Prescription Drug Abuse Larissa Mooney, M.D. Assistant Professor of Psychiatry UCLA Integrated Substance Abuse Programs David Geffen School of Medicine at UCLA

Overview Three classes of commonly abused Rx drugs (opioids, sedatives, stimulants) What are they? How do they act in the brain and body? What are their effects? Neurobiology

What are opioids? Opiate: derivative of opium poppy Morphine Codeine Opioid: any compound that binds to opiate receptors Semisynthetic (including heroin) Synthetic Oral, transdermal and intravenous formulations Narcotic: legal designation Heroin: semisynthetic derived from morphine Semisynthetic: derived by altering chemicals contained in opium

Effects of Opioids Sedation Pupil constriction Slurred speech Impaired attention/memory Constipation, urinary retention Nausea Confusion, delirium Seizures Slowed heart rate Respiratory depression 1st 4: DSM criteria for opioid intoxication Also: itchiness, myoclonus

Opioid Receptors Receptor types Receptors located throughout body mu, delta, kappa Receptors located throughout body Pain relief: central and peripheral nervous system Reward and reinforcement: deep brain structures Side effects: constipation, sedation, itch, mental status changes Receptor interactions Full agonists Partial agonists Antagonists Differences in mu receptor interactions related to clinical use and abuse liabaility

SOURCE: National Institute on Drug Abuse, www.nida.nih.gov.

Endogenous Opioids Produced naturally in body Act on opioid receptors Examples: endorphins, enkephalins, dynorphins, endomorphins Produce euphoria and pain relief; naturally increased when one feels pain or experiences pleasure

Pain: the Fifth Vital Sign JACHO Guidelines 2000: Mandated pain assessment and treatment Nurse and physician education required When opioids prescribed properly for pain, addiction rare in patients without underlying risk factors Vulnerabilities same as for other addictions: genetic, peer and social influences, trauma and abuse history Temperature, blood pressure, heart rate, respiration

Pain Pathway www.ccac.ca there are three primary sites at which modification of pain transmission can occur: the periphery; the spinal cord; the cerebrum.  Most drugs have actions at more than one site. At the periphery, the responsiveness of pain receptors is enhanced by the presence of prostaglandins.  These prostaglandins are formed in response to tissue trauma.  This means that the receptors will respond to a lesser stimulus than before they were sensitised.  A number of endogenous compounds (e.g., histamine, serotonin) may be responsible for the actual pain sensation. In the spinal cord, information on pain is received by cells in the dorsal horn and is passed on to higher centres in the brain along tracts in the spinal cord. Pain fibres coursing into the cerebrum may end in a number of sites, particularly the reticular formation, the thalamus and the cerebral cortex.  In the reticular formation, the pain stimuli may evoke arousal, changes in heart rate, blood pressure, respiration and other activities.  It is in the thalamus and cerebral cortex where the appreciation or conscious awareness of pain is to be found. The diagram above also shows pathways coming from the brain down to the spinal cord.  Stimulation of these descending pathways can reduce and even abolish some forms of pain. The body also produces chemicals including endorphins that act on the same receptors as externally administered opioids, to provide pain relief.  The significance of descending inhibitory pathways and chemicals in the control and modification of pain sensations is unclear, particularly in animals.  Many animals (and humans) appear to tolerate pain and show very few behavioural alterations following a painful insult.  This may be due in part to the central inhibitory effects and in part to other biological factors.  Opioids are effective as analgesics when given in minute doses. They excite neurones in the periaqueductal grey matter and nucleus reticularis paragigantocellularis, which project to the nucleus raphe magnus. Descending pathways from the midbrain exert a strong inhibitory effect on pain transmission in the dorsal horn (mediated by 5-HT, enkephalins and noradrenaline). Opioids also inhibit pain transmission by acting directly on the dorsal horn, and by inhibiting excitation of peripheral nociceptive afferent neurones. www.ccac.ca

Pain Control and Addiction “Pseudoaddiction”: Presence of drug-seeking behavior in context of inadequate pain control Behavior stops with adequate pain relief Description of a clinical interaction (not a true diagnosis) “Hyperalgesia”: exaggerated sense of pain with increasing opioid doses

How Opioid Use Escalates Short duration of action Exceptions: methadone and buprenorphine Has necessitated development of new delivery systems Tolerance Definition: with continued use, progressively higher doses necessary to produce the same effect Physical dependence Definition: with continued use, withdrawal syndrome produced by abrupt cessation, rapid dose reduction, and/or administration of an antagonist; occurs via neuroadaptation Not synonymous with tolerance or addiction

Opioid Withdrawal Dysphoric mood Nausea or vomiting Diarrhea Tearing or runny nose Dilated pupils Muscle aches Goosebumps Sweating Yawning Fever Insomnia

Protracted Withdrawal Low energy Anhedonia Sleep disturbance Emotional lability/dysphoria Anxiety Craving Can persist for months

Morphine Routes: oral, intramuscular, intravenous, rectal Sustained release preparations: MS Contin Oramorph Kadian Avinza

Codeine Opiate (naturally occurring in poppy) Low potency Pain relief via 10% conversion to morphine Most commonly prescribed opioid in the world Probably the most widely used analgesic (Excluding aspirin)

Semisynthetic Opioids Hydrocodone with Tylenol: Norco Lortab Vicodin Lorcet Hydrocodone with ibuprofen: Vicoprofen Hydromorphone: Dilaudid Oxycodone with Tylenol: Percocet Oxycodone with aspirin: Percodan OxyContin Heroin: semisynthetic

OxyContin Used to treat pain associated with arthritis, lower back injuries, and cancer Most commonly in tablet form: 10mg, 20mg, 40mg, 60mg, and 80mg tablets Dosed every 12 hours, half-life 4.5 hours Abuse: may be chewed, crushed, snorted or injected Eliminates time-release coating Enhances euphoria, “rush” Increases risk for serious medical consequences

Synthetic Opioids Methadone Demerol (meperidine) Fentanyl Suboxone (buprenorphine) Tramadol Complex mechanism of action Nonscheduled, less abuse potential

Opiates and Reward Opiates bind to opiate receptors in the nucleus accumbens: increased dopamine release

Sedative-Hypnotics Used to treat anxiety and sleep disorders Mechanism: enhances GABA act to slow normal brain function Barbiturates Phenobarbital Pentobarbital Fioricet (butalbital/acetaminophen/caffeine)

Sedative-Hypnotics Cont’d Benzodiazepines Librium (chlordiazepoxide HCL) Valium (diazepam) Restoril (tempazepam) Klonopin (clonazepam) Ativan (lorazepam) Xanax (alprazolam) Non-benzo hypnotics Ambien (zolpidem) Sonata (zaleplon) Lunesta (eszopiclone) Soma Cross-tolerance with alcohol (GABA related) Soma: muscle relaxant, metabolized to mebprobamate (Miltown) Non-benzo hypnotics bind to alpha 1 subunit of GABA-A receptor; thus sedating without anxiolytic or anticonvulsant properties

Sedative-Hypnotic Effects Sedation Slurred speech Incoordination Unsteady gait Impaired attention or memory Stupor or coma Overdose risk increased with barbiturates or in combination with other sedatives, including opioids and alcohol Toxicity: unsteady gait, impaired gag reflex, and blurry vision, obtundation

Sedating Drugs and Overdose Flumazenil: reverses BDZ-induced sedation

Other Sedative-Hypnotic Risks No significant adverse medical consequences of long-term use Amnesia Difficulty with recent memory Tolerance, physiological dependence, addiction Addiction risk factors same as for other drugs of abuse

Sedative-Hypnotic Withdrawal Increased pulse, blood pressure, or sweating Hand tremor Nausea or vomiting Transient hallucinations or illusions Agitation Anxiety Seizures (grand mal)

Protracted Withdrawal Abstinence syndrome Anxiety Muscle twitching Low mood Sweating Headache Derealization Rebound insomnia Especially with short-acting benzodiazepines

Sedative-Hypnotic Neurobiology Source: www.ccforum.com

Prescription Stimulants Amphetamines enhance alertness. Stimulant medications (e.g., amphetamines) are often prescribed to treat individuals diagnosed with attention-deficit hyperactivity disorder (ADHD). Substantial amounts of pharmaceutical amphetamines are diverted from medical use to non-prescription use. Amphetamines increase wakefulness and have been used by: The military, by pilots, truck drivers, and other workers to keep functioning past their normal limits Common amphetamines include Dexedrine (d-amphetamine), methamphetamine, Ritalin, and Adderall (dl-amphetamine). Source: Erowid.org

Street Names for Stimulants Dex Dexamphetamine Bennies, Minibennies Dexies Copilots Crank Eye Openers Uppers Wake Ups Black Beauties Whizz Ups Pep Pills Lid Poppers Source:Erowid.org

Short-Term Effects Euphoria Increased energy/productivity Increased concentration Decreased appetite Increased libido Decreased sleep *increased risk HIV/Hepatitis B&C transmission with increased libido/impulsivity *Short-term effects plus ease of manufacture and less stigma are what makes meth appealing to use among different groups. Also used to self-medicate depression/AHDH

Ritalin When this medication is used to treat ADHD, patients may find they have increased attention, decreased impulsiveness, and decreased hyperactivity. Milder stimulant that works by affecting the levels of chemicals (neurotransmitters) in the nervous system. May also be used in the treatment of depression in certain cases. Long-acting form: Concerta Methylphenidate * WebMD

Adderall Adderall is used to treat attention deficit hyperactivity disorder (ADHD). Adderall is a combination of stimulants (amphetamine and dextroamphetamine). It increases the ability to pay attention, focus, and control behavior problems. This drug may also be used to treat certain sleeping disorders (narcolepsy).

Medical Risks Norepinephrine release causes constriction of blood vessels, elevated blood pressure and rapid heart rate Increased activity levels Dangerously high body temperatures Increased risk of seizures Potentially fatal arrhythmias, heart attack, or stroke

Psychiatric Symptoms and Stimulants Psychiatric symptoms associated with use of larger doses of amphetamines include depression, anxiety, psychosis, and suicidal ideation Symptoms may depend on differences in sensitivity, frequency and quantity of use, and method of administration Abstinence syndrome may occur (dysphoria, anhedonia, irritability, insomnia/hypersomnia, anxiety, low energy) Users may appear manic (grandiosity, psychomotor agitation) Stimulant users: up to 60% with affective d/os, 40-50% with anxiety disorders Push towards “integrated treatment”

Neurobiology of Stimulants Hi-Dose MA: increases DA/NE in synaptic cleft 1. Binds to presynaptic membrane and induces presynaptic release into cleft 2. Increases DA release from DA reuptake transporter (reverse transport) 3. Increases DA release from presynaptic vesicles 4. Binds to MAO preventing DA degradation in dopaminergic neurons

Overview Introduction to medication treatment approaches for addictive disorders Medication treatment options within Rx drug classes: Opioids Sedative-hypnotics Stimulants Clinical implications of co-occurring psychiatric disorders

Medications to Treat Addiction Addiction is a chronic, relapsing brain disease characterized by compulsive use despite harmful consequences Medications as part of comprehensive treatment plan Treatment approaches: Medications (Bio) Therapy, lifestyle changes (Psycho-Social) Thorough evaluation and diagnosis essential Meds help but not a cure Screening/assessment covered in Module I FDA-approved vs. off-label meds…use in adolescents vs. adults.

Pharmacotherapy in Substance Use Disorders Treatment of withdrawal (“detox”) Treatment of psychiatric symptoms or co-occurring disorders Reduction of cravings and urges Substitution therapy Other forms of relapse prevention/harm reduction: aversive conditions if use, restore impulse control, Prevention: use of psych med that may delay or prevent onset of SUD: ex: evidence of tx of ADHD may delay onset of SUD in adolescence, tx of ADHD with bupropion may reduce rates of initiation of tobacco use. Replacement therapy: NRT, methadone, buprenorphine

Treating Opioid Dependence: Aims Detoxification: Opioid-based (methadone, buprenorphine) Non-opioid based (clonidine, supportive meds) Relapse prevention: Agonist maintenance (methadone) Partial agonist maintenance (buprenorphine) Antagonist maintenance (naltrexone) Lifestyle and behavior change Detox: Reverse neuroadaptation from chronic use; promote long term tx leading to life style changes. Maintenance: allow substitution of healthy life style for addict life style. Relapse prevention: forget it. How? With new habits

Opioid Detoxification Medications used to alleviate withdrawal symptoms: - Opioid agnonists (methadone, buprenorphine) - Clonidine (alpha-2 agonist) - Other supportive meds anti-diarrheals, anti-emetics, ibuprofen, muscle relaxants, BDZs

Opioid Substitution Goals Reduce symptoms & signs of withdrawal Reduce or eliminate craving Block effects of illicit opioids Restore normal physiology Promote psychosocial rehabilitation and non-drug lifestyle Basis of replacement therapy: replace w/ longer duration of action, less abuse potential, and better safety profile to prevent WD and craving.

Methadone: Clinical Properties Synthetic opioid agonist Analgesic Quick absorption, slow elimination Effects last 24 hours; once-daily dosing maintains constant blood level Prevents withdrawal, reduces craving and use Facilitates rehabilitation Clinic dispensing limits availability Methadone is recognised as the ‘gold standard’ of treatment for managing opioid dependence and has been found to be an effective public health and harm reduction measure. Methadone has been available in all jurisdictions since 1969, although to date remains unavailable in the Northern Territory. Its use is generally restricted to specific medical conditions, such as opioid dependence and the management of chronic pain Methadone is provided by public government services (public programs) and privately through trained GP prescribers Methadone is highly effective when taken orally. When used repeatedly, such as during maintenance for opioid dependence, its effects persist and the duration of its effect is extended Although a potent analgesic for chronic pain, the analgesic effect lasts for less than 24 hours because of its variable half-life. Methadone: is detectable in plasma for 30 minutes following ingestion has a peak concentration after about 4 hours has a single dose half-life of 15–22 hours (high variability) has a maintenance dosing half-life of 22 hours and suppression of withdrawal for 24–36 hours stability varies with metabolic rate, which varies according to genetic makeup, environmental and disease-state factors (e.g. pregnancy increases methadone metabolism) oral form only marginally less potent than IM form. Metabolism: CYP3A4, no organ toxicity or cognitive impairment with chronic use -improved outcomes w/ use: reduced HIV, IV drug use, crime, death Source: CDHA (Commonwealth Department of Health and Ageing) 2002, Illicit Drug Training for Pharmacists, CDHA, Canberra, p.86.

Buprenorphine for Opioid Dependence FDA approved 2002, age 16+ Mandatory certification from DEA Mechanism: partial opioid agonist Office-based, expands availability Analgesic properties Ceiling effect Lower abuse potential Safer in overdose

Buprenorphine Formulations Sublingual administration Subutex (Buprenorphine) Suboxone (4:1 Bup:naloxone) Dose: 2mg-32mg/day Once-daily dosing

MYTH: Patients are still addicted FACT: Addiction is pathologic use of a substance and may or may not include physical dependence. Physical dependence on a medication for treatment of a medical problem does not mean the person is engaging in pathologic use and other behaviors.

Case Vignette #1 34 y.o. African American female with 3-year history of Vicodin use Using 10-12 pills/day for back pain suffered in an automobile accident No history of heroin or other opiate use Sometimes takes more than prescribed by her physician, but would like to stop taking all medications. Employed, lives with her husband and two children, and has private insurance Considerations: COST, use history, is she dependent??

Medications for Sedative-Hypnotic Dependence Taper: slowly decrease dose to minimize withdrawal symptoms May first convert to longer-acting agent Role for anticonvulsants Use non-addictive medications for residual anxiety symptoms SSRIs and other antidepressants Other anti-anxiety agents

Treatment of Stimulant Dependence Behavioral therapies effective for treating stimulant addiction. At this time, there are no proven medications for the treatment of stimulant addiction. Outpatient taper: slowly decrease dose Medications to treat withdrawal symptoms Anxiety Depression * NIDA

Medications for Stimulant Dependence Medications used to treat stimulant-induced psychiatric symptoms: Antidepressants Antipsychotics Anti-anxiety agents Medications to treat agitation, violence ER and outpatient settings Medications to treat co-occurring psychiatric disorders

Medication Management in COD For patients with anxiety d/o’s and SUDs: Try to avoid BDZs Consider: SSRIs For patients with ADHD and SUD, consider: Atomoxetine (Strattera) Bupropion SR or XL (Wellbutrin) Modafinil (Provigil) If stimulant necessary: Long-acting formulations (e.g., Concerta), Daytrana patch

A Delicate Balance Adequately address symptoms while maintaining safety Screen all patients for risk before prescribing controlled medications Perform comprehensive exam Establish that non-controlled Rx has failed Discuss benefits and pitfalls of long-term controlled Rx Steps to prevent doctor-shopping Urine drug testing Comprehensive follow-up

In Conclusion Addiction is a serious, chronic and relapsing disorder, but treatments are available Medications should be considered as part of a comprehensive treatment plan, addressing both disordered physiology and disrupted lives Medications should be considered for treatment of: psychiatric sx’s, addictive d/o’s, and co-occurring d/o’s Emerging research supports use of meds in individuals with SUDs and psychiatric comorbidity Detox alone is insufficient for long-term outcomes

UCLA Integrated Substance Abuse Programs Thank you! Larissa Mooney, M.D. UCLA Integrated Substance Abuse Programs lmooney@mednet.ucla.edu