OpiatesBrian J. Piper, Ph.D.

Goals

History

Examples

Pharmacodynamics

Treatment

Epidemiology

Terminology

• Opiate: family of substances• Narcotic: class of drugs including opiates• Opioid: family receptors• Analgesics: drugs that decrease pain without

unconsciousness• Anesthetic: drugs that decrease pain with

unconsciousness• Naloxone (Narcan): short acting opioid antagonist

• Naltrexone: long-acting opioid antagonist

History129-199 1783-1841

1817-1884

Widespread use of morphine in US between 1865-1906

Mrs. Winslow's Soothing Syrup was an indispensable aid to mothers and child-care workers. Containing one grain (65 mg) of morphine per fluid ounce, it effectively quieted restless infants and small children. It probably also helped mothers relax after a hard day's work. The company used various media to promote their product, including recipe books, calendars, and trade cards such as the one shown here from 1887 (A calendar is on the reverse side.).

Source: Prof. Anagnostaras, UCSD

Origin Chemistry Schedule

Morphine Opium

poppyII (II-III)

Heroin Felix Hoffman, Bayer

Production in 1898

Acetyl=OCOH3

OH to Acetyl

Diacetylmorphine

I

Oxycodone Synthesized in 1916, Oxycontin produced in 1995

H to OH

OH to =OII (II-IV)

Codeine Identified in 1832? -OH to 0CH3

MethylmorphineII

(III-IV)

History

Source: Prof. Anagnostaras, UCSD

In the following years, Heroin was a drug marketed by Bayer as a cough syrup without the nasty side effects of morphine.

Potency (x-axis) vs. Efficacy (y-axis)

100

75

50

25

1Log dose (mg)

10 100

HydromorphineMorphineCodeineAspirin

Response

Safety

• Effective Dose

ED50 - Dose that produces an effect in 50% of a population

Lethal/Toxic Dose

LD50 - Dose that kills 50% of a population

• Safety Factor

LD50 /ED50

Drug B100

50

Log drug doseLow HighED50 TD50

100Drug A

50

Low HighLog drug doseED50 TD50

Pharmacodynamics

• Opioid Receptors• Mu: • Kappa:• Delta:

Delta Opioid Receptor

Delta Opiate Receptor

Tradham (2011) Trends in Pharmacological Science, 32, 581-590.

Mu Receptor Distribution

Kappa Opiate Receptor

More terminology

• Pro- larger precursor proteins (peptides)

• Protease- enzyme that cut propeptide

Endogenous Substances

Knock-out

• Knock-out: animal with gene made inoperative

• Allele: alternative forms of gene

• Diploid: organism with two sets of genes for each trait

• Homozygote: +/+ or -/-• Heterozygote: +/-

Genotype Response

+/+ Full

+/- Partial

-/- Absent

C57 Mouse

KO Example

• Different opiate receptor (OR) knock-outs were tested

• Male and female mice were placed on hot plate and time until jumping was recorded.

• Filled Star: p < .05 sex difference within genotype (e.g. 1 vs. 2)

• Open Star: p < .05 genotype difference within sex (e.g. 1 vs. 3)

• What do you conclude?

Martin, M. (2003). Eur J. Neurosci 17, 701-708.

1 2 3 4

KO Example

• Some evidence for sex difference A,D vs. B,C.

• Mu opiate receptor is important for thermal pain (males).

• Other receptors also play a role in females.

Martin, M. (2003). Eur J. Neurosci, 17, 701-708.

A

B

C

D

Comparison of Opioid Receptors

Receptor Ligand Location Function

Mu Endorphin Striatum, NAc, PAG Analgesia

Delta Enkepahlin Striatum, NAc, spinal cord Analgesia, olfaction

Kappa Dynorphin Striatum, NAc,hypothalamus Temperature

PAG: periaqueductal grayNAc: nucleus accumbens

Periaqueductal Gray

• Midbrain structure

• Near cerebral aqueduct

OppositesEffect Administration Withdrawal

Temperature Hypothermia Hyperthermia

Blood pressure ↓ ↑

Pupils constriction dilation

Breathing depressed panting/yawning

Pain ↓ ↑

Arousal relaxed restless

G.I. function constipation diarrhea

Sex ↓ sex drive Spontaneous

ejaculation

Mood euphoria depression

Grilly, D.M. (1998). Drugs and human behavior. Allyn: Needham Heights.

Dopamine & Behavior

Murphy et al. J Neurochem (2001) 79, 626-635.

Mice of different strains: C57 (black), 129SV (white), and DBA2 (grey) received 3 mg/kgof morphine or saline (arrows). Motor-activity (left) and dopamine in the striatum (right) was recorded.

Naltrexone

• The opiate antagonist naltrexone (5 ng/kg) blocks the conditioned place preference to morphine (5 mg/kg).

• Conditioned Place Preference (CPP)

– Pretest: Drug Treatment– Test: no Drug, animals

choose whether to spend time in environment associated with drug injections

Olmstead et al. (2005). Psychopharm, 181, 576-81.

Codeine Addiction

• Codeine -----> Morphine• Fluoxetine inhibits 2D6• Will fluoxetine help

codeine addicts reduce their use?

• All groups reduced codeine intake by >40%.

2D6

Daily dose of codeine in people that receivedcounseling and fluoxetine (circles), quinidine (triangles), or placebo (squares).

Fernandes et al. (2002). J Clin Psychopharm, 22, 326-329.

Opiate Addiction Therapies

• Narcotics Anonymous: 12 step program, limited effectiveness

• Methadone: long-acting opiate agonist (oral)

• LAAM: L-alpha-acetyl-methadol: longer acting opiate agonist

Tx: Methadone

• Pill form used to prevent opiate withdrawal

• Pros: limits use of other opiates

• Cons: philosophical

Epidemiology (MtF)

Epidemiology: Heroin

MTF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

Epidemiology: Heroin

MTF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

Epidemiology: Vicodin

MTF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

Urban vs. Rural

Epidemiology: College Plans

MTF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

Epidemiology: Non-Heroin

MTF: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

Celebrity Overdoses

1943-19701979-2008 1964-1997

1943-1971

1949-1982 1960-1988

Celebrity Overdoses

1943-19701979-2008 1964-1997

1943-1971

Heath Ledger Janis Joplin Chris Farley Jim Morrison

1949-1982 1960-1988

John Belushi Jean-Michel Basquiat

Overdose

Summary

• History/Examples

• Pharmacodynamics: Mu, Delta, Kappa

• Epidemiology

3 min: http://www.npr.org/player/v2/mediaPlayer.html?action=1&t=1&islist=false&id=12131233&m=12131234