Overview of Prescription Drugs of Abuse

Overview of Prescription and Non-Prescription Drugs of AbuseDevon A. Sherwood, PharmD, BCPPAssistant ProfessorUniversity of New EnglandCollege of PharmacyLearning ObjectivesDescribe the epidemiology and overall impact of medications commonly abused.Explain the pathophysiology of abuse and dependence for commonly abused drugs.List common over-the-counter (OTC) and prescription (Rx) drugs of abuse.Identify side effect profiles and withdrawal symptoms of OTC and Rx drugs of abuse.Review available options for detoxification therapy and abstinence maintenance regarding common drugs of abuse.Which of the following increases the risk of abuse potential?Rapid absorption

Potency of drug

Lipophilicity and distribution leads to abrupt offset

Short-half life / duration of effect

All of the aboveWhich of the following should not be recommended for opiate abstinence? Clonidine

Methadone

Suboxone

Naltrexone

Laxative Abuse: True or False?Effective for weight controlTrueFalse

Physical dependency does not occurTrueFalse

Long term abuse may contribute to colon cancerTrueFalseWhich of the following herbals when abused is known to cause hallucinations?Ma-huang

Kratom

Nutmeg

Betel nut

Kava

Which of the following herbals has effects on mu and delta receptors, causing analgesic and addictive properties similar to opiates?SalviaMorning GloryKratomYohimbineKhat

EpidemiologyIn 2010, 23.1 million Americans aged 12 or older (9.1% of US population) needed specialized treatment for a substance abuse problem, but only 2.6 million (11.2%) received it.

It is estimated 22.6 million Americans aged 12 or older (8.9%) were current (past month) illicit drug usersIncludes marijuana/hashish, cocaine/crack, heroin, hallucinogens, inhalants or prescription-type psychotherapeutics used nonmedically.1.) National Survey of Drug Use and Health, SAMHSA, 20132.) National Survey on Drug Use and Health 2013; National Institute on Drug Abuse (NIDA), National Institute of Health (NIH) 3.) Monitoring the Future; University of Michigan - http://www.monitoringthefuture.org/Illicit drugs among americans increased between 2208 and 2010 according to a national surbey conducted by SAMHSA. The National Survey on Drug Use and Health *NSDUH) shows 22.6million Americans 12 and older (9%) were current illicit drug users

Marijuana seems to be the prime factor in the overall rise in illicit drugs. In 2010, 17.4 million Americans used compared to 14.4 million in 2007 = rise from 5.8% to 6.9% in 12yo and older.8First Specific Drug Associated with Initiation of Illicit Drug Use among Past Year Illicit Drug Initiates Aged 12 or older: 2010

Results from the 2010 National Survey on Drug Use and Health, US Department of Health and Human Services, 2012; http://oas.samhsa.gov/NSDUH/2k10NSDUH/2k10Results.htm#Fig5-1Epidemiology Psychotropic Rx DrugsThe incidence of nonmedical usage of psychotropic drugs has been increasing over the past 10 years

NSDUH Report from April 11, 2013 identified an increase in nonmedical prescription drug use from the 2011 survey:15.7 million (6.3% of US population) use in last year6.7 million (2.7% US population) use in last month1.) National Survey of Drug Use and Health, SAMHSA, 20122.) National Survey on Drug Use and Health 2010; National Institute on Drug Abuse (NIDA), National Institute of Health (NIH)12th grade seniors:1 in 12 abused Vicodin1 in 20 abused Oxycontin

70% stated they were given them by a friend or relative.10Epidemiology - Psychotropic Rx DrugsIn 2010, about 7 million persons (2.7% of US population) were current users in the past month of psychotherapeutic drugs taken nonmedically5.1 million = pain relievers2.2 million = tranquilizers1.1 million = stimulants0.4 million = sedatives.

National Survey on Drug Use and Health 2010; National Institute on Drug Abuse (NIDA), National Institute of Health (NIH)

NIDA-NIH: http://www.nida.nih.gov/tib/prescription.html

12EpidemiologyMonitoring the Future Study (NIH grant in 2011)

Any prescription drug abused in 12th grade = 15.2%Drug Name8th grade10th grade12th gradeMarijuana/Hashish12.5%28.8%36.4%Vicodin2.1%5.9%8.1%Amphetamines3.5%6.6%8.2%Tranquilizers2.0%4.5%5.6%OxyContin1.8%3.9%4.9%OTC Cough/Cold2.7%5.5%5.3%Salvia1.6%3.9%5.9%1.) National Survey on Drug Use and Health 2011; National Institute on Drug Abuse (NIDA), National Institute of Health (NIH) 2.) Monitoring the Future; University of Michigan - http://www.monitoringthefuture.org/

DSM-IV-TR Diagnosis Review:Substance Related DisordersSubstance Use Disorders:DependenceAbuseSubstance Induced DisordersIntoxicationWithdrawalPolysubstance Dependance

Substance AbuseA maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one or more of the following (one symptom in 12 months):

1.) Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home

2.) Recurrent substance use in physically hazardous situations

3.) Recurrent substance-related legal problems

4.) Continued substance use despite having persistant or recurrent social or interpersonal problems caused or exacerbated by the effects of substance abuseSubstance DependenceA maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by three or more of the following, occurring at any time in the same 12-month period:

1.) Tolerance: A need for markedly increased amounts of the substance to achieve intoxication or desired effect, or markedly diminished effect with continued use of the same amount of the substance

2.) Withdrawal: As manifested by the characteristic withdrawal syndrome for the substance, or the same (or closely related) substance is taken to relieve or avoid withdrawal symptoms.Substance Dependence3.) Substance is taken in larger amounts or over a longer period than was intended

4.) Persistent desire or unsuccessful efforts to cut down or control substance use

5.) A great deal of time is spent in activities necessary to obtain the substance

6.) Important social, occupational, or recreational activities are given up or reduced because of substance use.

7.) The substance use continues despite knowledge of having a persistent or recurrent physical or psychological problem that is likely caused or exacerbated by the substance.Risk Factors for Addictive Disorderswww.drugabuse.gov

Ineffective parentingChaotic home environmentLack of mutual attachments/nurturingInappropriate behavior in the classroomFailure in school performancePoor social coping skillsAffiliations with deviant peersPerceptions of approval of drug-using behaviors in the school, peer, and community environments

18Risk FactorsPrevention research reveals there are many risk factors for drug abuse, each representing a challenge to the psychological and social development of the individual and each having a different impact depending on the phase of a young persons development. For this reason, those factors that affect early development in the family are probably the most crucial such as:-ineffective parenting, especially with children with difficult temperaments and conduct disorders;-chaotic home environments, particularly in which parents abuse substances or suffer from mental illnesses and; -lack of mutual attachments and nurturing.Other risk factors relate to children interacting with other socialization agents outside of the family, specifically the school, peers, and the community. Some of these factors include:-inappropriate behavior in the classroom-failure in school performance-poor social coping skills-affiliations with deviant peers-perceptions of approval of drug-using behaviors in the school, peer, and community environmentsProtective Factorswww.drugabuse.gov

Strong family bondsParental monitoringParental involvementSuccess in school performanceProsocial institutions (ie. family, school, religious organizations)Conventional norms about drug usehttp://www.yanksarecoming.com/wp-content/uploads/2009/12/BubbleBoy1.jpg

19Protective FactorsCertain protective factors also have been identified. These factors are not always the opposite of risk factors. Their impact also varies along the developmental process. The most salient protective factors include: -strong family bonds -parental monitoring -parental involvement -success in school performance-prosocial institutions (e.g. such as family, school, and religious organizations)-conventional norms about drug use

DRUG ADDICTION IS A COMPLEX ILLNESSwww.drugabuse.gov

20Drug Addiction: A Complex IllnessDrug addiction is a complex illness. The path to drug addiction begins with the act of taking drugs. Over time, a persons ability to choose not to take drugs is compromised. This in large part is a result of the effects of prolonged drug use on brain functioning, and thus on behavior. Addiction, therefore, is characterized by compulsive, drug craving, seeking, and use that persists even in the face of negative consequences.

www.drugabuse.gov

21Brain Regions and Their FunctionsCertain parts of the brain govern specific functions. For example, the cerebellum is involved with coordination; the hippocampus with memory. Nerve cells (neurons) are the basic unit of communication in the brain. Information is relayed from one area of the brain to other areas through complex circuits of interconnected neurons. Information via electrical impulses transmitted from one nueron to many others is done through a process called neurotransmission.

www.drugabuse.gov

22The Reward PathwayOne pathway important to understanding the effects of drugs on the brain is called the reward pathway. The reward pathway involves several parts of the brain, some of which are highlighted in this slide: the ventral tegmental area (VTA), the nucleus accumbens, and the prefrontal cortex. When activated by a rewarding stimulus (e.g, food, water, sex), information travels from the VTA to the nucleus accumbens and then up to the prefrontal cortex.

Summary: addictive drugs activate the reward system via increasing dopamine neurotransmissionIn this last image, the reward pathway is shown along with several drugs that have addictive potential. Just as heroin or morphine and cocaine activate the reward pathway in the VTA and nucleus accumbens, other drugs such as nicotine and alcohol activate this pathway as well, although sometimes indirectly (point to the globus pallidus, an area activated by alcohol that connects to the reward pathway). Although each drug has a different mechanism of action, each drug increases the activity of the reward pathway by increasing dopamine transmission. Because of the way our brains are designed, and because these drugs activate this particular brain pathway for reward, they have the ability to be abused. Thus, addiction is truly a disease of the brain. As scientists learn more about this disease, they may help to find an effective treatment strategy for the recovering addict.

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www.drugabuse.gov

24NeurotransmissionAs mentioned earlier (slide 3), information is communicated in the brain via a process called neurotransmission. Neurotransmission involves a variety of chemical substances called neurotransmitters. One such neurotransmitter is called dopamine. In the normal communication process, dopamine is released by a neuron into the synapse (the small gap between neurons). The dopamine then binds with specialized proteins called dopamine receptors (see slide) on the neighboring neuron thereby sending a signal to that neuron.

www.drugabuse.gov

25Neurotransmission (continued) After the signal is sent to the neighboring neuron, dopamine is transported back to the neuron from which it was released by another specialized protein, the dopamine transporter (see slide).

www.drugabuse.gov

26Cocaine and NeurotransmissionDrugs of abuse are able to interfere with this normal communication process in the brain. Cocaine, for example, blocks the removal of dopamine from the synapse by binding to the dopamine transporters. As shown in this slide, this results in a buildup of dopamine in the synapse. In turn, this causes a continuous stimulation of receiving neurons, probably responsible for the euphoria reported by cocaine abusers and other stimulants when abused.

27Slide 18: Opiates binding to opiate receptors in the nucleus accumbens: increased dopamine releaseShow how opiates activiate the reward system using the nucleus accumbens as an example. Explain that the action is a little more complicated than cocaine's because more than two neurons are involved. Point out that 3 neurons participate in opiate action; the dopamine terminal, another terminal (on the right) containing a different neurotransmitter (probably GABA for those that would like to know), and the post-synaptic cell containing dopamine receptors. Show that opiates bind to opiate receptors (green) on the neighboring terminal and this sends a signal to the dopamine terminal to release more dopamine. [In case an inquisitive student asks how - one theory is that opiate receptor activation decreases GABA release, which normally inhibits dopamine release - so dopamine release is increased.]Common Prescription Drugs of AbuseOpiates

Anxiolytics / sedativesBenzodiazapinesBarbituratesNon-benzodiazepines

Stimulants

Opiate UsageStudies have shown properly using opiates exactly as prescribed is safe, manages pain effectively, and has a low chance of addiction.

Taken by persons not prescribed the medication, using more than recommended or using an alternate route than prescribed (snorting, smoking or injecting) carries a high risk of addiction and/or overdosageNIDA Infofacts: Prescription and Over the Counter Medications; http://www.nida.nih.gov/infofacts/PainMed.html

NIDA-NIH: http://www.nida.nih.gov/tib/prescription.htmlOpiate ActionsOpiate enters the brain and influences a range of mechanismsMu, delta & kappa agonists

Boosts the activity of dopamine Pleasure circuit Blocks painSlows the heart beat

Constricts the pupils

Decreases breathingSometimes causing breathing cessationPotentially death

32Slide 18: Opiates binding to opiate receptors in the nucleus accumbens: increased dopamine releaseShow how opiates activiate the reward system using the nucleus accumbens as an example. Explain that the action is a little more complicated than cocaine's because more than two neurons are involved. Point out that 3 neurons participate in opiate action; the dopamine terminal, another terminal (on the right) containing a different neurotransmitter (probably GABA for those that would like to know), and the post-synaptic cell containing dopamine receptors. Show that opiates bind to opiate receptors (green) on the neighboring terminal and this sends a signal to the dopamine terminal to release more dopamine. [In case an inquisitive student asks how - one theory is that opiate receptor activation decreases GABA release, which normally inhibits dopamine release - so dopamine release is increased.]

33Slide 20: Summary; opiate binding in nucleus accumbens and activation of the reward pathwayShow the "big picture". As a result of opiate actions in the nucleus accumbens (point to the sprinkles of opiates in the nuc. acc.), there are increased impulses leaving the nucleus accumbens to activate the reward system (point to the frontal cortex). As with cocaine, continued use of opiates makes the body rely on the presence of the drug to maintain rewarding feelings and other normal behaviors. The person is no longer able to feel the benefits of natural rewards (food, water, sex) and can't function normally without the drug present.Opiates/Opiods

Pharmacotherapy: A Pathophysiologic ApproachHeroin, morphine, and some prescription painkillers (e.g., OxyContin, Vicodin, and Fentanyl) belong to the class of drugs known as opiates. They act on specific (opiate) receptors in the brain, which also interact with naturally produced substances known as endorphins or enkephalins important in regulating pain and emotion. And while prescription painkillers are highly beneficial medications when used as prescribed, opiates as a general class of drugs have significant abuse liability. Currently, approximately 1 million people in the United States are addicted to heroin (Office of National Drug Control Policy, 2000), and more than 3 million people over the age of 12 have used heroin at least once [National Survey on Drug Use and Health (NSDUH), 2004]. What's more, an estimated 1.4 million people are dependent on or abusing other opiate drugs, including prescription painkillers [NSDUH (Ibid)]. Scientific research has led to effective treatments for opiate addiction: In the 1960's, methadone gained recognition as an effective treatment for heroin addiction. Administered daily, methadone treatment is currently regulated so that only specialized clinics can provide it. Naltrexone, an opioid receptor blocker, joined the medications inventory in 1984. It proved to be highly effective in reversing the effects of opiate overdose, but poor treatment adherence has hampered its utility to promote abstinence. Buprenorphine, the newest medication in our toolkit, is a long-acting partial agonist that acts on the same receptors as heroin and morphine, relieving drug cravings without producing the same intense "high" or dangerous side effects.

Opioids act on the brain and body by attaching to specific proteins called opioid receptors, which are found in the brain, spinal cord, and gastrointestinal tract. When these drugs attach to certain opioid receptors, they can block the perception of pain. Opioids can produce drowsiness, nausea, constipation, and, depending upon the amount of drug taken, depress respiration. Opioid drugs also can induce euphoria by affecting the brain regions that mediate what we perceive as pleasure. This feeling is often intensified for those who abuse opioids when administered by routes other than those recommended. For example, OxyContin often is snorted or injected to enhance its euphoric effects, while at the same time increasing the risk for serious medical consequences, such as opioid overdose.34Opiates WithdrawalFlu-like symptoms:Runny noseTear secretionYawningSneezingNauseaVomiting DiarrheaMydriasisGeneral effects Sedation AnxietyLack of interestSlurred speech

35Opioid Effects: Degree of Tolerance Developed High Intermediate Limited/None analgesia bradycardia miosis euphoria, dysphoria constipation mental clouding convulsions sedation antagonist actions respiratory depression antidiuresis nausea/vomiting cough suppression adapted from Figure 31-4: Way, W.L., Fields, H.L. and Way, E. L. Opioid Analgesics and Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p. 505.Abuse of Opioid:Some Symptoms of Opioid Withdrawal rhinorrhea lacrimation chills hyperventilation muscular aches vomiting anxiety diarrhea hostility piloerection yawning hyperventilation Opioid Drug Listing alfentanil (Alfenta)butorphanol (Stadol)codeinedezocine (Dalgan)fentanyl (Sublimaze)hydromorphone (Dilaudid)levorphanol (Levo-dromoran)meperidine (Demerol)methadone (Dolophine)morphinenalbuphineoxycodone (Roxicodone)oxymorphone (Numorphan)pentazocine (Talwain)propoxyphene (Darvon)sufentanil (Sufenta)Combinations Codeine/acetaminophenCodeine/aspirinPropoxyphene/aspirinCodone/acetaminophenOxycodone/aspirin

Heroin, morphine, and some prescription painkillers (e.g., OxyContin, Vicodin, and Fentanyl) belong to the class of drugs known as opiates. They act on specific (opiate) receptors in the brain, which also interact with naturally produced substances known as endorphins or enkephalins important in regulating pain and emotion. And while prescription painkillers are highly beneficial medications when used as prescribed, opiates as a general class of drugs have significant abuse liability. Currently, approximately 1 million people in the United States are addicted to heroin (Office of National Drug Control Policy, 2000), and more than 3 million people over the age of 12 have used heroin at least once [National Survey on Drug Use and Health (NSDUH), 2004]. What's more, an estimated 1.4 million people are dependent on or abusing other opiate drugs, including prescription painkillers [NSDUH (Ibid)]. Scientific research has led to effective treatments for opiate addiction: In the 1960's, methadone gained recognition as an effective treatment for heroin addiction. Administered daily, methadone treatment is currently regulated so that only specialized clinics can provide it. Naltrexone, an opioid receptor blocker, joined the medications inventory in 1984. It proved to be highly effective in reversing the effects of opiate overdose, but poor treatment adherence has hampered its utility to promote abstinence. Buprenorphine, the newest medication in our toolkit, is a long-acting partial agonist that acts on the same receptors as heroin and morphine, relieving drug cravings without producing the same intense "high" or dangerous side effects.

Opioids act on the brain and body by attaching to specific proteins called opioid receptors, which are found in the brain, spinal cord, and gastrointestinal tract. When these drugs attach to certain opioid receptors, they can block the perception of pain. Opioids can produce drowsiness, nausea, constipation, and, depending upon the amount of drug taken, depress respiration. Opioid drugs also can induce euphoria by affecting the brain regions that mediate what we perceive as pleasure. This feeling is often intensified for those who abuse opioids when administered by routes other than those recommended. For example, OxyContin often is snorted or injected to enhance its euphoric effects, while at the same time increasing the risk for serious medical consequences, such as opioid overdose.

One of the most commonly abused prescription drugs80mg Oxycontin tablet = 16 Percocet tablets

Propagated by illicit transactions, theft, and overprescribing (ie. Pain clinics)

Sustained-release delivery is thwarted by cracking, chewing, smoking and injecting

OxycontinMethamphetamine is a central nervous system stimulant drug that is similar in structure to amphetamine. Due to its high potential for abuse, methamphetamine is classified as a Schedule II drug and is available only through a prescription that cannot be refilled. Although methamphetamine can be prescribed by a doctor, its medical uses are limited, and the doses that are prescribed are much lower than those typically abused. Most of the methamphetamine abused in this country comes from foreign or domestic superlabs, although it can also be made in small, illegal laboratories, where its production endangers the people in the labs, neighbors, and the environment. How Is Methamphetamine Abused?Methamphetamine is a white, odorless, bitter-tasting crystalline powder that easily dissolves in water or alcohol and is taken orally, intranasally (snorting the powder), by needle injection, or by smoking.How Does Methamphetamine Affect the Brain?Methamphetamine increases the release and blocks the reuptake of the brain chemical (or neurotransmitter) dopamine, leading to high levels of the chemical in the braina common mechanism of action for most drugs of abuse. Dopamine is involved in reward, motivation, the experience of pleasure, and motor function. Methamphetamines ability to release dopamine rapidly in reward regions of the brain produces the intense euphoria, or rush, that many users feel after snorting, smoking, or injecting the drug.Chronic methamphetamine abuse significantly changes how the brain functions. Noninvasive human brain imaging studies have shown alterations in the activity of the dopamine system that are associated with reduced motor skills and impaired verbal learning.1 Recent studies in chronic methamphetamine abusers have also revealed severe structural and functional changes in areas of the brain associated with emotion and memory,2,3 which may account for many of the emotional and cognitive problems observed in chronic methamphetamine abusers.Repeated methamphetamine abuse can also lead to addictiona chronic, relapsing disease characterized by compulsive drug seeking and use, which is accompanied by chemical and molecular changes in the brain. Some of these changes persist long after methamphetamine abuse is stopped. Reversal of some of the changes, however, may be observed after sustained periods of abstinence (e.g., more than 1 year).4

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http://www.prescriptionbuyers.com/freeboard/ubbthreads.php/topics/1045193/NEW_OXYCONTIN_MARKINGS_SEPT_20. Accessed April 1, 2012.Long Term Opiate EffectsPhysical/Psychological addictionInjection-related problemsInfectious diseasesHIV / AIDS Hepatitis B and CCollapsed veinsBacterial infectionsAbscessesPhysical injuries

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Opiate Addiction TreatmentsDetoxificationTaper off opiate + opiate substituteClonidine (Catapres)Buprenorphine Formulations (Buprenex, Suboxone)

Maintenance of Opiate AbstinenceMethadoneBuprenorphine/NaloxoneNaltrexone

41Clonidine (Catapress)Attenuates the sympathetic response to withdrawal

Causes a rapid and significant decrease in withdrawal signs and symptoms

Usual oral dose is 0.1-0.2mg Q6h POWatch BP!Methadone ProgramsUse methadone as an opiate substitute

Medication is taken orally

Suppresses withdrawal for 24 to 36 hours and relieves cravings

Detox: 15-40 mg/day not to exceed 21 days

Maintenance: 20-120 mg/day Methadone Restricted to inpatient Side effectsConstipation, lack of energy, nausea

Drug Addiction Treatment Act of 2000 (DATA 2000)Physicians must be credentialed to do office-based detoxificationNo more than 30 patients at a time for the first year licensed, then can petition for up to 100 patients per the DATA 2000 waiver

Buprenorphine/Naloxone (Suboxone) approved in October 2002Use buprenorphine monotherapy only in pregnancyhttp://samhsa.gov: Buprenorphine Clinical GuideBuprenorphine/Naloxone (Suboxone)A mixed opiate agonist / antagonistCeiling effect if dosed too highSafer for respiratory depression

Suboxone is a 4:1 ratio of buprenorphine to naloxone (if taken po only!!)

Usual dose4-24mg sublingually daily

Buprenorphine/Naloxone (Subutex; Suboxone)Office based treatmentPhysician training requiredNumber of patients restrictedSide effects:Sweating, nausea, constipation, headache

SuboxoneSafe and effective for office-based detox16mg buprenorphine dailyUp to 21% avoided outside opiates vs. 5.8% on placebo (p methadoneDoses > 8mg/d have best successQOD dosing also successful

NEJM 2003;349:949-958. / Cochrane Database of Systematic Reviews 2003;(2):CD002207. / Addiction 2003;98(4):441-452.Naltrexone (Revia, Vivitrol)Competitive antagonists at opioid receptor sites

Not to be used during active withdrawal

Studies with long acting depot form Vivitrol in Russia demonstrated extraordinary outcomes regarding drug abstinance, treatment retention, and decreased cravings

Naltrexone (Revia, Vivitrol)Must wait 7-14 days or withdrawal will occurReduces opiate cravingsIncreases risk for unintentional overdoses Studies show a reduction in (re)incarcerations when used with behavior therapyCompliance and motivation are major factors32-58% successful in compliant patientsAbstinence rates diminish over time

Cochrane Database of Systematic Reviews 2003;(2):CD001333.Drug & Alcohol Dependence 1997;47(2):77-86. / Drugs 1988;35(3):192-213.Which of the following should not be recommended for opiate abstinence? Clonidine

Methadone

Suboxone

Naltrexone

Naloxone (Narcan)Short acting opiate receptor blocker

Not used for abstinence

Counteracts the effects of opiods and can be used to treat overdose

Dosing for overdose of opiate: 0.4 2mg IV, repeat every 2 to 3 min prnNo response after 10mg = reconsider diagnosis!May administer IM or SUBQ if IV route is unavailable

Micromedex Healthcare Series: Drugdex Drug PointRespiratoryDepressionComa/AnesthesiaAtaxiaSedationAnxiolyticAnticonvulsantDOSERESPONSEBARBSBDZsKatzung BG. Basic & Clinical Pharmacology. 10th ed. New York, NY: McGraw Hill; 2007Hypnotic Drugs: Dose-response relationshipsNot difference in dose-multiples from anxiolytics and coma for two classes51Benzodiazepines/Non-benzodiazepines

Goodman LS, Gilman A, Brunton LL. Goodman & Gilman's Manual of Pharmacology and Therapeutics. 11th ed. New York, NY : McGraw Hill; 2008.

52BenzodiazepinesEnhance GABAGABA decreases brain activity of NTs = drowsiness or calming effect

Prescribed to treat anxiety, acute stress reactions, panic attacks, convulsions, and sleep disorders.Short-term relief from sleep problems due to tolerance and addiction potentialAdditive Benzodiazepine FactorsRapid absorption leads to quick onset

Potency of drug

Lipophilicity and distribution leads to abrupt offset

Short-half life / duration of effect

Intradose withdrawalWhich of the following increase the risk of abuse potential?Rapid absorption

Potency of drug

Lipophilicity and distribution leads to abrupt offset

Short-half life / duration of effect

All of the aboveBenzodiazepine Withdrawal SymptomsAgitation Increased anxietyLoss of appetiteDiaphoresisNauseaFatigue and lethargyDizzinessPsychosisInsomniaSeizuresPoor concentrationHeadachesIncreased acuity of sensesParesthesiasPhotophobiaDysphoriaConfusion

Severity of Withdrawal SymptomsBased on:Drug variablesHigher dosesLonger duration of BZD treatmentDrug half-lifeRapid taperingClinical variables Higher pre-taper anxiety and depressionMore personality pathologyie. neuroticism, dependencyPanic disorder diagnosisHistory of recreational alcohol or drug abuse

Benzodiazepine Detoxification TreatmentInpatient versus outpatient treatment

Detoxification is similar to alcohol treatmentLength of treatment may be longer because onset of withdrawal symptoms may be delayed up to 7 days after discontinuing the drug

After the acute withdrawal phase, minor abstinence symptoms may last for weeks Anxiety, insomnia, irritability, sensitivityto light & sound, and muscle spasmsSuccess best if CBT is adjunctiveAm J Psychiatry 2004;161:332-342.58Benzodiazepine OverdosageIn case of overdosage, flumazenil (Romazicon) can be used:0.2mg IV over 30min, increase to 0.3 if no effect after another 30 min, Further doses of 0.5mg over 30min up to max of 3mg if no response, or max of 5mg if partial reponse

Micromedex Healthcare Series: Drugdex Drug PointCocaineMethamphetamineDextroamphetamine (Dexedrine)Methylphenidate (Concerta, Methylin, Ritalin)Amphetamines (Adderall)Modafinil (Provigil)

OTC:Watch for ephedrine-related compounds!Ma-huang, psuedoephedrineStimulantsMethamphetamine is a central nervous system stimulant drug that is similar in structure to amphetamine. Due to its high potential for abuse, methamphetamine is classified as a Schedule II drug and is available only through a prescription that cannot be refilled. Although methamphetamine can be prescribed by a doctor, its medical uses are limited, and the doses that are prescribed are much lower than those typically abused. Most of the methamphetamine abused in this country comes from foreign or domestic superlabs, although it can also be made in small, illegal laboratories, where its production endangers the people in the labs, neighbors, and the environment. How Is Methamphetamine Abused?Methamphetamine is a white, odorless, bitter-tasting crystalline powder that easily dissolves in water or alcohol and is taken orally, intranasally (snorting the powder), by needle injection, or by smoking.How Does Methamphetamine Affect the Brain?Methamphetamine increases the release and blocks the reuptake of the brain chemical (or neurotransmitter) dopamine, leading to high levels of the chemical in the braina common mechanism of action for most drugs of abuse. Dopamine is involved in reward, motivation, the experience of pleasure, and motor function. Methamphetamines ability to release dopamine rapidly in reward regions of the brain produces the intense euphoria, or rush, that many users feel after snorting, smoking, or injecting the drug.Chronic methamphetamine abuse significantly changes how the brain functions. Noninvasive human brain imaging studies have shown alterations in the activity of the dopamine system that are associated with reduced motor skills and impaired verbal learning.1 Recent studies in chronic methamphetamine abusers have also revealed severe structural and functional changes in areas of the brain associated with emotion and memory,2,3 which may account for many of the emotional and cognitive problems observed in chronic methamphetamine abusers.Repeated methamphetamine abuse can also lead to addictiona chronic, relapsing disease characterized by compulsive drug seeking and use, which is accompanied by chemical and molecular changes in the brain. Some of these changes persist long after methamphetamine abuse is stopped. Reversal of some of the changes, however, may be observed after sustained periods of abstinence (e.g., more than 1 year).4

60StimulantsMechanism of Action:Increase the release and block reabsorption of dopamineDopamine is involved in reward, motivation, experiencing pleasure, and motor function. Levels too high in the brain reward center = euphoria and add to addiction potential.

The more rapid dopamine is released to reward centers of the brain, it higher chance of stimulant abuse.

Snorting vs smoking cocaine: different addictive liabilitiesHistorically cocaine abuse involved snorting the powdered form (the hydrochloride salt). When cocaine is processed to form the freebase, it can be smoked. Heating the hydrochloride salt form of cocaine will destroy it; the freebase can be volatilized at high temperature without any destruction of the compound. Smoking gets the drug to the brain more quickly than does snorting. Show the audience why this happens. Snorting requires that the cocaine travels from the blood vessels in the nose to the heart (purple arrow), where it gets pumped to the lungs (purple arrow) to be oxygenated. The oxygenated blood (red arrows) carrying the cocaine then travels back to the heart where it is pumped out to the organs of the body, including the brain. However, smoking bypasses much of this, the cocaine goes from the lungs directly to the heart and up to the brain. The faster a drug with addictive liability reaches the brain, the more likely it will be abused. Thus, the time between taking the drug and the positive reinforcing or rewarding effects that are produced can determine the likelihood of abuse. 62

www.drugabuse.gov

63Where Cocaine Has Its Effects in the BrainUsing cocaine as an example, we can describe how drugs interfere with brain functioning. When a person snorts, smokes, or injects cocaine, it travels to the brain via the bloodstream. Although it reaches all areas of the brain, its euphoric effects are mediated in a few specific areas, especially those associated with the reward pathway discussed in the previous slide.

www.drugabuse.gov

64Cocaine and NeurotransmissionDrugs of abuse are able to interfere with this normal communication process in the brain. Cocaine, for example, blocks the removal of dopamine from the synapse by binding to the dopamine transporters. As shown in this slide, this results in a buildup of dopamine in the synapse. In turn, this causes a continuous stimulation of receiving neurons, probably responsible for the euphoria reported by cocaine abusers and other stimulants when abused.

Cognitive Performance Enhancing Medications (CPEMs)Poll from Nature in the April 2008 newsletter revealed 20% of researchers utilized a CPEM1400 people from over 60 countries responded

Nature 452, 674-675 (2008)Most common age group reported from NIDA was 18-25 years old and students.

Methylphenidate most common66Long Term Stimulant UsageTaken repeatedly or in high doses, stimulants can cause:AnxietyParanoiaDangerously high body temperaturesIrregular heartbeatSeizuresDepression67Common OTC & Herbal Drugs of AbuseDextromethorphanAntihistamines:DiphenhydramineDimenhydrinateLaxativesSynthetic Cannabinoids:K2, Spice, othersOpiate Like Compound:KratomBath Salts

DextromethorphanSynthetic opioid dextro-isomer of levorphanol

MOA: Decreases sensitivity of cough receptors & interrupts cough impulse transmission

Indication: Antitussive/Cough suppressant,

T = 2-4 hrs; renal excretion

Popular products of abuse: Coricidin, Corcidin C&C, Robitussin DM

Street names: Dex, DXM, CCC, Triple C, Robo, Skittles, Poor Mans PCP

691. Cough and cold preparations are commonly abused OTC medications because many contain dextromethorphan as an active ingredient. Dextromethorphan is a synthetic opioid and is the dextro-isomer of the codeine analogue, levorphenol.

2. At therapeutic doses of 1530 mg, dextromethorphan decreases the sensitivity of cough receptors and interupts cough impulse transmission in the medullary cough center in the brain to produce cough suppression. It does not produce other opioid effects such as analgesia, CNS depression, and respiratory suppression.

3. Its FDA indication is for use as a cough suppressant being dosed at 10-20mg q.4 hrs with a maximum therapeutic dose of 120mg/day.

4. Popular products of abuse include Coricidin Cough & Cold (known as Triple Cs) and Robotussin DM. Coricidin products are frequently abused because of their higher dose of dextromethorphan per unit tablet (30 mg/tablet). A package of Coricidin HBP contains two cards of eight gel tabs each. Recreationally users refer to sheeting, administering eight to 16 geltabs per dose. Robitussin DM and Delsym have high concentrations as well (abuse of this product known as robo-tripping). .

DextromethorphanWithdrawal symptoms:Dysphoria, intense cravingsTolerance develops with continued useMax dose = 120mg/day

100-200mg mild stimulant effect with hyperexcitability200-400mgmild hallucinations, slurred speech and memory impairment300-600mgout-of-body state with altered senses and nystagmus600-1500mgfull dissociative phaseDextromethorphanAcute overdose: CNS depression, coma, hypotension, tachycardia and respiratory distress are notedPolyingestion increases risk of cardiorespiratory complications and can be fatalUse supportive measuresDehydration fluidsHyperthermia Cooling/SedativesAgitation BZD Chronic (over 2-4 weeks): toxic syndrome (bromism) characterized by irritability, headache, confusion, anorexia, slurred speech and lethargy

71Recreational users describe several plateaus of effect based on the dose ingested of dextromethorphan. First, at doses of 100200 mg, there is a mild stimulant effect with hyperexcitability. Second, at doses of 200400 mg, there is an intoxication phase with mild hallucinations, slurred speech andmemory impairment. Third, at doses of 300600 mg, there is an out-of-body state with altered senses and nystagmus. Finally, a full dissociative phase occurs at doses of 6001500mg [13,24]; dissociation is a feeling of being separate from ones body and environment, it involves impaired motor function/anxiety, tremors, numbness, memory loss and nausea. For DXM specifically euphoria; slurred speech; confusion; dizziness; distorted visual.

These effects are dependent on the subjects metabolism of the drug and body weight. Approximately 10% of the Caucasian population population have difficulty metabolizing dextromethorphan due to genetic polymorphism and may not experience the dissociative effects of the drug

3. Experienced users of dextromethorphan report tolerance to the drug, as well as craving for repeated use. There is also an abstinence syndrome which is reported to be associated with dysphoria and intense cravings [25]. 4. Care for suspected dextromethorphan toxicity is mainly supportive. Although deaths rarely occur due to dextromethorphan alone, impaired judgment can place the patient at risk for injury and death. Polyingestion can lead to cardiorespiratory complications. Intravenous fluids and benzodiazepines should be used to treat dehydration and agitation. Hyperthermia should be aggressively treated with cooling and sedatives initially.

Timeline of Dextromethorphan (DM) abuse as reported by new DAWN-ED:National Estimates of Non-Medical Dextromethorphan ED Visits.73This graph illustrates the ebb and flow of dextromethorphan abuse over time.1. Dextromethorphan was approved by the U.S. FDA in 1958 as an OTC cough suppressant.2. During the 1960s and 1970s, dextromethorphan became available in an over-the-counter tablet form by the brand name Romilar. In 1973, Romilar was taken off the shelves because of an increase in abuse, and was replaced by new formulations with unpleasant tastes (like cough syrup) in an attempt to reduce abuse. 3. In the 1990s, dextromethorphan geltabs (Ex: Coricidin) were introduce into the market which led to resurgence in abuse. Recreational users of dextromethorphan refer to the new geltabs formulations as robo, triple C, skittles or red hots because of their brand names and similarity to specific candies. 4. In 2004, the American Medical Association (AMA) raised formal concerns about the misuse of dextromethorphan and made recommendations to restrict OTC use of this substance. Legislative attempts in several states in the United States continue to propose increased control and restriction over the sale of dextromethorphan-containing products, especially to minors. 5. The FDA issued a formal warning against the abuse of dextromethorphan after five reported deaths of youths in 2005.

Prevalence of Dextromethorphan abuseThe NSDUH Report - - Misuse of Over-the-Counter Cough and Cold Medications among Persons Aged 12 to 25

True prevalence of DM misuse is unknownNSDUH suggests it is most common in 12 20yo

Since 2006, SAMHSA's NSDUH reported a 17.2% decrease in usage in 2011.However, the true prevalence of dextromethorphan misuse is not known because of a lack of prevalence measures. The only data available is fromthe National Survey on Drug Use and Health (NSDUH) report, which assessed dextromethorphan misuse

It found that 5.3% of subjects aged 12 to 25 yoa report ever using OTC cough & cold medication to get high. A racial difference was found; the rate among Whites (2.1%), Hispanics (1.4%), Blacks (0.6%) used OTC cough & cold meds to get high in past year

Another source of prevalance data came from the DAWN 2004 report evaluating the rate of ED visits from nonmedical use of DM 0.71% for youth ages 1220 0.26% for other age groupsAccording to DAWN data, the age group from 12 to 20 is the one most commonly shown to misuse dextromethorphan.

74Trends in Annual use of OTC Cough & Cold meds among 8th, 10th, and 12th Graders20062007200820092010201120128th grade4.24.03.63.83.22.73.010th grade5.35.45.36.05.15.54.712th grade6.95.85.55.96.65.35.6Monitoring the Future 2012 Executive ReportLevel of significance of difference between the two most recent classes: s = .05, ss = .01, sss = .001. indicates data not available. indicates some changein the question. See relevant footnote for that drug. Any apparent inconsistency between the change estimate and the prevalence estimates for the two mostrecent years is due to rounding.75

Each year, the Monitoring the Future (MTF) survey assesses the extent of drug use among 8th-, 10th-, and 12th graders nationwide.

The number is 2009 are similar to the numbers in 2007

762009 Annual prevalence of use of OTC Cold & Cough meds among 8th, 10th, and 12th Graders: Racial and Gender comparisons

OTC Cold & Cough Medicines8th10th12thTotal466Male3.75.98.1 *Female3.86.04.1White3.76.45.9Black2.72.14.5Hispanic3.65.56.0Source. The Monitoring the Future study, the University of Michigan, 2009*= significant increase from previous year,2008. (+1.8), P