Lecture 8 pain, narcotic and non narcotic analgesics (analgesic antipyretics)

DRUGS USED IN DISORDERS OF THE CENTRAL NERVOUS SYSTEM AND TREATMENT OF PAIN Lecture 8:

Pain, Narcotic (Opioid) and Non-Narcotic Analgesics Marc Imhotep Cray, M.D.

(NSAIDs & Other Analgesic Antipyretics)

Learning Objectives:

CNS Pharmacology Lecture 8

OPIOID ANALGESICS: 1. Familiarity with the brain’s opioid system; in particular the major opioid receptors, their principal endogenous ligands and the signal transduction pathways that they utilize.

2. The role of opioid transmission in the pain experience and how opioid agonists induce analgesia.

3. The concepts of opioid-induced tolerance, physical dependence, addiction and pseudoaddiction, and how to recognize each.

4. The indications, mechanism of action, clinical effects, adverse effects and contraindications of the major classes of opioid analgesics used in the management of pain.

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Learning Objectives cont.

CNS Pharmacology Lecture 8

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) 1. The role of cyclooxygenase enzymes and prostaglandins in the etiology of inflammation, pain and fever.

2. The role of prostaglandins in the homeostatic regulation of: a) gastric function, b) kidney function, c) regulation of vasoconstriction and platelet activation 3. The indications, mechanism of action, adverse effects, contraindications and potential drug interactions of: a) Aspirin and the salicylates, b) Traditional NSAIDs e.g. ibuprofen and naproxen c) Celecoxib, d) acetaminophen 4. The rationale behind the unique indication for low dose aspirin as a prophylactic treatment in the prevention of platelet aggregation and the development of cardiovascular heart disease.

5. The pharmacokinetics of aspirin and the mechanisms that lead to the development of salicylate toxicity 6. The mechanisms underlying acetaminophen poisoning and its treatment

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CNS Pharmacology Lecture 8

Learning Objectives cont.

TREATMENT OF HEADACHES 1. Recognition of the primary headache disorders, including migraine, cluster headache, and tension headache 2. The major differences between primary and secondary headache disorders 3. The current concepts in migraine pathophysiology 4. Identification of the treatment strategies for the various headache disorders 5. The indications for the various abortive migraine-specific medications and headache preventive medications.

6. The mechanisms of action and adverse effects of the various abortive migrainespecific medications and headache preventive medications.

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Classification Schema: Narcotic (Opioid) and Non-Narcotic Analgesics: A. Analgesics Morphine Hydromorphine Methadone Meperidine Fentanyl Codeine Oxydocone Hydrocodone Propoxyphene Dextromethorphan

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CNS Pharmacology Lecture 8

B. Mixed Receptor AgonistAntagonists Pentazocine Nalbuphine Buprenorphine Butorphanol C. Opioid Antagonists Naloxone Naltrexone

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CNS Pharmacology Lecture 8

Analgesics Classification Schema cont.

A. Aspirin and Salicylic Acids Aspirin (Bayer) Diflusinal (Dolobid) Salsalate (Disalcid) B. Non-Selective and traditional NSAIDs Ibuprofen (Advil/Motrin/Nuprin) Naproxen (Aleve/Anaprox/Naprosyn) Oxaprozin (Daypro) Ketoprofen (Actron) Indomethacin (Indocin) Diclofenac (Cataflam) Sulindac (Clinoril) Ketorolac (Toradol) Marc Imhotep Cray, M.D.

NSAIDS cont.

Tolmetin (Tolectin) Meloxicam (Mobic) Piroxicam (Feldene) Meclofenamate (Meclomen) Mefenamic acid (Ponstel) Etodalac (Lodine) C. Coxibs: COX-2 specific inhibitors Celecoxib (Celebrex) D. Non-NSAID Related Analgesic Acetaminophen (Tylenol/ Paracetemol)

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CNS Pharmacology Lecture 8

Analgesics Classification Schema cont.

DRUGS USED IN TREATMENT OF HEADACHES: (A)Triptans Sumatriptan Naratriptan Rizatriptan Zolmitriptan Almotriptan Frovatriptan (B) Ergot Alkaloids Ergotamine Dihydroergotamine

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(C) Migraine preventative agents Propranolol Topiramate Divalproic acid Amitriptyline Flunarizine Verapamil Methysergide

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CNS Pharmacology Lecture 8

Pain Pathways:  Tissue injury can lead to cellular changes involving release of chemicals (e.g., histamine) that start or quicken neuronal impulses that are interpreted as pain  Many neuronal pathways transmit pain sensation  For example, pain from peripheral injury reaches CNS via primary afferent neurons, whose cell bodies form the dorsal root ganglia (DRG)  Disorders such as phantom limb pain may involve abnormal DRG structure or function

 Primary afferents end mainly in the dorsal horn of the spinal cord Secondary neurons cross spinal cord and ascend in pathways to the thalamus, the cerebral cortex, and other sites

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CNS Pharmacology Lecture 8

Pain Pathways(2) A descending system of opioid (endorphins, enkephalins), 5-HT (e.g., from raphe nuclei), and noradrenergic (e.g., from locus ceruleus) pathways can lessen afferent signals Drugs that act at pathways mediating pain sensation or perception are:  local (e.g., lidocaine) and  general (e.g., halothane) agents,  opioids (e.g., morphine), and  nonopioids (e.g., aspirin and acetaminophen)

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Pain Pathways

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CNS Pharmacology Lecture 8

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MedPharm Case 19

CNS Pharmacology Lecture 8

An 18-year-old man is brought into the emergency department after being found on the street unresponsive. He is lethargic and does not answer questions. He has been given 1 ampule of Dextrose intravenously without result. On examination, his heart rate is 60 beats per minute, and respiratory rate is 8 per minute and shallow. His pupils are pinpoint and not reactive. There are multiple intravenous track marks on his arms bilaterally. The emergency physician concludes that the patient has had a drug overdose.  What is the most likely diagnosis?  What is the most appropriate medication for this condition?  In addition to its therapeutic actions, what other effects might this medication produce?

From: MedPharm Clinical Case Studies Marc Imhotep Cray, M.D.

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Opioids: Endogenous Opioid Pathway

CNS Pharmacology Lecture 8

 Morphine and related compounds (opioids) mimic effects of endogenous opioid neurotransmitters —endorphins and enkephalins  Endogenous opioid receptors are located throughout pathways that relay pain signal from its source to higher CNS centers for processing, evaluation, and response (such as via the spinoreticular tract (see previous slide)

 Descending pathways, including endogenous opioids, NE, and 5-HT, modulate transmission of incoming pain signals  These pathways can be activated subconsciously or consciously, which may account for a large analgesic placebo effect

 Opioids alter perception of pain  Such modulation of affective component of pain can improve a patient’s quality of life even in presence of a continuing sensation of pain

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Endogenous Opioid Pathway (2)

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CNS Pharmacology Lecture 8

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Opioids: Receptor-Transduction Mechanisms

CNS Pharmacology Lecture 8

Opioids activate 7-transmembrane GPCRs located presynaptically and postsynaptically along pain transmission pathways  High densities of opioid receptors- known as μ, δ, and κ-are found in dorsal horn of spinal cord and higher CNS centers  Most currently used opioid analgesics act mainly at μ-opioid receptors  Opioids have an onset of action that depends on route of administration and have well-known adverse effects  constipation  respiratory depression  abuse potential Marc Imhotep Cray, M.D.

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Opioids Receptor-Transduction Mechanisms (2)

CNS Pharmacology Lecture 8

 Cellular effects of opioids involve enhancement of neuronal K+ efflux (hyperpolarizes neurons and makes them less likely to respond to a pain stimulus) and inhibition of Ca2+ influx (decreases NT release from neurons located along pain transmission pathway)  Brainstem opioid receptors mediate respiratory depression produced by opioid analgesics  Constipation results from activation of opioid receptors in CNS and GI tract  Nausea and Vomiting associated with opioids results from activation CTZ of medulla

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Cellular effects of opioids:

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Narcotic (Opioid) Analgesics

CNS Pharmacology Lecture 8

A. PROTOTYPE, MORPHINE, is extracted from opium poppy in which 10% of alkaloid content is morphine and 1% is codeine B. Morphine and codeine can be modified to form semisynthetic derivatives, including: 1. Heroin (diacetylmorphine), which is more lipid-soluble and has a more rapid onset of action 2. Oxycodone (Roxicodone)

C. Many synthetic narcotics have also been produced, such as 1.

2.

3.

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5.

6.

Meperidine (Demerol) Levorphanol (Levo-Dromoran) Methadone (Dolophine) Fentanyl (Duragesic) Propoxyphene (Darvon, Dolene) Dextromethorphan

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CNS Pharmacology Lecture 8

Opioid Analgesics (2) D. PROPERTIES of Morphine are representative of most of drugs in this class 1. Morphine is least lipophilic opioid, but it can still cross BBB a. Absorption from gut is good, but serum morphine concentration is variable due to first-pass metabolism by liver b. Distributes in the total body water c. It is metabolized by glucuronide conjugationďƒ morphine-6gluconoride is more active than parent drug d. Parenteral administration is commonly used to induce a rapid, predictable analgesic effect

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CNS Pharmacology Lecture 8

Opioid Analgesics (3) 2. Binding sites for morphine are endorphin, dynorphin, and enkephalin Receptors μ-, κ,- and δ-receptor subtypes have been identified; opioids act primarily on the μ-receptors a. Opioid receptors are present in pain-integrating areas of CNS and PNS b. Receptors are also present in the GI tract and brain stem, which leads to some undesirable effects of opioids (constipation, depression of respiration)

Morphine effects on pain pathway neurons: (illustrated next slide) (1) decreasing presynaptic cAMP formation (2) decreasing presynaptic calcium influx (3) decreasing presynaptic glutamate and substance P release from vesicles (4) increasing postsynaptic hyperpolarization due to an increase in potassium efflux

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Opioid Analgesics (4)

CNS Pharmacology Lecture 8

3. Opioids multiple effects on pain pathway neurons shown:

Weiss ST. High-yield pharmacology, 3rd ed. 2009

 Analgesia occurs due to a decrease of pain perception and a decrease in psychological response to pain  An inhibitory action on substance P release in spinal cord may account for some of analgesic effects is accompanied by a mental clouding or drowsiness  Although first dose can be dysphoric, subsequent doses produce euphoria Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 8

Opioid Analgesics (5) Morphine induces many additional pharmacological effects: a. Respiratory depression is induced by a reduction in sensitivity of medullary respiratory centers to CO2 This occurs with all narcotic analgesics and is primary cause of death from an acute overdose b. Physical dependence and tolerance occur with long-term use, which means that a withdrawal syndrome will develop when the drug is discontinued Cross-tolerance occurs with all other narcotic analgesics c. Emesis is often observed with initial doses due to chemoreceptor(CTZ) stimulation in area postrema in medulla d. Miosis is induced by increased parasympathetic tone to pupil via stimulation of Edinger-Westphal nucleus This is less pronounced with meperidine due to an anticholinergic effect

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CNS Pharmacology Lecture 8

Opioid Analgesics (6) Morphine pharmacological effects cont. e. Constipation results from decreased GI motility, even though there is increased tone of GI smooth muscle f. Histamine release can be inducedďƒ morphine can be dangerous to use in patients with asthma g. Tone of biliary tract and ureters can be increasedďƒ causing urinary retention and inhibiting voiding reflex h. Antitussive (cough suppressant) actions are prominent i. Hyperthermia can occur j. An increase in intracranial pressure can occur due to dilation of cerebral blood vessels

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Opioid Analgesics (7)

CNS Pharmacology Lecture 8

E. NARCOTIC ANTAGONISTS have a structure that is very similar to morphine ďƒ A bulky substitution on the nitrogen results in antagonistic actions

1. The pure antagonists have no analgesic activity a. Naloxone (Narcan) will i. reverse respiratory depression from an overdose of a narcotic ii. not affect respiratory depression from a sedativehypnotic iii. induce a withdrawal syndrome in a narcotic addict

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CNS Pharmacology Lecture 8

Opioid Analgesics (8) Narcotic antagonists (2)  Modification of narcotic structure (at N) results in narcotic antagonists  Diagram shows structure of morphine

Weiss ST. High-yield pharmacology, 3rd ed. 2009 Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 8

Opioid Analgesics (9) Narcotic antagonists (3) b. Naltrexone (Revia) is more effective orally and has a longer duration of action than naloxone 2. Weak agonist/antagonist analgesics, such as pentazocine (Talwin), have analgesic activity in addition to antagonistic activity a. They will not reverse respiratory depression caused by a narcotic b. They will induce a withdrawal syndrome in a narcotic addict c. Most new narcotic analgesics are in this groupďƒ rationale behind their use is that these analgesics should cause less respiratory depression and be less likely to be abused

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Opioid Analgesics (10)

CNS Pharmacology Lecture 8

F. THERAPEUTIC USES of the narcotic analgesics include: 1. Analgesia a. Morphine is more potent than codeine, which is more potent than aspirin b. Narcotics are used primarily for short term analgesia (e.g., myocardial infarction, surgery), except in terminally ill patients analgesic antipyretics are preferred to treat chronic pain 2. Diarrhea Diphenoxylate with atropine (Lomotil) or loperamide (Imodium) are preferred as they have few CNS effects 3. Neuroleptic anesthesia (e.g., fentanyl) 4. Antitussive activity a. Codeine induces more cough suppression than morphine b. Dextromethorphan (Benylin DM) has little narcotic activity, but it does have cough suppressant activity Guaifenesin an expectorant, is also a common ingredient in combination products with codeine or dextromethorphan 5. Reduction of narcotic withdrawal symptoms requires a drug, such as methadone, with a long duration of action 6. Maintenance of a narcotic addict using methadone Marc Imhotep Cray, M.D.

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Opioid Analgesics (11)

CNS Pharmacology Lecture 8

G. CLINICAL USES of narcotic antagonists include: 1. Analgesia with agonist/antagonist analgesics (pentazocine) 2. Tx of respiratory depression from an acute narcotic overdose using naloxone 3. Diagnosis of physical dependence to a narcotic Naloxone will precipitate withdrawal in narcotic addicts 4. Management of a narcotic addict. Naltrexone will reduce t euphoric effects of the narcotics 

Buprenorphine (T 12h) (Subutex), a partial agonist, is now available for outpatient treatment of opioid addicts 0.5

5. Management of an alcoholic Naltrexone reduces craving for ethanol

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CNS Pharmacology Lecture 8

Opioid Analgesics (12) H. TRAMADOL (Ultram) is an atypical, narcotic-like analgesic that binds to Îź-receptors and also inhibits reuptake of serotonin and norepinephrine 1. It is indicated for moderate to severe pain 2. Seizures are a serious potential side effect of tramadol; other side effects include ulcers and GI bleeding 3. Although there is some potential for abuse, tramadol is currently not categorized as a controlled substance in U.S.

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CNS Pharmacology Lecture 8

Headaches:  Primary headaches are generally mediated via vasodilation  Most common types of headaches are migraine, tension-type, and cluster headaches  Migraine can usually be distinguished from cluster headaches and tension-type headaches by its characteristics (next slide)  Migraines, for example, present as a pulsatile, throbbing pain, whereas cluster headaches present as excruciating, sharp, steady pain  This is in contrast to tension-type headaches, which present as dull pain, with a persistent, tightening feeling in head

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Characteristics of migraine, cluster, and tension-type headaches

CNS Pharmacology Lecture 8

Modified from: Lippincott Illustrated Reviews-Pharmacology 6th Ed.. 2015

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Summary of drugs used to treat migraine headache: TRIPTANS Almotriptan AXERT Eletriptan RELPAX Frovatriptan FROVA IMITREX, ALSUMA Rizatriptan MAXALT Zolmitriptan ZOMIG ERGOTS Dihydroergotamine MIGRANAL NSAIDs Aspirin BAYER, BUFFERIN, ECOTRIN Ibuprofen ADVIL, MOTRIN Indomethacin INDOCIN Ketorolac TORADOL Naproxen ALEVE, ANAPROX, NAPROSYN

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PROPHYLACTIC AGENTS Anticonvulsants Beta-blockers Calcium channel blockers Tricyclic antidepressants

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CNS Pharmacology Lecture 8

Sumatriptans and Reuptake inhibitors:  Certain types of pain are sometimes successfully treated with drugs that are not analgesic for other types of pain  Two examples are sumatriptan and related compounds (triptans) and inhibitors of neuronal reuptake of NE or 5-HT  Triptans (e.g., almo-, ele-, frova-, nara-, riza-, and sumatriptan) are often first-line therapy for treatment of acute severe migraine attacks

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CNS Pharmacology Lecture 8

Sumatriptans and Reuptake inhibitors(2)  Reuptake inhibitors (e.g., tricyclics and more selective NE or 5-HT reuptake inhibitors) are used for some patients with migraine and for some patients experiencing neuropathic pain with hyperalgesia (increased sensitivity to painful stimuli) or allodynia (painful sensitivity to nonpainful stimuli)  Neither triptans nor reuptake inhibitors are very effective against inflammatory or acute pain  Adverse cardiovascular effects can occur with triptans, and numerous ANS effects can occur with reuptake inhibitors

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CNS Pharmacology Lecture 8

Migraine Headaches:

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CNS Pharmacology Lecture 8

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Summary of drugs useful in treatment and prophylaxis of migraine headaches:

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Modified from: Lippincott Illustrated Reviews-Pharmacology 6th Ed.. 2015

CNS Pharmacology Lecture 8

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Nonopioids: NSAIDs, Cyclooxygenase- 2 inhibitors, and Acetaminophen

CNS Pharmacology Lecture 8

Nonsteroidal antiinflammatory drugs have good analgesic efficacy (but often less than that of opioids), relatively rapid onset, and adverse effects (e.g., possibly fatal gastrointestinal bleeding and disturbed salt and water balance) All NSAID effects— analgesic, antiinflammatory, antipyretic, and antiplatelet —are thought to be due to decreased prostanoid biosynthesis via COX inhibition Traditional NSAIDs inhibit both COX-1 and -2 isoforms, but newer COX-2 inhibitors are more selective Marc Imhotep Cray, M.D.

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Nonopioids: NSAIDs, Cyclooxygenase- 2 inhibitors, and Acetaminophen (2)

CNS Pharmacology Lecture 8

 Analgesic efficacy of selective COX-2 inhibitors (coxibs) is approximately equal to that of traditional NSAIDs, but adverse effects of COX-2 inhibition have yet to be fully characterized and are somewhat controversial  risk of thrombosis, Sulfa allergy  Ability to selectively inhibit COX-2 has been related to difference in amino acids at position 523 of COX-1 and COX-2: isoleucine in COX-1, valine in COX-2  Mechanism of action of acetaminophen is uncertain but thought to be via CNS effects  Elevates pain threshold, possibly by inhibiting NO (nitric oxide) pathway Marc Imhotep Cray, M.D.

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NSAIDs and Cyclooxygenase- 2 inhibitors

CNS Pharmacology Lecture 8

Note: Celecoxib (CELEBREX) MECHANISM Reversibly inhibits specifically the cyclooxygenase (COX) isoform 2, which is found in inflammatory cells and vascular endothelium and mediates inflammation and pain; spares COX-1, which helps maintain gastric mucosa. Thus, does not have the corrosive effects of other NSAIDs on GI lining. Spares platelet function as TXA2 production is dependent on COX-1.

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NSAIDs and Cyclooxygenase- 2 inhibitors

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CNS Pharmacology Lecture 8

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CNS Pharmacology Lecture 8

Analgesic Antipyretics: Specific Agents A. All analgesic antipyretics act by inhibiting cyclooxygenase (COX), thereby reducing prostaglandin synthesis B. ASPIRIN (acetylsalicylic acid) is a salicylate that acetylates and irreversibly inhibits COX-1 and COX-2ďƒ New COX must be synthesized to recover from effects 1. Major therapeutic effects include: a. Mild analgesia, due to reduced prostaglandin synthesis at sensory nerve endings b. Antipyresis, due to reduced prostaglandin synthesis in hypothalamic temperature control center c. Anti-inflammatory actions at high doses, due to reduced prostaglandins at sites of inflammation d. At very low doses, prophylaxis of MI in older people at high risk 2. These effects occur without tolerance and without euphoria Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 8

Analgesic Antipyretics (2) ASPIRIN cont.

3. Side effects from aspirin include: a. Gastric ulcerations (NSAID-induced ulcers) and gastric hemorrhaging, which can be increased by ingesting ethanol and decreased by taking with food or misoprostol 

Of course, aspirin is contraindicated in persons with known peptic ulcer disease (PUD)

b. Reducing platelet aggregation by inhibiting formation of thromboxane A2 (inhibits TXA2 synthesis)  This adverse effect is taken advantage of when managing patients i.

After a myocardial infarction ii. With transient ischemic attacks iii. With angina, especially unstable angina iv. With atrial fibrillation Marc Imhotep Cray, M.D.

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CNS Pharmacology Lecture 8

Analgesic Antipyretics (3) Side effects from aspirin cont. c. Hypersensitivity reactions that i. Are not immunologically mediated ii. May be due to increased leukotrienes d. Reduced renal uric acid secretion at low doses and reduced uric acid reabsorption (uricosuria) at high doses e. Reye’s syndrome, which involves a fatal, fulminating hepatitis and cerebral edema, in children with chicken pox (varicella) or influenza viral infections  Thus, aspirin is best avoided in children

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Analgesic Antipyretics (4)

CNS Pharmacology Lecture 8

4. Aspirin induces acute toxic effects in following order as dose is increased from therapeutic to toxic range: a. Tinnitus is an early indicator of toxicity b. Uncoupling of oxidative phosphorylation CO2 production, which respiration and can lead to hyperthermia at toxic doses c. Direct medullary stimulation also enhances respiration, leading to respiratory alkalosis and HCO3 excretion (loss) d. At even higher doses, metabolic acidosis occurs due to i. ii. iii.

Marc Imhotep Cray, M.D.

Direct respiratory depression Acidic products of aspirin metabolism, which leads to fluid and electrolyte loss Previous loss of HCO3

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CNS Pharmacology Lecture 8

Analgesic Antipyretics (5) 5.

C.

Management of aspirin overdoses involves a. Emesis, lavage, or dialysis b. Fluids with HCO3 c. Monitoring blood aspirin concentration beginning 6 hours after ingestion IBUPROFEN (Motrin, Advil) and naproxen (Aleve) reversibly inhibit COX and have 1. Effects that are very similar to aspirin, including a. Mild analgesic activityďƒ is especially effective for dysmenorrhea b. Antipyretic activity c. Anti-inflammatory activity

2. Side effects that are similar to, but milder than, the side effects for aspirin, including: N.B.-All NSAIDs can cause non-dose-related a. Gastrointestinal bleeding episodes of acute renal failure and nephrotic b. Increased bleeding times syndrome. They should be used with caution in those with renal insufficiency or in patients c. Overdose toxicity like that of aspirin taking other potentially nephrotoxic agents.

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CNS Pharmacology Lecture 8

Analgesic Antipyretics (6) D. KETOROLAC (Toradol) is an unusual NSAID in that it can be given intramuscularly as well as orally 1. It is only used for the treatment of acute pain 2. It has a clinical efficacy similar to morphine

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Analgesic Antipyretics (7)

CNS Pharmacology Lecture 8

A. ACETAMINOPHEN (Tylenol) elevates pain threshold, possibly by inhibiting NO (nitric oxide) pathway 1. Primary effects of acetaminophen are quite different from aspirin, and include: a. Mild analgesic activity b. Antipyretic activity c. No anti-inflammatory activity d. None of side effects of aspirin 2. Major adverse effect from high doses is delayed hepatic necrosis a. A toxic phase 1 metabolite builds up in liver because of depletion of glutathione  N-acetyl-p-benzoquinone imine (NAPQI) b. Toxicity is especially prominent in combination with ethanol c. Hepatotoxicity can be avoided by early administration of Nacetylcysteine, which replenishes stores of glutathione Remember: N-acetylcysteine is the antidote for acetaminophen toxicity Marc Imhotep Cray, M.D.

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THE END

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Further study (SDL):

CNS Pharmacology Lecture 8

MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders Companion eNotes: CNS- Central Nervous System Pharmacology Textbook Reading: Schumacher MA, Basbaum AI & Way WL. Ch. 31. Opioid Analgesics & Antagonists. Pgs. 543-61 Furst DE,. Ulrich RW & Prakash S. Ch. 36 NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout. Pgs. 635-43 In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed.

Online resource center: Medical Pharmacology Cloud Folder

Lectures/discussions to follow: 9. Drugs of Abuse

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