Chapter 10

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)

 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

 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

 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  18 th century - development of opium smoking in China  China - first laws against Opium use in 1729  Dependence problem recognized

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

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

 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

 morphine separated from opium  Increased dependence potential  Morphine 10 X opium potency  Morpheus, the Greek God of dreams  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 “ soldier ’ s disease ” )

 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

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

 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

 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

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

 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*. 15 * lifetime

16 Percent Using in Past Year NSDUH, 2005

17 Monitoring the Future, th grade

18 % reporting medical use Past Year Nonmedical Use ** * *p < 0.05, ** p < 0.01 based on Pearson chi-square tests Source: McCabe, Teter, Boyd, 2006

19 Specific Prescription Opioids Used Nonmedically (Past Year) The past year use was 2% or less for fentanyl, hydromorphone, meperidine, methadone, and tramadol. % Source: Addict Behav 2006\7 Source: McCabe, Cranford, Boyd & Teter, 2007" Addict Behav 2006\7 SLS, 2005

20 Gender Differences in Motives for nonmedical Use of Prescription Opioids *** *p<.05, **p<.01, ***p<.001 Source: McCabe Source: McCabe Cranford, Boyd & Teter, Add Behaviors, 2007 SLS, 2005; check all that apply

 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)

 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 min to reach significant brain concentrations

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

 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

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

 Subtype  Mu (µ)  Delta (  )  Kappa (  )  Subtypes have subtypes

 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

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

Spinal actions  inhibit incoming pain signals Opioid receptor 12.8

 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

 Vomiting  very common with first dose  Respiratory depression  Decrease sensitivity to CO 2  Occurs at low doses - those common for analgesia  Increase dose - increase depression  Most common cause of death in overdose  Biliary Constriction

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

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

 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

 Withdrawal - onset related half-life of opiate. 6-8 hrs => drug seeking behavior, restless, anxious 8-12 hrs => Pupils dilated, reactive to light; increased pulse rate,  blood pressure, yawning; chills; rhinorrhea; lacrimation; gooseflesh; sweating; restless sleep hrs (peak) => 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

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 hrs after last dose  withdrawal symptoms reported to be less intense  however, much greater duration  can take months to clear all withdrawal symptoms

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