Opioids in Anaesthetic Practice

"""
Postgraduate Anaesthesia Exam Answer – Opioids (30 marks)
Built with ReportLab
"""

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm, mm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether, PageBreak
)
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY

# ── Output path ──────────────────────────────────────────────────────────────
OUT = "/tmp/workspace/opioids-exam/Opioids_PG_Anaesthesia_30marks.pdf"

# ── Colour palette ────────────────────────────────────────────────────────────
DARK_BLUE   = colors.HexColor("#0D2B4E")
MID_BLUE    = colors.HexColor("#1A5276")
LIGHT_BLUE  = colors.HexColor("#D6EAF8")
ACCENT      = colors.HexColor("#C0392B")
PALE_GREY   = colors.HexColor("#F4F6F7")
MID_GREY    = colors.HexColor("#BDC3C7")
TBL_HEADER  = colors.HexColor("#1A5276")
TBL_ALT     = colors.HexColor("#EBF5FB")
WHITE       = colors.white
BLACK       = colors.black

# ── Document ──────────────────────────────────────────────────────────────────
doc = SimpleDocTemplate(
    OUT,
    pagesize=A4,
    leftMargin=2*cm, rightMargin=2*cm,
    topMargin=2.2*cm, bottomMargin=2.2*cm,
    title="Opioids – PG Anaesthesia Exam Answer",
    author="Orris AI",
    subject="Postgraduate Anaesthesia 30-mark Answer",
)

W = A4[0] - 4*cm   # usable width

# ── Styles ─────────────────────────────────────────────────────────────────────
base = getSampleStyleSheet()

def PS(name, parent="Normal", **kw):
    return ParagraphStyle(name, parent=base[parent], **kw)

styles = {
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    "h1":  PS("h1",  fontSize=13, fontName="Helvetica-Bold",
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                    textColor=ACCENT, spaceBefore=0, spaceAfter=0),
}

# ── Helper flowables ───────────────────────────────────────────────────────────

def section_header(text, mark_hint=""):
    """Dark-blue banner for major section headings."""
    label = f"{text}  <font size='8' color='#{LIGHT_BLUE.hexval()[2:]}'>{mark_hint}</font>" if mark_hint else text
    tbl = Table([[Paragraph(label, styles["h1"])]], colWidths=[W])
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        ("ROWPADDING", (0,0), (-1,-1), 6),
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        ("BOTTOMPADDING", (0,0), (-1,-1), 6),
        ("BOX",        (0,0), (-1,-1), 0.5, MID_BLUE),
    ]))
    return tbl

def sub_header(text):
    return Paragraph(text, styles["h2"])

def h3(text):
    return Paragraph(text, styles["h3"])

def body(text):
    return Paragraph(text, styles["body"])

def bullet(text, level=1):
    s = styles["bullet"] if level == 1 else styles["sub_bullet"]
    return Paragraph(f"&#8226;&nbsp;{text}", s)

def spacer(h=4):
    return Spacer(1, h*mm)

def rule(color=MID_GREY, thickness=0.5):
    return HRFlowable(width="100%", thickness=thickness, color=color,
                      spaceAfter=3, spaceBefore=3)

def clinical_box(title, items):
    """Pale-blue inset box for clinical pearls / danger signs."""
    inner = []
    inner.append(Paragraph(f"<b>{title}</b>", styles["clinical_box"]))
    for i in items:
        inner.append(Paragraph(f"&#9658;&nbsp;{i}", styles["clinical_box"]))
    tbl = Table([[inner]], colWidths=[W - 8])
    tbl.setStyle(TableStyle([
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        ("TOPPADDING",    (0,0), (-1,-1), 6),
        ("BOTTOMPADDING", (0,0), (-1,-1), 6),
    ]))
    return tbl

def danger_box(title, items):
    """Red-tinted warning box."""
    RED_LIGHT = colors.HexColor("#FADBD8")
    RED_BORDER = colors.HexColor("#C0392B")
    inner = []
    inner.append(Paragraph(f"<b>&#9888; {title}</b>",
                            ParagraphStyle("db", parent=styles["clinical_box"],
                                           textColor=RED_BORDER)))
    for i in items:
        inner.append(Paragraph(f"&#9679;&nbsp;{i}",
                                ParagraphStyle("dbi", parent=styles["clinical_box"],
                                               textColor=colors.HexColor("#641E16"))))
    tbl = Table([[inner]], colWidths=[W - 8])
    tbl.setStyle(TableStyle([
        ("BACKGROUND",    (0,0), (-1,-1), RED_LIGHT),
        ("BOX",           (0,0), (-1,-1), 1.5, RED_BORDER),
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        ("RIGHTPADDING",  (0,0), (-1,-1), 8),
        ("TOPPADDING",    (0,0), (-1,-1), 6),
        ("BOTTOMPADDING", (0,0), (-1,-1), 6),
    ]))
    return tbl

def make_table(headers, rows, col_widths=None, alt=True):
    """Formatted data table."""
    if col_widths is None:
        col_widths = [W / len(headers)] * len(headers)

    header_style = ParagraphStyle("th", fontSize=9, fontName="Helvetica-Bold",
                                  textColor=WHITE, leading=12)
    cell_style   = ParagraphStyle("td", fontSize=8.5, fontName="Helvetica",
                                  textColor=DARK_BLUE, leading=12)

    data = [[Paragraph(h, header_style) for h in headers]]
    for ri, row in enumerate(rows):
        data.append([Paragraph(str(c), cell_style) for c in row])

    ts = [
        ("BACKGROUND",    (0,0), (-1,0),  TBL_HEADER),
        ("ROWBACKGROUNDS",(0,1), (-1,-1), [WHITE, TBL_ALT] if alt else [WHITE]),
        ("GRID",          (0,0), (-1,-1), 0.4, MID_GREY),
        ("TOPPADDING",    (0,0), (-1,-1), 4),
        ("BOTTOMPADDING", (0,0), (-1,-1), 4),
        ("LEFTPADDING",   (0,0), (-1,-1), 5),
        ("RIGHTPADDING",  (0,0), (-1,-1), 5),
        ("VALIGN",        (0,0), (-1,-1), "TOP"),
    ]
    t = Table(data, colWidths=col_widths)
    t.setStyle(TableStyle(ts))
    return t

# ═══════════════════════════════════════════════════════════════════════════════
# BUILD DOCUMENT
# ═══════════════════════════════════════════════════════════════════════════════
story = []

# ── COVER ─────────────────────────────────────────────────────────────────────
cover_bg = Table(
    [[Paragraph("OPIOIDS IN ANAESTHETIC PRACTICE", styles["cover_title"]),
      Paragraph("Postgraduate Anaesthesia Examination  •  30 Marks", styles["cover_sub"]),
      Spacer(1, 6*mm),
      Paragraph("Miller's Anesthesia 10e  •  Barash Clinical Anesthesia 9e  •  "
                "Morgan &amp; Mikhail 7e  •  Goodman &amp; Gilman", styles["cover_tag"]),
    ]],
    colWidths=[W]
)
# wrap in a single-cell table for background
wrapper = Table([[cover_bg]], colWidths=[W])
wrapper.setStyle(TableStyle([
    ("BACKGROUND",    (0,0),(-1,-1), DARK_BLUE),
    ("TOPPADDING",    (0,0),(-1,-1), 20),
    ("BOTTOMPADDING", (0,0),(-1,-1), 20),
    ("LEFTPADDING",   (0,0),(-1,-1), 10),
    ("RIGHTPADDING",  (0,0),(-1,-1), 10),
    ("BOX",           (0,0),(-1,-1), 2, MID_BLUE),
]))
story.append(wrapper)
story.append(spacer(8))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 1 – OPIOID RECEPTORS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("1. OPIOID RECEPTORS & SIGNAL TRANSDUCTION", "[~5 marks]"))
story.append(spacer(3))

story.append(sub_header("1.1  Classification"))
story.append(body(
    "Opioid receptors are <b>7-transmembrane G protein-coupled receptors (GPCRs)</b> belonging to "
    "the class A (rhodopsin) subfamily, sharing 55–58% sequence homology. Four receptor subtypes "
    "exist: mu (μ), kappa (κ), delta (δ), and the nociceptin/orphanin FQ receptor (NOPr/ORL-1). "
    "The <b>mu receptor</b> mediates virtually all clinically important analgesia and adverse effects "
    "of currently used opioids."
))
story.append(spacer(3))

story.append(make_table(
    ["Receptor", "Endogenous Ligand", "Analgesia Site", "Key Effects", "Clinical Relevance"],
    [
        ["μ (Mu)", "β-Endorphin,\nEnkephalins", "Supraspinal +\nSpinal + Peripheral",
         "Analgesia, euphoria, resp. depression,\nmiosis, ↓GI motility, dependence",
         "Target of all clinical opioid analgesics"],
        ["κ (Kappa)", "Dynorphins", "Spinal", "Spinal analgesia, sedation,\ndysphoria, psychotomimesis",
         "Pentazocine, butorphanol; dysphoria\nlimits clinical use"],
        ["δ (Delta)", "Enkephalins", "Spinal + Peripheral", "Analgesia, mood modulation,\nreduced GI motility",
         "Modulates mu-receptor activity;\nnot yet clinical target"],
        ["NOPr/ORL-1", "Nociceptin\n(orphanin FQ)", "Supraspinal +\nSpinal", "Modulates pain,\nanxiety, stress response",
         "Cebranopadol (NOP/mu agonist)\nin development"],
    ],
    col_widths=[2.5*cm, 3*cm, 3*cm, 5*cm, 4.5*cm]
))
story.append(spacer(4))

story.append(sub_header("1.2  Signal Transduction Mechanism"))
story.append(body(
    "Opioid receptor activation couples to pertussis toxin-sensitive <b>G<sub>i</sub>/G<sub>o</sub> "
    "proteins</b>. The downstream cascade produces:"
))
for b_text in [
    "<b>Inhibition of adenylate cyclase</b> → reduced intracellular cAMP → decreased PKA activity",
    "<b>Inhibition of voltage-gated Ca²⁺ channels</b> → reduced neurotransmitter release at pre-synaptic terminals",
    "<b>Activation of inwardly rectifying K⁺ channels (GIRK)</b> → membrane hyperpolarisation → reduced neuronal firing",
    "Activation of MAP kinase pathways (ERK, JNK) → gene expression changes; linked to long-term tolerance",
]:
    story.append(bullet(b_text))

story.append(body(
    "Net result: <b>reduction in neuronal excitability</b> at supraspinal (PAG, RVM), spinal (dorsal horn), "
    "and peripheral (sensory afferents) levels, interrupting the pain transmission arc."
))
story.append(spacer(2))

story.append(clinical_box("Practical Point: Tolerance Mechanism", [
    "Long-term opioid exposure → superactivation of adenylyl cyclase (counterregulatory cAMP upregulation) "
    "→ acute withdrawal hyperactivation; explains withdrawal syndrome and dose escalation",
    "Receptor internalisation, G-protein uncoupling, and NMDA system sensitisation all contribute to tolerance",
]))
story.append(spacer(4))

story.append(sub_header("1.3  Endogenous Opioid Peptides"))
story.append(make_table(
    ["Precursor", "Key Peptides", "Receptor Preference", "CNS Locations"],
    [
        ["Preproenkephalin",  "Met-enkephalin, Leu-enkephalin", "δ > μ",  "Dorsal horn, limbic system, striatum"],
        ["Preprodynorphin",   "Dynorphin A & B, neo-endorphins", "κ",     "Spinal cord, hypothalamus, hippocampus"],
        ["POMC",              "β-Endorphin (+ ACTH, MSH)",      "μ",      "Hypothalamus, PAG, pituitary, limbic"],
    ],
    col_widths=[4*cm, 4.5*cm, 3.5*cm, 6*cm]
))
story.append(spacer(6))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 2 – INDIVIDUAL AGENTS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("2. INDIVIDUAL OPIOID AGENTS: PHARMACOKINETICS & CLINICAL USE", "[~8 marks]"))
story.append(spacer(3))

story.append(sub_header("2.1  Comparative Pharmacokinetics Table"))
story.append(make_table(
    ["Drug", "Relative\nPotency", "Onset\n(IV)", "Duration", "Vd (L/kg)", "Protein\nBinding",
     "Metabolism", "Active\nMetabolite", "CSHT*"],
    [
        ["Morphine",     "1×",    "3–5 min",  "3–5 h",  "3–4",    "35%", "Hepatic glucuronidation\n(UGT2B7)", "M6G ⚠", "Moderate ↑"],
        ["Fentanyl",     "100×",  "1–2 min",  "30–60 min","4–6",  "84%", "Hepatic CYP3A4",         "Norfentanyl (inactive)", "Markedly ↑ with\nlong infusions"],
        ["Alfentanil",   "10–20×","<1 min",   "10–20 min","0.5",  "90%", "Hepatic CYP3A4/3A5",     "None active", "Modest ↑"],
        ["Sufentanil",   "500–1000×","1–3 min","30–60 min","2.5", "93%", "Hepatic CYP3A4",         "None active", "Moderate ↑"],
        ["Remifentanil", "100×",  "<1 min",   "5–10 min","0.4",  "70%", "Plasma/tissue esterases\n(non-hepatic)", "None",   "~2 min\n(CONSTANT)"],
        ["Methadone",    "~equal", "5–10 min", "12–150 h","3–8",  "85%", "Hepatic CYP2B6",         "None active", "N/A – oral"],
        ["Tramadol",     "~1/10", "15–30 min","4–6 h",  "3–4",    "20%", "Hepatic CYP2D6\n(prodrug)", "O-desmethyl (active)", "Moderate"],
    ],
    col_widths=[2.3*cm, 1.6*cm, 1.5*cm, 1.8*cm, 1.5*cm, 1.7*cm, 3.2*cm, 2.8*cm, 2.1*cm]
))
story.append(Paragraph("* CSHT = Context-Sensitive Half-Time (time for plasma concentration to fall 50% after stopping infusion)", styles["caption"]))
story.append(spacer(4))

story.append(sub_header("2.2  Morphine – Practical Considerations"))
for b_text in [
    "<b>Dose:</b> 0.05–0.1 mg/kg IV bolus; PCA: 1–2 mg bolus with 5–10 min lockout; infusion 0.5–5 mg/h",
    "<b>M6G accumulation:</b> Active full mu-agonist; renal failure → M6G builds up → profound, late-onset "
    "respiratory depression and loss of consciousness. Avoid in GFR &lt;30 mL/min",
    "<b>M3G:</b> No opioid activity but contributes to neuro-excitation (myoclonus, allodynia) in renal failure",
    "<b>Histamine release:</b> Direct mast cell degranulation (not IgE) → flushing, urticaria, hypotension, "
    "bronchospasm; minimised by slow IV injection",
    "<b>Biliary effects:</b> Sphincter of Oddi spasm – can worsen biliary colic and complicate ERCP; glucagon "
    "or naloxone can relieve this",
    "<b>Neuraxial use:</b> Intrathecal 0.1–0.3 mg; epidural 2–5 mg; delayed respiratory depression up to 24 h "
    "due to rostral CSF spread – requires prolonged monitoring",
]:
    story.append(bullet(b_text))
story.append(spacer(3))

story.append(danger_box("Morphine in Renal Failure", [
    "Morphine-6-glucuronide (M6G) accumulates rapidly when GFR <30 mL/min",
    "Can cause delayed loss of consciousness and respiratory arrest many hours after last dose",
    "Preferred alternatives: fentanyl, alfentanil, remifentanil (Morgan & Mikhail, p.1270)"
]))
story.append(spacer(4))

story.append(sub_header("2.3  Fentanyl – Practical Considerations"))
for b_text in [
    "<b>Induction supplementation:</b> 1–3 mcg/kg IV; attenuates haemodynamic response to laryngoscopy",
    "<b>Infusion (TIVA/balanced):</b> 1–5 mcg/kg/h; for cardiac surgery 50–100 mcg/kg total dose",
    "<b>Context-sensitive half-time warning:</b> After a 4-hour fentanyl infusion, the CSHT may be >200 min "
    "– plan postoperative analgesia accordingly and anticipate residual effect",
    "<b>Transdermal (Duragesic):</b> 25–100 mcg/h patches; 12–16 h to steady state; reservoir in skin – "
    "concentration continues rising for 24 h after removal",
    "<b>Neuraxial:</b> Intrathecal 10–25 mcg with local anaesthetic enhances block quality; epidural 1–2 mcg/mL "
    "in infusion; lipophilic → primarily spinal (not rostral spread); minimal delayed resp. depression",
    "<b>MAC reduction:</b> 1.67 ng/mL plasma concentration reduces isoflurane MAC by ~50%; ceiling effect – "
    "cannot replace volatile agent entirely",
]:
    story.append(bullet(b_text))
story.append(spacer(4))

story.append(sub_header("2.4  Remifentanil – Practical Considerations"))
for b_text in [
    "<b>Mechanism unique:</b> Methyl ester side-chain hydrolysed by <b>non-specific tissue and plasma "
    "esterases</b>; clearance 3–5 L/min (exceeds liver blood flow) – unaffected by renal or hepatic failure",
    "<b>CSHT ~2 min regardless of infusion duration</b> – the only opioid with this property; permits precise "
    "titration and rapid offset",
    "<b>TCI dosing (Minto model):</b> Induction 4–8 ng/mL effect-site; maintenance 2–6 ng/mL; "
    "spontaneous ventilation procedures 1–2 ng/mL",
    "<b>Weight-based:</b> Induction 0.5–1 mcg/kg over 30–60 sec; infusion 0.05–2 mcg/kg/min",
    "<b>Abrupt offset:</b> Pain scores spike within minutes of stopping – <b>must pre-empt with morphine "
    "(0.1–0.15 mg/kg) or other long-acting analgesic 20–30 min before end of surgery</b>",
    "<b>OIH risk:</b> High-dose remifentanil infusions (>0.3 mcg/kg/min) associated with post-operative "
    "hyperalgesia; co-administration of ketamine 0.25–0.5 mg/kg attenuates this",
    "<b>Cannot be given intrathecally or epidurally</b> – contains glycine (inhibitory neurotransmitter) "
    "as diluent → potential neurotoxicity",
    "<b>Muscle rigidity:</b> Rapid boluses of remifentanil cause thoracic rigidity; inject slowly or "
    "use neuromuscular blockade",
]:
    story.append(bullet(b_text))
story.append(spacer(4))

story.append(sub_header("2.5  Alfentanil & Sufentanil"))
story.append(body("<b>Alfentanil:</b>"))
for b_text in [
    "Low Vd + high protein binding → rapid equilibration with effect site; t½ke0 ~1 min",
    "Useful for short procedures; supplement for laryngoscopy: 10–20 mcg/kg; infusion 0.5–3 mcg/kg/min",
    "CYP3A4/3A5 metabolism → large interindividual variability; CYP3A inhibitors (erythromycin, azoles) "
    "dramatically prolong effect",
]:
    story.append(bullet(b_text))
story.append(body("<b>Sufentanil:</b>"))
for b_text in [
    "5–10× more potent than fentanyl; high mu-receptor selectivity",
    "Preferred for cardiac anaesthesia high-dose technique and neuraxial use (intrathecal 2.5–10 mcg)",
    "Haemodynamic stability; minimal histamine release; may be more analgesic in some patient subsets "
    "due to higher receptor affinity",
]:
    story.append(bullet(b_text))
story.append(spacer(4))

story.append(sub_header("2.6  Methadone"))
for b_text in [
    "Dual mechanism: <b>full mu-agonist + NMDA receptor antagonist</b> (useful for neuropathic pain and OIH prevention)",
    "Oral bioavailability 60–95%; active as perioperative IV analgesic (single intraoperative dose 0.1–0.3 mg/kg)",
    "<b>Long and unpredictable half-life (24–150 h)</b> – methadone-associated deaths from respiratory depression "
    "typically occur 3–5 days after starting or increasing dose",
    "<b>QTc prolongation</b> – risk of torsades de pointes, especially >100 mg/day oral or IV; ECG monitoring mandatory; "
    "avoid other QT-prolonging drugs",
    "CYP2B6 metabolism – significant drug interactions (e.g., rifampicin accelerates clearance → withdrawal)",
]:
    story.append(bullet(b_text))
story.append(spacer(4))

story.append(sub_header("2.7  Buprenorphine"))
for b_text in [
    "<b>Partial mu-agonist / kappa-antagonist</b>: ceiling effect on respiratory depression at high doses; "
    "ceiling effect on analgesia limits utility in severe acute pain",
    "Very high mu-receptor affinity (>morphine): may require 10–40× usual naloxone doses for reversal; "
    "standard doses ineffective",
    "Half-life 24–72 h; used for opioid use disorder (Suboxone = buprenorphine + naloxone)",
    "<b>Perioperative management:</b> Continue buprenorphine rather than stopping; supplement with higher "
    "doses of full mu-agonists for breakthrough pain intraoperatively",
]:
    story.append(bullet(b_text))
story.append(spacer(4))

story.append(sub_header("2.8  Codeine, Tramadol, Pethidine"))
story.append(make_table(
    ["Drug", "Mechanism", "Key Practical Points", "Avoid When"],
    [
        ["Codeine",   "Prodrug → morphine\nvia CYP2D6",
         "~10% of Caucasians are poor metabolisers (no effect);\nultra-rapid metabolisers at risk of toxicity;\nbanned post-tonsillectomy in children <18",
         "Paediatric airway surgery; CYP2D6 poor metabolisers;\nrenal failure (morphine metabolite accumulation)"],
        ["Tramadol",  "Weak μ-agonist +\nSNRI",
         "Dose: 1–2 mg/kg PO/IV; lowers seizure threshold;\nrisk of serotonin syndrome with SSRIs/MAOIs;\nnausea common (20–30%)",
         "Epilepsy; concurrent serotonergic drugs;\n<12 years (post-tonsillectomy)"],
        ["Pethidine\n(Meperidine)", "μ-agonist",
         "Metabolite norpethidine: neuro-excitatory (seizures,\nmyoclonus); accumulates in renal failure;\nused for post-op shivering 0.35 mg/kg IV",
         "Renal failure; concurrent MAOIs (hypertensive crisis);\n>72 h continuous use"],
    ],
    col_widths=[2.5*cm, 3.5*cm, 7.5*cm, 5*cm]
))
story.append(spacer(6))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 3 – SYSTEMIC EFFECTS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("3. PHARMACOLOGICAL EFFECTS BY SYSTEM", "[~5 marks]"))
story.append(spacer(3))

story.append(sub_header("3.1  Respiratory System – The Critical System"))
story.append(body(
    "Respiratory depression is the most feared consequence of opioid use and the primary cause of "
    "opioid-related mortality. Opioids act on mu-receptors in the pre-Bötzinger complex (respiratory "
    "rhythm generator) and parabrachial nucleus."
))
story.append(spacer(2))

story.append(make_table(
    ["Effect", "Mechanism", "Clinical Implication"],
    [
        ["↓ Respiratory rate\n(dominant effect)", "Direct depression of brainstem respiratory neurons;\nblunted CO₂ ventilatory response curve",
         "PaCO₂ rises; response curve shifts right\nand decreases in slope"],
        ["Apnoea (rapid bolus)", "No time for CO₂ accumulation to stimulate\ncompensation; pre-Bötzinger neurons silenced",
         "Remifentanil/fentanyl rapid bolus;\nalways have airway equipment ready"],
        ["Thoracic rigidity\n('wooden chest')", "High-dose synthetic opioids → pharyngeal\nand thoracoabdominal muscle rigidity",
         "Manage: succinylcholine, NMBD,\nor small-dose naloxone (40 mcg IV)"],
        ["Upper airway\nobstruction", "Loss of upper airway tone (brainstem\nneurons + sedation); impaired arousal reflex",
         "Central + obstructive apnoeas;\nPulse oximetry on supplemental O₂\nmasks hypoventilation – monitor ETCO₂"],
        ["OIH hyperventilation", "Paradoxical pain sensitisation",
         "Seen after high-dose remifentanil;\ncountered with ketamine"],
    ],
    col_widths=[3*cm, 6*cm, 9*cm]
))
story.append(spacer(3))

story.append(danger_box("Monitoring Caution – Supplemental Oxygen", [
    "Pulse oximetry + supplemental O₂ masks early hypoventilation – SpO₂ may remain >95% despite PaCO₂ >80 mmHg",
    "MANDATORY: end-tidal CO₂ monitoring for all patients on opioid infusions in recovery or HDU",
    "Capnography is the only bedside monitor that detects opioid-induced hypoventilation before desaturation (Barash 9e, p.1568)"
]))
story.append(spacer(4))

story.append(sub_header("3.2  Cardiovascular System"))
for b_text in [
    "<b>Bradycardia:</b> Central vagal stimulation – morphine and fentanyl; profound with high-dose fentanyl "
    "(>10 mcg/kg); treat with atropine or glycopyrrolate",
    "<b>Vasodilation:</b> Morphine directly degranulates mast cells → histamine release → peripheral "
    "vasodilation, hypotension; fentanyl/remifentanil have minimal histamine effect",
    "<b>High-dose opioid anaesthesia:</b> 50–100 mcg/kg fentanyl provides haemodynamic stability in "
    "cardiac surgery (blunts sympathetic response to sternotomy); still requires supplemental volatile "
    "or propofol as opioids have a ceiling on MAC reduction",
    "<b>Methadone QTc:</b> Dose-dependent hERG channel block → torsades; ECG pre-operatively for all "
    "patients on >40 mg/day oral methadone",
    "<b>Intracranial effects:</b> Opioids do not directly increase ICP in normoventilated patients; "
    "respiratory depression → hypercapnia → cerebral vasodilation → ↑ICP; maintain PaCO₂ 35–40 mmHg",
]:
    story.append(bullet(b_text))
story.append(spacer(4))

story.append(sub_header("3.3  CNS Effects"))
for b_text in [
    "<b>Analgesia:</b> Supraspinal (PAG → RVM descending inhibition), spinal (Rexed lamina I, II – "
    "direct inhibition of substantia gelatinosa), peripheral (inflammatory states – immune cell "
    "β-endorphin release)",
    "<b>Miosis:</b> Stimulation of Edinger-Westphal nucleus; does not habituate with tolerance; "
    "useful clinical sign of opioid effect; bilateral fixed miosis with pinpoint pupils = opioid toxidrome",
    "<b>Nausea/Vomiting:</b> CTZ stimulation (area postrema, lacks blood-brain barrier) + vestibular "
    "sensitisation; worsened by movement; first-line: ondansetron, cyclizine; second-line: haloperidol",
    "<b>Sedation:</b> ↓ cortical ACh (morphine injection into substantia innominata reduces prefrontal ACh); "
    "reduces awareness but cannot provide complete anaesthesia",
    "<b>Euphoria/Dysphoria:</b> Mu → mesolimbic dopamine release → euphoria/reward (basis of addiction); "
    "Kappa → dysphoria (limits clinical utility of kappa agonists)",
    "<b>Sleep architecture:</b> ↓ slow-wave sleep, ↓ REM, ↑ stage 2; central sleep apnoea prevalence "
    "~24% in chronic opioid users",
    "<b>Antitussive:</b> Suppression of medullary cough centre; codeine classically used",
]:
    story.append(bullet(b_text))
story.append(spacer(4))

story.append(sub_header("3.4  Gastrointestinal System"))
for b_text in [
    "<b>Constipation:</b> Peripheral μ-receptors in enteric nervous system → ↓ peristalsis, ↑ segmental "
    "tone, ↓ intestinal secretions; <b>does NOT habituate with tolerance</b> – co-prescribe laxatives "
    "from day one of opioid therapy",
    "<b>Postoperative ileus (POI):</b> Opioids delay return of GI function after abdominal surgery; "
    "opioid-sparing techniques (epidural, regional, NSAIDs) reduce POI duration",
    "<b>Sphincter of Oddi spasm:</b> ↑ biliary pressure; morphine > fentanyl; can masquerade as "
    "biliary colic; glucagon 1 mg IV or naloxone reverses this",
    "<b>Delayed gastric emptying:</b> ↑ aspiration risk; relevant to emergency cases, labour analgesia, "
    "and patients on long-term opioids",
    "<b>Treatment for opioid-induced constipation:</b> methylnaltrexone (SC), naloxegol, or naldemedine – "
    "peripherally restricted antagonists; do not reverse central analgesia",
]:
    story.append(bullet(b_text))
story.append(spacer(4))

story.append(sub_header("3.5  Urinary & Endocrine Effects"))
for b_text in [
    "<b>Urinary retention:</b> ↑ urinary sphincter tone + ↓ detrusor contraction; especially with "
    "neuraxial opioids; treat with naloxone 40–80 mcg IV or bethanechol",
    "<b>HPG axis suppression (chronic use):</b> ↓ GnRH → ↓ LH, FSH → ↓ testosterone/oestrogen; "
    "opioid-induced hypogonadism; sexual dysfunction and osteoporosis in chronic pain patients",
    "<b>Antidiuretic effect:</b> ADH release potentiated (morphine); rare clinical significance",
    "<b>Immunosuppression:</b> Mu-receptor-mediated ↓ NK cell activity, impaired T-lymphocyte function; "
    "relevance in cancer pain management and high-dose perioperative opioids",
]:
    story.append(bullet(b_text))
story.append(spacer(6))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 4 – TOLERANCE, OIH, SPECIAL POPULATIONS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("4. TOLERANCE, OIH, & GENETIC VARIATION", "[~4 marks]"))
story.append(spacer(3))

story.append(sub_header("4.1  Opioid Tolerance"))
story.append(body(
    "Tolerance is the requirement for increasing doses to produce the same effect. Several mechanisms operate "
    "at different timescales:"
))
story.append(make_table(
    ["Mechanism", "Time-course", "Clinical Significance"],
    [
        ["Receptor internalisation\n& downregulation", "Hours–days",
         "Reduced receptor availability; opioid rotation exploits incomplete cross-tolerance"],
        ["G-protein uncoupling\n(desensitisation)", "Minutes–hours",
         "Acute tolerance; relevant to intraoperative remifentanil"],
        ["cAMP superactivation\n(adenylyl cyclase upregulation)", "Days–weeks",
         "Physical dependence; withdrawal if stopped abruptly;\ndo not abruptly stop perioperatively"],
        ["NMDA receptor\nsensitisation", "Hours–days",
         "Contributes to both tolerance and OIH;\nketamine (0.25–0.5 mg/kg) attenuates"],
        ["Neuroinflammation\n(CXCL1/CXCL12 chemokines)", "Days–weeks",
         "Spinal glial cell activation; emerging target "
         "for adjunctive anti-neuroinflammatory treatment"],
    ],
    col_widths=[4.5*cm, 3*cm, 10.5*cm]
))
story.append(spacer(3))

story.append(clinical_box("Practical: Acute Opioid Tolerance (AOT) in Theatre", [
    "Remifentanil 0.3 mcg/kg/min (vs 0.1 mcg/kg/min) → significantly higher postoperative morphine requirements "
    "and pain scores (Miller's Anesthesia 10e, p.2744–2745)",
    "Strategy: use lowest effective remifentanil rate; add ketamine 0.25–0.5 mg/kg IV intraoperatively; "
    "give long-acting opioid (morphine 0.1 mg/kg) 20–30 min before emergence",
    "Propofol-based TIVA may attenuate remifentanil-induced OIH compared to sevoflurane (Miller 10e, p.2742)",
]))
story.append(spacer(4))

story.append(sub_header("4.2  Opioid-Induced Hyperalgesia (OIH)"))
story.append(body(
    "OIH is a paradoxical state where opioid treatment <b>increases</b> sensitivity to painful stimuli, distinct "
    "from tolerance (where analgesic effect diminishes). Patients become more sensitive to nociceptive stimuli, "
    "not just less opioid-responsive."
))
for b_text in [
    "<b>Mechanisms:</b> NMDA receptor sensitisation (spinal), spinal dynorphin upregulation → enhanced "
    "pronociceptive transmitter release, descending pain facilitatory pathway activation",
    "<b>Triggers:</b> High-dose remifentanil infusions most studied; all potent opioids capable; "
    "dose-dependent relationship established",
    "<b>Clinical clue:</b> Patient on opioid infusion complaining of diffuse hyperalgesia/allodynia beyond "
    "the surgical site; paradoxically worsened by opioid dose increase",
    "<b>Long-term consequence:</b> Intraoperative remifentanil dose predicts chronic thoracic pain at "
    "1 year after cardiac surgery; OIH links to development of chronic post-surgical pain",
]:
    story.append(bullet(b_text))
story.append(spacer(2))

story.append(make_table(
    ["Intervention", "Mechanism", "Evidence"],
    [
        ["Ketamine 0.25–0.5 mg/kg IV ±\ninfusion 0.1–0.2 mg/kg/h", "NMDA antagonist",
         "Prevents AOT and reduces OIH in RCTs; best evidence base (Miller 10e, p.2744)"],
        ["Magnesium sulfate 30 mg/kg\nat induction + 10 mg/kg/h", "NMDA antagonism\n(Mg blocks channel)",
         "RCT in thyroidectomy: prevented remifentanil-induced hyperalgesia"],
        ["Low-dose naloxone\n0.05 mcg/kg/h IV", "μ-receptor modulation\n(paradoxical anti-OIH)", "Reduced OIH after remifentanil 4 ng/mL in thyroid surgery"],
        ["COX-2 inhibitor\n(parecoxib)", "Blocks COX-2 in OIH pathway", "Prevented hyperalgesia after 30-min remifentanil infusion"],
        ["Propofol TIVA\n(vs sevoflurane)", "Unclear; possibly\npropofol's effects on\nspinal sensitisation", "Significantly less OIH vs sevoflurane in breast cancer surgery (Miller 10e, p.2742)"],
    ],
    col_widths=[4.5*cm, 4*cm, 9.5*cm]
))
story.append(spacer(4))

story.append(sub_header("4.3  Pharmacogenomics – A118G Polymorphism"))
story.append(body(
    "The <b>A118G SNP</b> of the OPRM1 gene (μ-opioid receptor) is the most clinically important "
    "pharmacogenetic variant in anaesthesia:"
))
for b_text in [
    "A-to-G substitution in exon 1 → asparagine to aspartate at position 40 (N40D)",
    "Meta-analysis of >4,600 patients: <b>A118G carriers require significantly higher opioid doses</b> "
    "postoperatively (Miller 10e, p.2681–82)",
    "Reduces analgesic response to M6G but does not significantly attenuate M6G-induced "
    "respiratory depression – clinically important dissociation",
    "Associated with susceptibility to opioid dependence/addiction in Asian populations (meta-analysis)",
    "Practical implication: do not dismiss inadequate analgesia as 'behavioural' – pharmacogenetics "
    "may explain higher requirements; titrate to effect",
]:
    story.append(bullet(b_text))
story.append(spacer(4))

story.append(sub_header("4.4  CYP2D6 Polymorphism – Codeine"))
story.append(make_table(
    ["Phenotype", "Frequency", "Clinical Impact"],
    [
        ["Poor metaboliser (PM)", "7–10% Caucasians", "No analgesia from codeine; frustration + dose escalation"],
        ["Ultra-rapid metaboliser (UM)", "1–3%; higher in NE Africa/Middle East", "Excessive morphine production → overdose, neonatal death (breastfeeding UM mothers)"],
        ["Normal metaboliser", "~85% population", "Expected analgesic response"],
    ],
    col_widths=[4*cm, 4*cm, 10*cm]
))
story.append(Paragraph("FDA/EMA: codeine contraindicated post-tonsillectomy/adenoidectomy in children <18 years", styles["caption"]))
story.append(spacer(6))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 5 – ANTAGONISTS & REVERSAL
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("5. OPIOID ANTAGONISTS & REVERSAL", "[~3 marks]"))
story.append(spacer(3))

story.append(sub_header("5.1  Naloxone – Practical Reversal"))
for b_text in [
    "<b>Mechanism:</b> Pure competitive antagonist at μ, κ, δ receptors; highest affinity for μ",
    "<b>Dose:</b> Titrated 40 mcg IV increments every 2–3 min until adequate respiratory rate "
    "(>12 breaths/min) – goal is to restore ventilation, NOT fully reverse analgesia",
    "<b>Onset:</b> 1–2 min IV; <b>Duration:</b> 30–90 min",
    "<b>Re-narcotisation warning:</b> ALL clinical opioids outlast naloxone; patient must be observed "
    "for ≥2 h after reversal; infusion 2/3 of effective bolus dose per hour may be needed for "
    "long-acting opioids (e.g., sustained-release morphine, methadone)",
    "<b>Precipitation of acute withdrawal:</b> Massive sympathetic surge → hypertension, pulmonary "
    "oedema, VF, cardiac arrest – dose carefully in opioid-dependent patients",
    "<b>Buprenorphine reversal:</b> High receptor affinity means standard naloxone doses insufficient; "
    "use 10–40× normal doses (400 mcg–4 mg); may need naloxone infusion",
]:
    story.append(bullet(b_text))
story.append(spacer(3))

story.append(clinical_box("Naloxone Infusion Protocol", [
    "Calculate bolus dose required for effect, then give 2/3 of that dose as hourly infusion",
    "Dilute in 0.9% saline or 5% dextrose; typical infusion 0.4–2 mg/h for morphine overdose",
    "Monitor respiratory rate, consciousness, and pain score – re-emergence of pain is a sign of adequate reversal"
]))
story.append(spacer(4))

story.append(sub_header("5.2  Peripherally Restricted Antagonists"))
story.append(make_table(
    ["Drug", "Route", "Indication", "Dose", "Note"],
    [
        ["Methylnaltrexone", "SC", "Opioid-induced constipation\nin palliative care/chronic pain",
         "Weight-based: 8–12 mg SC\nevery other day", "Does NOT cross BBB; preserves central analgesia"],
        ["Naloxegol", "Oral", "OIC in chronic pain (non-cancer)", "25 mg OD",
         "Pegylated naloxol; FDA-approved; CYP3A4 substrate"],
        ["Alvimopan", "Oral", "Post-operative ileus prevention", "12 mg pre-op\n+ 12 mg BD ×7d",
         "Hospital use only; accelerates GI recovery after bowel surgery"],
        ["Naldemedine", "Oral", "OIC in chronic opioid use", "0.2 mg OD",
         "Most recent; good tolerability profile"],
    ],
    col_widths=[3*cm, 1.5*cm, 4.5*cm, 3.5*cm, 5.5*cm]
))
story.append(spacer(6))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 6 – SPECIAL SITUATIONS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("6. OPIOIDS IN SPECIAL CLINICAL SITUATIONS", "[~5 marks]"))
story.append(spacer(3))

story.append(sub_header("6.1  Renal Failure"))
story.append(make_table(
    ["Opioid", "Renal Risk", "Recommendation"],
    [
        ["Morphine", "M6G & M3G accumulate → delayed resp. depression, LOC,\nneurological excitation; AVOID GFR <30",
         "Use fentanyl or remifentanil instead;\nif morphine must be used: reduce dose, extend intervals"],
        ["Pethidine", "Norpethidine accumulates → seizures, dysphoria,\nmyoclonus; half-life 14–48 h in renal failure",
         "AVOID completely in renal impairment;\ndo not use >48–72 h even in normal renal function"],
        ["Fentanyl", "Norfentanyl (inactive); moderate ↑ CSHT with\nprolonged infusions but no active metabolites",
         "Preferred agent for moderate-severe renal impairment;\nmonitor CSHT closely with infusions >2–3 h"],
        ["Remifentanil", "Esterase-mediated; completely unaffected by\nrenal (or hepatic) function",
         "First choice for infusions in renal failure;\nremember pre-emptive postoperative analgesia"],
        ["Alfentanil", "Minor renal excretion; minimal accumulation",
         "Acceptable choice; use with caution in\nGFR <10 mL/min"],
        ["Tramadol", "Active metabolite O-desmethyltramadol accumulates;\nrisk of seizures and serotonin syndrome",
         "REDUCE dose by 50% and extend to 12-hourly;\nAVOID if GFR <30 mL/min"],
    ],
    col_widths=[2.8*cm, 7.5*cm, 7.7*cm]
))
story.append(spacer(4))

story.append(sub_header("6.2  Hepatic Failure"))
for b_text in [
    "All hepatically-metabolised opioids (morphine, fentanyl, sufentanil, alfentanil) have reduced "
    "clearance in severe hepatic failure → prolonged effect; fentanyl and sufentanil's high extraction "
    "ratios may actually be maintained if residual hepatic blood flow preserved",
    "<b>Remifentanil:</b> Extrahepatic esterase metabolism completely unaffected by hepatic failure – "
    "ideal for critically ill patients with liver failure",
    "<b>Morphine:</b> ↓ glucuronidation capacity → ↑ bioavailability and t½; use with caution in Child-Pugh C",
    "Reduce protein binding: hypoalbuminaemia → ↑ free fraction → enhanced pharmacological effect "
    "even at 'normal' plasma concentrations",
    "Monitor for hepatic encephalopathy – opioids may precipitate or worsen encephalopathy in "
    "cirrhotic patients",
]:
    story.append(bullet(b_text))
story.append(spacer(4))

story.append(sub_header("6.3  Obstetrics"))
for b_text in [
    "All opioids cross the placenta via simple diffusion; ionisation and protein binding affect rate",
    "<b>Morphine/pethidine IM:</b> Avoid within 1–2 h of delivery; neonatal respiratory depression "
    "(treat with naloxone 0.01 mg/kg IM/IV to neonate)",
    "<b>Epidural opioids:</b> Fentanyl 50–100 mcg or sufentanil 10–20 mcg; lipophilic → minimal "
    "rostral spread; negligible systemic foetal transfer; combined spinal-epidural (CSE) technique "
    "for labour analgesia",
    "<b>Intrathecal:</b> Fentanyl 15–25 mcg or sufentanil 5 mcg added to local anaesthetic for spinal; "
    "enhances and extends block quality",
    "<b>Remifentanil PCA:</b> 0.2–0.4 mcg/kg bolus, 2 min lockout; effective labour analgesia "
    "alternative to epidural; requires 1:1 midwife ratio and SpO₂ monitoring – rapid onset/offset "
    "means apnoea risk at peak; MUST ensure bolus is patient-administered at contraction onset",
    "<b>GA for CS:</b> Fentanyl 1–2 mcg/kg acceptable at induction (neonatal effect transient); "
    "remifentanil 1 mcg/kg bolus blunts intubation response without prolonged neonatal effect",
]:
    story.append(bullet(b_text))
story.append(spacer(4))

story.append(sub_header("6.4  Paediatrics"))
for b_text in [
    "Neonates: ↑ BBB permeability, ↓ protein binding, ↓ hepatic metabolism → enhanced and prolonged "
    "effects; morphine infusions in NICU require careful dose adjustment",
    "Premature infants: immature respiratory centre → greater sensitivity to opioid-induced apnoea; "
    "monitor 12–24 h post-procedure",
    "Fentanyl dose: 1–4 mcg/kg IV (induction supplement); 0.5–2 mcg/kg/h infusion",
    "Codeine: CONTRAINDICATED in children <18 years post-tonsillectomy/adenoidectomy (FDA black box)",
    "Tramadol: contraindicated <12 years for routine pain; <18 years post-tonsillectomy",
]:
    story.append(bullet(b_text))
story.append(spacer(4))

story.append(sub_header("6.5  Opioid-Tolerant and Opioid-Dependent Patients"))
story.append(body(
    "This increasingly common perioperative scenario requires careful planning:"
))
for b_text in [
    "<b>Do NOT stop long-term opioids abruptly:</b> Acute withdrawal increases sympathetic activity, "
    "pain, and distress; convert oral opioid to IV equivalents perioperatively",
    "<b>Continue methadone at usual daily dose:</b> Methadone provides baseline opioid effect; "
    "supplement with additional mu-agonist for surgical pain; do NOT use agonist-antagonist "
    "drugs (pentazocine, nalbuphine) – will precipitate withdrawal",
    "<b>Buprenorphine patients:</b> Do not discontinue; supplement with high-dose full mu-agonists; "
    "titrate carefully as ceiling effect reduces respiratory depression safety margin when "
    "co-administering full agonists",
    "<b>Markedly increased intraoperative requirements:</b> Chronic users may need 3–5× normal dose; "
    "use regional techniques as primary modality wherever feasible",
    "<b>Multimodal opioid-sparing:</b> Regular paracetamol + NSAIDs + gabapentinoid + regional; "
    "reduces opioid requirements, risk of relapse, and facilitates discharge",
    "<b>Addiction medicine liaison:</b> Involve pre-operatively; brief intervention and referral "
    "at time of surgery may reduce long-term opioid prescribing",
]:
    story.append(bullet(b_text))
story.append(spacer(6))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 7 – MULTIMODAL & OPIOID-SPARING
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("7. OPIOID-SPARING MULTIMODAL ANALGESIA & ERAS", "[Bonus context]"))
story.append(spacer(3))

story.append(body(
    "The opioid crisis and recognition of opioid adverse effects have driven the adoption of "
    "<b>opioid-sparing multimodal analgesia (MMA)</b> as the standard of care, codified in "
    "Enhanced Recovery After Surgery (ERAS) protocols."
))
story.append(spacer(3))

story.append(make_table(
    ["Agent / Technique", "Mechanism", "Opioid-Sparing Effect", "Practical Dose"],
    [
        ["Paracetamol (IV/PO)", "Central COX inhibition,\nendocannabinoid modulation",
         "15–20% opioid reduction", "1 g QDS (max 4 g/day;\n15 mg/kg if <50 kg)"],
        ["NSAIDs / COX-2 inhibitors", "Peripheral + central\nPG synthesis inhibition",
         "25–35% opioid reduction", "Ibuprofen 400 mg TDS;\nparecoxib 40 mg IV"],
        ["Ketamine", "NMDA antagonist;\nanti-OIH; anti-tolerance",
         "30–40% opioid reduction;\nparticularly in opioid-tolerant pts",
         "0.25–0.5 mg/kg IV sub-anaesthetic;\ninfusion 0.1–0.2 mg/kg/h"],
        ["Dexmedetomidine", "α2-agonist:\nspinal + supraspinal analgesia",
         "20–30% opioid reduction;\nminimal resp. depression",
         "0.2–0.7 mcg/kg/h infusion;\n0.5–1 mcg/kg loading dose"],
        ["Gabapentinoids\n(Pregabalin/Gabapentin)", "Voltage-gated Ca²⁺ channel\n(α2δ subunit) blockade",
         "20–30%; especially\nneuropathic pain component",
         "Pregabalin 75–150 mg BD;\ngabapentin 300 mg TDS"],
        ["Epidural (thoracic/lumbar)", "Local anaesthetic ± opioid;\ncentral neuroaxial block",
         "Near-complete in covered dermatomes;\nreduces POI, PONV, DVT",
         "0.125–0.25% bupivacaine +\nfentanyl 2 mcg/mL"],
        ["TAP / QL / ESP block", "Peripheral nerve block;\nsomatic trunk wall",
         "30–50% opioid reduction\nfor abdominal surgery",
         "Ropivacaine 0.2–0.375%\n20 mL each side"],
        ["Lidocaine infusion (IV)", "Systemic LA:\nspinal modulation,\nanti-inflammatory",
         "15–25%; reduces POI\nand chronic pain risk",
         "1.5 mg/kg bolus then\n1.5 mg/kg/h intraop"],
    ],
    col_widths=[3.5*cm, 3.5*cm, 4.5*cm, 6.5*cm]
))
story.append(spacer(6))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 8 – NEURAXIAL OPIOIDS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("8. NEURAXIAL OPIOIDS – PRACTICAL GUIDE"))
story.append(spacer(3))

story.append(make_table(
    ["Drug", "IT Dose", "Epidural Dose", "Onset", "Duration", "Key Concern"],
    [
        ["Morphine",    "0.1–0.3 mg",      "2–5 mg",             "30–60 min", "12–24+ h",
         "Delayed resp. depression 6–24 h (rostral spread); 24 h monitoring mandatory"],
        ["Fentanyl",    "15–25 mcg",        "50–100 mcg bolus;\n1–2 mcg/mL infusion", "5–10 min", "2–4 h",
         "Lipophilic → minimal rostral spread; minimal delayed resp. depression"],
        ["Sufentanil",  "2.5–10 mcg",       "10–30 mcg bolus;\n0.5–1 mcg/mL infusion", "3–5 min",  "3–5 h",
         "Very lipophilic; same as fentanyl; enhanced sensory block"],
        ["Diamorphine", "0.2–0.4 mg",       "2–5 mg",             "15–30 min", "12–18 h",
         "Used in UK; intermediate lipophilicity; less rostral spread than morphine"],
        ["Hydromorphone","0.05–0.15 mg",    "1–1.5 mg",           "15–30 min", "10–20 h",
         "Moderate hydrophilicity; some delayed respiratory depression risk"],
    ],
    col_widths=[2.8*cm, 2.3*cm, 3.5*cm, 2*cm, 2*cm, 5.4*cm]
))
story.append(spacer(3))

story.append(danger_box("Neuraxial Morphine – Monitoring Requirements", [
    "Mandatory SpO₂ monitoring and respiratory rate observation every 1–2 h for 24 h post-IT morphine",
    "First respiratory depression episode may occur 6–12 h after injection when patient appears comfortable",
    "PONV is near-universal with neuraxial morphine – pre-emptive ondansetron 4–8 mg IV + dexamethasone 4–8 mg",
    "Urinary retention in ~30% of patients – insert urinary catheter or ensure easy access to catheterisation",
    "Have naloxone immediately available on ward; written reversal protocol must be in place",
]))
story.append(spacer(6))

# ══════════════════════════════════════════════════════════════════════════════
# CLOSING SUMMARY
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("SUMMARY & HIGH-YIELD EXAMINATION POINTS"))
story.append(spacer(3))

summary_points = [
    "Opioids act via Gi/Go-coupled GPCRs; μ-receptor mediates clinical analgesia AND adverse effects",
    "Remifentanil has a constant CSHT (~2 min) due to esterase hydrolysis; must pre-empt post-op pain",
    "Morphine is CONTRAINDICATED in severe renal failure due to M6G accumulation → delayed resp. depression",
    "Context-sensitive half-time of fentanyl increases markedly after prolonged infusions – plan recovery accordingly",
    "High-dose remifentanil (>0.3 mcg/kg/min) causes OIH → counter with ketamine 0.25–0.5 mg/kg IV",
    "Naloxone duration (30–90 min) is shorter than ALL clinical opioids → re-narcotisation is the rule, not the exception",
    "Buprenorphine requires 10–40× normal naloxone doses to reverse due to very high receptor affinity",
    "Codeine is a prodrug; AVOID in children <18 post-tonsillectomy; CYP2D6 genotype determines response",
    "A118G OPRM1 polymorphism → significantly higher opioid requirements; do not dismiss as behavioural",
    "Methadone: QTc prolongation → ECG all patients on >40 mg/day; drug interactions via CYP2B6 and CYP3A4",
    "Neuraxial morphine: 24 h monitoring mandatory; delayed resp. depression 6–12 h after IT injection",
    "Multimodal opioid-sparing (ERAS): paracetamol + NSAID + ketamine + regional reduces requirements 40–60%",
    "Supplemental oxygen on pulse oximetry MASKS opioid-induced hypoventilation – use capnography (ETCO₂)",
    "In opioid-dependent patients: NEVER use agonist-antagonists; continue methadone/buprenorphine perioperatively",
]

for i, pt in enumerate(summary_points, 1):
    story.append(Paragraph(f"<b>{i}.</b> {pt}", styles["bullet"]))

story.append(spacer(6))
story.append(rule(DARK_BLUE, 1))
story.append(spacer(3))

# References
story.append(sub_header("Key References"))
for ref in [
    "Miller RD et al. <i>Miller's Anesthesia</i>, 10th ed. (2023) — Chapters 22 (Opioid Pharmacology) & 35 (Pain)",
    "Barash PG et al. <i>Barash, Cullen & Stoelting's Clinical Anesthesia</i>, 9th ed. (2022) — Chapter 20 (Opioid PK/PD) & Chapter 55 (Perioperative Pain)",
    "Morgan GE, Mikhail MS. <i>Clinical Anesthesiology</i>, 7th ed. — Chapter 10 (Opioid Agonists & Antagonists)",
    "Brunton LL et al. <i>Goodman & Gilman's Pharmacological Basis of Therapeutics</i>, 14th ed. — Chapter 23 (Opioid Analgesics)",
    "Colvin LA, Bull F, Hales TG. Perioperative opioid analgesia — when is enough too much? <i>Lancet</i> 2019;393:1558–1568.",
]:
    story.append(Paragraph(ref, styles["ref"]))

story.append(spacer(4))
story.append(Paragraph(
    "Generated by Orris AI · Based on Miller's Anesthesia 10e, Barash 9e, Morgan &amp; Mikhail 7e, Goodman &amp; Gilman 14e",
    styles["caption"]
))

# ── Build ─────────────────────────────────────────────────────────────────────
doc.build(story)
print(f"PDF written to: {OUT}")