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 RXAccording 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 EffectsSYSTEM ACUTE CHRONIC

CNS AnalgesiaEuphoriaSedationCough suppression

DependencePeripheral NeuropathySpinal diseaseVisual impairmentMood instability

Respiratory Respiratory depression Respiratory disease(pneumonia, TB)

Gastro-intestinal

Decreased propulsionsDecreased digestive

secretions

Constipation

Eyes Pupillary contraction

Kidneys Inhibition of urinaryvoiding reflex

Kidney disease

Sexual Reduced libido Irregular menstruation

Pharmacodynamics

• Opiates bind to opioid receptors, including the – mu, delta, epsilon,

kappa receptors• These G-protein-

coupled 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

Morphinefirst 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 timesAnd 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 beta-

endorphins, “normal” longer form and shorter form; in brains of normal rats ratio between 1:1 and 1.5:1 (normal:short)

“normal”(agonist)

“short” acts asantagonist

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)

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

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