration in the CNS with chronic pain results in

– Sensitization– Remodeling/reorganization

that allows brain to “initiate” pain sensation and potential for circuit to become established, uninterruptable

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Chronic pain


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Chronic Pain– Most common cause of disability is noncancer pain

• Interferes with life, living, work, relationships, more!

– Trends in using opioids for chronic noncancer pain is relatively new (1990s) and remains somewhat controversial

• Chronic opioid therapy does relieve moderate‐to‐severe pain for both neuropathic and nonneuropathic pain

– Most patient’s pain improves 2‐3 points on a 1—point scale– No evidence that one opioid is better than another for initial therapy

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Guidelines for chronic opioid therapy for adults with chronic noncancer pain. 2009. J Pain 10: 113‐20

Additional Considerations: Managing Chronic Pain with Opioids

• Use an interdisciplinary approach. Do not rely on opioids alone for symptom management.

• Perform periodic monitoring– Assess level of function– Pain severity– Adverse events– Compliance with regimen– Progress to goals of therapy

• Taper therapy (and stop) when risks outweigh benefits:– When aberrant drug‐related behaviors occur– When intolerable adverse effects present– When progression toward goals does not occur

A 10% reduction/week is advised to ↓ symptoms of withdrawal when opioids have been used for > 90 days

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Additional Considerations: Managing Chronic Pain with Opioids

• So what is a “high” opioid dose?– Up to 40 mg of morphine equivalent is considered low dose in chronic therapy management

– 41‐90 mg is moderate dose– > 91 mg is high dose

• Constipation is VERY problematic. Monitor and co‐prescribe a bowel regimen

• Methadone has the most challenges in terms of starting & titrating but when it works, it works really well! – Pharmaco‐kinetics and ‐dynamics are complex and less predictable that other opioids

• Consider an ECG at start, at 30 days and yearly thereafter due to interactions with drugs, food and cardiac cycle.

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Manchikanti et al. 2012, ASIPP guidelines for opioid prescribing in chronic noncancer pain (2 parts) Pain Physician (Suppl)


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Clinical Pearls related to Opioid Treatment of Chronic Pain

• Trends in using opioids for chronic noncancer pain is relatively new (1990s) and remains somewhat controversial

• Chronic opioid therapy does relieve moderate‐to‐severe pain for both neuropathic and nonneuropathic pain

– Most patient’s pain improves 2‐3 points on a 10 point scale

• No evidence that one opioid is better than another for initial therapy– Generally safer to start with a short‐acting opioid (less risk of accidental overdose)

• Insufficient evidence to recommend staring with short‐acting opioid• Long acting opioids provide more consistent control of pain, improved compliance , and lower risk of addiction or abuse.

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Guidelines for chronic opioid therapy in noncancer pain, 2009

Application: Acute Pain• A 14 year old boy (64 inches, 110 pounds) is admitted to the

pediatric clinical unit following an exploratory laparotomy and appendectomy. During his 60‐minute stay in the postanesthesia care unit, he received ketorolac 7.5 mg intravenous (IV) and fentanyl 25 micrograms IV (a one‐time PACU dose). Vital Signs (VS): 116/74, 84, 18, 98F. On arrival he reports pain 7 out of 10; he looks distressed.

• Which of the following are indicated?– Acetaminophen 650 mg IV every 6 hours; transition to oral

administration when able to take fluids– Morphine 1‐4 mg IV every 2 hours as needed for pain– A patient care analgesia (PCA) device delivering morphine

continuously at 1mg/hour and providing a bolus of 1 mg with a lock out of 2 mg/hour

– Fentanyl 25 mcg IV every hour as needed for pain

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Application: Acute Pain Plan of Care• A 14 year old boy (64 inches, 110 pounds) is admitted to the pediatric clinical

unit following an exploratory laparotomy and appendectomy. During his 60‐minute stay in the postanesthesia care unit, he received ketorolac 7.5 mg intravenous (IV) & now scheduled for every 6 hours, and fentanyl 25 micrograms IV (a one‐time PACU dose). VS: 116/74, 84, 18, 98F. On arrival he reports pain 7; he looks distressed.

• Which of the following are indicated?– Acetaminophen 650 mg IV every 6 hours; transition to oral

administration when able to take fluids– Morphine 1‐4 mg IV every 2 hours as needed for pain

• The range of dose is supported by the American Society for Pain Management Nursing and the American Pain Society. Godon et al. 2004: The use of “as‐needed” range orders for the opioid analgesics in the management of acute pain: A consensus statement.

– A patient care analgesia (PCA) device delivering morphine continuously at 1mg/hour and providing a bolus of 1 mg with a lock out of 2 mg/hour

– Fentanyl 25 mcg IV every hour as needed for pain– Ask the nurse to initiate relaxation breathing exercises to control pain

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Selected Guidelines and Sources• World Health Organization: http://www.who.int• International Association for the Study of Pain: http://www.iasp‐pain.org• American Pain Society http://www.ampainsoc.org/ Resource page for PCPs, patients

– Principles of Analgesic Use in the Treatment of Acute and Cancer Pain. Glenview, Ill: American Pain Society, 2008.

– Chronic opioid therapy in noncancer pain. J Pain, 2009.– Pain Control In The Primary Care Setting (booklet $8)– Guidelines for specific conditions: low back pain, sickle cell, arthritis (RA and OA), fibromyalgia, cancer

pain (children and adults)• American Society of Anesthesiologists Task Force on Acute Pain Management.

http://www.asahq.org/– Practice guidelines for acute pain management in the perioperative setting: An updated report.

Anesthesiology, 2012; 116: 248‐73– Practice guidelines for chronic pain management. Updated. 2010. Anesthesiology 112(4):810‐33.

• American Academy of Pain Management http://www.aapainmanage.org/– mostly for members but a 2012 free CE on Geriatric Pain

• American Academy of Pain Medicine (mostly MDs): http://www.painmed.org• American Pain Foundation: http://www.painfoundation.org/ Patient‐centered. Also

posts as National Pain Foundation.• American Society of Interventional Pain Physicians http://www.asipp.org/

– Guidelines for responsible opioid prescribing in chronic noncancer pain. 2012, Pain Physician, Suppl.– Agency for Healthcare Research and Quality (DHHS): http://guidelines.gov

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Selected Guidelines and Sources con’t• Specialty organizations

– Example: http://www.americangeriatrics.org or http://www.cancer.org– The VA algorithm describes decision points in chronic care

http://www.healthquality.va.gov/COT_312_SUM‐er.pdf– Institute for /Clinical Systems Improvement: http://www.icsi.org/guidelines– American Society for Pain Management Nursing : http://www.aspmn.org/– American Society of Addiction Medicine http://www.asam.org

• The Ohio Pain Initiative http://www.ohiopaininitiative.org “Tools to aid you in clinical practice.”

• Mayday Pain Project: http://www.maydayfellows.org/index.htmInterdisciplinary (SW, JD, MD, Psych, APRN, RN, more!)

• Pasero & McCaffery (eds.) 2011. Pain Assessment and Pharmacologic Management. St. Louis: Mosby

• Springer has a book/ebook series: Critical Care/Trauma, and ED Pain Management; Cancer Pain Management; Infant and Child Pain Management; Acute Pain Management; Geriatric Pain Management; and Chronic Pain Management.

• The Institute of Medicine report on chronic pain in America (2011): "Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research."

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GuidelinesWorld Health Organization Analgesic ladder, 1996• Developed for cancer painPrescribers do not need to try lower step; start with strong opioid if pain is severe

Strong opioids ± non opioids ±adjuvants

Weak opioids ± non opioids ±adjuvants

Non opioids ± adjuvantsMild‐to‐moderate pain

Moderate‐to‐severe pain

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Fill in the BlanksWhat medications and dose are associated with each step?

Strong opioids: ________________________

Weak opioids: _________________________

Non opioids: ________________________

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Fill in the BlanksWhat medications and dose are associated with each step?

Strong opioids: Schedule 2 drugs like morphine, fentanyl, hydromorphone, methadone. Moderate opioid: oxycodone

Weak opioids: Codeine and Schedule 3 or 4 drugs like hydrocodone (combination products). Possibly moderate opioid: oxycodone.

Non opioids: nonsteroidal drugs like OTC acetaminophen, ibuprofen, naproxen, aspirin, and legend drugs like diclofenac, and COX‐2 inhibitors

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Guidelines do not exclusively advocate opioids!Non opioids• COX 1, 2, and 3 inhibitors

– NSAIDs, acetaminophen

• Antidepressants– Heterocylics: amitriptyline (Elavil), desipramine (Norpramin),

nortripyline (Pamelor, Aventyl)– SSRIs/SNRIs :Duloxetine (Cymbalta). FDA approved for diabetic

neuropathy and Venlafaxine (Effexor) used for menopausal symptoms

– Atypicals (off‐label)

• Anticonvulsants– Gabapentin– Pregabalin for certain types of neuropathic pain

• Local anesthetics• Antispasmodics and muscle relaxants• Glucocorticoids (systemically and as an injection)• Anti histamines• Benzodiazepines• Topical agents (e.g., capsaicin)

Adjuvants• Heat/cold• Distraction

– Music therapy– Relaxation– Breathing

• Physical and occupational therapy

• More!• Look at the

Guidelines!!!

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Remember: Prescribing ≠ Dispensing

APNs may not dispense Schedule 2 drugs

From DEA website: The term "dispense" means to deliver a controlled substance to an ultimate user or research subject by, or pursuant to the lawful order of, a practitioner, including the prescribing and administering of a controlled substance and the packaging, labeling or compounding necessary to prepare the substance for such delivery. The term "dispenser" means a practitioner who so delivers a controlled substance to an ultimate user or research subject.

The term "distribute" means to deliver (other than by administering or dispensing) a controlled substance or a listed chemical. The term "distributor" means a person who so delivers a controlled substance or a listed chemical.

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Safe Prescribing

Drug overdose deaths in U.S. are at an all‐time high– In Ohio, poisoning is the most common cause of death in those aged 25‐44 years (2011)

– Nationally, more deaths from prescription drugs than heroin and cocaine combined

– Expensive: hospital costs related to opioid overdoses are more likely to be paid with public rather than private funds

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Opiate analgesic use patterns that distinguished abusers and others*

• Impaired Control– Multiple prescription providers– Early prescriptions refills– Emergency Department visits for analgesics

• Compulsive Behavior– Independently and rapidly increases analgesic dose/frequency

– Use analgesics for non‐pain symptoms– Saves or hoards unused medication– Supplements with alcohol/psychoactive drugs– Route of administration preference

*(p


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Safe Prescribing and Management of Schedule 2 Drugs when used Chronically

• Stratify Risk for Abuse with each Patient– Low, medium, high

• Develop a process and follow it: – History, exam: Identify a clear diagnosis

• Previous drug use or abuse is addressed

– Patient is informed about risks & benefits of chronic opioid therapy

• Opioid consent form. Multiple websites. http://www.painmed.org/files/opioid‐consent‐form.pdf

– Written management plan• Next slide

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Safe Prescribing and Management of Chronic Opioid (or other Schedule 2) Therapy

• Write the management plan– Goals of therapy– (random) Urine drug screens– Instructions for dispensing including caveat that opioids are obtained from only one provider

– Pill counts• If patients report pills were stolen, required that they report loss to police and patient bring police report

– Consequences for misuse: “Your decision to misuse this medication has taken away our ability to prescribe it.”

– Safe storage at home away from children and teens• Properly dispose of partially used or unneeded drugs

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Example


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Risk Evaluation and Mitigation Strategy: REMS

• More than 20 opioid manufacturers must make available to prescribers continuing education programs on the proper use of opioids

• REMS can be for an individual drug or for a class of drugs that share common risks (e.g., transmucosal immediate release opioids)

– REMS program depends on• The nature of the risk• The patient population• The health care settings in which the drug is dispensed

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REMS: Example• Restricted distribution program to reduce the risk of abuse, misuse, addiction and overdose– Prescribers must be specially certified

• And agree to educate patients– Pharmacy that dispense must be specially certified

• Wholesalers and distributors must be enrolled in REMS program, too

– Drugs can only be used in certain settings• Transmucosal immediate release fentanyl is restricted to inpatient settings of hospitals, hospices, or long‐term care facilities

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Summary: Opioid Pharmacokinetics

• Absorption– Most drugs are well

absorbed– Morphine,

hydromorphone, and oxymorphone undergo extensive first‐pass metabolism

• Distribution– WIDE!

Cross placenta, breast milk exerting effects on fetus, including dependence in neonates continuously exposed

• Metabolism– Metabolized by hepatic enzymes, usually to

inactive glucuronide conjugates– Impaired metabolism (increased actions/duration

of actions and adverse effects with impaired liver enzymes/liver disease

– Exception: some metabolites are active:• Morphine‐6‐glucuronide is equianalgesic to morphine• Morphine‐3‐glucuronide is neuroexcitatory• Meperidine metabolites are notoriously poorly

tolerated, especially in older adults– Codeine, oxycodone, and hydrocodone are

metab’d by CYP2D6• Wide genotypic variability

– Codeine must be converted to active form– 2D6 variability may explain nonresponse

• Elimination– Elimination half‐life increased with kidney disease

or in older adults due to aging kidney function• Active metabolites can also circulate for a longer

period with reduced glomerular filtration/kidney disease

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Summary : Pharmacodynamics• The goal of pain management is to decrease suffering and avoid the costs and complications of pain (both chronic and acute)

• Opioid drugs activate opioid receptors– Activation of opioid receptors leads to inhibition of pain signal—desired effect!

– Activation of opioid receptors leads to adverse drug effects, tolerance, and addiction

• Tolerance is loss of effectiveness• Addiction is characterized by drug use and drug‐seeking behaviors despite disruption in social, work, and daily life activities. Health, safety, and/or welfare endangered.

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Summary: Safe, Effective Pain Management

• Follow Ohio Law– Be familiar with the BON formulary and rules

• Use Guidelines/Best Practices• Assess risk for abuse and develop/follow a plan to reduce risk– Use OARRS with every patient, every prescription

• It the law!– REMS (risk evaluation and mitigation strategy)

• Educate yourself and your patients

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Ohio Association of Advanced Practice

Nurses

OAAPN is a membership organization – CRNAs, CNMs, APRNs (CRNPs), and CNSs– First meeting in 1990

• Current membership is > 9000 across Ohio– Purpose: professional and patient advocacy

• Education of APNs, consumers, and policymakers• Lobby for legislative changes

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Stimulants

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