Opiates
Opiate Overview
• Opiates are derived from the poppy plant
(Papaver somniferum) first cultivated in
Mesopotamia (the ‘joy plant’)
• Opium = crude resinous exudate, often
dried and powdered, can be used
unprocessed
• Used for medicinal purposes (pain relief,
diarrhea, etc.) and for recreation
• Active ingredients include over 25 alkaloids,
most importantly morphine (10% of opium),
codeine (3% of opium), and thebaine
Continued
• Opiates include opium, morphine, codeine, derivatives
(e.g. diacetylmorphine or heroin) and synthetics (e.g.
methadone)
• Refinement of opium
– Morphine made from opium - increased strength 10X
– Heroin refined from morphine (more lipid soluble), made it even
stronger (3X)
– Codeine 1/5 the strength of morphine
Use and Abuse
Pain medication is the second most common type of drug
abuse in adolescents and adults behind marijuana.
Use and Abuse (cont)
Generation RX
According to the Partnership for a Drug Free America, the most popular
prescription drug abused by teens is Vicodin followed by Oxycontin.
Common Pharmacokinetics
• Opiates administered by various routes
–
–
–
–
Oral: 20-30 min to reach brain
Insufflated: 5-8 min
IV: 15-30 seconds
Smoked: 7-10 seconds
• Metabolized into active and inactive
components by kidneys
• Eliminated mostly in urine
Opiate Effects
• Opiates inhibit brain centers (depress CNS activity)
controlling:
– pain, coughing, breathing, heart rate and intestinal motility.
• Opiates depress nerve transmission in sensory pathways
of the spinal cord and brain that signal pain.
• Widening of blood vessels (vasodilation - produces a
warm feeling, sweating, reduces bowel activity)
• Overall lethargy and lack of motivation
• At high doses, sedation occurs (overdose results in coma,
unconsciousness, death)
• Combined with other depressants (e.g., alcohol) can be
deadly (>50% of overdose cases involve alcohol)
Transmission of Pain
• Stimulus Nocioceptors
• Nocioceptors are ~ 80% C fibers (unmyelinated –
slow pain) and 20% A delta fibers
(cold/pressure/fast pain).
• About 50% of sensory fibers have nocioceptive
functions.
• C fibers are blocked in the presence of opiates.
• A delta fibers are unaffected by opiates
Acute/Chronic Effects
SYSTEM
ACUTE
CHRONIC
CNS
Analgesia
Euphoria
Sedation
Cough suppression
Dependence
Peripheral Neuropathy
Spinal disease
Visual impairment
Mood instability
Respiratory
Respiratory depression
Respiratory disease
(pneumonia, TB)
Gastrointestinal
Decreased propulsions
Decreased digestive
secretions
Constipation
Eyes
Pupillary contraction
Kidneys
Inhibition of urinary
voiding reflex
Kidney disease
Sexual
Reduced libido
Irregular menstruation
Pharmacodynamics
• Opiates bind to opioid
receptors, including
the
– mu, delta, epsilon,
kappa receptors
• These G-proteincoupled receptors are
involved in the
transmission of pain
signals.
Neurotransmitters
Endorphins, Dynorphins, Enkephalins,…
• Called natural opiates
• Involved in glucose regulation
• natural neural peptides that bind to opioid
receptors to produce euphoric effects
• Released by brain when exposed to opiates
Neurotransmitters
GABA
• Affects dopaminergic cells
• Opiates and opioid NTS’s
activate the presynaptic
opioid receptors on GABA
neurons
• This inhibits the release of
GABA in the VTA
• Inhibiting GABA allows the
dopaminergic neurons to
fire faster
Morphine
first isolated in 1804 by Friedrich Serturner
• Direct/indirect agonist
• Most often administered subcutaneously; also smoked, taken
orally, or via mucosa
• Not very lipid soluble, doesn’t cross BBB easily
"Oh, jab me with your needle a hundred times
And a hundred times I will bless you, Saint Morphine"
Jules Verne (1828 - 1905)
Codeine
(methylated morphine)
• Direct/indirect agonist
• Alkaloid found naturally in opium in low
concentrations (0.1-2%); usually
synthesized from morphine
• Usually administered orally
• 0.1 times as potent as morphine
• Converted into morphine after crossing
BBB
• Used for cough suppression, diarrhea,
moderate pain
Heroin (diacetylmorphine)
• Direct/indirect agonist
• Synthesized from morphine
• Administered IV, SC, snorted or
smoked
• IV and smoked lead to fast onset and
“rush”
• 3 times as potent as morphine
• Not directly an efficacious mu
agonist, but more lipid soluble than
morphine
• Enters brain quickly, converted into
morphine for action
Methadone (methadone hydrochloride)
• Partial agonist
• Completely synthetic
• Orally administrated
• Mild/moderate effects over long
time period (days)
• Used in treatment of opiate
addiction to prevent withdrawal
and craving
• Minimizes effects of short-term
opiates taken under influence of
methadone
Methadone treatment
•
•
•
•
•
Safer, less contaminated
Taken orally - avoids injection
No worries about where next hit is coming from
Lasts longer in the body (taken once a day)
Allows withdrawal from drug use with less
discomfort
• Reduces criminal activity
• Cuts connection with drug scene
• It’s cheaper
Oxycodone
• Opioid Analgesic
• Synthesized from opium-derived
thebaine; structurally similar to
codeine
• Ingested orally in tablet form
• Schedule II controlled substance
• Can only be legally obtained by
prescription
• OxyContin is time release oral
oxydodone.
Vicodin
• Narcotic Analgesic
• Hydrocodone bitartrate (opioid
analgesic) and Acetaminophen
(non-opiate analgesic)
• Ingested orally in tablet form
• Schedule III controlled substance
• Can only be legally obtained by
prescription
Naloxone (Narcan)
• Synthetic direct antagonist
• Administered IV; onset = 2 min
• Few low-dose effects on normal
persons
• Rapidly precipitates withdrawal in
opiate-dependent persons
• Elicits tobacco craving in dependent
individuals
• Used to reverse respiratory
depression from overdoses
Naltrexone (Trexan)
• Direct antagonist
• Administered orally
• Works like naloxone but since oral
more useful for long-term
• Used after recovery from
withdrawal period (also used to
treat alcoholism)
• Prevents opiate agonists from
having an effect
Tolerance
• Develops to respiratory depression,
analgesia, euphoria, sedation
• Little tolerance to pupil-constriction
and constipation
• Profound behavioral/associative
tolerance
• Cross-tolerance develops between
different opiates and between
opiates and opioids
Mechanisms for Tolerance
• Downregulation (conversely, antagonists upregulate)
• Decreased receptor sensitivity
• Reduced synthesis of opioid peptides
• Also, another possible mechanism, based on synthesis...
Change in Opioid Synthesis
1) POMC yields two major species of betaendorphins, “normal” longer form and
shorter form; in brains of normal rats
ratio between 1:1 and 1.5:1
(normal:short)
2) Hammonds et al. (1984) showed short
version seems to be an antagonist
capable of reversing many of the effects
of the “normal” long version
3) Bronstein et al. (1990) showed rats made
tolerant to morphine (3 days with
subcutaneous pellets) have ratio of
almost 1:2 (in favor of short version)
“normal”
(agonist)
“short” acts as
antagonist
Opiate Withdrawal (5-10 days)
A. Either of the following:
(1) Cessation of (or reduction in) opiate use that has been heavy and prolonged
(several weeks or longer)
(2) Administration of an opioid antagonist after a period of opioid use (rapid vs slow
abstinence)
B. Three or more of the following, developing within minutes to days after Criterion A:
(1) Dysphoric mood, depression
(2) Nausea or vomiting
(3) Muscle aches, cramps, tremors
(4) Watery eyes or runny nose
(5) Dilated pupils, goosebumps, or sweating
(6) Diarrhea
(7) Yawning
(8) Fever
(9) Insomnia
C. Symptoms in Criterion B cause clinically significant distress or impairment in social,
occupational, or other important areas of functioning.
Protracted Abstinence Syndrome
• Can last up to 6-7 months after
withdrawal
• Vague sense of feeling abnormal
• Depression (increased propensity to
sleep)
• Abnormal response to stress
• Abnormal respiration and temperature
• Decreased self-esteem
• Anxiety
• Craving
• Confounded by high comorbidity with
other psychiatric disorders
Additional Problems
• Neonatal Effects: cross the placental barrier giving large
doses to unborn fetus
• Overdose: occurs when so much of the drug enters the
brain the nervous system shuts down. Blood pressure
drops, heart becomes to weak to pump blood, lungs labor
& fill with fluid
• Dirty & Shared Needles: Hepatitis B & C, HIV, flesh eating
bacteria, gangrene, endocarditis, malaria, syphilis
Polydrug Use
• Mixing: Opioid users often mix cocaine or
amphetamine, “speedball” - combine heroin &
marijuana to give it more kick.
Alcohol & benzodiazepines create synergistic effects
increase potential for overdose, respiratory
depression & death
• Cycling: Addicts go on & off their drug of choice.
Lowers tolerance & tissue dependence so the body
can attempt to return to normal.
Switch to alcohol, marijuana, barbiturates,
benzodiazepines
Treatment
• Conventional Detox Centers
– Buprenorphine, Subutex
• Opioid partial agonist
– Once abstinence begins,
buprenorphine minimizes
discomfort
– When fully detoxed,
buprenorphine is phased out.
– Lasts 10-14 days.
Treatment (cont)
• Rapid Opiate Detox
– Lasts 4-6 hours, released 24-48 hours
after
– Patient is anesthetized so that the
patient does not experience withdrawal
– Naltrexone
• opioid blocker
– Naloxone
• counteracts effects of opioid
Treatment (cont)
• Detox is only the beginning
– Continuing programs are needed to prevent relapse
• Methadone-based programs exist…
– But not as popular
– Methadone is only a replacement
• Cognitive therapy, 12-steps, meditation/hypnosis, etc