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Opioids
Lisa Anselmo Pharm.D. BCOP University of New Mexico Cancer Center
History
! Opos- Greek word for “juice” ! Natural opiates derived from opium poppy
! Opioid- any chemical that has the function and pharmacological property of opiates ! Mimics endorphins that our body produces normally
! Narcotic- derived from Greek work narkotokos- meaning numbing or sleep ! Now synonymous with substances with abuse or addictive potential
History
! Opium contains 20 different substances
! 1806- pharmacist’s assistant isolated morphine ! Named after Morpheus Greek god of dreams
! Use of this pure substance became more common at the same time the use of hypodermic needle and syringe, allowing injection of morphine
! Side effects and addictive potential identified during the civil war ! “soldier’s joy” “soldier’s disease”
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History
! Led to search for non addictive substance ! Heroin in 1874
! Used as a cough suppressant and sedative
! All this led to the synthesis of new antagonists and agonist- antagonist compounds
! 1970s- 3 separate receptors hypothesized mu, kappa, and delta ! Multiple binding sites on brain cell receptors
http://chemwiki.ucdavis.edu/Biological_Chemistry/Drug_Activity/Narcotic_Analgesic_______Drugs
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http://flipper.diff.org/app/pathways/info/6953
Receptors
! Opioids produce different adverse effects based on receptor preference
! Adverse effects are caused by receptor stimulation in brain and periphery ! CNS- analgesia, euphoria, drowsiness
! When given to patients not in pain can lead to drowsiness, apathy, at higher doses respiratory depression
! Periphery- GI motility, smooth muscle tone ! Light touch, temperature sensation are unaffected
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Consequences of receptor activation
! Desensitization- occurs over minutes to hours
! Tolerance- days to weeks ! Reduction in the maximal effect of the opioid
! Can be overcome with larger doses
! Different organs develop tolerance at different rates ! Euphoria effects leave quickly
! Emesis, analgesia, sedation (constipation?)- moderate tolerance
! Pupillary miosis- no tolerance develops
Consequences of receptor activation
! Dependence- occurs during the tolerance phase of receptor activation ! Symptoms occur due to enhanced cellular activity
! Release of excitatory amino acids, cytokines
! Excitatory cell activation also in GI tract
! At organ system level somatomotor and autonomic outflow ! Agitation, hyperalgesia, hyperthermia, hypertension, diarrhea, dysphoria,
anxiety and depression.
Consequences of receptor activation
! Addiction ! Behavior pattern
! Trying to avoid withdrawal symptoms ! The euphoric effect is subject to tolerance
! Drive to obtain drug occurs despite physical, emotional or societal damage caused by the drug, drug seeker may be addicted ! Unlawful behavior to obtain drug
! Stealing, getting drug from non medical sources
! Dependence is NOT addiction ! Anyone on opioids for a time will develop tolerance and dependence ! Tolerance and dependence are not predictors of addiction
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Adverse effects
! Respiratory depression ! Opiates affect all phases of respiratory activity
! Slow rate of breathing with high doses down to 3-4 breaths per min
! Patients will breath if instructed
! Use with caution in patients with COPD, asthma, hypoxia other respiratory illness
! Used therapeutically ! dyspnea in patients with COPD
! air hunger that leads to anxiety
! patients on artificial ventilation
Respiratory depression
! Opiate overdose leads to death from respiratory depression ! Combined with other medications that decrease respiration
! Alcohol, benzodiazepines, sleeping medications ! The “trinity”- opioid, benzodiazepine and carisoprodol
! Age ! Newborns can have lower APGAR scores when mother given opioid before
delivery ! Elderly- reduced lung elasticity, decreased capacity
! Disease- ! COPD ! Renal dysfunction
! Relief of pain ! Pain stimulates respiration, reduce pain
Sedation
! Usually occurs during initiation or dose escalation ! Predisposing factors- dementia, enchephalopathies or brain tumors
! Maximal respiratory depression occurs 5-10 mins after IV administration
! 30-90 mins after IM or sub q
! Reverse with antagonist ! May need to redose antagonist- it may have a shorter half life than
the opioid ! Half life of naloxone (Narcan) 0.5 to 1.5 hours
! May need to re-dose every 2 to 3 mins
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Seizures
! High doses can cause EEG slowing in adults and older children
! Myclonus and seizures can occur at high doses in patients who are tolerant to opioids ! Patients in hospice
! Meperidine can cause seizures with repeated dosing and in patients with renal dysfunction
! Withdrawal can cause seizures
Nausea and vomiting
! Morphine-like medications stimulate the chemoreceptor trigger zone in the CNS ! More common in patients who are ambulatory
! Suggests a vestibular component
! Gastric stasis contributes to nausea
! Treatments involve serotonin receptor antagonists, drugs used for motion sickness and metoclopramide ! Tardive dyskenesia
! Promethazine- antihistamine
Constipation
! Reduced rate of passage of intestinal contents ! Reduced intestinal secretion
! Increased water absorption
! Reduced attention to stimuli to defecate due to central actions of opioid
! Reflex relaxation in response to rectal distention is decreased
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Flushing/itching
! Morphine causes a release of histamine that causes dilation of cutaneous blood vessels ! Skin becomes flushed
! Itchy, perspire more
! More common with morphine and meperidine ! Itching can be more intense when opioid administered intrathecally or
epidurally
Methadone
! Boxed warning for QTc interval prolongation and arrhythmias ! Most often in patients on higher doses for pain on large multiple times
day doses ! Obtain baseline ECG
! Do not use if baseline QTc interval is >500 msecs
! Monitor and replete electrolytes ! Avoid medications that prolong QTc interval
! Recommended monitoring ! ECG 2-4 weeks after initiating therapy and after significant dose
increase ! Repeat ECG when doses reach 30 to 40 mg/day and at 100 mg/day
Absorption
! Most opioids absorbed from GI tract ! Morphine and hydromorphone are absorbed through rectal mucosa
! Fentanyl absorbed through buccal mucosa and transdermally due to lipid solubility
! Most go through a first pass effect through the liver that decreases oral bioavailability ! Duration is longer with oral route
! Given IV the onset quickest
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Metabolism ! Morphine metabolized to morphine-6-glucuronide (active metabolite)
and morphine-3-glucuronide ! Morphine-6-glucoronide is excreted through the kidneys
! Can accumulate and result in toxicity
! Codeine is metabolized to morphine ! CYP2D6 metabolizes the conversion
! Polymorphisms in CYP2D6 occur in approx 10% of the Caucasian population lead to inadequate pain relief due to low conversion to morphine
! Polymophisms for rapid metabolizers occur in 4-5% of US population and 16-28% of North Africans, Ethiopians and Arabs
Excretion ! Morphine metabolite excreted renally
! CrCl 10 to 50 ml/min reduce by 25%
! Oxycodone ! Serum concentrations increased by 50% with crcl<60
! Fentanyl/hydromorphone ! Moderate renal impairment reduce dose by 50%- when initiating treatment
! Excreted in urine (fentanyl unchanged drug) hydromorphone inactive metabolite
! Methadone ! Dose reduce for crcl<10 ml/min
! <10% excreted in urine unchanged- rest inactive metabolites
Meperidine
! Similar structurally are diphenoxylate and loperamide
! Mepreidine is metabolized to normeperidine in liver ! Normeperidine excreted by kidneys and liver
! When it accumulates can cause seziures, hallucinations, tremors, twitching
! AVOID in renal impairment
! Use is NOT recommended for longer than 48 hours or doses greater than 600 mg/d
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Clinical pharmacology and drug interactions
! Multiple mechanisms for drug interactions ! Hepatic enzyme competition ! Pharmacodynamic interactions ! Pharmaceutically active metabolite
! Cocaine and alcohol consumption produces cocaine-like product that adds to adverse effects of cocaine
! Altered absorption when GI motility is changed
! Am J Addict. 2010 ; 19(1): 4–16. doi:10.1111/j.1521-0391.2009.00005.x.
Cytocrome P450 liver enzymes
! Family of iso-enzymes that metabolize many medications
! They are also susceptible to genetic polymorphisms
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Cytochrome P450 enzymes
! Enzyme inducers result in lower levels of parent drug and higher levels of metabolites ! Can reduce the effectiveness of the drug- OR if the parent is a
prodrug- metabolized to an active metabolite, get increased effectiveness
! Polymorphisms of CYP enzymes ! 2D6- has over 100 genetic variants
! Patient can be a poor metabolizer with 2D6 will not get good pain control with codeine ! Unable to metabolize it to morphine
CYP P450 enzymes
! Different levels of inducers and inhibitors ! All defined by the FDA in tests that the manufacturer must perform
! Strong increases AUC>5 fold
! Moderate increases AUC 2-5 times
! Weak increases AUC 1.25 to 2.5 times
OTC medications that have drug interactions
! Inducers ! St. John’s wort
! Valerian
! Ginkgo biloba
! Inhibitors ! Grapefuit juice
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Serotonin syndrome and Fentanyl
! Phenylpiperdine opioids are weak serotonin re-uptake inhibitors and have a higher risk of serotonin syndrome
! Fentanyl, meperidine
! Other opioids do not have the same potential for serotonin syndrome
! Classification of opioids
class drugs
Phenanthrenes Codeine, hydromorphone, levorphanol, morphine, oxycodone, hydrocodone and pentazocine
Phenylheptane Methadone, propoxyphene
Phenylpiperidine
Fentanyl, meperidine
Drug interactions
! Respiratory depression
! September 2014 article in Pharmacy Times by Jeffrey Fudin ! Describes the “holy trinity” of medications that are know to cause
more overdose deaths
! Commonly prescribed by “pill mills”
! Carisoprodol, benzodiazepine and opioid
! Synergistic respiratory depression
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Carisoprodol
! Metabolized by the liver to meprobamate ! Half life of 10 hours
! Sedative properties similar to barbiturates
! With other medications or alone- caused 30,000 ER visits in 2009 ! According to CDC
Overdose deaths in United States
! According to the CDC in 2013 43,982 drug overdose deaths in US
! 37% or 16,235 involved opioids
! From 1999 to 2013 overall death from drug overdose doubled ! Same time period overdose deaths involving opioids quadrupled
Drug interactions ! Azelastine nasal spray contraindicated with CNS depressants
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Drug interactions ! Azelastine nasal spray contraindicated with CNS depressants
Drug interactions ! Azelastine nasal spray contraindicated with CNS depressants
Drug interactions ! Azelastine nasal spray contraindicated with CNS depressants
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New formulations of opioids
! Goal is to produce safer opioid analgesics through products that deter abuse
! FDA considers this a public health priority
Abuse deterrent formulations
! Physical chemical barriers ! Use tablet formulation to prevent extracting the opioid through solvents
! Agonist/Antagonist combinations ! Antagonist can be sequestered and released upon maniupulation
Abuse deterrent formulations
! Delivery system ! Drug release designs or drug delivery formulations that deter abuse-
example depot formulations
! Prodrug ! Drug lacks activity until it is metabolized to active opioid
! Combination ! Combine methods
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Single agent hydrocodone (Zohydro ER)
! Metabolized through the CYP2D6 (minor) and CYP3A4 (major) ! Patient should take whole capsule- do not crush, chew or dissolve
pellets
! Capsule size available ! 10mg, 15mg, 20mg, 30mg, 40mg, 50 mg
! Cost- $7 to $8 per capsule
Oxymorphone (Opana and Opana ER)
! Available as a solution for IV, IM or SubQ, immediate release formulation, ER 12 hour abuse deterrent oral and 12 hour oral (generic) ! Opana ER and Opana must be taken on an empty stomach
! Cmax and AUC were 38% higher when taken with food
! Dose reduce for hepatic and renal dysfunction ! Plasma levels of ER 40% higher in patients >65 yo
Oxymorphone
! Metabolized by glucuronidation to active and inactive metabolites ! Most drug interactions are CNS depression combinations
! Starting doses in opioid-naive ! Short acting 10mg to 20 mg q 4-6 hours
! ER 5 mg q 12 hours
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Oxymorphone
! Short acting and long acting abuse deterrent formulation formulations ! Bioavailablilty of oral formulation is 10%
! Converting from IV to oral use 10 X the IV dose
! ER give q 12 hours, short acting give 4 to 6 times a day
! Cost ! 1 ml of 1mg/ml solution = $3.75
! ER 5 mg tab cost = $2.45 40 mg cost = $15.69
! Short acting tabs 5 mg = $4.55 generic 5mg = $3.23
Oxymorphone (Opana and Opana ER)
! This table is ONLY for conversion to Opana ER (not from Opana ER to other oral opioids
Prior Oral Opioid Approximate Oral Conversion
Factor
Oxymorphone 1
Hydrocodone 0.5
Oxycodone 0.5
Methadone 0.5
Morphine 0.333
Exalgo (hydromorphone extended released tabs)
! Available in 8, 12, 16, 32 mg tabs
! Same conversion factor
! Claims of abuse deterrent formulation with physical barrier
! When converting from another opioid convert to oral hydromorphone ! Then give half of the dose in long acting formulation once a day
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Exalgo (hydromorphone extended released tabs)
! Cost (generic which has same claim as abuse deterrent) ! 8 mg = $13.53
! 12 mg = $20.30
! 16 mg = $27.07
! 32 mg = 54.15
Tapentadol (Nucynta)
! Opioid agonist indicated for ! Pain requiring ATC long-term treatment
! Neuropathic pain associated with diabetic nephropathy
! Starting dose of ER formulation is 50 mg BID ! Titrate in 50 mg increments
! Short acting formulation 50mg, 75 mg or 100 mg every 4-6 hours
! No abuse deterrent strategy noted in PI
Tapentadol (Nucynta)
! Drug interactions ! CNS depressants
! Serotonin syndrome with serotonergic drugs
! Anticholinergics- potential increase in urinary retention and constipation
! Metabolized by glucuronidation and excreted in urine ! Do not use in severe renal impairment
! Reduce dose in moderate hepatic impairment
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Tapentadol (Nucynta)
! Cost ! Short acting 50 mg = $3.19
! 75 mg = $3.69
! 100 mg = $49.20
! ER 50 mg = $3.40
! ER 150 mg = $8.10
! ER 250 mg = $10.32
Morphine/naltrexone (Embeda)
! Novel agent- contains pellets of morphine and sequestered naltrexone
Morphine/naltrexone (Embeda)
! Initial doses start at 20mg/0.8mg once a day ! Titrate every 1 to 2 days
! Conversion from oral morphine ! Give half of the total daily morphine dose as Embeda q 12 hours OR
all of the patient’s total daily dose as Embeda once a day
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Morphine/naltrexone (Embeda)
! Conversion from other opioids to Embeda ! Dc all opioids, initiate Embeda at 30mg/1.2mg once a day
No established conversion ratios to Embeda
! Conversion from IV morphine ! Oral dose 3x the IV
Oxycodone formulations
! Oxycontin ! New formulation approved since April 2013
! Tablet more difficult to crush
! Forms viscous hydrogel when crush and dissolved
! Performed abuse deterrent studies ! Gave crushed “original” oxycontin, powder oxycodone, or crushed
newer formulation oxycontin to 30 recreational opioid users
! Blinded crossover study
! New formulation preferred the least
Oxycodone formulations
! Xartemis XR-oxycodone and acetaminophen ER tabs ! 7.5 mg oxycodone/325 mg acetaminophen
! Indicated for treatment of acute pain ! Dose
! As first opioid analgesic 2 tabs q 12 hours, second dose can be as soon as 8 hours after first if patient requires, then go back to q 12 hours
! Contains an immediate release portion of the tablet. ! Tablet swells in gastric fluid and, slowly releases the remainder of dose
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Biblioraphy
! LH Chen, H Hedegaard, M Warner QuickStats: Rates* of Deaths from Drug Poisoning† and Drug Poisoning Involving Opioid Analgesics§ — United States, 1999–2013 Internet accessed 4/2015 fromhttp://www.cdc.gov/mmwr/preview/mmwrhtml/mm6401a10.htm
! J Fudin, The Perfect Storm: Opioid Risks and 'The Holy Trinity’ Internet accessed 4/2015 http://www.pharmacytimes.com
! Lexicomp data base on internet Accessed 4/2015
! Addict. 2010 ; 19(1): 4–16. doi:10.1111/j.1521-0391.2009.00005.x.
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