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

2. 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

4. 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

5. 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

6. 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

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

8. 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

9. 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

10. 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.

11. 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

12. 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

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

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

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

16. 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)

17. 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

18. 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

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

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

23. 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)

24. 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

25. 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

26. Sedating Drugs and Overdose
Flumazenil: reverses BDZ-induced sedation

27. 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

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

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

30. Sedative-Hypnotic Neurobiology
Source:

32. 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

33. 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

34. 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

35. 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

36. 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).

37. 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

38. 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”

39. 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

40. 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

41. 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.

42. 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

43. 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

44. 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

45. 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.

46. 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.

47. 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

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

49. 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.

50. Case Vignette #1
34 y.o. African American female with 3-year history of Vicodin use
Using 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??

51. 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

52. 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

53. 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

54. 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

55. 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

56. 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

57. UCLA Integrated Substance Abuse Programs
Thank you!
Larissa Mooney, M.D.
UCLA Integrated Substance Abuse Programs