PSY 320 - Ch 13 - Opioids
PSY 320 - Ch 13 - Opioids PSY 320
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PSY 320 Drugs & Behavior Chapter 13 Opioids Opioids • Psychoac▯ve substances that elicit pharmacological eﬀects by ac▯ng on opioid receptors in CNS & other parts of body ◦ Prescrip▯on pain medica▯ons & non medical use of heroin ◦ Highly eﬀec▯ve pain-relieving medica▯ons ◦ Substances of abuse • Narco▯c: La▯n for "sleep inducing" ◦ Though opioids are used as analgesics rather than sleeping aids • Natural opioids - found in opium exudant from poppy plants ◦ Paver Somniferum ◦ Substances derived from opium poppy ◦ Primary naturally occurring opioids found in opium - Morpheme & Codeine • Semisynthe▯c opioids - synthesized from morphine or codeine ◦ Created from naturally occurring hydromorphine, hydrocodone, oxycodone, diacetyl morphine (heroin) • Fully synthe▯c opioids - not derived from any naturally occurring opioid ◦ Fentanyl, methadone History Ancient history • Opium - Raw plant substance containing morphine & codeine • One of the oldest discovered drugs • Sumerians in Mesopotamia were among ﬁrst ppl iden▯ﬁed to have cul▯vated poppy plant CB 00 43 dnuo◦r A ◦ Hul Gil - "The Joy Plant" ◦ Eaten to ease pain/suﬀering • 1500 BC Ancient Egyp▯an medical textbook described medical uses • Opium use eventually spread thru ancient world to every major civiliza▯on in Europe & Asia & was used to treat pain/ailments PSY 320 Drugs & Behavior • 400 - 300 BC Greece & Rome ◦ Hippocrates detailed sleep inducing & pain relieving eﬀects of opium ◦ Galen also promoted beneﬁcial eﬀects for a range of ailments • 900 - 1100 AD Arabic world ◦ Arab physicians wrote widely about medical use ◦ Wrote about addic▯ons & medical prac▯ces ◦ Spread to India & China thru trade ◦ Used as social drug Opium Wars • 1644 Tobacco smoking banned in China • Contributed to increase in opium smoking • Opium smoking in combina▯on w/ tobacco gained popularity ◦ Rapid absorp▯on/onset of eﬀects • 1729 Chinese law banned opium smoking, mandated opium shop owners be strangled • Smuggling business grew • Britain proﬁted from trading w/ China & selling opium • 1839 - Opium Wars set oﬀ by Bri▯sh sailors killing a Chinese ci▯zen ◦ Britain won in 2 yrs • 1906 Britain passed a bill to end the opium trade by 1913 Pa▯erns of Abuse in the US • Transforma▯on of the prac▯ce of medicine ini▯ated tension btwn desire to make medicinal beneﬁts available & recogni▯on of abuse & addic▯on • 2 beneﬁts: ◦ Reduces diarrhea & subsequent dehydra▯on from dysentery, a leading cause of death in developing countries ◦ Relieves anxiety • 1803 morphine was extracted from opium by Friedrich Serturner in Germany • Dr. Charles Wood (Sco▯sh physician) invented hyperdermic needle to inject morphine to relieve pain from neuralgia • Dr. Eduard Livenstein (German physician) produced 1st accurate & comprehensive descrip▯on of addic▯on to morphine, including withdrawal symptoms & relapse ◦ Argued that craving for morphine was a physiological response • Diacetylmorphine (brand name Heroin) synthesized & brieﬂy promoted as more eﬀec▯ve & less addic▯ve than morphine • Early 1900s Heroin was legally marketed in pill form, used by young Americans to elicit euphoric high by crushing heroin pills into powder for inhala▯on or injec▯on • 3 types of dependence developed in the US in the late 1800s ◦ Oral intake increased as patent medicines spread ◦ Opium smoking increased a▯er 1850 • Chinese laborers arrived in the US ◦ Injec▯on of morphine - the most dangerous use • Number & propor▯on of Americans dependent on opioids peaked in the beginning of 1900s ◦ Possibly as high as 1% of the popula▯on • Dependence ini▯ally not viewed as a major social problem ◦ Opium smoking limited to certain groups ◦ Patent medicines socially acceptable PSY 320 Drugs & Behavior ◦ Opioid dependence viewed as a "vice of middle life" • Typical uses 30-50 y/old middle class white women wives/mothers • Drugs purchased legally in patent medicines • High levels in medicines made withdrawal symptoms severe & relieved only by consuming more 1914 Harrison Act • Revenue regula▯ons • Aﬀected court decisions & enforcement prac▯ces • 1915 Supreme Court decided possession of smuggled opioids was a crime • 1920s opioid clinics were closed due to pressure from federal oﬃcials • Number of oral opioid users declined ◦ Remaining group primarily injected morphine or heroin • Increased prices of illicit heroin lead to increased use in lower-class city areas ◦ Heroin became associated w/ black & La▯no users • 1973 Rockefeller Drug Laws ◦ Mandated minimum prison sentences of 15 yrs-life for possession of heroin in New York ◦ 2009 reformed by Gvnr Pa▯erson to reduce harsh sentences Vietnam War • ~1960s/70s • 10-15% of soldiers dependent on heroin ◦ Most returning soldiers were not dependent ◦ Only 1-2% con▯nued use 8-12 months a▯er returning from Vietnam Current Trends • Popular prescrip▯on opioids: ◦ Hydrocodone (Vidocin, Lortab) ◦ Oxycodone (Oxycon▯n, Percocet) • Prevalence of use: ◦ 2012 - 2% / 12 million Americans reported past year use ◦ Routes of administra▯on include oral, insuﬄa▯on, injec▯on • Safety concerns: ◦ DAWN data: prescrip▯on opioids rank 3rd for ER visits & 1st for deaths ◦ Most opioid overdoses occur in combina▯on w/ other seda▯ves like alcohol • Special problem of Oxycon▯n (Schedule II drug) ◦ Illicit users crush capsules to obtain a high dose Prescrip▯on opioid abuse: A ﬁrst step to heroin use? • Prescrip▯on opioid pain medica▯ons like Oxycon▯n & Vicodin have similar eﬀects to heroin when taken in doses/other ways than prescribed ◦ Currently among most commonly abused drugs in the US • Research suggests abuse of these drugs may open the door to heroin abuse • In 3 recent survey studies: almost half of young ppl who inject heroin reported abusing prescrip▯on opioids before star▯ng to use heroin ◦ Some individuals reported taking up heroin b/c it's cheaper & easier to obtain than prescrip▯on opioids ◦ Many report that crushing prescrip▯on pills to snort or inject provided their ini▯a▯on to these methods of drug administra▯on PSY 320 Drugs & Behavior Treatment of Chronic Pa in During most of 1900s: • Widely held percep▯on among US professionals was long-term use of opioid therapy to treat chronic pain was contraindicated by risk of addic▯on ◦ Increased disability & lack of eﬃcacy over ▯me During 1990s: • Major change driven by medical & nonmedical factors • Use of opioids for chronic pain increased • Substan▯al year-to-year rise that con▯nues today • Increased use for medical purposes accompanied by increase in prevalence of nonmedical use of prescrip▯on opioids • Inven▯on of PCA pump for pa▯ents to control morphine ﬂow a▯er surgery ◦ Found pa▯ents consumed less morphine when controlling it themselves Increases in prescrip▯on use: • Na▯onal Survey on Drug Use & Health reports # of ﬁrst ▯me abuses of prescrip▯on opioids increased from 628,000 in 1990 to 2.4 million in 2004 • Emergency room visits involving prescrip▯on opioid abuse increased 45% from 2000 to 2002 • Treatment admissions for primary abuse of prescrip▯on opioids increased 186% from 1997 to 2002 • Opioid abuse indices rose most for 2 frequently prescribed opioids: ◦ Hydrocodone & controlled-release (CR) oxycodone Current public health crisis: • March 22, 2016: FDA announced enhanced warnings for immediate-release opioid pain medica▯on (oxycodone) ◦ Related to risk of misuse, abuse, addic▯on, OD, & death • "Opioid addic▯on & overdose have reached epidemic levels over the past decade" • FDA's ac▯ons one of the largest undertakings for informing prescribers of risks across opioid products Public health crisis background: • In any given year, approx. 100 million ppl in the US suﬀer chronic pain • 9-12 million have chronic/persistent pain, while the remainder have short-term pain from injuries, illnesses, or medical procedures • All should beneﬁt from appropriate pain management: sen i c i dem d i o i po f o esu s uo i c i d◦ u J ◦ In conjunc▯on w/ other methods of treatment • In reality, physicians have been over-prescribing ◦ Short-term injury suﬀerers prescribed months worth of medica▯ons ◦ Seek prescrip▯ons from other doctors or illicit providers • Current crisis due to the devasta▯ng results of misuse/abuse • Leads to addic▯on of pa▯ents who've been prescribed opioids for pain treatment & increasingly diversion to ppl for whom the prescrip▯on was not wri▯en • # of annual opioid prescrip▯ons wri▯en in the US roughly equal to # of adults in the US • CDC: In 2014 there were 19,000 OD deaths in the US associated w/ prescrip▯on opioids • # of deaths from opioid overdoses now exceeds the # of deaths caused by motor vehicle accidents PSY 320 Drugs & Behavior • New FDA warnings (03/22/16) indicate b/c of extreme risks associated w/ use of IR opioids, they should be reserved for trea▯ng pain severe enough that alterna▯ve treatment op▯ons are inadequate • New boxed warning on IR opioid analgesics: ◦ Requires precau▯on against maternal use ◦ Use during pregnancy can result in neonatal opioid withdrawal syndrome (NOWS) ◦ Baby withdrawals may be fatal 3rd category of opioids: • Known as medica▯on-assisted treatment (MAT) • Drugs such as methadone & buprenorphine • Used as form of treatment for opioid addic▯on • In combina▯on w/ behavioral therapy & counseling Opium Characteris▯cs • Raw opium 10% morphine by weight • With added acetyl groups, heroin passes thru blood-brain barrier faster ◦ Makes heroin 2-3x more potent than morphine • Researchers have been searching for ways to separate analgesic & dependence-producing eﬀects of opioids Pharmacology: Mechanism of Ac▯on • Opioids act on selec▯ve receptors in the CNS & gastrointes▯nal tract • Opioids ac▯vate: ◦ Enkephalins - Morphine-like neurotransmi▯ers found in the brain & adrenals • Released from adrenal gland ◦ Endorphins - Morphine-like neurotransmi▯ers found in the brain & pituitary gland • Released from pituitary in response to stress • Natural & synthe▯c opioid drugs & endogenous opioids act on mul▯ple types of opioid receptors in the brain • Body can naturally release its own morphine-like substances for survival: ◦ I.E. Soldiers ba▯ling thru injuries or women enduring natural child birth More on Mechanism of Ac▯on • Ac▯va▯on of peripheral nocicep▯ve ﬁbers cause release of substance P & other pain-signaling neurotransmi▯ers from nerve terminals in the dorsal horn of spinal cord • Release of pain-signaling neurotransmi▯ers is regulated by endogenous endorphins or by exogenous opoid agonists by ac▯ng presynap▯cally to inhibit substance P release, causing analgesia • Reduc▯on or inhibi▯on of neurotransmission due largely to opioid-induced presynap▯c inhibi▯on of neurotransmi▯er release • Involves changes in tansmembrane ion conductance ◦ Increase potassium conductance (hyperpolariza▯on) ◦ Inac▯va▯on of calcium channels • Opioid receptors: ◦ Mu-1 - Found throughout the brain, responsible for analgesia & euphoria ◦ Mu-2 - Found throughout the brain, responsible for respiratory depression ◦ Kappa - Located in the brain stem & spinal cord, responsible for contrac▯on of eye pupils & seda▯on PSY 320 Drugs & Behavior ◦ Sigma - Located in the amygdala, hippocampus, & limbic system, responsible for anxiety & hallucina▯ons ◦ Delta - Located in the limbic system, responsible for analgesia as well as reinforcing proper▯es • Opioids almost always operate on receptors: ◦ Mu ◦ Kappa ◦ Delta Pharmacological Eﬀects • Pain Relief ◦ Diminish pa▯ent's awareness/response to pain • Primarily emo▯onal response to pain (suﬀering) ◦ O▯en used to reduce pain w/o inducing sleep, though many pa▯ents become drowsy • Seda▯on & anxiolysis ◦ Drowsiness & lethargy ◦ Apathy ◦ Cogni▯ve treatment ◦ Sense of tranquility • Some cogni▯ve impairment • Some memory loss • Depression of respira▯on ◦ Main cause of death from opioid overdose ◦ Combina▯on of opioids & alcohol especially dangerous • Cough suppression ◦ "An▯tussive" ◦ Opioids suppress "cough center" in the brain (medulla) ◦ At high doses, produces hallucinogenic eﬀects by blocking a type of glutamate receptor • Pupillary constric▯on ◦ Pupillary constric▯on in the presence of analgesics characteris▯c of opioid use • Nausea & vomi▯ng ◦ S▯mula▯on of receptors in the medulla (chemoreceptor trigger zone) causes nausea & vomi▯ng ◦ Unpleasant, but not life threatening side eﬀect • Gastrointes▯nal symptoms/disorders ◦ Relieve diarrhea due to direct ac▯ons on intes▯nes ◦ Counteracts diarrhea, prevents death by dysentery (severe intes▯nal infec▯ons) • Other eﬀects: ◦ Opioids can release histamines causing itching or more severe allergic reac▯ons including bronchoconstric▯on ◦ Opioids can aﬀect white blood cell func▯on & immune func▯on Marke▯ng Cul▯va▯on • Produced & available for collec▯on for only a few days of the plant's life ◦ Opium harvesters use sharp clawed tools to make shallow cuts in the unripe seedpods PSY 320 Drugs & Behavior ◦ Resinous substance oozes out of cuts & is collected ◦ Raw opium is the substance from which morphine is extracted & heroin is derived Current Opium Produc▯on • Worldwide opium produc▯on is increasing • Driven by a sharp rise in poppy cul▯va▯on in Afghanistan ◦ Afghanistan currently #1 producer of the drug • During Taliban rule: produc▯on signiﬁcantly decreased • A▯er US toppled Taliban in 2001, produc▯on increased again • Opium exports make up large por▯on of Afghanistan's GDP • DEA Sta▯s▯cs: Afghanistan's produc▯on of oven-dried opium increased to 1,278 metric tons a▯er US's invasion in 2002 • DEA Sta▯s▯cs: Produc▯on more than doubled by 2003, doubled again in 2004 • UN considers Afghanistan accountable for 92% of world's opium supply • 2009 opium exports from Afghanistan valued at $2.8 billion Prescrip▯on Analgesics • Natural products: ◦ Morphine en i e◦o C • Semisynthe▯cs ◦ Heroin • Synthe▯cs ◦ Methadone ◦ Meperidine ◦ Oxycodone *popular e nohpro my◦x O ◦ Hydrocodone *popular ◦ Hydromorphone en i edo co rdyh◦i D ene hpyxopo◦r P ◦ Pentazocine ◦ Fentanyl • Opioid Antagonists - Drugs that block the ac▯on of morphine, heroin, or other opioid agonists Morphine - the primary ac▯ve agent in opium • 1806 ac▯ve ingredient in opium isolated ◦ 10x as potent as opium • Named morphium a▯er Morpheus, god of dreams • 150 years a▯er commercial introduc▯on, morphine con▯nues to be most valuable postsurgical analgesia available • Sympoma▯c relief of moderate to severe pain • Relief of certain types of labored breathing • Suppression of severe cough • Suppression of severe diarrhea • 1853 hypodermic syringe invented to deliver morphine directly to the blood/▯ssue ◦ Believed that injec▯ng reduced risk of cravings - disproved • Injec▯ons used on soldiers in the American Civil War, Prussian-Austrian War, & Franco-Prussian War PSY 320 Drugs & Behavior ◦ Relieved pain & dysentery ◦ Returning veterans were dependent ◦ "Soldier's disease" or "Army disease" Codeine - the secondary ac▯ve agent in opium • Isolated alkaloid discovered in 1832 • Highly eﬀec▯ve cough suppressant & moderate analgesic • Once available OTC, now requires prescrip▯on Heroin - diacetylmorphine, a potent deriva▯ve of morphine • Heroin = Diacetylmorphine ◦ 1874 - 2 acetyl groups were a▯ached to morphine ◦ 1989 - marketed as Heroin (brand name) by Bayer • 3x as potent as morphine ◦ Due to increased lipid solubility of the heroin molecule ◦ Lipid contents of brain hold morphine ◦ Faster absorp▯on & onset • Originally marketed as non-addic▯ve cough suppressant ◦ Replacement for codeine & morphine ecnedneped o t dekn i l r e t◦ a L • Produc▯on & Purity: ◦ Most heroin used in the US is derived from poppies grown in Mexico & Colombia ◦ Purity of heroin has increased drama▯cally in recent years • Mid-70s: purity 5% • 1980s: 25% • Currently: 20-40% ◦ Heroin: 0.2% of Americans report past year use Oxycon▯n • Opium derivate available by prescrip▯on • Extremely potent & addic▯ve analgesic • Prescribed to cancer pa▯ents & chronic pain suﬀerers • Comes in ▯me release tablets designed to be swallowed whole • Abusers can crush pills to snort or inject powder ◦ Rapid absorp▯on Fentanyl • Pharmacokine▯cs: ◦ Routes of administra▯on - Oral, transdermal, possibly intravenous ◦ Highly lipophilic ◦ Latency to onset - 7-15 min oral, 12-17 hrs transdermal ◦ Dura▯on of ac▯on - 1-2 hrs oral, 72 transdermal ◦ 80-85% plasma protein bound ◦ 90% metabolized in the liver to inac▯ve metabolites • 80x the analgesic potency of morphine • 10x analgesic potency of hydromorphone • High eﬃcacy for MU 1 receptors • Most eﬀec▯ve opiate analgesic Dependence Poten▯al PSY 320 Drugs & Behavior Tolerance • Tolerance develops to most eﬀects from both medical & recrea▯onal usage ◦ Higher doses needed to maintain eﬀects • Cross-tolerance exists among all opioids • Psychological processes play key role in tolerance ◦ Dependent individuals develop a condi▯oned reﬂex response to the s▯muli associated w/ taking the drugs ◦ Animal experiments show that placebo injec▯ons produce body changes opposite to those produced by morphine ◦ Shows the body counteracts an▯cipated eﬀects of the drug • Behavioral tolerance: ◦ Rats adjusted to high consump▯on of heroin injec▯ons ◦ Rats given the same amount in a new environment mostly died ◦ Showed that tolerance reﬂexes are environment-speciﬁc ◦ Condi▯oning is very crucial to tolerance Physical Dependence • Symptoms of withdrawal appear in sequence following the ▯ming of the most recent dose & the individual's history of use • Opioid withdrawal is unpleasant, but rarely life-threatening ◦ Not necessary to be medically supervised during withdrawals ◦ Withdrawals feel similar to the ﬂu (vomi▯ng, diarrhea, aches, pains, etc.) • Methadone: ◦ Long-las▯ng synthe▯c opioid ◦ Produces withdrawal symptoms that appear later & are less severe than those from heroin • May last longer Reinforcing Eﬀects • Subjec▯ve eﬀects occur during 4 phases: ◦ Rush - ini▯al/rapid onset of euphoria ◦ High - feelings of joy/goodwill ◦ Nod - calm, disinterest, unawareness of surroundings ◦ Straight - period of normalcy • Subjec▯ve eﬀects of opioids readily pair w/ environmental s▯muli ◦ Condi▯oned place preference procedures are used to study reinforcing eﬀects of opioids like heroin Psychological Dependence • Posi▯ve reinforcement - posi▯ve eﬀects reliably follow use of the drug (rapid onset of eﬀects) • Nega▯ve reinforcement - use of the drug removes withdrawal symptoms ◦ Appearance of early withdrawal symptoms just hours a▯er injec▯on typically leads to stronger dependence • Fast-ac▯ng injectable opioids are most likely to lead to dependence • Needle habit: ◦ Each heroin administra▯on is followed by: • A decrease in discomfort • An increase in pleasure deno▯ i dnoc em oc eb s r e◦s U PSY 320 Drugs & Behavior ◦ Process of using heroin becomes rewarding in itself PSY 320 Drugs & Behavior Toxicity Poten▯ al Acute Toxicity • Opioids depress respiratory centers in the brain ◦ Breathing becomes slower & shallower • Respiratory depression is the primary cause of death from OD • Opioid overdose triad: ◦ Coma no▯a r i pse r des se rp ◦e D ◦ Pinpoint pupils • Clouding of consciousness Chronic Toxicity • Associated w/ injec▯on method • Infec▯ons & spread of blood-borne diseases (HIV, hepa▯▯s) • Constant pain suppression may conceal early symptoms of illnesses like pneumonia • Lack of money & food may cause malnutri▯on ◦ Increased suscep▯bility to diseases Misconcep▯ons & Preconcep▯ons • Not all users experience euphoria from ini▯al dose • Many experience nausea/discomfort • Tolerance to nega▯ve eﬀects may develop more rapidly than tolerance to posi▯ve eﬀects • Withdrawal o▯en similar to mild case of intes▯nal ﬂu • Ppl don't become dependent a▯er 1 dose, takes ▯me & persistence Trea▯ng Opioid Addic▯on • Pharmacological treatments for opioid addic▯on include: ◦ Detoxiﬁca▯on - Process that uses an opioid agonist or antagonist to reduce withdrawal symptoms ◦ Management of comorbid disorders • Opioid Antagonists: ◦ Drugs that block the ac▯on of opioids ◦ Examples: Naloxone, nalorphine ◦ Eﬀects: • Reverse depressed respira▯on from opioid OD • Precipitate withdrawal syndrome • Prevent dependent individuals from experiencing a high from subsequent opioid use • Naltrexone ◦ Use of injectable, intranasal, & intramuscular eﬀorts to develop new ways of administering drug to save lives ◦ Carried by doctors, ﬁrst-responders, police, etc. for emergencies ◦ Can be used to stop overdoses ◦ 3/23/16 - Canada decided Naloxone can be available w/o prescrip▯on • EVZIO - FDA approved Naloxone auto-injector • All examples of medicinal responses to abuse/OD rates ◦ Pharmacokine▯cs: • Latency to onset - oral tablet 15-30 min • Dura▯on of ac▯on - 24-72 hrs • Peak eﬀect - 6-2 hrs PSY 320 Drugs & Behavior ◦ Structural dis▯nc▯on: • Diﬀers from Naloxone since the allyl group on nitrogen atom is supplanted by cyclopromethyl group ◦ Eﬀects: • Reverses psychotomime▯c eﬀects of opiate agonists • Reverses hypotension & cardiovascular instability secondary to endogenous endorphins (potent vasodilators) • Inhibits Mu, Delta, Kappa receptors • Clonidine ◦ Alpha-adrenergic agonist • Alpha-adrenergic receptors found together w/ opioid receptors in the brain ◦ Treats high blood pressure ◦ Can diminish severity of withdrawal symptoms • DEA released documentary aimed at educa▯ng students & young adults about dangers of addic▯on - "Chasing the Dragon"