Comprehensive Notes: Atomoxetine, Opioid Agents, Antagonists, AUD Pharmacotherapies, Alpha-2 Agonists & Cognitive Drugs

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• Atomoxetine capsule strengths: 10, 18, 25, 40, 60 mg.

• Pediatric dosing (≤ 70 kg):
– Start $0.5\,\text{mg}/\text{kg}/\text{day}$ for ≥ 3 days.
– Increase to target $1.2\,\text{mg}/\text{kg}/\text{day}$.
– May give once AM or split AM + late-PM.
– MAX $\min(1.4\,\text{mg}/\text{kg},100\,\text{mg})$.

• Patients > 70 kg & adults:
– Start $40\,\text{mg}/\text{day}$ (≥ 3 days).
– Target $80\,\text{mg}/\text{day}$; after 2–4 wk may ↑ to $100\,\text{mg}$ (absolute max).

• Overdose > 2× recommended: no specific data; treat symptomatically.

• Contra-indication: narrow-angle glaucoma.

• Intro to opioid receptor agonists (“narcotics”): morphine, hydromorphone, codeine, meperidine, oxycodone, buprenorphine, etc. High efficacy for pain but dependence, diversion.

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• Additional agents: hydrocodone, tramadol, fentanyl; heroin street drug; methadone for pain + addiction.

• Multiple receptor types. μ vs κ produce opposite mood states.

Table-21-52 (core):
– μ agonism ⇒ analgesia, euphoria, antidepressant effect; μ antagonism ⇒ anxiety, hostility.
– κ agonism ⇒ analgesia, dysphoria, depression; κ antagonism ⇒ antidepressant, anxiolytic.

• Buprenorphine: μ-partial agonist & κ-antagonist (mixed).

• Investigational psychiatric uses: refractory depression, self-harm (borderline PD).

• Chronic opioid use ⇒ tolerance, dependence, withdrawal.

• Rising prevalence of prescription-opioid abuse.

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• Pre-use checklist for off-label psychiatric opioid trials: drug-history screen, written consent, ground rules, no early refills.

• Pharmacokinetics
– Methadone oral F ↓≈50 % via first-pass; adjust dose.
– Buprenorphine: virtually 0 oral F; give sublingual.
– Methadone $t<em>{1/2}$: 4–6 h (naïve) → 24–36 h (steady-state); highly protein-bound. – Buprenorphine elimination biphasic: $t</em>{1/2(\text{α})}=3–5\,\text{h}$; t_{1/2(\text{β})}>24\,\text{h} ⇒ q48h dosing OK.

• Receptor profile: methadone = full μ-agonist; buprenorphine = μ-partial, κ-antagonist, δ-inactive.

• Indications (see next page).

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• Methadone programs (MMTPs): detox 7–30 d, long-term 180 d, maintenance > 180 d.

• Schedule II; tightly regulated.

• Benefits: ↓ mortality 70 %, ↓ illicit use/crime, ↓ HIV/HepB/C, better pregnancy outcomes.

• Step-down detox (heroin → methadone → buprenorphine → naltrexone) often paired w/ clonidine.

• Above 60 mg/day methadone yields best abstinence.

• Pregnancy: use lowest effective dose, avoid taper; faster metabolism 3rd trimester (split doses). No teratogenicity.

• Neonatal withdrawal Sx: tremor, high-pitched cry, hypertonia, poor feeding, seizures, delayed/prolonged.

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• Breast-feeding discouraged while mother on methadone.

• Buprenorphine: ceiling effect ⇒ safer, less respiratory depression.

• Requires CYP3A4 N-dealkylation → genetic / grapefruit / fluoxetine / fluvoxamine interactions cause non-response.

• Side-effects typical opioid profile (sedation, N/V, constipation, etc.).

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• Suboxone = buprenorphine + naloxone (4 : 1) sublingual: deterrent to IV misuse (naloxone precipitates withdrawal if injected).

• Induction: must be in mild–moderate withdrawal (short-acting opioid abstinent ≥ 12–24 h; methadone ≥ 24–48 h).

• Day-1: start 2–4 mg SL, reassess q1–2 h; total day-1 2–16 mg.

• Subsequent titration: aim 6–16 mg/day; no evidence > 32 mg/day.

• 4 mg SL bup ≈ 40 mg oral methadone.

• Alternate-day / 3×-week dosing effective.

• Monoproduct (Subutex): pregnancy or naloxone allergy.

• Newer delivery: transdermal patch, IM depot (Sublocade), 6-mo implants (Probuphine).

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• Tramadol: weak μ-agonist + complex monoaminergic/antagonist actions (5-HT/NE reuptake blockade, DA release, NMDA antagonism, etc.). Structurally akin to venlafaxine (cross-reactive LC tests). Less misuse potential due to long $t_{1/2}$.

• Requires CYP2D6 activation to O-desmethyl metabolite → poor metabolizers / inhibitors get ↓ effect (same as codeine).

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• Common opioid agonist AEs: light-headedness, dizziness, sedation, N/V, constipation, sweating, weight gain, sexual dysfunction, insomnia.

• CNS: euphoria/dysphoria, depression, seizures, rare delirium.

• Other: edema, urinary retention, rash, bradycardia, hypotension, hypoventilation, ADH-like effect, pruritus, menstrual irregularities.

• Overdose triad: sedation, miosis, respiratory depression; risk highest week 1 induction; methadone deaths at $50–60\,\text{mg}$ early.

• Buprenorphine OD risk lower but ↑ with benzodiazepines.

• Withdrawal: methadone onset 3–4 d → peak day 6 → resolves ≈2 wk; protracted insomnia possible. Buprenorphine milder.

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• DDIs: additive CNS depression w/ alcohol, BZDs, barbiturates, TCAs, MAOIs.

• Enzyme inducers (carbamazepine, phenytoin, rifampin, EtOH) ↓ methadone/bup levels ⇒ withdrawal.

• Enzyme inhibitors (cimetidine, erythromycin, ketoconazole, fluoxetine, fluvoxamine, quinidine, alprazolam) ↑ levels ⇒ toxicity.

• Urinary alkalinizers ↓ methadone excretion.

• Methadone ↑ desipramine, fluvoxamine, zidovudine; protease inhibitors inhibit methadone metabolism (significance unclear).

• Fatal MAOI interactions with fentanyl & meperidine (not methadone/bup).

• Tramadol + SRIs ⇒ seizures, serotonin syndrome; risk ↑ w/ bupropion.

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• Lab: specific urine assays separate methadone/bup from other opioids.

• Methadone dosage forms: 5,10,40 mg tabs/wafers; 5 mg/5 mL, 10 mg/5 mL, 10 mg/mL soln; 10 mg/mL parenteral.

• Induction: 15–20 mg suppresses withdrawal; up to 40 mg first day if needed; avoid higher.

• Maintenance: titrate over weeks to ≥ 70 mg/day; usual max 120 mg; > 60 mg/day best abstinence.

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• Maintenance duration individualized; studies show long-term (> 1 y) superior; many programs restrict ≤ 6 mo—leads to 80 % relapse within 2 y.

• Buprenorphine SL tablets (mono or 4 : 1 with naloxone). Private-office therapy requires certification.

• Extended release forms need special training.

• Tramadol psych dosing case-reports: 50–200 mg/day, short-term; long-term unstudied.

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• Opioid antagonists: naltrexone (PO, long $t_{1/2}$, non-dysphoric), naloxone (OD reversal), nalmefene.

• Naltrexone tried across psychiatric disorders; FDA-approved AUD 1994; XR monthly inj (Vivitrol) 2006.

• Nalmefene IV for OD; oral abroad; also AUD.

• Pharmacokinetics: oral absorption good, but 1st-pass ↓; naltrexone $t<em>{1/2}=1–3\,\text{h}$, active 6-β-naltrexol $t</em>{1/2}=13\,\text{h}$; functional blockade ≈72 h (traces 125 h).

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• Receptor antagonism profile explains GI side-effects (μ blockade → nausea). Nalmefene equal μκδ antagonist → fewer GI effects.

• Naloxone highest μ affinity, short action.

• AUD benefit mechanism multi-system (opioid & non-opioid).

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• Naloxone challenge test protocol (0.8 mg total) to prove opioid-free state before starting naltrexone.

• Observe vitals & withdrawal S/S (runny nose, yawning, goose-flesh, cramps, etc.). Any sign ⇒ defer antagonist ≥ 24 h.

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• Gradual detox hierarchy: heroin → methadone → buprenorphine/LAAM → 7–10 d washout → naltrexone/nalmefene.

• Adherence critical; without CBT many stop antagonists ≤ 3 mo.

• High relapse risk if antagonist discontinued.

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• Rapid detox 48–72 h: clonidine + BZD + immediate oral antagonist; monitor BP (clonidine hypotension risk).

• AUD: antagonists halve heavy-drinking relapse when combined with CBT. Nalmefene advantages: no hepatotoxicity, minimal nausea, longer blockade.

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• Naltrexone hepatotoxicity dose-related (≥ 300 mg/d); monitor LFTs monthly × 6 mo.

• Pregnancy: use only if benefit outweighs risk.

• Analgesia while on antagonist: avoid opioids, use BZDs/non-opioid.

• High opioid doses can override blockade → fatal.

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• Contra: current opioid use (even OTC cough), acute hepatitis/failure, hypersensitivity.

• Naltrexone OD treated supportively.

• Nalmefene may not reverse buprenorphine respiratory depression due to high-affinity binding.

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• Possible EMIT false-positive opiate screens from naltrexone/nalmefene; chromatographic assays unaffected.

• Initiation: wait ≥ 5 d (short-acting opioids) or ≥ 10 d (methadone) unless rapid protocol.

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• Dosing: naltrexone initial 12.5–25 mg → titrate to 50 mg/d; may use $100\,\text{mg}\,/2\,\text{d}$ or $150\,\text{mg}/3\,\text{d}$ for adherence.

• Nalmefene target 20 mg/d (split BID).

• Direct-observed dosing + random tox screens recommended; typical course ≥ 6 mo.

• Nalmefene parenteral forms 100 µg/mL, 1 mg/mL; longer action than naloxone in OD reversal.

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• Rapid detox schedule: day 1 clonidine up to $1.8\,\text{mg}$ divided (monitor BP), oxazepam 30–60 mg, naltrexone 12.5 mg; day 2 clonidine/oxazepam + naltrexone 25 mg; day 3 start 50 mg maintenance; taper adjuncts 5–10 d.

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• Disulfiram vs acamprosate in AUD.

• Disulfiram: aldehyde dehydrogenase inhibitor → acetaldehyde build-up up to 10× → aversive reaction.

• Half-life $60–120\,\text{h}$; elimination 1–2 wk after last dose.

• Severe reaction possible: respiratory depression, CV collapse; contraindicated in heart/lung disease.

• Plasma EtOH vs reaction: mild at $5–10\,\text{mg/100 mL}$, severe coma at $125–150\,\text{mg/100 mL}$.

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• Other precautions: nephritis, hepatic dz, seizures, pregnancy, etc.

• Without alcohol: fatigue, dermatitis, impotence, optic neuritis, psychosis/catatonia (via dopamine-β-hydroxylase inhibition), hepatitis.

• Interactions ↑ levels of diazepam, phenytoin, TCAs, anticoagulants, THC, etc.

• Dosing: 500 mg/d × 1–2 wk then 250 mg/d (range 125–500 mg). Must be EtOH-free ≥ 12 h; reaction possible up to 2 wk after last pill.

• Patient education: avoid all alcohol sources incl. topicals; carry ID card.

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• Acamprosate: putative NMDA antagonism / glutamate modulation.

• Indication: maintain abstinence post-detox in AUD; ineffective if still drinking.

• Side-effects: mild—HA, diarrhea, gas, paresthesia, rash; no withdrawal or dependence.

• Contra: CrCl < 30 mL/min.

• Dosing: 666 mg (two 333 mg tabs) TID with meals; moderate renal impairment 333 mg TID.

• Interactions minimal; naltrexone ↑ acamprosate levels but no dose change.

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• Clonidine & guanfacine: α2-agonists → ↓ NE release, ↓ sympathetic tone.

• PK: clonidine $t<em>{1/2}=6–20\,\text{h}$; guanfacine $t</em>{1/2}=10–30\,\text{h}$.

• Uses: opioid/alcohol/BZD/nicotine withdrawal autonomic Sx; Tourette’s; other tic disorders; pediatric ADHD/hyperactivity/aggression; PTSD (mixed data); adjunct mania, anxiety; sialorrhea from clozapine; HPPD.

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• Detox protocols (Table 21-55): oral clonidine 0.1–0.2 mg q6h or patch-based weight algorithms; hold if SBP < 90 mmHg.

• Tourette’s pediatric dosing: start 0.05 mg/day up to 0.3 mg/day; onset 4–6 mo; ~70 % respond.

• ADHD/aggression: similar dosing; efficacy may wane months.

• Combination with stimulants possible; monitor CV status (rare sudden deaths reported).

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• Adverse effects: dry mouth/eyes, fatigue, sedation (clonidine>guanfacine), dizziness, hypotension, constipation, sexual dysfunction. Guanfacine milder but similar > 3 mg/day.

• Contra: baseline hypo-BP (< 90/60) or bradyarrhythmias.

• Withdrawal rebound hypertension 20 h after last clonidine; taper slowly.

• OD: clonidine—coma, miosis, brady-hypotension; guanfacine milder.

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• DDIs: additive sedation with CNS depressants; ↑ AV-block risk with β-blockers, CCBs, digoxin; TCAs blunt clonidine antihypertensive effect.

• Dosage forms:
– Clonidine tabs 0.1/0.2/0.3 mg: start 0.1 mg BID up to 1.2 mg/day.
– Patches 0.1/0.2/0.3 mg/24 h changed weekly (q5d kids).
– Guanfacine tabs 1/2 mg: start 1 mg HS → 2 mg as needed.
– XR guanfacine (Intuniv): start 1 mg/day, titrate ≤ 4 mg/day; dose by $0.05–0.12\,\text{mg}/\text{kg}$; avoid high-fat meals; do not crush.

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• Cognitive-enhancement drugs (brief mention): cholinesterase inhibitors donepezil, rivastigmine, galantamine for mild–moderate AD; memantine (NMDA blocker) for moderate–severe AD. Tacrine obsolete due hepatotoxicity.