PHAR 507 EXAM IV Lecture Review

(11/7) Golembiewski Lecture: Chronic Pain Management Phases of Pain Acute Pain Post-Acute Pain Chronic Pain

Usual Timeframe 1-4 days, 7 if severe 4-45 days >45 days Direction of Pain

Management Degree of pain and speed of resolution varies by patient

During this time, patients are highly susceptible for transitioning to long-term opioid use

Beyond the normal expected time of tissue healing. Evaluate pathology.

Chronic Pain - Etiology: HA or fibromyalgia (26%) > back pain (20%) > arthritis (13%)

o Anatomy: lower back (30%) > hip (25%) > neck and shoulders (25%) > knee (24%) o Socio-demo: female, elderly, lower socio-economic status, employment status, history of abuse/violence

- Type of chronic pain o Identifiable cause: Can be visualized or detected by examination, such as XRay or MRI o No identifiable cause: The origin of pain is unable to be detected, yet the nervous system is sending pain

signals despite lack of ongoing tissue damage – an exaggeration of pain. Its presentation may be d/t changes in how the CNS perceives pain. In this case, pain becomes the disease and it can significantly interfere with the patient’s lifestyle, leading to depression and anxiety. These precipitative changes in the nervous system may be permanent.

o Neuropathic pain: This refers to pain resulting from abnormal functioning of the nervous system or damage to the nerves. Whereas nociceptive pain derives from a noxious stimulus, neuropathic pain can be elicited without stimuli or an innocuous stimulus (allodynia). The pain signals are out of proportion (hyperalgesia) and the is no identifiable cause.

Management of Neuropathic Pain Goal: ³ 30% reduction in pain intensity (considered to be the threshold for clinical effectiveness in chronic pain) Start low, and go slow when titrating the dose. Continue to increase the dose until the patient reports clinical effectiveness or excess adverse effects – this may take up to 2 months. If only partial pain relief is achieved and the side effects are tolerable, increase the dose. If the side effects are intolerable, return to the tolerable dose and add an additional first-line agent with a different mechanism of action. Similarly, if experiencing inadequate pain relief after an adequate trial of first-line agents at the target dose, add an additional first-line agent or switch to one with a different mechanism of action.

Management of Neuropathic Pain (NeuPSIG 2015)†

Drug Dosing Pearls FIRST-LINE: Strong Recommendation

TCAs: amitriptyline, desipramine, nortriptyline amitriptyline: 10-150mg QHS

Especially in the elderly (65yo+), secondary are preferred over tertiary amines d/t a reduced ADR profile

SNRIs: duloxetine, venlafaxine duloxetine: 60-120mg QDaily venlafaxineER: 150-225mg QDaily

SSRIs are not enough, we need NE involved. Counsel: may take weeks to take effect. Abrupt discontinuation may elicit withdrawal symptoms

Gabapentinoids: gabapentin, pregabalin Also referred to as the anticonvulsants

gabapentin: 400-1200mg TID (min 1800mg/d) pregabalin: 75-300mg BID

Gabapentin may take a while to get adjusted to. Titrate slowly as patient familiarizes themselves with the ADRs

SECOND-LINE: Weak Recommendation

Tramadol 200-400mg/d divided TID if ER, BID if IR

Initial use of tramadol is a risk factor for long-term opioid use d/t its euphoric, stimulant, and relaxing effects. Opioid withdrawal Sx may occur following abrupt discontinuation, chronic tramadol use is not advised.

Patches: lidocaine, capsaicin Lidocaine: Apply 1 to 3 patches locally QDaily for up to 12 hours

Patches are ideal for localized pain. Lidocaine patches may be preferred first-line in very frail, elderly patients

THIRD-LINE: Weak Recommendation

Instant-Release Opioids Take the lowest effective dose with individualized titration

D/t issues with chronic use, IR opioids are only recommended for short-term interim coverage in the right patients while titrating first-line agents

† Finnerup et al., Lancet Neurol, 2015 - TCAs and SNRIs work in the brain to enhance the descending inhibitory 5HT/NE pathway from the brain

projecting towards the dorsal horn. They affect the descending modulation. Pain reduction ¹ antidepressive effect - Gabapentinoids work by inhibiting Ca2+ channels in the spinal cord at the ascending input. This decreases the

release of excitatory neurotransmitters.

Management of Lower Back Pain (LBP): LBP is a musculoskeletal-type pain and is one of the most common reasons for physician visits. It is classified by its symptom duration: acute (£4w), subacute (4-12w), and chronic (³12w)

- Diagnosis: Physicians look for anatomical and/or radiographic abnormalities to identify the source of LBP o Radicular Sx: Unilateral lower extremity pain and/or paresthesia that radiates down from the lower back

to the knee or below – caused by nerve root impingement. This is most common with agitation of the sciatica nerve, often d/t herniation of a disc in the lower back. (Can be detected by MRI)

- Acute/Subacute LBP: Pain, tenderness, impaired range of motion o Etiology: Often follows a strenuous activity or jarring trauma that introduces pull, strain, stretch, or sprain

of muscles, ligaments, connective tissue, or cartilage o Pathology: Release of inflammatory mediators inflame and spasm the muscles in the surrounding tissue o Treatment†: Regardless of treatment, patients will improve over time († Foster et al. Lancet 2018)

§ First-Line: Non-pharmacologic àHeat wrap, stay active, consider getting a massage/acupuncture § Adjunctive: NSAID, skeletal muscle relaxants Last: SNRI, gabapentinoids

• NSAIDs are the pharmacologic treatment of choice d/t the inflammatory pathology • Skeletal muscle relaxants may be considered, but they are not associated with

improvements in function like the NSAIDs are. If used, short-term (<1w) therapy is advised d/t sedative effects. Cyclobenzaprine will not sedate and is the most studied.

• There is insufficient data to support use of SNRI or gabapentinoid therapies • APAP is not recommended.

- Chronic LBP: LBP and tenderness that does not subside. o All patients with chronic LBP require non-pharmacologic therapy: Optimal treatment of chronic LBP

involves staying active and strengthening associated muscle groups. Evidence supports the intervention of stress reduction therapy based on mindfulness, exercise, multidisciplinary rehabilitation, and acupuncture. Lower quality of evidence supports integration of tai chi, progressive relaxation, electromyography biofeedback, CBT.

§ If there is inadequate response to non-pharmacologic management à consider pharmacologic o Pharmacologic Treatment is indicated for pain not sufficiently managed by non-pharm options

§ First-Line: NSAIDs - Though, only offers a small to moderate improvement in pain relief § Second-Line: • Tramadol – Poor evidence with long-term use. Useful for acute-on-chronic

• Duloxetine – Small improvement, though ideal for pain of neuropathic origin § Last-Line: Opioids – Should only be used in select patients who are educated on the risks-versus-

benefits of opioid therapy, having also failed non-opioid treatment - Chronic LBP with Radicular Symptoms: If neuropathic pain is suspected: gabapentinoid, duloxetine, TCA

Pharmacologic Options for Chronic Pain: Pro’s and Con’s

Drug/Class Place in therapy Benefit Harms APAP First-line alternate to NSAIDs for

musculoskeletal pain (OA, RA) Small Hepatotoxicity with chronic therapy at high-doses

NSAIDs First-line for musculoskeletal pain (OA, RA) Small-moderate Cardiovascular risks, GI disturbances, renal toxicity

Gabapentinoids First-line option for neuropathic pain, pain from nerve injury, and fibromyalgia Small-moderate Sedation, dizziness, ataxia

Topical Products

Capsaicin: neuropathic, OA, RA Lidocaine: localized neuropathic pain NSAID: localized musculoskeletal pain, OA, RA

Small-moderate Capsaicin: Initial burning and irritation of mucus membranes

Antidepressants (SNRI, TCA)

First-line option for neuropathic pain, pain from nerve injury, and fibromyalgia. May be used in musculoskeletal pain, headache, and phantom limb pain

Small-moderate TCAs: Anticholinergic effects and cardiotoxicity (arrhythmia)

Adverse Effects of our Therapy Options

- NSAIDs: Avoid use in recent MI, unstable angina, poorly compensated HF, CKD (III<), high-risk of AKI o Gastrointestinal (Non-selective > COX-2 selective): heartburn, GI bleed, PUD o Cardiovascular: [BBWchronic = MI, stroke], exacerbate heart failure o Renal: Inhibition of prostaglandin activity at the kidney may precipitate acute kidney insufficiency (AKI) o Alliance for Rational Use of NSAIDs: “lowest effective dose for shortest period of time”

- Gabapentinoids: sedation, dizziness, fatigue, visual disturbances, difficulties with mentation - Duloxetine: sedation, fatigue, dry mouth - Opioids: sedation, N/V/C, and more

What are skeletal muscle relaxants? à Drugs used to treat muscle spasms! Place in therapy: Studies have shown that their pain relief is equivalent to NSAIDs though they do not promote faster functional recovery in patients with lower back pain. They should only be used short-term (< 1 week) d/t adverse effects

- Antispasmodic MoA: Alter CNS conduction to reduce muscle spasms ~sedate o Unique: Cyclobenzaprine is a centrally-acting a2 agonist

- Antispastic MoA: Direct action on the muscle/spinal cord to improve muscle hypertonicity & involuntary spasms

- Chronic treatment: Diazepam and tizanidine Chronic Pain and the Role of Opioids In patients with chronic pain, the primary outcome of interest for pharmacologic therapy is restoring quality of life and achieving functional goals. With chronic opioid use, the analgesic efficacy will progressively decline – and ‘titrating to effect’ is not an appropriate response. Chronic opioid therapy will delay functional recovery/returning to work, thereby hindering improved quality of life. Patients who ‘want’ or ‘need’ opioids are the ones at highest risk for complications. • Adverse events associated with chronic/high-dose opioid use: hyperalgesia, falls and fractures in the elderly, substance-use disorders, overdose, and potentially death.

- Patient-centered outcomes: Less likelihood of functional recovery, less likelihood of returning to work, less likelihood of being able to ween off drug, and future difficulty in controlling acute pain – such as after a surgery.

- Opioid-related endocrinopathy (HPA axis suppression): hypogonadism, testosterone deficiency o Related Sx: Impaired sexual function, decreased libido, infertility, osteoporosis

• Principles of Safe Chronic Opioid Prescribing: Document, document, document!!! - H&P: Complete a full history and physical, summarized by a diagnosis and assessment of the risk versus benefit - Risk of Misuse: Assess the risk of opioid misuse during therapy by monitoring and supply the appropriate

treatment. Screening tools exist, such as the Opioid Risk Tool (ORT) and the SOAPP - Investigate: Check the Prescription Monitoring Data (PDMP) software with each prescription

o Check baseline urine drug test, and in the future as deemed fit - Safety: Do not use concurrent sedative-hypnotics. Avoid or carefully justify high doses (³90MME/d)

o In patients with doses ³ 50 milligram morphine equivalents/day, prescribe naloxone† († cdc.gov) - Plan: Have a written agreement “contract” with established goals: fill at 1 pharmacy, no early fills, target dose

o Prepare to taper and discontinue if goals are not met • Transdermal Fentanyl Patch

- Place in therapy: Opioid-tolerant patients with pain that is stable and controlled for at least 48 hours. This product is indicated for stable pain – high fluctuations in pain are not compatible. This drug lasts 72 hours

- MoA/PK: A medication depot forms in the subcutaneous fat that permits a slow rise in plasma [drug] which level off in the first 12-24 hours. The patch lasts for 72 hours. There are select patients who require more frequent (48h) dosing with patches, but this should never be used in the initial therapy. è Upon initiation, continue PO opioid for 12 hours after applying patch to treat pain

- Conversion: When switching from PO opioids to transdermal fentanyl, there is variability in recommendations. Depending on the reason for switching, the conversions is between 60-90mg/d PO Morphine = 25mcg/hr fentanyl

- ADRs: Less constipating than chronic PO opioids. Sedation o Following patch removal, it takes 20 hours for plasma levels to drop by 50%, so patients should be

monitored for at least 24 hours if the patch is removed d/t oversedation/respiratory depression - Counseling: Remove old patch after placing new patch. Do not cut the patch. Patient should be educated on

proper placement, storage, and disposal of fentanyl patches. • Methadone

- Place in therapy: Methadone is the ideal pain reliever for mixed pain (nociceptive + neuropathic) - MoA: Three-fold: µ-agonist, 5HT/NE reuptake inhibitor, and NMDA receptor antagonist - PK: Highly lipophilic with rapid distribution and slow-release back into the plasma, conferring a long t1/2 (15-60h)

and a slow steady state (5-7d). Thus, the dose cannot be adjusted quickly o Metabolized by CYP3A4 and CYP2B6

- ADR: Methadone exhibits many of the typical ADRs of opioids but in addition has a risk of QT prolongation and the life-threatening torsades de pointes. This is dose-dependent, and therefore it should be initiated slowly

- Conversion: One of the major issues with methadone is the significant variability in drug response associated with converting to or from methadone.

o One dependable trend: the higher the dose of the other opioid, the more potent methadone will be o Theory: the NMDA receptor antagonism may reverse opioid tolerance

o Theory: High levels of morphine-3-glucoronide and hydromorphine-3-glucuronide may have a pain-producing effect that is blunted/unnoticed by the analgesic effects.

o Overall, interconverting opioids with methadone requires experience and a significant depth of knowledge. Be careful, be conservative, otherwise you risk overshooting and causing harm.

(11/8) Jaki Lecture: Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are prescribed for their analgesic, antipyretic, and anti-inflammatory effects. As such, they relieve pain, fever, and inflammation by mechanisms different than narcotics and steroid hormones. According to Dr. Jaki, the world’s favorite drug is the NSAID, aspirin (acetylsalicylic acid, ASA). ASA is an acetylated derivative of salicylic acid, a benzoic acid first extracted from the bark of the willow tree (Salix). In 1828, Henri Leroux isolated the crystalline form of salicylic acid. Users found the high doses of salicylic acid to be discomforting to the stomach. Chemists (Gerhardt, 1853) made the acid body smaller by acetylating the ortho-OH to form ASA, which is more bioavailable allowing lower doses. By 1899, Bayer marketed ASA worldwide. Arachidonic Acid Pathway: Upon injury, disturbances in cell walls activate membrane phospholipids. Phospholipase these lipids to arachidonic acid. Then, cyclooxygenase (COX) catalyzes the synthesis of cyclo-endoperoxides, which are precursors to the inflammatory mediators prostaglandin and thromboxane. [NSAIDs block COX] • Prostaglandin Biosynthesis: Arachidonic acid is a simple unsaturated fatty acid with 4 double bonds. COX sequentially adds 2 moles of O2 to cyclize it into prostaglandins (PGG2) • Inflammatory Mediators

- PGE2 : Promotes inflammation, fever, and pain - PGI2 : Confers anti-aggregatory and hyperalgesic properties - TXA2 : Promotes platelet aggregation [ASA acts here to prevent blood clotting]

Gastric Prostaglandin Activity There are two-three isoforms of cyclooxygenase. COX1 protects the stomach lining and maintains kidney function via activity of prostaglandins (PGs). • PGs in the GI tract are responsible for inhibiting acid secretion and stimulating the production of protective mucus. After being synthesized in the cell membranes, (1) PGs act upon parietal cells to inhibit the Proton Pump (H+-K+) which pump H+ into the stomach to produce the acid environment. (2) At the superficial epithelial cells of the stomach, membrane-produced PGs induce and support the production of a protective mucus layer (pH = 7)

à NSAID Dual Insult - Primary Insult: Direct acid damage by increasing gastric acidity - Secondary Insult: Reducing the levels of protective PGs (mucus)

• Overall, inhibition of PG synthesis in the GI causes increased gastric acid secretion, diminished bicarbonate secretion, and diminished mucus secretion on the epithelial mucosa. Classical NSAIDs: A structurally diverse class of compounds that each have carboxylic acid esters and aromatic ring functions for binding to and blocking the COX enzyme • Salicylates and Pyrazolones

- Salicylates: Salicylic acid, acetylsalicylic acid - Pyrazolones: Phenylbutazone, oxyphenbutazone

• Fenamates ~ A salicylic acid with an aniline moiety - Compounds: meclofenamic acid, efenamic acid, flufenamic acid, diclofenac acid

• Propionates ~ also known as arylalkanoic acids - Compounds: Ibuprofen, flubriprofen, naproxen, ketoprofen

• Oxicams ~ N-Sulfoxide group - Compounds: piroxicam, lornoxicam, meloxicam

• Indole Derivative – Indomethacin

Cyclooxygenase Enzyme (COX): Our understanding of COX is a rather recent advancement. We first sequenced the dimeric, membrane-bound protein in 1988. But not much was known until both the COX1 and COX2 crystal structures was elucidated in 1996. Now, we have a plethora of NSAID drugs and can individualize their use. There are two known isoforms of cyclooxygenase. Traditional NSAIDs block the activity of both COX1 and COX2

- COX1 is the constitutive form. It produces PGs and thromboxanes (TXA2) in the stomach, GI tract, platelets, and kidneys for tissue homeostasis. In the stomach, COX1 acts to protects the gastric lining and maintains kidney function via activity of prostaglandins

- COX2 is the inducible form whose activity is triggered by cytokines, growth factor, and endotoxins when joints are damaged or inflamed. PGs produced at these sites contribute to inflammation and hyperalgesia

• COX Active Site Structure and Binding - COX1: Ile523† and basic His513 - COX2: Val523† and more basic Arg513

(† Some sources, and the picture, suggest this to be residue 532) • Arachidonic acid’s 4 double bonds are bound throughout the active site and are acted upon by oxidative reactions • NSAID drugs compete with arachidonic acid for active site binding. The aromatic moieties mimic arachidonic acid’s double bond character. Therefore, to be effective, they must have greater affinity • The different AA found in the active site of COX2 produce an extra pocket that is not found in COX1. This side pocket can accommodate bulky groups such as a methyl-sulfonyl moiety (~celecoxib). By exploiting these differences, we can develop selective COX2 inhibitors. Everything that binds in COX1 can bind in COX2. Here are NSAID selectivity ranges:

- > 50-fold COX2 selective: Rofecoxib - 5-50-fold COX2 selective: etodolac, meloxicam, celecoxib, nimesulide - 1-5-fold COX2 selective: diclofenac, sulindac, meclofenamate, piroxicam, diflunisal - COX1 > COX2: ketorolac, flubriprofen, ketoprofen, indomethacin, ASA, naproxen

• Modes of Enzymes Inhibition: All NSAIDs compete with arachidonic acid, but the mechanism may vary - Competitive: Ibuprofen - Weak binding + time-dependent: Naproxen and oxicams - Tight binding + time-dependent: Indomethacin - Covalent: ASA. This is usually irreversible. The only way to recover is by newly synthesizing enzyme

o Mechanism: Arg120 positions ASA in the pocket. It’s positive charge attracts the carboxylate of ASA. The Ser530-OH group attacks and hydrolyzes the ASA ester, forming an acetylated Ser530 and free SA.

o Thus, irreversible COX inhibition by ASA is via carboxylation/acetylation of active site Ser residue. Propionic Acids/Arylalkanoic Acids (ibuprofen, naproxen, ketoprofen, flubriprofen)

- Overview: Non-selective NSAIDs. These have a lower incidence of GI toxicity than ASA. They undergo extensive metabolism and most of their metabolites have significant anti-inflammatory activity

- Ibuprofen’s S-isomer is more active, regardless, the R-isomer is rapidly metabolized to the S-isomer in vivo - Ketoprofen: Has additional inhibitory activity towards 5-lipoxygenase and therefore can inhibit leukotriene

biosynthesis from arachidonic acid. Heteroarylacetic Acids (Sulindac, Etodolac)

- Sulindac Overview: Non-selective NSAID (2>1). Sulindac is a prodrug that is not effective until its sulfoxide is converted to a methyl sulfide by reductase enzymes of the liver. As a result, it has lower GI toxicity than ASA and the propionic acids.

- Etodolac Overview: Non-selective NSAID (2>>1). Etodolac is a newer drug, only S-isomer is active. It is significantly more selective for COX2 than 1.

- Ketorolac Overview: Non-selective NSAID (1>2). Ketorolac is the only NSAID available parenterally. It has potent analgesic activity but has only moderately effective anti-inflammatory activity

o ADR: Has significant GI and Renal side effects. As a result, it is only intended for short-term use – maximum 5 days. This is thought to be related to COX1 selectivity

o ADME: Over 90% is eliminated via the kidneys, 60% unchanged and the rest glucuronides Fenamates (meclofenamic acid, efenamic acid, flufenamic acid, diclofenac acid)

- Overview: Since these compounds have a second aromatic ring, they are far more potent. Among other members of this class, diclofenac appears to be the most toxic (associated with its para-hydroxylated metabolites)

Acetaminophen (APAP) Toxicity APAP is not an NSAID, though it shares many similar characteristics. Of note, it has few-none anti-inflammatory effects. Despite being widely used, it’s MoA remains unclear

- Theory1: Inhibits COX3 – Research has shown COX3 activity is unrelated to inflammation, so this could work. - Theory2: APAP acts as a suicide substrate during Tyr and Fe oxidation during prostaglandin synthesis. Tyr

oxidation and Fe oxidation are essential for PGG2 synthesis – normally peroxides perform this oxidation activity. Strangely, at low peroxide concentrations, APAP can compete, but at high peroxide concentrations it cannot. During inflammation, there are higher concentrations of peroxides. This may explain why APAP is ineffective against inflammatory states. APAP activity in the CNS, including temperature reduction, is retained.

Booze + APAP: APAP has minor metabolites that can be hepatotoxic. When combined with alcohol, there is increased formation of the hepatotoxic APAP metabolites, including N-acetylimidoquinone. This is an extremely reactive compound that can covalently bind to hepatic proteins, leading to hepatic necrosis and renal failure. Normally, the body can handle low doses of these hepatotoxic compounds, detoxifying them with glutathione or sulfation. If the detoxification reserves are depleted, increased formation of the hepatotoxic metabolite by CYP2E1 can lead to big problems. (11/14) Schlemmer Lecture: Pharmacology of NSAIDs NSAID drugs have four pharmacologic properties we need to be aware of. They reduce the sensation of pain (analgesia), they reduce elevations in body temperature (antipyresis), they reduce inflammation (anti-inflammatory), and they have anti-platelet activity (ASA>>). These activities occur via interactions with COX enzymes

- COX1: Constitutively expressed in non-inflammatory cells under healthy conditions à Role: Produce prostaglandins to support platelets and provide gastric protection

- COX2: Inducibly expressed in inflammatory cells (+lymphocytes and PMNs) when activated à Role: Mediate pain signaling, fever, and inflammation

In the body, prostaglandins (PGs) serve many roles. They operate in the stomach to decrease acid and increase mucus production. They increase bloodflow to the kidneys. They promote uterine motility during labor. They induce fever and nociceptor sensibility during inflammatory reactions. And they cause vasodilation for increased capillary permeability. Physiology of Prostaglandins Activity, versus the intervention of NSAID therapy • Analgesia

- Prostaglandins sensitize pain receptors: Following tissue damage or pain-provoking stimuli in the periphery, arachidonic acid is released and is metabolized into prostaglandins (PGs). PGs block the K+ efflux from nociceptors, preventing hyperpolarization and conferring a net depolarizing effect – making the nociceptor more sensitive. As a result, PGs lower the threshold for activation of nociceptive nerve terminals. The increase in action potentials transiting through Ad and C fibers to the spinal cord and brain may be routed to the cerebral cortex and elicit an emotional, distracting response.

- NSAID Activityà Block synthesis of PGs to prevent sensitization. Analgesia occurs - Opiates or NSAIDs? Compared to opiates, NSAIDs do not have the risk of addiction,

sedation, or respiratory depression, but do still have the benefits of anti-inflammatory and anti-platelet effects

- Place in therapy: Mild-moderate pain, including HAs, toothache (Naproxen > IBU), back pain, menstrual pain, arthritis, ankylosing spondylitis, and sports injuries.

o Ketorolac (Toradol): Only used for short-term treatment of moderately severe acute pain

• Antipyretic - Prostaglandins induce fever: During an immunologic/infectious process, cytokines are released and may enter

the brain. There, the arachidonic acid pathway is stimulated to produce PGE2 which signal through receptors of the hypothalamus to increase the reset temperature a few degrees above normal (37º C, 98.6º F).

- NSAID Activityà Inhibit PGE2 synthesis at the thermoregulatory centers of the hypothalamus. The ‘normal’ body temperature will be restored and other mechanisms will activate to lower fever (sweating).

• Anti-inflammatory - Prostaglandins promote the inflammatory response: Inflammation is a natural response following tissue injury

designed to increase local blood flow and chemotaxis. Similar to the previously discussed ‘Analgesia’ section, tissue injury releases phospholipids and results in formation of arachidonic acid. Arachidonic acid is metabolized by cytokine-induced COX2 into PGE2 (erythema) and PGI2 (vasodilation) which act in concert to produce inflammation and sensitize pain receptors, leading to inflammatory pain. Additionally, PG activity potentiates other vasodilators (bradykinin and histamine), which affect vascular permeability, provoking edema and swelling

- NSAID Activityà Inhibit COX2’s synthesis of inflammatory mediators, diminishing erythema, edema, and pain - Dosing: To achieve the anti-inflammatory effects of NSAIDs, much higher doses than are used OTC for analgesia

are required. OTC IBU is generally limited to 1200mg/day, but the effective anti-inflammatory activity appears at 2400mg/day. In contrast, naproxen achieves anti-inflammatory effects early, 275-550mg/day (max 1500mg/day), capable of lasting 8-12h

- Risk of targeting inflammation: If we are targeting the mediators of inflammatory disorders, selective inhibition of COX2 would be a logical technique. Most NSAID drugs are non-selective, such as ibuprofen (IBU), hitting both COX1 and COX2. Celecoxib (Celebrex) was the first COX2-selective NSAID approved by the FDA. It was shown to produce less GI-related pain, but these products have their own inherent risks. They are associated with increased cardiovascular events.

COX and Cardiovascular Risk Selective COX2 Inhibitors are more likely to cause thrombosis - COX1: Vasoconstriction + Platelet Aggregation

o Normally, COX1 produces thromboxane A2 (TXA2) in platelets, a prothrombotic peptide. Inhibition of COX1 will prevent TXA2 production and confer an anti-thrombotic effect.

o Selective COX2 Inhibitor: If COX1 goes uninhibited, pro-thrombotic TXA2 will be produced. Further, all the arachidonic acid that would normally be dedicated to COX2 metabolism will be funneled into COX1 activity, increasing the risk of thrombosis!

- COX2: Vasodilation + Inhibition of Platelet Aggregation o Normally, COX2 produces PGI2, a prostacyclin that elicits vasodilation and inhibits platelet aggregation

for an anti-thrombotic effect. o Selective COX2 Inhibitor: Inhibition of COX2 will prevent the natural vasodilatory and anti-thrombotic

effects of COX2 – increasing the risk for thrombosis! - Patients with Cardiovascular Risk

o Avoid COX2 Inhibitors: Patients with coronary artery disease (CAD), MI Hx, angina, stroke Hx o Naproxen is safest: In patients with (CAD), naproxen is the safest non-selective NSAID

NSAID Pearls - Monitoring parameters: BP and Renal function annually. Short-term use can harm the kidneys! NSAIDs can BPÝ! - ADRs: Short-term use can cause dyspepsia; long-term use can cause peptic ulcers and GI bleeds! - NSAID-induced asthma: Patients who have hives (urticaria) or other symptoms of allergy with NSAID use should

avoid them in asthma. NSAID Prototype Agents

- Aspirin (salicylates): ASA irreversibly acetylates COX - Acetic acid derivatives

o Diclofenac: Inhibits COX and lipoxygenase. Available IM, PO, topical. Good for actinic keratosis. Diclofenac is moderate potency

o Indomethacin: More effective as an anti-inflammatory drug than analgesic. Also used to close ductus arteriosus. Available as a suppository. Can be used in gouty arthritis

o Ketorolac: More effective as an analgesic drug than an anti-inflammatory agent. Often used for post-operative analgesia, though it frequently causes ulcers and has a high risk of upper GI bleed, should be used no longer than 5 days. It is available PO, IV, IM.

- Ketoprofen (arylalkanoic/propionic acids): From a popular class of analgesic agents, ketoprofen is available in PO and topical formulations. IBU belongs to this class.

- Mefenamic acid (fenamates): Hey guess what, this drug doesn’t need dose adjustment for renal dysfunction!

- Diflunisal: A garbage antipyretic - Selective COX2 Inhibitors: Useful in patients unable to tolerate conventional NSAIDs, though they are linked

with CV mortality ASA Toxicities ASA toxicities, also known as salicylisms, are not seen too often anymore. They have unique presentations that are somewhat interesting!

- Mild salicylism: tinnitus, vertigo, respiratory stimulation - Severe salicylism: respiratory + renal depression, hallucinations, delirium, hyperthermia, metabolic acidosis

Acetaminophen (APAP) APAP is the most commonly used OTC analgesic and most common cause of OTC toxicity. APAP has analgesic and antipyretic properties, but lacks anti-inflammatory activity. Relative to NSAIDs, it does not have gastric toxicities

- MoA: APAP’s activity is mostly unknown. Some evidence suggests that APAP is a weak inhibitor of COX1 and COX2. Other theories suggest APAP inhibits COX3 in the CNS, a COX that is not associated with anti-inflammatory activity.

- Place in therapy: Monotherapy for pain in osteoarthritis (2-4g/day), simple headaches, and synergy with opioids

o The manufacturer recommends a maximum of 3g daily - APAP Toxicity: Once doses exceed 10g in 24h (>150mg/kg peds),

APAP poisoning becomes a concern. Formation of the N-acetyl-p-benzoquinone imine (NAPQI) is the toxic agent that binds to hepatocytes in the liver to produce injury. NAPQI toxicity has a delayed presentation, starting with N/V in the first 24 hours

o N-acetylcysteine (NAC) is the indicated antidote. (11/15) Meyer-Junco Lecture: Pharmacology of Drug Abuse Word Bank: Describing Problematic Behaviors

- Abuse: Using a drug for a non-therapeutic intent - Misuse: Inappropriate use of a drug for a therapeutic intent (deliberate or unintentional)

o Chemical coping: reliance on a drug for psychological stability - Diversion: Transfer of a prescription from a lawful to unlawful method of distribution

Differentiating addiction and dependence - Addiction: Compulsive drug use despite negative consequences. It is considered psychological dependence, as the

cravings and desire to abuse for euphoric effects make the drug the first and foremost important thing in their life. Drug addictions are now formerly known as “Substance Use Disorders.” They follow the 4 C’s:

o Out-of-control, compulsive, continued use despite harm to personal well-being, triggered by cravings o Pseudoaddiction: Appearing like addictive behavior, but the ‘need’ for drug is because of unrelieved pain

- Physical Dependence: With chronic use, the body adapts to presence of the drug. If removed, withdrawal occurs

Physiology of Addiction Deep within the cerebral cortex is the age-old limbic system, frequently referred to as the brain’s reward system. Following an activity linked to reward, the mesolimbic dopamine system mediates the pleasurable response

- (1) Activation of cells in the dopamine-rich ventral tegmental area (VTA), which project along DA-ergic neurons synapse at the nucleus accumbens (NAc) of the ventral striatum (VS)

- (2) The NAc is the ‘pleasure center,’ mediating reward-related activities upon stimulation. From there, it projects to the prefrontal cortex

- (3) The prefrontal cortex is the ‘decision-making center,’ which critically evaluates input and makes associations Feelings of pleasure motivates us to repeat the associated activity. After consuming a meal or engaging in intercourse, extracellular [DA] in the mesolimbic system is elevated. Thus, the mesolimbic DA system is essential for survival. But, this system can be taken advantage of by drugs like cocaine. Cocaine blocks the DA transporter (DAT), flooding the synapse with DA producing profound euphoria. Besides DAT, there are other sites of action for drugs of abuse:

- Class I: G protein-coupled receptors (GPCRs, Gio): opioids, cannabinoids, hallucinogens - Class II: Ionotropic receptors/Ion channels: nicotine, alcohol, BZDs, dissociative anesthetics, heroin

o The number and frequency of action potentials hitting the VTA effects the [DA] release into the synapse - Class III: Monoamine transporters (MAT, specifically DAT): Cocaine, AMP, MAMP, MDMA

Apart from these classifications, there are numerous other mechanisms that exist. For instance, AMP can in dose-dependent fashion increase the rate at which DA is released from vesicles independent of action potential frequency. In any case, the common theme is all addictive drugs increase DA in the mesolimbic system Ever wonder what neurotransmitters (NTs) do? Here’s a table!

NT Role in the Body

ACh -Used by spinal cord motor neurons to cause muscle contraction -Used by brain neurons to regulate memory

DA -Released in the mesolimbic system to produce feelings of pleasure GABA -Major inhibitory NT. GABA produces sleep, reduces anxiety

Gly -Utilized by neurons in the spinal cord -Acts as an inhibitory neurotransmitter

Glu -Most common excitatory neurotransmitter in the brain (LSD) -Important in learning and memory

NE -Aids in Fight or Flight response in peripheral nervous system -In brain, regulates blood pressure/calmness

5-HT -Involved in mood, appetite, and sensory perception -Involved in thermoregulation. Inhibitory in spinal pain pathways

Drugs of Abuse: Activation of GPCRs • Heroin (H, smack, dope, china white) [GPCR Activator] [DEA: CI]

- MoA: Opioids bind to the pre-synaptic µ-opioid GPCRs (MOR) of GABA neurons in the VTA, inhibiting intracellular Ca2+ flux through voltage-gated channels. This prevents release of GABA into the synapse. By preventing the release of GABA, the synapsing DA neuron proceeds to fire uninhibited, releasing DA into synapses.

- Effects (4-6h): Rush à Trance-like state o CNS: Euphoria, analgesia, respiratory depression, clouded thinking, alternate wakeful-drowsy states o Circulatory: Bradycardia, endocarditis, pneumonia o GI: Decreased GI motility, N/V/C o Signs of abuse: Collapsed veins, scarring (‘track marks’), itching (histamine) [DEA: CII]

• Prescription Opioids (codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone) - RoA: Each of the prescription opioids can be prepared/manipulated for IV injection.

Addicts tend to prefer the RoA with the highest Cmax: IV injection o Onset: Inhale > Inject > Nasal inhalation > PO/GI o Cmax: Inject > Inhale > Nasal inhalation > PO/GI o Hydromorphone is a more potent, fast-acting opioid formulation

- Abuse Deterrent Formulations (ADF): Many abusers goal is ‘dose-dumping.’ Newer opioid formulations are designed as ADFs, to curb the known and expected routes of abuse. There are 6 ADFs:

• Physical/Chemical Barrier: This is the most common – designed to prevent crushing, cutting, chewing • Agonist/Antagonist combination • delivery system • Aversion • prodrug • a combination of systems

- Monitor for aberrant drug-related behavior: There are numerous behaviours to watch out for during treatment with a controlled substance that can raise suspicion for addiction, abuse, or diversion

o Serious: selling prescription drugs, forging prescriptions, stealing or borrowing another person’s medications, injecting PO formulations, obtaining prescription drugs from nonmedical sources, concurrent use of illicit drugs, multiple unapproved dose escalations, recurrent loss of prescription

o Less serious: aggressive complaining about need for higher doses, drug hoarding, requesting specific drugs, acquiring similar medications from other medical sources, unapproved dose escalation 1-2x, unapproved use of medication to treat another Sx, reporting effects not intended by clinician

- Risk Assessment Tools: Prior to prescribing a controlled/high-risk medication, risk assessment tools should be used to detect the risk of opioid-related aberrant behavior. The tools do not diagnose addiction or opioid use behavior. Also, they do not capture other known risks for aberrant behavior, including stress, poor social support, and negative home/social environments. Therefore, it is pertinent that the assessor speaks with the patient and takes the time to learn about their life. The available risk assessment tools include: ORT, SOAPP, DIRE

o Opioid Risk Tool (ORT): The higher the risk, the more monitoring we do and the more restrictions we should incorporate, such as: pill counts, urine drug screens, frequent office visits, decreased prescription quantities

§ Low risk: 0 – 3 points § Moderate risk: 4 – 7 points § High risk: ³ 8 points

- Before starting therapy and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. To mitigate risk, clinicians should consider incorporating naloxone when factors increase the risk of overdose

• Marijuana, Cannabis (bud, weed, pot, hash) [GPCR Activator] [DEA: CI]

- MoA: THC binds to the cannabinoid 1 receptor (CB1R, a GPCR) on the GABA neuron to inhibit release of GABA, disinhibiting VTA dopaminergic neurons, increasing DA release

o THC (D9-tetra-hydrocannabinol): Confers the psychoactive effects o CBD (cannabidiol): Lacks psychoactive effects

- RoA: Smoked, Vaporize, Flash vaporize, o Inhale: Onset: seconds to minutes • Time to peak: 30mins • Duration: 1-3.5h o Flash vaporizing (“dabbing”): Using hashish oil or wax dabs, THC content can

range as high as 90% in some products, increasing the intoxicating effects o PO: Variable onset: 30mins-2h • Duration of effect: 5-8h

§ First-pass: Metabolizes to an equipotent + longer lasting THC metabolite - “This is not your grandfather’s joint”: THC potency in recreational cannabis continues to rise, reports suggest

today’s users get more THC in a single puff than an entire joint had in the ‘70s - Effects (1-3.5h)

o CNS: Euphoria, altered perception of time, learning and memory impairment, heightened sensory perception, anxiety, panic, paranoia, acute psychosis

o Cardio/Resp: HRÝ, chronic cough, frequent respiratory infections o GI: Increased appetite, decreased nausea, decreased vomiting

- Regulation: At the time this document was written, 33 states+ Wash DC have legalized some form marijuana. On August 28th, 2018, Illinois enacted the Alternatives to Opioid Act of 2018, which is currently in its pilot stage. It involves offering marijuana as an alternative to a patient who’s condition was or could have been prescribed opioids. Some conditions include: CA, seizures, PD, MS, HIV/AIDs, ALS, glaucoma, spinal cord injury, TBI, RA

• Synthetic Cannabinoids (spice, K2, skunk) [GPCR Activator] [DEA: CI] - FDA-Approved: Marinol, Syndros, Cesamet, Epidiolex, Sativex. With the discovery of endogenous mammalian

cannabinoid systems, there have been increased study into cannabinoid compounds for the management of conditions like pain, MS, Alzheimer’s, nausea, and appetite stimulation

- MoA: Synthetic cannabinoids are far more potent and have higher binding affinity than THC - Effects: Although synthetic cannabinoids can also produce relaxation and calmness, they are more associated with

intense stimulation, hallucinations, delirium, prolonged psychosis, acute renal failure, MI, seizures, stroke, death

Family Hx of Substance Abuse Female Male Alcohol 1 point 3 points Illegal Drugs 2 points 3 points Prescription Drugs 4 points 4 points Personal Hx of Substance Abuse Female Male Alcohol 3 points 3 points Illegal Drugs 4 points 4 points Prescription Drugs 5 points 5 points Age (16 to 45 years old) 1 point 1 point Preadolescent sexual abuse 3 points 0 points Depression 1 point 1 point ADD, OCD, Bipolar or Schizo. 2 points 2 points

• Lysergic acid diethylamide, LSD (acid, blotter) [GPCR Activator] [DEA: CI] - MoA: Unclear. LSD is a hallucinogen that acts as an agonist to stimulate post-synaptic 5-HT2A receptor on

glutamate neurons to induce release of glutamate. Glutamate activates NMDA receptors, among others, in the prefrontal cortex. Agonist activity has also been seen at cortical 5-HT receptors

o Hallucinogens are not addictive because they do not involve DA release - Effects (6-12h)

o CNS: Distortion of reality, rapid emotional swings, enlarged pupils, numbness, insomnia, tremors, inability to think or communicate rationally, increased body temperature, sweating

o Cardio/Resp: HRÝ, BPÝ • GI: loss of appetite - History: LSD is one of the most potent and popular, perception-altering hallucinogenic drugs derived from a rye

fungus. Check Albert Hofmann’s 1943 scenic bike ride into discovery (https://www.youtube.com/watch?v=HBOPFWmZCdM) • Nicotine/Tobacco (Cigz, square) [Ionotropic] [DEA: None]

- MoA: Nicotine binds to the presynaptic nicotinic acetylcholine receptor (nAChR) of DA neurons in the VTA to excite the neuron with action potentials to induce the release of DA into the synapse. The DA neurons that project into the nucleus accumbens and prefrontal cortex are also stimulated to release DA.

- Effects (Seconds-minute): Quick kick (epi). o PK/PD: Nicotine has impressive PK, rapidly distributing to the brain within 10 seconds of inhalation, but

these effects dissipate as quickly as they arrive, as do the feelings of reward o CNS: Euphoria, enhanced alertness, HA, dizziness, lightheadedness o Cardio/Resp: Increase BP, RR, HR • GI: Dyspepsia, N, weight loss

- Addictive potential: Addiction is caused by the nicotine component of tobacco. The time to first cigarette and total cigarettes per day are the two strongest predictors of nicotine addiction

- Smoking Cessation: Bupropion, varenicline • Benzodiazepines (tranks, downers) [Ionotropic, GABA Cl-] [DEA: CIV]

- MoA: Similar to THC, BZDs lead to increased DA release by disinhibition of VTA dopaminergic neurons, though this occurs by a more complicated, balancing-type mechanism at different receptors. BZDs can bind to both a1 and a3 GABAA receptors in the VTA; though they bind far more strongly at the a1receptors of GABA neurons. Binding at the a1 receptor inhibits the GABA neuron, reducing its release of GABA upon the a3 receptors of DA neurons – thereby keeping the DA neurons more active – secreting more DA.

- Addiction is mediated by the mildly increased release of DA. o Anxiolytic effect comes from BZD activity at a2 subunits of the GABAA

- Effects: Duration is BZD-Drug-specific o CNS: Euphoria, memory impairment, drowsiness, poor concentration, imbalance o Cardio/Resp: BPß, respiratory depression

- BZDs of abuse o Speed of onset is a major factor in the euphoric effects from BZDs. Fast onset drugs, like alprazolam and

diazepam are commonly abused. Slow onset drugs, like clonazepam or oxazepam, have lower abuse rates. - Types of abuse

o Deliberate abuse: Abused for their euphoriant effects, to get high o Unintentional Abuse: Prescribed for anxiety but using inappropriately or at higher doses than prescribed

• Alcohol (booze) [Ionotropic receptors or ion channels] [DEA: None] - MoA: Alcohol alters the function of the following ionotropic receptors or ion channels: GABAA, NMDA, 5-HT3,

glycine, Kir3/GIRK channels. Alcohol’s pharmacology is complex - no single receptor mediates all of its effects • Dissociative Anesthetics: Ketamine is not addictive, it alters perception without causing sensations of reward/euphoria • Cocaine (coke, blow, rock) [Monoamine transporters] [DEA: CII]

- MoA: Cocaine increases the activity of 3 NTs by one mechanism: It inhibits the presynaptic reuptake of DA, NE, and 5-HT by inhibiting their transporters. This enhances the residence time of these NT permitting increased activity. Cocaine’s secondary MoA is its ability to block voltage-gated Na+ channels, conferring its local vasoconstrictive and anesthetic effect (at the cost of cardiac arrhythmias)

- Effects: o CNS: Euphoria, alertness, restlessness (NE), erratic and violent behavior, panic attacks, paranoia,

psychosis, insomnia, increased body temperature (5-HT)

o Cardio/Resp: Constricted blood vessels, BPÝ, HRÝ, arrhythmia, MI, stroke o GI (5-HT): N, abdominal pain, decreased appetite, GI ischemia

• Methamphetamine (meth, crank, ice) [Monoamine transporters] [DEA: CII] - MoA: At high doses, MAMP enters into vesicles to promote vesicular release along with DA into the synaptic

cleft. At any dose, MAMP blocks the DA transporter, preventing reuptake, prolonging its residence time for 6-12 hours. Similar activity, to a lesser extent, occurs with NE and 5-HT.

- Extraordinarily Euphoric: MAMP is far more euphoric than cocaine. It is highly addictive and has the power to devastate communities

o With sufficient time spent abstinent, the DA D2 receptors can recover some of their former functioning, as demonstrated by studies involving tracers and PET scans

- Effects (6-12h) o CNS: Euphoria, increased wakefulness, decreased fatigue. Long-term: anxiety, confusion, psychosis o Cardio/Resp: BPÝ, HRÝ, RRÝ, TÝ o Cosmetic: Meth mouth, picking, lesions (from picking at skin)

• Methylene-dioxymethamphetamine, MDMA (molly, ecstasy) [Monoamine transporters] [DEA: CI†] - MoA: MDMA functions similar to MAMP, but can enter the vesicles of all 3 NT (5-HT > NE > DA) to increase

synaptic release as well as inhibit the reuptake transporters (SERT > NET > DAT). With MDMA, there is a much greater emphasis on increasing the activity of 5-HT and less with DA activity.

- Addiction: Yes, but less addictive than its AMP and its phenethylamine analogue counterparts - Effects (3-6h):

o CNS: Disinhibition, enhanced sensory perception, sense of well-being, emotional warmth/empathy, euphoria o Cardio/Resp: BPÝ, HRÝ, risk of heart failure • Risk of kidney failure d/t hyperthermia o Misc: bruxism

(11/20) Hamidovic Lecture: Brain Disease Model of Addiction Assessing and Interviewing Patients Suspected of Substance Use Disorder (SUD)

- Style: Open-ended questions, phrased in an honest, respectful, matter-of-fact manner - Patient’s Status

o At the time of the interview, is the patient intoxicated, in withdrawal, relapsing, or in maintenance? o Last use: Within the last 3 months, what substance, quantity, frequency, RoA, and time of day is use

Interview Content - Hx of SUD: Age of first use. Amount, frequency, and RoA. Personal and social consequences. Tx history - FHx of SUD: To check for genetic predisposition (multifactorial summation of genetic makeup). SUD frequently

do pass on along generations, usually of the same drug type - SHx and Developmental Hx: Family situation, relationship status, and how it influences SUD. What supportive

and harmful relationships does the patient have. Is there a history of childhood physical or sexual abuse? - Med Hx: Prescriptions use, Overdose history, reasons for hospitalizations - Psychiatric Hx: Co-occuring SUD and psychiatric disorders often worsen the prognosis of the other disorder –

they must be treated simultaneously. *Additionally, avoid sending them to another clinic to have separate treatments, optimal treatment involves an integrated, multimodal, healthcare model. Psychiatric illnesses and SUDs are treated simultaneously because

o (1) Symptom overlap: Psychiatric symptoms and effects of intoxication may be indiscernible o (2) Pharmacodynamic effect: Substance use can exacerbate or worsen psychiatric conditions o (3) Pharmacokinetic effect: Persistence of SUD will involve drug use that interferes with the therapeutic

attempts to treat psychiatric illnesses

Patient Placement Criteria based on severity - Level 0.5: Early intervention: Patient should be educated on the consequences of drug abuse - Level 1: Outpatient services: Regularly-scheduled sessions; help individual make permanent changes in their SU

behavior - Level 2: Intensive Outpatient Services: make treatment available before and after school/work, as well as a 24h

crisis service - Level 3: Residential/Inpatient Services: A 24 hour live-in setting to prevent imminent danger - Level 4: Medically managed intensive inpatient service: Board-certified MDs in addiction medicine. UIC has one!

Diagnosis a Substance Abuse Disorder (DSM-V guided) • A SUD is a problematic pattern of use of an intoxicating substance that leads to clinically significant impairment or distress, as manifested by at least two of the following occurring within a 12-month period: - (1) Using bigger doses or for longer periods than intended - (2) Persistent desire or unsuccessful efforts to cut down or

control use of the substance - (3) Spending a lot of time involved in activities to obtain,

use, or recover from effects of the substance - (4) Craving, or strong desire/urge to use the substance - (5) Continued use despite persistent or recurrent social or interpersonal problems caused or exacerbated by its use - (6) Important social, occupational, or recreational activities are given up or reduced because of substance use - (7) Recurrent use of the substance in situation in which it is physically hazardous - (8) Substance use continues despite knowledge of having a persistent or recurrent physical or psychological problem

that is likely to have been caused or exacerbated by the substance - (9) Tolerance, defined by either: • A need for markedly increased amounts to achieve intoxication or the desired effect

• A markedly diminished effect with continued use of the same amount of the substance - (10) Withdrawal, manifested by • characteristic withdrawal syndrome for the substance, or

• substance is taken to relieve or avoid withdrawal symptoms • Intended1 to cut-down2 but the time spent3 craving4 leads to interpersonal problems5, giving up social activities6, to live in danger7, even when you know8 its bad, even though you have a tolerance9, because you’re afraid you’ll withdraw10 Diagnosing Withdrawal

- Part 1: Withdrawal occurs via: o Option 1: A cessation/reduction of __[drug]__ use that has been heavy and prolonged (> several weeks)… o Option 2: Administration of a(n) __[drug class]___ antagonist after a period of __[drug]__ use…..

- Part 2: Leads to the presentation of 3 or more withdrawal symptoms associated with that drug lasting for a period appropriate for the pharmacokinetic properties of that drug

Drug/Class Withdrawal Symptoms Alcohol Autonomic hyperactivity (e.g., sweating or pulse rate greater than 100 bpm; Increased hand tremor; Insomnia; Nausea or

vomiting; Transient visual, tactile, or auditory hallucinations or illusions Caffeine Headache; Marked fatigue or drowsiness; Dysphoric mood, depressed mood, or irritability; Difficulty concentrating; Flu-like

symptoms Cannabis Irritability, anger, or aggression; Nervousness or anxiety; Sleep difficulty (e.g., insomnia, dreams); Decreased appetite or

weight loss Opioids Dysphoric mood; N or V; Muscle aches; Lacrimation or rhinorrhea; Pupillary dilation; Sweating; Diarrhea; Yawning Sedatives, hypnotics, or benzodiazepines

Autonomic hyperactivity (e.g., sweating or pulse rate greater than 100 bpm); Hand tremor; Insomnia; Nausea or vomiting; Transient visual, tactile, or auditory hallucinations or illusions

Stimulants Fatigue; Vivid, unpleasant dreams; Insomnia or hypersomnia; Increased appetite; Psychomotor retardation or agitation. Tobacco Irritability, frustration, or anger; Anxiety; Difficulty concentrating; Increased appetite; Restlessness

Drug of Abuse Testing (DOA) - Urine point of care testing is the most common, though there is limited value in the acute clinical management of

most patients, so there is no absolute indication - Indication: drug treatment programs, pain management programs, psychiatric treatment - Playing Games

o False Positives: Potential for cross-reactivity with other meds, food types. (Recall efavirenz from 506) o False Negatives: Patients employ many techniques to test negative

§ Drinking more than 2L of water (Counter method: Urinary specific gravity evaluation) § Addition of adulterants, such as bleach or Zn(SO4) (Counter methods: Kits to detect tampering) § Substitution of a drug-free urine sample (Counter method: Temperature measurement on kit)

DSM-V Drugs of Abuse SUBSTANCE USE DISORDER INTOXICATION WITHDRAWAL

Alcohol X X X Caffeine X X

Cannabis X X X Phencyclidine X X Hallucinogens X X

Inhalants X X Opioids X X X

Sedatives, hypnotics, or anxiolytics X X X

Stimulants X X X Tobacco X X

Other (or unknown) X X X

- Positive result timeframes o AMP: 1-4 days. There can be false positives d/t the structural similarity of other drugs and herbal DS

§ Designer amphetamine analogues, atomoxetine, and methylphenidate are not detected o THC: Up to 2 months. False positives are extremely rare, second-hand smoke is considered impossible o Cocaine: 2-6 days. False positive: Drinking coca tea or eating coca leaves. o Opioids: 1-7 days False positive: Poppy seeds (unlikely)

Stages of SUD • It is only recently that we’ve been able to better understand the relationship addicts have with drugs of abuse. We have identified 3 stages of addiction

- Intoxication o Chronic users experience less euphoric effects to the same dose of drug o Chronic users experience little reward activity (DA) when using the drug

- Preoccupation and Craving o Incentive Sensitization Theory of Addiction: As time progresses, the liking for the drug decreases, but the

‘wanting’ increases. This is similar to the Pavlovian classical conditioning model. o First Order Stimuli: Drug or stimuli provides a rewarding experience via sharp

increases in DA release. However, after repeated exposure to the same stimuli, the response to the reward dampens, DA stops signaling.

o Second Order Stimuli: The experience of reward becomes paired to an environmental stimulus. So when the environmental stimulus presents, DA cells fire in an anticipatory response. This provides an intense craving, a want for more

o A study that investigated craving using a smart phone-enabled ecological momentary assessment (EMA) determined that craving predicted an episode of drug use

o Neurophysiology of Craving: Extraordinarily complex, even in mice models. This is one explanation for why we do not yet have control over SUD.

- Negative Affect and Withdrawal o Continued drug use leads to neuroadaptations which involve increased dysphoria and anxiety when not

using drugs. This manifests as withdrawal and a negative affect. This marks the transition period where patients no longer take drugs for pleasure, rather for relief from dysphoria

• This is why addicts continue to use despite the negative consequences

Addiction as a Systemic Disease

- Yeh HS et. al showed that smoking cessation was linked to the development of T2DM. The risk of developing T2DM was highest in the first 3 years since quitting smoking. This is thought to be related to patients substituting the rewarding effects of tobacco for the rewarding effects of food.

FDA Approved Treatment Options for SUDS - Opioid use disorder (OUD): Buprenorphine/naloxone, buprenorphine, methadone, naltrexone - Alcohol use disorder (AUD): Naltrexone, acamprosate, disulfiram - Nicotine addiction: Nicotine replacement therapies, bupropion, varenicline

Many drug abuse disorders are lacking effective and/or approved treatment options, especially the stimulant use disorders - Stimz:?? d-AMP, methylphenidate, modafinil, desipramine, amantadine, buprenorphine, progesterone??? - Cannabis use disorder

o N-Acetylcysteine (NAC) § MoA: Restores glutamate homeostasis § Efficacy: Studies have shown that NAC more than doubles the rates of abstinence

o Nabiximol: Cannabinoid agonist that may be useful for replacement therapy during cannabis withdrawal

(11/21) Jhawar Lecture: Alcohol Use Disorder Excerpt from page 30 of Alcoholics Anonymous “We alcoholics are men and women who lost the ability to control our drinking. We know that no real alcoholic

ever recovers control. All of us felt at times that we were regaining control, but such intervals - usually brief – were inevitably followed by still less control, which led in time to pitiful and incomprehensible demoralization”

Pharmacokinetics of Alcohol - Absorption: EtOH is rapidly absorbed within 5 to 10 minutes of ingestion - Metabolism of Alcohol (EtOH): More than 90% of EtOH’s metabolism occurs in the liver

𝐴𝑙𝑐𝑜ℎ𝑜𝑙'()*+*(

,-+./0*1-234-𝐴𝑐𝑒𝑡𝑎𝑙𝑑𝑒ℎ𝑦𝑑𝑒

'(/-+./-,-+./0*1-234-

𝑊𝑎𝑡𝑒𝑟 + 𝐶𝑂? o The full process of ethanol’s degradation requires two saturable hepatic enzymes, alcohol and aldehyde

dehydrogenase. Excess intake or accumulation of metabolites can lead to toxicity o Acetylaldehyde toxicity: flushing

Laboratory measures for alcohol abuse and intoxication - Blood Alcohol Level (BAL): Specific to alcohol

o 0.02-0.10% Exhilaration and loss of inhibition. Reduced coordination. Impaired ability to drive o 0.10-0.20% Reduced coordination in most activities, marked motor impairment, euphoria o 0.20-0.30% Memory blackout, impairments in thinking. Nausea and vomiting o 0.30-0.40% Amnesia, excessive stupor, sleepiness or unconsciousness. o 0.40-0.80% Coma is likely. Urinary and bowel incontinence. Decreased vitals. Death.

- Carbohydrate-deficient transferrin (CDT): A highly sensitive and specific test for alcohol abuse, though it is very expensive. It is an FDA-approved biomarker for alcohol abuse disorder

- Liver Function Tests: These are not specific to alcohol abuse, but 2:1 AST:ALT level is a good hint - Gamma-glutamyltransferase (GGT): Rarely used and non-specific - Mean Corpuscular Volume (MCV): Rarely used and non-specific

Neurobiology of Alcohol -Alcohol is a total CNS depressant- - GABA: Inhibition

o Acutely, drinking increases GABA’s activity at GABAA receptors (CNS depression) o Chronically, the body seeks homeostasis and decreases GABAA receptors and receptor response

(Alterations in receptors) - Glutamate: Excitation

o Acutely, Alcohol inhibits glutamate activity at NMDA receptors (CNS depression) o Chronically, there is an upregulation of NMDA receptors (Alterations in receptors)

- Once alcohol is removed, the presence of altered receptors adapted to alcohol presence brings withdrawal - DA and Opioid: Pleasure

o Boozing increases release of DA in the nucleus accumbens to yield pleasure and euphoria. It also induces the release of opioid peptides

Alcohol Withdrawal (DSM-V) - Following cessation (or reduction) of alcohol use that has been heavy and prolonged, sx of alcohol withdrawal

will present. Withdrawal can be identified by ³ 2 of the following symptoms presenting within hours-days • Hand tremor (most common) • Autonomic hyperactivity • N or V • Insomnia • Transient hallucinations • Psychomotor agitation • Anxiety • Seizures (biggest concern)

- Timeline: The course of withdrawal can vary widely, but usually peaks at 72h and resolves over 5-7 days o 6-12h: tremor, insomnia, anxiety, GI upset, diaphoresis, tachycardia, anorexia o 12-24h: hallucinations (auditory, visual, tactile) o 24-48h: seizures – though they can present early. After 2-3 days without a seizure is a good sign o 48-72h: Delirium tremens occurs in 3-5% - an extreme form of withdrawal, involving hallucination,

disorientation, tachycardia, HTN, fever, agitation, diaphoresis - Complication: Delirium Tremens (DT): A severe disturbance of consciousness and cognition

o Can be fatal d/t the cardiovascular issues (arrhythmia), respiratory collapse à Requires tx ASAP o Risk factors for DT: concurrent acute medical illness, heavily alcohol use (especially immediately before

presentation), older age, abnormal LFTs, and severe symptoms upon presentation - Complication: Wernicke-Korsakoff

o Type: Wernicke’s Encephalopathy § Triad of Sx: Confusion, ataxia (trouble initiating movement), nystagmus (eye wiggles) § Wernicke’s Encephalopathy has a 20% mortality rate and can progress to Korsakoff

o Type: Korsakoff Psychosis § Sx: Retrograde/anterograde amnesia, confabulation (making up answers to questions),

hallucinations - this may be permanent - Patient Assessment Tools

o Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar): A validated tool for assessing the severity of alcohol withdrawal

§ Scoring (rated 0-7): sweating, anxiety, tremor, hallucinations, agitation, N/V, HA, orientation • Severity of withdrawal: Minimal (0-8), moderate (9-15), and severe (³ 16) • Total scores ³ 8 are symptomatic patients, ³ 15 require scheduled medications

§ Depending on the setting, different nurses may give different scores Wernicke-Korsakoff (WK) Treatment

- Prevention: Dosing thiamine will encourage the brain to use glucose, which is needed for proper functioning. There is very little risk with thiamine, so most patients presenting at risk of withdrawal will receive it

o Thiamine 100mg PO/IM QDaily x3-5days the PK of PO is too variable, prefer IM or IV o Thiamine 100-500mg IM/IV QDaily for high-risk patients

- Treatment: Treatment of WK also centers on thiamine o Thiamine 500mg IM/IV TID x3-5d, then 100mg PO thereafter

Triage and Treatment of Alcohol Withdrawal • Acute Management

- Benzodiazepines: o Place in therapy: BZDs are the drugs of choice, especially the ones

with long t1/2: Chlordiazepoxide, diazepam, lorazepam, and oxazepam § Fast onset, long t1/2 is preferred: Diazepam > Chlordiazepoxide § Slow onset, long t1/2 is less preferred: Lorazepam > oxazepam § Patients with high LFTs, prefer lorazepam and oxazepam d/t metabolism

o MoA: Bind to GABAA receptor to potentiate the inhibitor effects of GABA, providing an anxiolytic, hypnotic, anticonvulsant, and muscle relaxant effect. Their mechanism directly overlaps with EtOH, which is why they work well

o Dosing: There is more than one approach for the dosing of BZDs in the acute management of withdrawal § Fixed Dose: Start with a standardized dose, taper over several days (Monitor with CIWA score)

• Pros: Greatly decreases seizure risk, ideal for medically compromises, less nurse burden • Cons: Prolongs hospitalization, involves more medications

§ Symptom-Triggered: Drug administration depends on CIWA score, if > 8, slam the BZD • Pros: Has been shown to shorten hospitalization and decrease total BZD given • Cons: Highly nursing-dependent and intensive, patients will be pushed into withdrawal sx • ContraX: pregnant, concurrent opioids, opioid withdrawal, Hx seizures/DT, CIWA > 15

§ Individualized Symptom-Triggered: Calculate the total dose of symptom-triggered BZD dosing for the last 24 hours, then taper that amount over the next several days, include hourly CIWA

§ Loading Dose: Check the shelves for a long t1/2 drug like diazepam, give huge doses until the patient is appropriately sedated (~60-100mg) – then send them home. This is rarely done, and should only be done when there is high confidence the patient will not seizure or go into DT

• If they go home and start boozing on this high dose, they’ll be KOed. Don’t do this. o ADRs: sedation, ataxia, and confusion, disorientation (fall-risk), and anterograde amnesia. In excess, they

can cause respiratory depression – thus, finding the middle ground sweet spot is key § ContraX: Do not use in acute alcohol intoxication, COPD, hepatically-impaired (liver metab.),

elderly patients, or concomitant high-risk interacting medications (opioids) § Pregnancy: The risk of seizure to the unborn fetus is greater than the risks with BZD use. § SUD Hx: Yea yea, we won’t send ‘em outpatient with it – but inpatient is ok § Reversal Agent (BZD overdose): Flumazenil, 0.2mg/min IV initially, repeat q30-60sec up to

3mg maximum (beware that this may precipitate seizures) o Metabolism: Liver

§ LOT: Lorazepam, oxazepam, and temazepam are not hepatically metabolized

Drug Onset T1/2 Chlordiazepoxide Intermediate >100h

Diazepam Fast >100h Lorazepam Intermediate 10-20h Oxazepam Slow 5-14h

- Anticonvulsants o Place in therapy: Although the data is not as good for anticonvulsants as it is for BZDs, the

anticonvulsants are less addictive, produce less amnesia, and are ideal for seizure activity. They should certainly be used when seizures are refractory to BZDs. Options: CBZ, VPA, GBP, PB

§ Downside: No reversal agent – risk of excessive sedation and decreased respirations (PB) o Dosing: Fixed dose only. Data does not support the use of PHT

- Adjunctive/Supportive Tx o Thiamine: Should be administered prior to giving glucose, otherwise there is increased risk for Wernicke’s o Folic Acid: Used for Vitamin B absorption o Clonidine: Good for the autonomic sx of withdrawal and BP

- Monitoring: Electrolytes (hypophos, hypokalemia, hypomagnesemia), glucose (hypoglycemia) - Medications to avoid: Antipsychotics (increased risk of seizure and complications), EtOH – not commonly used

anymore d/t the difficulty in titration and risk of exacerbating organ damage, PHT. • Maintenance Treatment

- Naltrexone (ReVia, Vivitrol): First-line option o WARNING: Patients must be opioid-free for 7-10 days or longer (risk of life-threatening withdrawal) o Place in therapy: Naltrexone is a first-line maintenance option for alcohol use disorder. It has once daily

dosing or monthly gluteal injections. It can be used concurrently for OUD o MoA: Opioid Antagonist used to decrease the euphoria, exhilaration, and overall pleasurable response to

help reduce cravings and heavy drinking o ReVia: 50-100mg PO QDaily (100mg shown to be more effective in heavy drinking and craving) o Vivitrol: 380mg IM q4w into the gluteal muscle, ideal for patients with adherence issues o ADRs (strong): PO formulation can elicit intolerable GI distress, N/V, abdominal pain, HA, anxiety,

insomnia, dizziness. Injection formulations have frequent painful injection site reactions, N, and abdominal pain. There seems to be a genetic link with naltrexone, so if family member tolerates - good

§ PO Intolerable: Try decreasing to 25mg dose if necessary or take food with it § REMS (for Inj): D/t high frequency of injection site reactions, pts must be educated on special

techniques. Also, significant warnings to convey about hepatotoxicity, abscesses, necrosis, blunted response to opioids, and precipitated opioid withdrawal

§ Medical Bracelet or Wallet Card: Carry so that EMS/hospital can adapt pain management § ContraX: Current opioid use, currently in opioid withdrawal, hepatitis or hepatic impairment

o Monitoring: LFTs, opioid withdrawal - Acamprosate (Campral)

o MoA: Glutamate NMDA antagonist, blocking glutamate transmission and enhancing GABA transmission to mimic effects of alcohol and decrease cravings.

o Place in therapy: First-line alternative. Acamprosate is most effective when used after being sober for ³ 4 days. Compared to naltrexone, acamprosate does not carry a hepatotoxic risk and therefore is more appropriate in patients with hepatic impairment. Additionally, acamprosate has no drug interactions and can be used if relapse occurs. Otherwise, naltrexone is a better option because acamprosate has a large pill burden, TID dosing, and can cause GI distress, also, many patients are afraid of the 666mg dosing

o Dosing: Take two 333mg tabs PO TID § Renal Adjustment: CrCl 30-50mL/min: 333mg PO TID. ContraX in CrCl < 30mL/min

o ADR: Diarrhea, insomnia, suicidal ideation - Disulfiram (Antabuse)

o MoA: Inhibits aldehyde dehydrogenase, forcing the toxic accumulation of acetaldehyde when consuming alcohol. The disulfiram reaction is N/V, flushing, diaphoresis, HA, chest pain, tachycardia, palpitations, hypotension, weakness, confusion. Therefore, this drug is used as a deterrent. If they continue drinking they will experience cardiotoxic effects

o Place in therapy: Second-line agent. For this drug to be effect, you need an understanding, dedicated patient with a strong system. It is highly effective and is only dosed once daily.

o ADRs: Hepatotoxicity (monitor LFTs), fatigue, metallic/garlic taste, HA § ContraX: Concurrent or previous (<14d) use of metronidazole/alcohol containing products,

severe myocardial disease, psychosis, cognitive impairment (b o Dose: 500mg/day x1-2w, then 250mg/daily thereafter. Initiate when BAL = 0 or 12 hours post drink

o Counseling: Avoid any and all alcohol containing products, that includes foods, perfumes, and mouthwash. Avoid these products for 14 days since last disulfiram dose. Family or friend involvement can help increase success. It is very dangerous if the patient continues to drink

- Gabapentin o Place in therapy: GBP is eliminated purely by renal excretion, making it an ideal option for patients

contraindicated with naltrexone d/t liver issues. Studies have shown it decreases heavy drinking with and without concurrent naltrexone therapy. It is linked with improved sleep in patients with AUD and increased likelihood of abstinence > 12w. Nevertheless, GBP’s place in therapy that is not well-defined

o Dosing: 900-1800mg/day split BID or TID (studies did TID) • Non-Pharmacologic Treatment

- The focus of treatment for AUD should be on the non-pharmacologic treatment, it is the mainstay. Medications will not work with all of the other lifestyle changes and behavioral trainings in place

- Options: psychotherapy, intensive outpatient therapy, sober living - Alcoholics Anonymous: 12-step meetings, In 90 days attend 90 meetings, get a sponsor - Motivational Interviewing: The most effective route is to meet the patient where they are at in their stage of

changing their behavior – identify their goals and help them move forward. Here are the stages: o Precontemplation, contemplation, preparation, action, maintenance, relapse

Long-term effects of alcoholism - Ulcers + gastritis, electrolyte abnormalities, pancreatitis, increased risk of cancer, HTN, cardiomyopathy, MIÝ

o Frequent pancreatitis is very painful - Late stage: hepatitis, cirrhosis

(11/27) Mucksavage Lecture: Pharmacotherapy of Opioid Use Disorder I Opioid Use Disorder (OUD) costs $504B annually according to a 2017 CEA report. More than 50% of users started their abuse buying or taking from a friend or relative. Of all Americans 26yo+, 0.8% are currently afflicted by OUD – which is recognized as the loss of control of opioid use, risky opioid use, impaired social functioning, tolerance, and withdrawal. Opioid abuse is fraught with negative consequences, including crime, disease, and a loss of societal productivity. Why is there abuse?

- Opioids induce a relaxed state and bring euphoria, which is best accomplished through rapid drug accumulation in the brain – achievable by smoking or intravenous administration.

Recognizing Acute Intoxication and Overdose - S/Sx: ßconsciousness, ßRR, hypotension, hypothermia, pinpoint pupils, cyanosis, bradycardia - Treatment: Naloxone – 2mg upon recognition (IV, IM) IM and IN4mg Commonly carried by EMS

Recognizing Opioid Withdrawal - Opioid withdrawal is often described as the worst flu you could possibly imagine. Although opioid withdrawal is

non-fatal, collecting a patient Hx is pertinent as co-abused drugs (ex: BZDs, Booze) can be fatal in withdrawal. The time of withdrawal onset depends on the opiate of abuse:

o Short-acting agents (diacetylmorphine): Initiates in 8-12h, peaks at 36-72h, resolves in ~5 days o Long-acting agents (methadone): Slower onset, peaking in 120-144h, resolving in 14-21 days

§ Getting off methadone is extremely difficult. - S/Sx: Secretions/leaking (vomiting, lacrimationtearing, rhinorrhea, sweating, diarrhea), mydriasis, yawning,

hypertensive, tachycardic, piloerection o Subjective complaints: ‘feel horrible’ – dysphoria, muscle aches, cramps, abdominal pain, insomnia

- Physiology: Sudden discontinuation following prolonged use will allow reflexive hyperactivity of the adrenergic neurons in the locus coeruleus

Pharmacotherapeutic Strategies and Treatment Options (Drug information discussed after the strategies) - Acute Detoxification: Using Anti-Withdrawal Agents: Buprenorphine, taper methadone, clonidine

o At a highly controlled, federally restricted location, licensed experts help patients (often celebrities) abruptly terminate opioid use

o DETOX option 1: Tapering methadone § Patients do very well on chronic methadone therapy, going on to have fully functional lives.

There are short and long tapering schedules available. Relapse is high post-detox o DETOX option 2: Buprenorphine

§ Buprenorphine is ideal for the lower-addiction cases o WITHDRAWAL Sx: Clonidine is used. Risk of sedation, hypotension

- Maintenance Therapy: The goals of maintenance therapy are to (1) reduce cravings, (2) prevent euphoria via controlled-dosing, and to (3) reduce withdrawal symptoms. The benefits of maintenance therapy are the decreases in risk of relapse, overdose, and criminal activity. Maintenance therapy helps patients re-adjust to society.

o Using an agonist: Methadone § The target methadone level is referred to as the methadone comfort zone: in which there is no

abusing, craving, or withdrawal, and the patient is capable of contributing to society § Start: Initial doses are 10-30mg/daily – federal law limits initial dosing to 30mg max. Lower

doses are recommended in patients with lower tolerance or following 5 days of abstinence § Titrate: Increase dose by 5-10mg increments over several days to target (80-120mg/daily).

Optimal dosing is highly individualized; use caution as death from overdose may occur o Using a partial agonist: Buprenorphine/naloxone

§ Induction (1 week): Start with 4mg/1mg-8mg/2mg buprenorphine/naloxone, max 8mg buprenorphine on day 1. First week titration occurs based on symptoms

• Therapy should be initiated during the early stages of withdrawal, which is 12-24 hours after last using short-acting agents or when instructed by experienced physicians for the long-acting agents. The goal level is the minimum dose that decreases the use of other opioids and reduces cravings without withdrawal.

§ Stabilization (4-8w): Dosing is adjusted up to a maximum of 32mg/8mg buprenorphine/naloxone • Monitoring for withdrawal sx, ADRs, and cravings

§ Maintenance (indefinite): Use stable dose to prevent relapse and eliminate withdrawal. Monitor for events of craving.

§ Note: Previously, Zubsolv (enhanced SL tab) was only indicated for opioid addiction maintenance. It is now indicated as well for induction. There is differing bioavailability among Zubsolv and Suboxone, so consider the dose conversions (PI) when transitioning therapies

o Using an antagonist: Naltrexone § Initial Detoxification: Perform a naloxone challenge! This involves IV dripping a small amount

of naloxone to ensure therapy will not precipitate withdrawal § Maintenance (indefinite)

• PO: Day1: 25mg, increase to 50mg on Day2 if no withdrawal. 50mg thereafter o Used infrequently d/t low adherence and lot retention in programs. Patients do

not see the benefit of using a therapy without opioid receptor stimulation. • IM: 380mg gluteal IM injection q4w: Favored option and better adherence because

patients have no choice. Once it’s in it’s in Pharmacologic Agents for the Management of Opioid Dependence and Withdrawal • Clonidine [a2 adrenergic agonist]

- MoA: Agonist activity at a2 autoreceptors decreases adrenergic neurotransmission at the locus coeruleus to counteract the hyperactivity associated with withdrawal.

o Role: Improves restlessness, secretion symptoms, muscle pain, but does not affect cravings - Dosing: On day one, take 0.1-0.2mg PO q4-6º. Taper to a max dose of 1mg/daily in 3-4 divided doses - ADR: Hypotension – this is significant. Dry mouth, orthostatic hypotension, dizziness, sedation, anticholinergic

• Lofexidine (Lucemyra) [a2 adrenergic agonist] - Though lofexidine has an extensive history in Europe, it is newly approved for use in the United States - MoA: Agonist activity at a2 autoreceptors decreases adrenergic neurotransmission at the locus coeruleus to

counteract the hyperactivity associated with withdrawal. - Dosing: Initially, take 3x 0.18mg tabs PO QID during peak withdrawal symptoms, *ensuring 5-6º between doses.

Continue medication for up to 14 days with a taper over 2-4 days prior to discontinuation to avoid rebound HTN. o Maximum 16 tabs in 24h or 4 tabs per dose. o Renal Adjustment is required

- ADR: Hypotension, bradycardia, syncope (faint), CNS depression, QT prolongation, HTN upon abrupt d/c

o DDI: Lofexidine accumulation with 2D6 inhibitors (paroxetine) – risk of bradycardia and hypotension • Methadone [µ/MOR Agonist]

- Methadone is a C-II drug used for detoxification and maintenance in OUD. Based on its pharmacokinetics, it has a decreased potential for euphoria and is effective at keeping the symptoms of withdrawal and craving at bay.

o PK: Slow onset (PO – 30-60mins), long and variable t1/2 (8-59h)

Estimated GFR Dosage 30-89mL/min 2x 0.18mg tabs PO QID < 30mL/min 1x 0.18mg tab PO QID

Source: Micromedex

- Dosing: Depends on the indication. Dosing is also highly specific to the patient’s history of opioid abuse and recent intake. A patient’s previous prescribers and specialty methadone clinic need to be consulted to verify dose and compliance – then the content of the conversation needs to be documented in the medical record. The goal of treatment in the hospital is to prevent withdrawal – we need to continue their dose. If at any point the patient exhibits AMS, stroke, or relevant complication – d/c methadone. Dosing styles include:

o Maintenance: Used for the foreseeable future • Pain: dosed TID o Detoxification: Short-term

- ADRs: CNS depression, respiratory depression, QT prolongation, hypotension, chronic constipation (impaction) o [BBW]: Of the opioids, Methadone has the highest risk for respiratory depression upon initiation.

§ Accidental ingestion can lead to fatal overdose • Risk of addiction, abuse, and misuse § Life-threatening QT prolongation • Neonatal opioid withdrawal syndrome § Conditions for distribution and use in opioid addiction

o DDI: BZDs, concurrent QTc prolonging drugs, 3A4 inhibitors - Abuse potential: Despite methadone’s advantageous pharmacokinetics, it is an opioid that can cause euphoria and

carries a risk of abuse • Buprenorphine/Naloxone (Suboxone, Zubsolv) [partial µ/MOR agonist + k/KOR antagonist, µ/MOR antagonist]

- Buprenorphine is a partial agonist with a ceiling effect for the MOR, which decreases the risk of respiratory depression. It is indicated for addiction maintenance and detoxification. It was the first office-based treatment modality owing to the Drug Addiction Treatment Act (DATA) of 2000. For this program, prescribers must be registered and board-certified to prescribe. A physician’s authorization to prescribe buprenorphine can be checked by dispensing pharmacies at http://www.samhsa.gov or 1866-BUP-CSAT

- Formulation Kinetics: Suboxone is an abuse-deterrent drug available as SL films and SL tabs. The terminal t1/2 = ~37h. Naloxone is added at a 4:1 ratio to prevent abuse if injected, it is only bioavailable intravenously

o *Must be consistent with administration. Dissolution (5 mins) and absorption occurs under the tongue, take SL tabs all at once or two at a time. Do not swallow – this alters the bioavailability.

o Zubsolv is a renovated version of the SL suboxone tabs with improved bioavailability - Dosing: l - ADR: N/V/C, respiratory depression (usually related to DDIs), precipitation of withdrawal

o DDI: BZDs, 3A4 inhibitors and inducers, on-board opioids (see ‘Safety’ below) o Monitor: LFTs o Safety: Because of buprenorphine’s affinity for the MOR is greater than other opioids, it may kick off

currently on-board opioids and precipitate withdrawal • Naltrexone [µ/MOR antagonist]

- Naltrexone is a long-acting opioid antagonist without abuse potential. Whether using its PO or IM formulation, users will have decreased responsiveness to opioid therapy – which is a concern in emergency medical situations. Patients are recommended to wear a medical bracelet or carry a wallet card signifying they receive naltrexone

- Formulations o PO Naltrexone: Opioid antagonism lasts 24-48h o IM Naltrexone (Vivitrol): Opioid antagonism lasts > 1 month

- ADRs: Eosinophilic pneumonia, N, abdominal pain, HA, dysphoria and depression (lack of opioid agonism) o Monitor: LFTs

• Adjunctive Therapies for Withdrawal Symptoms - Diarrhea: Loperamide (has risk of abuse in outpatient setting) - N/V: Prochlorperazine, ondansetron (risk of QT prolongation) - Insomnia: trazodone - Muscle Spasms: Cyclobenzaprine, baclofen

Role of the Pharmacist - Recommend non-opioid therapy when possible and limit doses and duration of opioid therapy. - Participate in opioid monitor programs - Counsel patients on the safe storage and disposal of opioid medications - Counsel patients on the safe and appropriate use of medications for OUD

(11/28) Hamidovic Lecture: Pharmacotherapy of Opioid Use Disorder II Almost 5% of the US adult population misuses opioids for non-medical purposes and about 1% are defined as having an OUD. No matter what graphic or subpopulation you look at, the annual number of deaths by opioids continues to rise. Most recently in the past four years, death by synthetic opioids other than methadone have skyrocketed, nearly to double that of heroin and semi-synthetic opioids. Below are the risk factors for opioid-induced death:

Medication-related • Using > 20 morphine mg equivs/daily • Using long-acting or ER opioid formulations • Recently starting long-acting or ER opioids (<2w) • Combining opioids with BZDs • Using opioids long-term (>3mo)

Patient-related • Age > 65yo • OSA • Comorbid depression • Hx of overdose • Hx of substance abuse disorder (including booze) • Renal or hepatic impairment

High-Potency Synthetic Opioids - Labor Comparison: To manufacture and prepare the naturally occurring and semi-synthetic opiates, extensive

time and effort must be expended to grow, harvest, and process opium paste. In contrast, the synthetic opioids are peperidine-based using precursor agents readily available in China

o Precursor: 4-fluoroisobutrylfentanyl, 3-methylfentanyl, acrylfentanyl, acetylfentanyl, carfentanil o Final Product: Average manufacturing expenses: Heroin (1kg) = $65k, Fentanyl (1kg) = $3.5k

§ Potency: fentanyl is ³ 50-fold more potent than heroin, meaning 40g fentanyl = 1kg heroin § Transportation: Fentanyl’s higher potency makes illicit marketing and transportation far easier

- Hazardous Potency o MoA: Fentanyl has high affinity for the GPCR µ-opioid receptors (MOR) which

are distributed widely throughout the body. Unique from other opioid agonists, fentanyl preferentially signals through a barrestin-2 signaling mechanism

§ barrestin activity (major): promotes respiratory depression § Gprotein activity (minor): induces analgesia

o Recognizing the opportunity for selectivity among the multiplicity of ligand effects on the MOR, new compounds (SR-17018) are being designed to be selective for analgesia for purposes of safety

Accurate Vocabulary: Tolerance, Physical dependence, and Addiction TOLERANCE PHYSICAL DEPENCENCE ADDICTION

DEFINITION Decrease in opioid potency with repeated administration

Physiological adaptations that are responsible for the emergence of withdrawal symptoms upon abrupt discontinuation of opioids

Chronic, relapsing disorder characterized by compulsive drug seeking, continued use despite harmful consequences, and long-lasting changes in the brain

PREDICTABILITY Excellent Excellent Poor CELLULAR

MECHANISM Counter-adaptations in opioid receptors and their intracellular signaling cascades

Counter-adaptations in opioid receptors and their intracellular signaling cascades

Poorly understood because, among other factors, it is difficult to study craving – cardinal feature of addiction

REVERSAL UPON DISCONTINUATION Rapid Rapid Addiction is a chronic condition – may never

be reversed - Long-term opioid use will require increasingly higher doses in order to maintain the initial level of analgesia (10x

original dose). Similarly addicts develop a tolerance to the rewarding, euphoric effects, requiring dose escalation – sometimes up to 800MME.

Screening Tools for OUD - Interview: “How many times in the past year have you used an illegal drug or rx med for non-medical reasons?” - Prescription Drug Monitoring Program (PDMP): 45 states update the PDMP daily to help reduce doctor-shopping

and overdose. This program has not been as effectively as originally hoped - Urine Screening: Should be completed before opioids are prescribed to identify patients at-risk

o After prescribing: Urine screening should be completed again to detect diversion or new illicit substances Abuse-Deterrent Strategies

- Combination Agonist/Antagonist: Buprenorphine-Naloxone o Naloxone has very poor (~20%) bioavailability when administered orally. In contrast, it has ~100%

bioavailability when administered intravenously. This makes it useful for combination with buprenorphine so that the sublingual tablets/films are taken orally as prescribed – because the agonist effect of buprenorphine will be lacking if crushed and injected

- Delivery in a form that cannot be extracted o Implant: Buprenorphine implant (Probuphine)

§ Indication: Moderate to severe OUD in patients whom have initiated tx with 8-24mg transmucosal buprenorphine-containing product for a minimum of 7 days

§ Administration: Four subdermal implants on the inner side of the upper arm – performed by clinicians with special training. Implants must be removed no later than 6 months after the date of insertion. Upon renewal, the next 4 implants are installed on the contralateral arm.

• Probuphine is currently only FDA-approved for 12months total therapy (6mo each arm). § [BBW]: Only clinicians with specialized training can insert and remove it. There is a chance the

product migrates, protrudes, or is expulsed. o Solid Depot: Buprenorphine depot (Sublocade)

§ Indication: For patients who have achieved and sustained prolonged clinical stability on low to moderate doses of transmucosal buprenorphine products for 3 months or longer

§ Administration: An abdominal subcutaneous injection. The solid depot gradually releases buprenorphine over time. Patients receive a 300mg monthly injection for the first 2 months and then a 100mg monthly maintenance injection thereafter. (administered ³26 days apart)

§ [BBW]: Risk of occlusion, tissue damage, and thromboembolic events § [REMS]: Provider, patient, and pharmacy must have met requirements and be certified

o OxyContin: (redone ER formulation. Upon crushing, turns into a pasty-sawdust) Naloxone

- Auto-Injector (Evzio) • 1 dose, 2mg o Administration: IM or SubQ into the thigh –may be injected through clothing

§ If the voice instruction system does not operate properly, the device will still deliver the intended dose of naloxone when properly given

o PK: • Onset: 2-5 mins • Peak: 15 mins • Repeat: in 2-3mins o For repeat administration, a new device must be used as each device contains

a single dose of naloxone - Intranasal (Narcan) • 2 containers, 4mg

o Administration: Patient in supine position, support back of neck to allow head to tilt back. Instill intranasally as soon as possible. Repeat administration should occur in alternating nostrils. Each container has a single IN spray. Priming is not required.

o PK: • Onset: 8-13 mins • Peak: 20-30 mins • Repeat: o Compared to the Evzio product, Narcan has a much less variable PK profile, though the onset is slow

- Re-Narcotization o Re-narcotization occurs when there is a mismatch between the t1/2 of naloxone (2h) and the on-board

opioid (fentanyl = 8h). Once naloxone is eliminated, the patient may re-enter into overdose, which can be life-threatening. As such, the package inserts of Narcan and Evzio warn: “ patients receiving naloxone in the out-of-hospital setting should seek immediate emergency medical assistance after the first dose d/t the likelihood that respiratory ± CNS depression will return”

- Controversial benefits: The Moral Hazard of Lifesaving Innovations o Since the dispersal of naloxone for out-of-hospital use, the efficacy data has not been as intended

§ Opioid-related deaths = no change • Fentanyl-related deaths = no change § Opioid-related ER visits: much more • Opioid-related theft: much more

o Outliers and other problems § In the Midwest, there was a sharp rise in fentanyl

o Carfentanil: The most potent fentanyl analogue – ‘one grain of salt’ will kill a person § Designed as a sedative for elephants and other large animals, it has 10,000x the potency of

morphine. In Ohio (7/16-12/16), there were nearly 400 carfentanil-involved deaths attributed to carfentanil

Neonatal Opioid Withdrawal Syndrome (NOWS) also known as neonatal abstinence syndrome (NAS) - Diagnosis: Using a newborn’s behavior, the s/sx of NAS can be monitored in cases of high-suspicion using the

Modified Finnegan NAS Sheet o S/Sx: high-pitched crying, tremors and shaking, increased muscle tone, Moro reflex

(hyperactive), less sleep following feeds - Treatment: Non-Pharm

o Swaddling (tight blanket wrapping) to reduce the motor hyperactivity. This helps the infant organize its behaviors to become calm and more interactive

o Remove tactile, auditory, and visual stimuli o Smaller, more frequent feedings (breastfeeding when available):

§ Recommend Breastfeeding: Following delivery, breastfeeding is recommended only for mothers whom have been abstinent from illicit or licit drugs of SUD for 90 days prior to delivery. *Post-partum, the mother should continue in the substance use disorder treatment, methadone and buprenorphine concentrate very little in breast milk

§ Breastfeeding not recommended: When mother has relapsed into illicit drug use or licit substance misuse (including marijuana) in the 30-day period prior to delivery. Also for mothers who will not continue in the substance use disorder treatment during the postpartum period

- Treatment: Pharmacologic (Depends on NAS score) o Initiation: If there are 2 consecutive NAS scores > 8 or 1 score > 12

§ IV Morphine: 0.02mg/kg/dose q3º • PO Morphine: 0.05mg/kg/dose q3º o Escalation: Increase dose q3º until average NAS score < 8 in 24h

§ IV Morphine: 0.01mg/kg/dose q3º • PO Morphine 0.03mg/kg/dose q3º o Stabilization: Maintain stable dosing for 48 hours o Wean: Decrease to 10% of the stabilization dose daily, discharging 48 hours after off drug.

- Reason to treat: The long-term consequences of NAS are significant cognitive impairment. Studies have shown large decreases in Composite Test Scores relative to matched controls.

(11/29) Schlemmer Lecture: Treatment of Childhood Behavioral Disorders

Childhood and adolescent behavioral disorders are often brought to attention by parents or teachers following the display of disturbing behavior. Other may go unrecognized and dismissed as ‘immature behavior.’ For those that are diagnosed, there are many concerns about the medications impairing the child’s growth and development. Another issue is that the patient is often passive and reluctant to participate in treatment.

Regardless, studies have continually shown that early and effective treatment lessens the long-term effects. Children with behavioral disorders that go untreated may have life-long effects, including: poor self-esteem, poor family and peer relationships, chronic underachievement, dropping out of school, substance abuse, legal problems. Therefore, treatment is highly recommended. Before discussing the treatment options, it is important to recognize the kinetic and dynamic issues of drug treatment in children:

• children metabolize and eliminate drugs faster • children may be more sensitive to drug effects • total body fat varies during growth (Vd) • fewer controlled drug studies are done in children

As a general rule with kids, start with a low dose and aim for the lowest effective dose Attention-Deficit Hyperactivity Disorder (ADHD)

- Epi: It is the most commonly treated childhood behavioral disorder, with an incidence of 3-5% of school-age children (with a high bound of 16%). More males are affected than females (2-3:1)

o Timeline: Symptoms usually emerge at 4yo, with a diagnosis occurring at age 6-7yo. This tends to be the case because the child is in school and can be compared to other children, or the parent is exhausted. ADHD persists into adolescence and for 40-70% of patients will last into adulthood to some degree.

- Neurophysiology: In the first few years of life, the prefrontal cortex (PFC) has excess neurons which outwardly manifests as the inability to sustain attention and easy distractibility. At age 6, the executive functions begin emerging as neurons decrease in number as a consequence of synaptic pruning – ‘if you don’t use it, you lose it.’ This is why many diagnoses occur at this age. ADHD is primarily a disorder of the PFC.

- Diagnosis: Using DSM-V Criteria o ADHD types: Combined type (inattention + hyperactivity), predominantly inattentive, predominantly

hyperactive-impulsive o 6 months: Symptoms occur for at least 6 months, either as inattention or hyperactivity-impulsivity o Sx before 12yo: Symptoms present prior to the age of 12, to a degree that is maladaptive and inconsistent

with developmental level. This condition is usually recognized between the ages of 6 and 7. o 2 settings: Involves symptoms presenting in at least two settings, causing social, academic, and/or

occupational dysfunction (usually school and home – where the individual is seen) o Other Contributors: assessment tools (Conner’s Rating Scale – baseline grade), parent input, teacher input

- ADHD Over Time o Inattention: Peaks at school age (6-7yo) and plateaus thereafter

continuing into adulthood à adults may require ADHD tx. o Hyperactivity + Impulsivity: Peaks immediately prior to school age,

then reduces to a minimum plateau by college age - Treatment: ‘Anti-ADHD’ drugs

o Psychostimulants are the first-line agents for the treatment of ADHD. They are highly effective, successfully treating 75-90% of patients. While tolerance will develop to the stimulation/euphoria in about one week of continuous use, tolerance does not develop to the anti-ADHD effects

o Atomoxetine: Second-line agent o Bupropion and TCAs are third-line o a-agonists: Clonidine and guanfacine, the presynaptic drugs, are last line

Psychostimulants (DEA C-II) • Studies have shown that psychostimulants (stims) provide therapeutic improvement in: attention, concentration, cognitive function, hyperactivity control, impulse control, motor skills, and social interactions. Their effectiveness is unparalleled in the treatment of ADHD.

- Psychostimulant treatment of ADHD Sx o Impulsivity is modulated by the orbitofrontal cortex (OFC) o Motor hyperactivity is modulated by the prefrontal cortex (PFC): Hypoactivation, mediated by low tonic

NE/DA firing in the PFC, producing the inattentive, impulsive, and hyperactive symptoms. Hyperactivation can lead to similar sx. In either case, AMP successfully returns this activity to normal.

- Amphetamine (racemic salts, 75% d, 25% l) (AMP, Adderall) o A popular stimulant choice, albeit an increased abuse potential – especially among parents. AMP is

equieffective to methylphenidate for the tx of ADHD, though it’s behavioral t1/2 is 2x methylphenidate o MoA: Dual effect: Inhibits the presynaptic reuptake of DA and NE and increases the release of DA and

NE – occurring in the PFC, NAc, and other areas of the brain. This normalizes the tonic rate of NE/DA firing to improve alertness, creativity, and problem-solving abilities. When used at doses of abuse, it also inhibits the reuptake of 5-HT.

§ Enantiomers: d-AMP is more potent, but l-AMP is longer acting o Alternate formulations

§ d-AMP (Dexedrine): This was the first drug identified to be effective, equieffective to methylphenidate in the tx of ADHD, though it is less expensive

• Onset: £ 1h, duration: 4-6h (longer acting than methylphenidate) • ADR: Pronounced appetite suppression – more than methylphenidate

§ lisdexamfetamine (Vyvanse): An AA-conjugated AMP prodrug of d-AMP with less abuse potential than d-AMP but still more than placebo.

- Methylphenidate (psychostimulants continued) o Formulation: Tabs (Ritalin), SR (Concerta), ER/CD (Metadate), Transdermal (Daytrana)

§ Dexmethylphenidate (Focalin, Focalin XR) o MoA: Same as AMP - Dual effect: Inhibits the presynaptic reuptake of DA and NE and increases the

release of DA and NE – occurring in the PFC, NAc, and other areas of the brain. § IR (Ritalin) Onset £ 1h, duration 3-4h § SR (Concerta): Peak occurs later, providing better control for the evening. The formulation has a

unique osmotic gradient mechanism permits once daily dosing § ER/CD (Metadate): Drug concentration is at steady-state throughout the school day. Permits once

daily dosing. o Dosing: Typically take at 8am and noon†

§ † This creates a problem because it must be administered in school – negative stigma o History: Methylphenidate HCl (Ritalin) was the original methylphenidate formulation, but it was too

short-acting so students were not being covered throughout the day. o Compared to AMP: Methylphenidate does not suppress appetite to the extent that d-AMP does. This is

important when considering the risk of growth suppression - Stim ADRs

o Anorexia/weight loss (9%): Can be mitigated by administering with or right after a meal o Irritability/insomnia (17%): Dose-related and related to the timing of administration o Abdominal pain (15%): Can be mitigated by administering with or right after a meal o Less common/serious: BPÝ and HRÝ - though this is not commonly seen with prescribed doses,

movement abnormalities (tic-like, thought to be an exacerbation of a subclinical tic disorder), nightmares. o [BBW]: Patients with heart conditions are at risk of major cardiovascular events when using Adderall

§ In a tight 8-7 vote, the FDA Advisory Committee decided to add this BBW in 2004. The rationale was arguably weak – evidence = Over a course of 4 years, there were 25 deaths (19 kids) and 54 cases of serious cardiovascular or cerebrovascular problems. In total, this amounted to 1.8 cases in every 1 million adults (0.00018%)

- Clearing the air o Psychostimulants do not significantly disrupt growth o Psychostimulants used to treat ADHD does not lead to drug abuse now or in the future. In fact, studies

have shown that psychostimulants reduces future substance and EtOH abuse o Clinical evidence proves that psychostimulants do not affect brain growth and maturation

- Monitoring: height, weight, vital signs. Effectiveness and safety will require parents, caregiver, and teacher involvement. Conner’s Scale: A behavioral rating scale used to assess the effects of the medication

Non-Stimulant Drugs - Atomoxetine (Strattera) Second-line therapy option

o Effectiveness: Has a 65% response rate, though it takes 2-4w to see the effects. Atomoxetine is significantly less effective than stims and has a slower-to-realize benefit. Stims works within hours/days

o MoA: Selective NE reuptake inhibitor (originally developed as an antidepressant) o Metabolism: Substrate of CYP2D6 – potential for DDI o ADRs: Decreased appetite, N/V, somnolence, sedation

§ [BBW]: Monitor for suicidal behavior while using (has the antidepressant label) - Tricyclic Antidepressants (TCAs) Third-line therapy options (equal weighting to bupropion)

o Effectiveness: They’re better than taking a placebo pill, and their benefit is less robust than the stims § Selected agents: Desipramine, imipramine, nortriptyline

- Bupropion (Wellbutrin) Third-line therapy option (equal w/ TCAs) o Effectiveness: Few studies have been completed. Bupropion is less

effective than stims and hardly more effective than placebo. Bupropion is typically prescribed to stimulant non-responders

o MoA: Increases the release of NE + DA in antidepressant fashion - a2 Noradrenergic Agonists Fourth-line therapy options

o Effectiveness: More effective than placebo, specifically for the tx of hyperarousal and hyperactivity. Less appropriate for the tx of distractibility and for ADHD in general d/t ADRs

§ Agents: Clonidine (Catapres), Guanfacine (Tenex) o ADRs: Dizziness and orthostatic hypotension are problematic, withdraw gradually to avoid hypertensive/adrenergic rebound

Childhood and Adolescent Depression - Epi: The risk of depression increases 2-4x following puberty, and is highest among girls. Etiology ranges among

psychosocial (body image), biological (early puberty), and physical/emotional trauma (sexual abuse). The overall prevalence is 2% of children and 4-8% of adults. Environmental risks include: perinatal insults, motor skill deficits, and caretaking instability.

o Risk factors: divorce/family discord, physical or sexual abuse o Suicide: Amidst depression, suicide is the 3rd leading cause of death in the 10-24yo cohort. The rate of

adolescent suicide quadrupled between 1950-1990. There were reports that this rate started declining between 1990-2000. In a 1999 survey, this group recorded a 19% rate of SI, 15% planning suicide, and 8% having attempted suicide.

§ 500k teens attempt suicide each year, 5k are successful. 3rd leading cause of death in adolescents - Age-Specific Clinical Presentation: In the younger ages, relapse is far more common than it is in adults.

o Children 5-12yo: MDD has a more easily recognized presentation with sx of : sadness, low self-esteem, guilt/self-blame, physical (somatic) complaints, stomach aches, acting out behaviors (school problems, lying, stealing, tantrums), accident proneness, auditory hallucinations

o Adolescents 10~19yo: MDD presents similar as to in adults: irritability sadness, anxiety, apathy, anhedonia, helplessness, sleep and appetite changes, social withdrawal, substance abuse, delusions (inappropriate guilt), suicidal ideations and attempts (impulsive behavior and thinking)

- Non-Pharmacologic Treatment: Psychotherapy o Play therapy: Use of toys to help children recognize, identify, and verbalize feelings o Cognitive behavioral therapy (CBT): First-line! Examination of thinking/behaviors and guide cognitive

shaping and behavioral modifications o Family therapy, group therapy (promote social skills)

- Pharmacologic Treatment: The need for treatment is difficult to interpret in this age-group because of the high placebo response rate. Much of the data used is transposed from adult studies, though children respond differently to antidepressant therapy. Nevertheless, SSRIs are the drug of choice and fluoxetine is FDA-approved for depression in children. In contrast, TCAs have questionable efficacy and serious concerns about safety (cardiac)

o Selective Serotonin Reuptake Inhibitors (SSRIs) § Fluoxetine (Prozac): Fluoxetine has demonstrated efficacy in children and it has a more favorable

side effect profile than TCAs • Efficacy: TADS study showed that the pediatric patients had similar response rates to

fluoxetine therapy as adults. Overall, fluoxetine + CBT > fluoxetine > CBT = placebo o Fluoxetine + CBT has a 71% success rate and decreased suicidal ideation

• ADR: GI distress, sedation, activation § There is concern that some SSRIs may cause suicidal or homicidal behavior in adolescents and

children. Currently, fluoxetine is the only SSRI demonstrating efficacy in tx patients < 18yo. If discontinuing antidepressant therapy, it is recommended to taper off rather than stopping abruptly

o Monitoring (especially at tx initiation): worsening depression, suicidality - Due to polarization and the taboo-nature of suicide in adolescents, many drug companies are reluctant to

develop or test drugs in this area – though they are desperately needed.

(12/4) Kim Lecture: Appetite Suppressants The first medication approved for the treatment of obesity was MAMP in 1947. Soon after were the AMP-like appetite suppressants, including phentermine. In 1973, concerned about the ongoing AMP abuse, the FDA gave notice that the indication of all obesity drugs should be limited to short-term (few weeks) use. This had little impact on prescribing practices, especially with the onset of the obesity epidemic. In the 1990s, the discovery of leptin changed the approach • Adipose Physiology

- Adipose Tissue: Peripheral adipose tissue is an active organ responsible for lipid mobilization and secretion of hormones. These tissues are innervated by the SNS, which upon adrenergic stimulation will facilitate lipolysis of fat cells and promote increased energy use. Adipose hormone secretions are directed towards the hypothalamus

- Hypothalamus: The hypothalamus is the key regulator of appetite and energy expenditure. Metabolic signals from the periphery are primarily received by the Arcuate nucleus (ARC) of the hypothalamus, which moderates feeding behaviors.

- Reward Circuitry: Consumption of food triggers the release of DA which besets the consumer with reward and euphoria. During phases of energy abundance, activity of this ‘hedonic’ reward circuitry may override the homeostatic mechanisms that regulate feeding, inducing excessive motivational drive to consume more food.

• Energy Homeostasis - Humoral (peripheral, hormonal) signals responsible for regulating food intake and energy expenditure project to

the hypothalamus ARC and originate from the large + small intestine, stomach, pancreas, and adipose tissue - Anorexigenic Response: Activation of the POMC/CART neurons of the ARC trigger the anorexigenic/catabolic

response by releasing a-MSH which binds to MC4R - signaling satiety and increased energy expenditure. Similarly, increased activity of the CART peptide stimulates anorexigenic neurons to suppress appetite. The CART peptide has been implicated in reward and addiction regulatory pathways. à Leptin (ßAppetite): Leptin is released from the white adipose tissue and travels to the POMC/CART neurons to bind to leptin receptors (LEPR) to exert an anorexigenic effect – manifesting as satiety, reduced food intake and increased energy expenditure. Fun fact: Leptin is found in the white adipose tissue at levels proportional to the mass of the adipose tissue

§ Stimulated by: Insulin, emotional stress • Inhibited by: Short-term fasting - Orexigenic Response: Activation of the NPY/AgRP neurons of the ARC trigger the orexigenic/anabolic response

which signals the increase in appetite and reduced energy expenditure. Agouti-related protein (AgRP) is co-expressed with neuropeptide Y (NPY) in NPY/AgRP neurons. Their production is stimulated by ghrelin, and inhibited by leptin, amylin, insulin, and 5-HT. AgRP is also highly expressed in the adrenal gland à Ghrelin (ÝAppetite): Also known as the ‘hunger hormone,’ ghrelin is released from cells of the stomach, travels to the AgRP/NPY neurons, and exerts an orexigenic effect: increasing hunger, gastric motility, and gastric acid production. This activity is promoted during the fasting state

§ Stimulated by: hypoglycemia, ßbody weight • Inhibited by: Stomach distention • Loss of DA control leads to obesity

- There are several NTs implicated in the rewarding effects of food, DA is the most thoroughly investigated. Upon exposure to food, DA neurons fire, increasing the DA release in the NAc ~ euphoria. When this pathway is disrupted, patients can develop an exaggerated reactivity to the food, whereby food consumption triggers potent responses. ‘Loss of control’ of the DA reward pathway prompts excessive motivation for food and development of obesity – which is especially more prone to occur in presence of highly palatable foods.

Obesity Drug Guidance (2007) • In response to the obesity epidemic, the FDA addressed the quandary of appetite suppressant use by issuing the Obesity Drug Guidance Document in 2007. The document outlined a plan of action and assigned definitive measures for the clinical utility of appetite suppressants.

- Target Population: BMI ³ 30kg/m2 or BMI ³ 27kg/m2 + a weight-related comorbidity o Body Mass Index (BMI) is a convenient predictor of ‘overweight’ and ‘obese,’ using height and weight.

Normal weight (18.5-24.9), Overweight (25.0-29.9), Class I Obesity (30.0-34.9), Class II Obesity (35.0-39.9) - Clinical Trials: Subjects must be studied for at least 1 year (for analyzing the ‘long-term’ risks and benefits) - Primary Endpoints (efficacy): • Statistically significant placebo-adjusted weight loss of > 5% at 1 year

• ³ 35% of patients achieve >5% weight loss, of which is ³ 2x placebo - Secondary Endpoints: BP, lipids, FPG, HbA1C

†, waist circumference, QoL, BMI († for DM subjects) o Waist: Since most of our fat is in the waist, this measure helps assign the health risk for T2DM and CVD

AACE 2016 Clinical Practice Guidelines: Medical Care of Patients with Obesity • The following are indications for the initiation of weight-loss medications

- Failure to lose weight: Whether by progressive weight gain or lack of benefit with lifestyle therapy alone - Weight regain on lifestyle therapy: Following initial success with lifestyle changes, weight is regained - Weight-related complications: ‘tertiary prevention’ – to achieve sufficient weight loss to ameliorate complications

• FDA-approved therapy options include: Short-term (Stims) Long-term (4 classes)

• Phentermine (Adipex) • Diethylpropion (Tenuate) • Phendimetrazine (Bontril) • Benzphetamine (Didrex)

• Orlistat (Xenical) • Phentermine-topiramate (Qsymia) • Lorcaserin (Belviq) • Naltrexone-bupropion (Contrave)

• Non-FDA-approved: bupropion, fluoxetine, sertraline, topiramate, zonisamide, somastatin, metformin, pramlintide, exenatide Pharmacologic Treatment • AMP-derivatives (CII-IV)

- Place in therapy: Used for short-term treatment (<12w). Because they were all approved (1959-60) before the FDA’s efficacy benchmarks were established, they were not tested or required to meet those requirements.

- MoA: The AMP-derivatives act centrally to elicit anorexiant effects through stimulation of satiety centers in the hypothalamic and limbic regions. These drugs enhance DA and NE activity in the POMC neuronal pathways to increase a-MSH binding to MC4R. This suppresses appetite and signals satiety

- ContraX: Hx of drug abuse, allergy to sympathomimetic amine drugs, MAOI use within 14 days, CVD, hyperthyroidism, glaucoma, pregnant, planning to become pregnant, breast-feeding

- Phentermine (Adipex, 1959) the most commonly prescribed o Efficacy: When used with lifestyle modification, 15-30mg/daily produces and average ß3.6kg weight

loss, with the majority occurring during the first few weeks then plateauing. Benefit does not persist upon discontinuation if lifestyle changes (exercise + diet) are not maintained

o Place in therapy: This is a cheap option considered to be first-line therapy for a short duration o ADRs: stimulant-like effects, dizziness, dry mouth, insomnia, irritability, N/V, diarrhea, constipation o Hx: Previously marketed as a combination product (fenfluramine-phentermine) – which was removed d/t

cardiotoxic effects (damaging heart valves). Now it is available as a single entity product and combination product with topiramate (Qsymia)

Pros: Cheap, patient satisfactionÝ Cons: Short prescribing time limit, abuse potential • Orlistat (Xenical, Alli, 1999, 2007)

- Efficacy: Over 1 year - 4% ßTBW, over 4 years – 2.6% ßTBW - Place in therapy: Obesity management/weight loss and weight maintenance for individuals with high-fat diets,

history of constipation, and contraindications to AMP-based appetite suppressants, - MoA: Inhibits pancreatic lipases, preventing the hydrolysis and absorption of fats (TGs) in the intestines

o Many patients also reduce their food intake to reduce the side effects - Dosing: Rx (Xenical): 120mg PO TID before meals OTC (Alli): 60mg PO TID before meals

o Take during or up to 1 hour after the meal. If the meal is missed or contains no fat, skip dose o *Should supplement the fat-soluble vitamins (ADEK) – at bedtime or 2 hours before dose o Separate administration of other drug that may be affected - levothyroxine

- ADRs: steatorrhea (greasy poops), fecal urgency, oily spotting, frequent bowel movements, incontinence, flatulence, abdominal pain, headache. There are rare reports of severe liver injury and cholestasis

o ContraX: Pregnancy, breastfeeding, chronic malabsorption syndrome, cholestasis, oxalate nephrolithiasis Pros: Safety, available OTC Cons: smelly greasy poops, ‘reimbursement’

• Alternate therapy options (Qsymia, Belviq, Contrave, Saxenda) - Place in therapy: These agents are indicated as adjunctive treatments to reduced-calorie diets and increase

physical activity for chronic weight management in adults who are obese (BMI ³ 30) or overweight (BMI ³ 27) with at least 1 weight-related comorbidity (HTN, T2DM, dyslipidemia)

- Counseling: Discontinue if ³ 5% weight loss is not achieved by week 12 - Phentermine/Topiramate (Qsymia, 2012) (C-IV)

o Efficacy: Over 1 year – 8.6-9.3% on high dose, 6.6% on standard dose. Over 2 years – 8.7% and 7.5% § In clinical trials, phen/TPM was shown to be superior to placebo in SBP/DBP, HR, lipids, FPG,

and waist circumference o Place in therapy: Ideal agent for obese patients who have seizures disorders and/or migraines o MoA: Dual; phentermine suppresses appetite and increases satiety by mediating the release of NE and

DA in the hypothalamus, while topiramate suppresses appetite and enhances satiety by an alternate unknown mechanism. Some evidence suggests it may be through multiple GABA/Glutamate pathways

o Dosing: I PO qAM Start with 3.75mg/23mg x14 days, then taper up to 7.5mg/46mg § Available strengths (3.75mg/23mg, 7.5mg/46mg, 11.25mg/69mg, 15mg/92mg) § If 3% weight loss is not achieved after 12w on the 7.5mg/46mg dose, escalate dose. If 5% weight

loss is not achieved after 12w the maximum dose (15mg/92mg), d/c § When discontinuing, taper down to prevent seizures (TPM component)

o ADRs: cognitive impairment~cloudy (TPM), HRÝ, suicidal behavior/ideation, metabolic acidosis, SCrÝ, dry mouth, tingling, constipation, memory loss, acute myopia

§ [REMS]: D/t increased risk of orofacial clefts in infants exposed to phen/TPM in the 1st trimester § DDI: Not contraX, but monitor closely when used concurrently with metformin (lactic acidosis)

and OCPs (Ýmenstrual spotting) § ContraX: glaucoma, pregnancy, MAOI use within 14 days, hyperthyroidism

- Lorcaserin (Belviq, 2013) (C-IV) o Efficacy: Over 1 year – 3.0-3.6%, over 2 years – 3.1% o Place in therapy: Ideal for patients with ‘mind hunger’ – always thinking about food o MoA: 5-HT2C agonist that activates the POMC appetite suppressing pathway to increase/promote satiety o Dosing: 10mg PO BID, or 20mg PO QDaily (XR product) o ADRs: N/D/C, HA, dizziness, fatigue, dry eye, nasopharyngitis, hyperprolactinemia.

§ Risk of Severe ADRs: Serotonin syndrome (w/ SSRIs), AMS, depression, priapism, hypoglycemia, leukopenia

- Naltrexone/Bupropion (Contrave, 2014) o Efficacy: Over 1 year, 4.2-5.2% o Place in therapy: Ideal for patients with a history of addiction as well as Sx of food addiction o MoA: Dual activity, producing synergistic effects that lead to decreased food intake and weight loss

§ Bupropion: May enhance POMC-mediated appetite suppression, activates opioid-mediated negative feedback loop (mitigates bupropion’s POMC activity)

§ Naltrexone: Removes the negative feedback – potentiating bupropion’s ability to ÝPOMC firing o Dosing: Titration schedule, starting at week one with I PO QDaily x1w, ending at week four II PO BID in

the morning and evenings. Four tablets daily is the maintenance dose § Discontinue after 3-4mo if having not lost 5% of baseline weight at 12w of maintenance dosing

o ADRs: insomnia, anxiety, N/V/C/D, HA, dizziness, xerostomia § ContraX: Hx of uHTN, Hx of suicide attempts or mental illness, anorexic or bulimic

• Opioids: Use or recent history of using opioids. Must stop 7-10 days priorà withdrawal - Liraglutide (Saxenda, 2014)

o Efficacy: Over 1 year, 5.6%, effective in reducing CVD events o MoA: A GLP-1RA used for DM, the proposed mechanism is stimulation of the POMC/CART

anorexigenic neurons directly via GLP-1 receptors on the neurons, as well as binding to GLP-1 receptors on the GABA neurons to inhibit ARC-NPY (orexigenic) neurons. Overall, decreased food intake.

o Dosing: Titrate weekly by 0.6mg SC inj as tolerated up to 3mg SC QDaily o ADRs: N/V/D/C, HA, dyspepsia, ÝHR, gastroparesis (use caution in patients with cholethiasis/gastrop)

§ ContraX: Personal or FHx of medullary thyroid cancer or MEN2, pancreatitis, gallbladder disease

(12/5,6) Koronkowski Lecture: Dementia ‘peeling away the onion, forgetting how to do more and more…’ Dementia is an acquired syndrome of decline in memory and other cognitive functions sufficient to effect daily life in an alert patient. While dementia is a progressive and disabling disease commonly found in older adults, it is not an inherent aspect of aging, though it is distinguishable from normal cognitive relapses. • Epidemiology of Dementia

- Prevalence (Alzheimer Dementia > Vascular Dementia > Lewy Body Dementia) o Prevalence increase with age, varying by type. 75% of the elderly in retirement homes have dementia o Alzheimer Dementia (AD): 6-8% or people ³ 65yo, prevalence doubles annually. Almost half of all

people 85yo+ have AD. This is the most common form, followed by Vascular dementia (which is a consequence of vasculopathies - such as HL, DM), followed by Lewy Body Dementia (LBD) – a dementia recognizable by parkinsonian features.

- Impact o Economic: The majority of the $604B is paid for by Medicare and Medicaid services, the remaining costs

~$203B rest on families. The average annual cost of care for patients w/ mod-severe dementia = 100k o Emotional: Although the direct toll of the disease lies with the patients. Many caregivers suffer

psychological distress, including depression - Risk Factors

o Proven: Age, FHx, APOE4* allele, Down syndrome o Theorized: Head trauma, deficient education, late-onset MDD, cardiovascular (HTN, DM, HL, obesity) –

bloodflow to the brain o Protective elements: Intellectual activity, physical activity, statin, antioxidants, NSAIDs, APOE2*/2*

§ Exercise has been proven to prevent and slow the conversion to status dementia o Genetics Determinants

§ [Chr 1,14, 21] Early onset (< 60yo) • Amyloid precursor protein (APP), Presenilin proteins (PS1/2)

§ [Chr 19, various SNPs] Late onset • Apolipoprotein E gene (APOE2/3/4), 4* alleles confer the greatest risk, dose-related

o 4*/4* = Will get AD. 2*/2* = Protective (but high risk of CVD) • Types of Dementia

- Alzheimer Disease (AD): o Course: A gradual onset and gradual progression over 8-10 years on average. AD usually presents with

cognitive symptoms earlier, and motor symptoms (apraxia) later. Labs are normal. o Pathophysiology: A proteinopathy triggered by oxidative stress that produces hyperphosphorylated Tau

proteins (which form neurofibrillary tangles) and abnormal homeostatic balance of b-amyloids which aggregate to form plaques

- Vascular Dementia o Course: Onset may be either sudden or stepwise, progressing according to continued ischemia. Both the

cognitive and motor symptoms correlate with anatomic ischemia. Labs are normal. - Lewy Body Dementia (LBD)

o Course: A gradual onset and gradual, but expedited progression relative to AD. Motor symptoms are parkinsonian and cognitive symptoms may be AD-like with added visuospatial hallucinations and fluctuations. Lab tests are normal.

o Pathophysiology: Cytoplasmic a-synuclein inclusion bodies - Frontotemporal dementia

o Course: An early (< 60yo) but gradual onset that progresses with expedited fashion relative to AD. This form of dementia lacks motor symptoms and its cognitive symptoms are more associated with poor executive function and therefore present with behavioral dysfunction

o Patho: Tau or ubiquitin proteins

Weight loss agents % weight loss > placebo in 1 year Phentermine (Adipex-P®, Fastin®) ~3.6 kg (duration of 12 weeks) Orlistat (Xenical®, Alli®) 4% Phentermine/Topiramate (Qsymia®) 8.6%-9.3% on high dose, 6.6% on tx dose Lorcaserin (Belviq®, Belviq Xr®) 3.0%-3.6% Naltrexone/Bupropion (Contrave®) 4.2%-5.2% Liraglutide (Saxenda®) 5.6%

• Presentation and Diagnosis - Differential diagnoses to consider: normal aging, mild cognitive impairment, delirium, depression, then dementia

o Mild-cognitive impairment: Defined as a decline in at least one noticeable and measureable cognitive domain - only 50% of patients with cognitive impairment will progress to dementia, the other 50% remain stable or return to normal. Cognitive impairment can be minimized by reducing environmental stress

o Delirium: Distinguished as acute onset, tremendous fluctuations, altered sleep cycle, impaired consciousness. Using the Confusion Assessment Method (CAM) can identify delirium.

o Depression: the symptoms of depression and dementia over overlap or co-exist. Signs of primary depression are: decreased motivation during cognitive tests, expression of cognitive complaints that exceed the measured deficits, and maintenance of language and motor skills.

- ‘Dementia is a disease of ruling out’ à Conduct an Interview: Ask questions about the date of onset for the current condition and the nature of the sx. Collect a medical history, medication history, patterns of alcohol use or abuse, current living arrangements

o Labs to r/o: The presentation of AMS may be due to a biochemical abnormality. Check labs! § Syphilis-RPR, TSH (hypothyroidism), B12 deficiency, HIV, FPG, CBC, BUN/SCr, Na+

- Symptoms: Patients should be evaluated for their cognitive, non-cognitive, and functional performance o Cognitive: The three cardinal sx: Aphasia (anomia), Apraxia (can’t learn), Agnosia (unable to recognize)

§ Addtl: Memory loss, disorientation (impaired perception of time), impaired executive function o Non-cognitive: Depression, psychotic sx (hallucinations + delusion), behavioral disturbances – including

physical and verbal aggression, motor hyperactivity, uncooperativeness, wandering o Functional: Inability to care for oneself and performing ADLs are typically the first sx to present. ADLs

including financing, operating the telephone, taking medications, as well as dressing, bathing, toileting - Neurologic Assessment: An ideal neurological exam involves spending 4-8h in a clinic for neuropsychologists to

determine what parts of the brain are functional. Screening tools are used to evaluate cognition: o Mini-Cog: Most frequently used tool (2-part), 3-item recall + clockdraw test o MoCA: Also frequently used (12-part), Scores ³ 26 are normal o Folstein MMSE: Proprietary (19-part), must be purchased – therefore is not often used (legally) o SLUMS: (11-part) o Screening for depression should also be included, as it is a frequent sequela of dementia

- Brain Imaging: Imaging is appropriate for patients < 65yo when neurological signs are asymmetric or focal or the patient recently endured a fall/head trauma. Imaging is predictive - but performing a $5000 scan does not solve the problem or change how the patient will be treated

o Technique: Tag with b-amyloid tracers to check localization in the brain, MRI, PET - Prognostic Indicators: Presenting with abnormal behaviors (acute depression, agitation, anxiety) at initial

diagnosis suggests a poor prognosis – their dementia will be an accelerated course • Progression of Dementia

- Stages 1-3: The first three stages of dementia are classified as mild and typically occur for 4-7 years o Stage 1: No cognitive impairment: Patients exhibit no memory problems and have no evidence of

symptoms when interviewed by a healthcare professional o Stage 2: Very mild cognitive decline: Individual notices they have memory lapses, especially in regards to

locations of their personal belongings or familiar names/words. Despite these problems, they are not evident to healthcare professionals, friends or family.

o Stage 3: Mild cognitive decline: Friends, family, coworkers begin to notice deficiencies. This is the first stage at which memory and concentration have clinically measurable defects

- Stage 4-7: These stages include moderate to severe cognitive decline. Diagnosis typically occurs at stage 3-4. Families experience significant struggle during stages 4-6, and stages 6-7 typically require 24h care

o Stage 4: Moderate cognitive decline: Medical interviews can detect clear-cut deficiencies o Stage 5: Moderately severe cognitive decline: Major gaps in memory, assistance with ADLs is essential o Stage 6: Severe cognitive decline: Significant personality changes may emerge; extensive help is needed

with daily activities. o Stage 7: Very severe cognitive decline: The final disease stage – individuals lose the ability to respond to

their environment, speak, and control movement • Treatment

- Goals: To enhance QoL and maximize functional performance by improve cognition, mood, and behavior - Prior to initiation, educate the patient and the patient’s family on the realistic expectations of treatment and the

importance of legal and financial planning

- Non-Pharmacologic Interventions: These are the mainstay of treatment. Implementation of an integrated system of family, friends, and healthcare professionals aware of the diagnosis and prepared to deal with its shortcomings – the workforce of which should be trained

o Exercises: cognitive rehabilitation, supportive individual and group therapy, physical and mental activities, regular appointments every 3 to 6 months, attention to safety (address need for supervision)

o Environmental modification: Using tools and cues such as clocks, calendars, to-do lists, and simple communication to facilitate optimal orientation/awareness and memory

- Pharmacologic Management of Alzheimer Dementia o Treatment should be individualized, monitored, and titrated up slowly. Prescribing these agents is

inappropriate if periodic assessment of cognitive benefits or adverse effects cannot be monitored. o Cholinesterase Inhibitors (donepezil, rivastigmine, galantamine)

§ Place in therapy: First-line agents – clinical trials have shown them to slow the progression of the disease. Choice of agent is made based on t1/2 and metabolic pathways as there is no evidence of differences in efficacy. Consider: more frequent and higher doses typically have more peripheral ADRs

§ MoA: Increase the availability of ACh by slowing its breakdown. Higher doses ensure more crosses the BBB for increased activity (at the expense of ADRs)

§ ADRs: N/V/D, anorexia (Side effects can be lessened using slow titration curves). Anorexia is a significant concern as frailty has consequences in the elderly

§ Donepezil: Best-tolerated agent at low doses, available for once daily dosing. The maximum dose is 23mg/daily, at which ADRs are significant without evidence of improving global functioning. This dose does not seem warranted.

§ *Duration of Therapy: Only 20-30% of patients with dementia respond to cholinesterase inhibitors, and they typically only work for one year. This is not a disease of NT imbalance such as depression, this is related to lessened and weakened neuronal functioning. At some point, maybe even initially, the risks (ADRs) will outweigh the benefits – patients need to weaned off therapy slowly so as to less ADRs

o Cognitive Enhancer: NMDA Antagonist (Memantine) § Place in therapy: Approved for moderate-severe AD, commonly used along with first-line tx’s § Efficacy: Modest benefit on cognition, ADLs, and behavior in AD § MoA: Neuroprotective effect, reducing glutamate-mediated excitotoxicity § ADRs: Constipation, dizziness, confusion, HA § Other cognitive enhancers:

• Vitamin E (a-tocopherol): Suggested to slow decline, albeit no evidence to support its use, people use it anyways. There is risk of mortality with high-dose supplementation

• Selegiline: Suggested to slow decline, albeit no evidence to support its use, used anyways • Ginkgo biloba: No evidence to slow the decline of MCI

o Additional add-on therapies targeting non-cognitive symptoms: Every dementia patient will undergo apathy, aggression, depression, anxiety. Before ascribing psychiatric agents, STOP, consider the overall anticholinergic burden. Consider medication ADRs that may increase the risk of falls or those that could worsen confusion. Behavioral disturbances are best managed non-pharmacologically by incorporating environmental modifications. Symptomatic therapy with psychiatric agents is only indicated for acute changes, safety issues, or when techniques to reduce environmental stress have failed.

§ Antidepressants: Targeting non-cognitive symptoms • Indication: May be effective for disinhibition or compulsive behaviors

§ Psychoactive meds: 1st/2nd-generation antipsychotics, VPA, CBZ, [SSRI] • Indications: Short-term tx of significant sleep disturbances, delusions, hallucinations, and

paranoia. Tx has little evidence of efficacy and is associated with increased mortality • Dosing: Make frequent attempts to taper off

o Avoid BZDs. Minimize or avoid Anticholinergics Cholinesterase inhibitors are only effective in Alzheimer Dementia and dementia’s with parkinsonian features.

- LBD: Rivastigmine is FDA-approved for mild to moderate dementia in Parkinsonian dementias - Vascular Dementia: There is no evidence to support using cholinesterase inhibitors in this dementia. Additionally,

there is a limited effect on cognition and poor evidence to support use of memantine in this disease.

- Frontotemporal Dementia: Cholinesterase inhibitors may worsen agitation. ContraX Reviewing Symptomatic Treatment Options of Dementia: Before reading, are you trying to treat an acute change? Address a safety issue? Have behavioral therapies been attempted?

Good luck Abbreviations General ADL: Activities of daily living DDI: Drug-drug interaction IR: Instant release MME: Morphine milligram equivalents PI: Package insert Malady AMS: Altered mental status HL: Hyperlipidemia, High cholesterol LBP: Lower back pain MDD: Major depressive disorder N/V/C/D: In any order or combination, nausea, vomiting, constipation, diarrhea OA: Osteoarthritis OSA: Obstructive sleep apnea RA: Rheumatoid Arthritis uHTN: Uncontrolled hypertension Anatomy NAc: Nucleus accumbens SNS: Sympathetic Nervous System VTA: Ventral tegmental area Biology NT: Neurotransmitter Drugs AMP: Amphetamine CBZ: Carbamazepine GBP: Gabapentin IBU: Ibuprofen MAMP: Methamphetamine MDMA: Methylene-dioxymethamphetamine OCP: Oral contraceptive pill PB: Phenobarbital PHT: Phenytoin THC TPM: Topiramate VPA: Valproic acid