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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.