Opiates

1
Opiates

• Chapter 10

2
Opiates/Opioids

• Opiates
• alkaloids found in the opium poppy (Papaver
  somniferum)
• Gk. opion poppy juice
• Opioids
• compounds with opiate-like actions, including,
  but not confined to opiates (e.g., synthetic,
  endogenous opioids)

3
Opiates/Opiods

• Opiates are natural and synthetic compounds that
  come from or are copied from OPIUM the resin of
  the opium poppy
• Natural Narcotics
• Opium
• Extracts Morphine Codeine
• Semisynthetic Narcotics
• Slight changes to chemical composition of
  morphine
• Heroin
• Synthetic Narcotics - Produce opiate-like
  responses
• Methadone, Talwin, Darvon, Demerol
• BUPRENORPHINE Partial agonist

4
History of Opium

• Native to many regions
• Middle East in areas bordering Mediterranean
• Laos, Thailand, Afghanistan
• Mexico Colombia
• Use dates back 6000 years to Sumerians
• Egyptians used it medically 3500 years ago
• Common use among Islamic peoples for medical
  recreational purposes

5
History of Opium

• Arab traders took to India China
• Western Europe learned about it from Arabs during
  crusades
• 1680 Laudanum Opium tincture (alcohol)
• Next 200 years, primary consumption of opium is
  as drink
• 18th century - development of opium smoking in
  China
• China - first laws against Opium use in 1729
• Dependence problem recognized

6
Opium the West

• Western societies
• Used opium as aspirin
• Cheaper than liquor
• No negative public opinion
• No real problem with cops
• Used to soothe infants children
• Teething, colic, or to keep them quiet
• Females used it more than males
• Greater addicted

7
Opium and the West

• Collision of cultures
• Chinese building railroad
• 1875 - San Francisco outlawed opium dens opium
  smoking
• Laws targeted not at opium (laudanum legal), but
  at Chinese
• Federal laws prohibiting opium smoking
  followed

8
Difference in Opium Use

• Major difference between opium use in China
  West was method of consumption
• Laudanum
• Identified with Victorian Era
• Opening of respectable parlors
• Chinese smoked it
• Identified with Opium Dens
• Ideal of lazy Chinese
• Seen as degrading dirty vice

9
Morphine the West

• 1803 - morphine separated from opium
• Increased dependence potential
• Morphine 10 X opium potency
• Morpheus, the Greek God of dreams
• 1856 - development of hypodermic needle
• Use became widespread
• Doctors began injecting opium solutions (thought
  to sidestep addiction, thought to be purer
  safer )
• Used during Civil War for injuries (dependency
  known as soldiers disease)

10
Heroin From Bad to Worse

• In 1874, British chemist altered morphine into
  heroin
• Unnoticed until rediscovered in 1898 (Bayer)
• 3-4 X more potent than morphine
• Thought to be safer than morphine
• Sold by Bayer - beginning in lieu of codeine as
  medicine for coughs, bronchitis, tuberculosis
• Heroin also began to replace morphine in addicted
  individuals

11
Opiates in US Early 1900s

• Harrison Act of 1914
• No ban on opiates, but doctors had to register
  with IRS
• Decreased prescriptions
• Users not seen as victims but as weak
• Heroin drug of choice in black market
• Shift of users from women to white urban adult
  males

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Opiates Use in 1960s

• Three Major Social Developments
• Crackdown caused shortage of heroin increased
  smuggling price
• Increased levels of crime
• Increased used by urban minorities
• Drug culture
• Vietnam War
• Many veterans came back hooked

13
Opiates Use in 1980 -Today

• Fentanyl China White
• Surgical anesthetic prescription painkiller
• 10 to 10,000 X stronger than heroin
• Growing illegal market growing deaths
• Heroin Schedule I
• Morphine Schedule II
• Vast majority of therapeutic opiates are
  synthetic
• Huge illegal market and trade with large
  dependence problem in U.S. and abroad

14
Opiates Today - OxyContin

• Killers
• OC
• OXY
• Oxycotton
• Hillbilly Heroin
• Cotton
• Blue

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Non-medical Use

• Studies indicate that the nonmedical use of
  prescription medications is increasing in the
  U.S. among adolescents and young adults.
• The nonmedical use of prescription medications is
  associated with higher rates of tobacco, alcohol
  and other drug use
• 5 of 12 to 17 year olds reported nonmedical use
  of scheduled pain medications
• 12 of 18 to 25 year olds reported nonmedical use
  of scheduled pain medications.

lifetime
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Nonmedical Use of Prescription
Medications, Ages 12-25
Percent Using in Past Year
NSDUH, 2005
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Annual Prevalence by Gender
Monitoring the Future, 2005 12th grade
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Past Year Nonmedical Use

reporting medical use

• p lt 0.05, p lt 0.01 based on Pearson
  chi-square tests Source McCabe, Teter,
  Boyd, 2006

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Specific Prescription Opioids Used Nonmedically
(Past Year)

The past year use was 2 or less for fentanyl,
hydromorphone, meperidine, methadone, and
tramadol.
SLS, 2005
Source McCabe, Cranford, Boyd Teter,
2007"Addict Behav 2006\7
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Gender Differences in Motives for nonmedical Use
of Prescription Opioids


SLS, 2005 check all that apply
plt.05, plt.01, plt.001
Source McCabe Cranford, Boyd Teter, Add
Behaviors, 2007
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Absorption, Distribution, Metabolism Excretion

• Most opiates poorly absorbed through GI tract
  (except codeine)
• Effective nasally and through lungs
• Opium frequently smoked, heroin snorted
• Most effective IV (heroin 100 times more potent
  IV than orally)

22
Absorption, distribution excretion

• In bloodstream, distributed throughout body
• accumulating in kidney, lung, liver, spleen,
  muscle brain
• Opiates and blood brain barrier
• Morphine does not cross BBB well
• only 20 of circulating enters brain
• 30-60 min to reach significant brain
  concentrations

23
Absorption, distribution excretion

• Heroin more lipid soluble, so penetrates BBB
  better
• - Heroin converted to morphine once it crosses
  the BBB

24
Absorption, distribution excretion

• All have somewhat different pharmacological
  effects
• Differ in potency, duration of action oral
  effectiveness
• Heroin more potent than morphine when injected,
  but same when taken orally

25
Mechanism of Action

• Act via the endogenous opiate system
• 1960s - discovery of the opiate antagonist
  naloxone
• 1973 - discovery of "opiate receptors in brain
• Led to discovery of several endogenous opiates
  in 1975
• Endorphin
• Enkephalin
• Dynorphin

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Opioid receptors

• Subtype
• Mu (µ)
• Delta (?)
• Kappa (?)
• Subtypes have subtypes

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Pharmacological Actions

• Primary sites of action - CNS and GI tract
• Abuse of opiate use due to
• Analgesia (best for dull continuous pain, not
  sharp)
• Due to CNS not PNS effects
• Euphoria (dream-like state with intense visions)
• Relieves negative mood states

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Medical Use

• Analgesia
• Sedation - markedly differs between individuals
• poor sedative in general
• Anti-diarrheal agents
• extremely effective for dysentery (1800s)
• were the only effective agents in that time

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Analgesia

• Spinal actions
• inhibit incoming pain signals

Opioid receptor
12.8
30
Reinforcing effects

• All classical opioid drugs of abuse have a
  preference for µ sites (e.g., morphine, heroin,
  methadone, fentanyl etc.)
• µ compounds
• Increase DA cell firing
• Increase DA release in NA
• Kappa compounds have opposite effect
• Dynorphin likes kappa receptors

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Side Effects

• Vomiting
• very common with first dose
• Respiratory depression
• Decrease sensitivity to CO2
• Occurs at low doses - those common for analgesia
• Increase dose - increase depression
• Most common cause of death in overdose
• Biliary Constriction

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Side Effects

• Body temperature
• Resetting of body temperature thermostat
• with limited use, lowers temperature by about 1
  degree
• can persist for a month
• Sex hormones
• Inhibited
• Males - decreased testosterone levels, decreased
  sex drive
• Females - decreased estrogen

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Side Effects

• Cardiovascular effects
• increased skin blood flow - gives them a warm
  feeling
• Blood pressure decrease upon standing - faint
• Pinpoint pupils
• Signs of overdose
• Seizures

34
Tolerance Dependence

• Develops fast with repeated use
• More rapidly and to greater degree as potency
  increases
• Constipation and biliary constriction not subject
  to tolerance
• Cross-tolerance based on receptor affinity
• Neuroadaptation to numerous brain areas leads to
  dependence

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Withdrawal

• Withdrawal - onset related half-life of opiate.
• 6-8 hrs gt drug seeking behavior, restless,
  anxious
• 8-12 hrs gt Pupils dilated, reactive to light
  increased pulse rate, blood pressure, yawning
  chills rhinorrhea lacrimation gooseflesh
  sweating restless sleep
• 48-72 hrs (peak) gt All of the above plus
  muscular weakness, aches (cramps) and twitches
  nausea, vomiting and diarrhea temperature and
  respiration rate elevated heart rate and blood
  pressure elevated dehydration.
• Withdrawal managed in a number of ways
• Cold Turkey
• Medically managed
• Ultra-rapid Detox

36
Methadone Maintenance

• Methadone used as a replacement for heroin and
  other opiates in dependent individuals
• Longer half-life
• Slower, less intense effects no euphoria
• Can be taken orally no needles
• Cheap
• Blocks heroin effect
• Methadone withdrawal 24-48 hrs after last dose
• withdrawal symptoms reported to be less intense
• however, much greater duration
• can take months to clear all withdrawal symptoms

37
Buprenorphine

• Partial Agonist
• Low levels agonist
• High levels antagonist
• Can be managed by physician
• Taken sublingually every 24-48 hours
• Can bridge the gap between methadone and nothing
  or used long-term