---

OPIOIDS: COMPLETE LEARNING NOTE

From Absolute Beginner to MBBS Examination Mastery

---

SECTION 1: BIG PICTURE OVERVIEW

What Problem Does the Opioid Drug Class Solve?

• A cancer patient in the last weeks of life, writhing in agony
• A patient after major surgery, unable to breathe deeply because every breath hurts
• Someone with a kidney stone so painful they cannot sit still
• A woman in labor
• A soldier with blast injuries on the battlefield

---

• Pain signals travel from injury site → spinal cord → brain
• The brain perceives this as "pain"
• This causes suffering, prevents normal function
• We need something that stops or reduces this signal

• Binds to special "lock-and-key" receptors in the brain and spinal cord
• These receptors, when activated, turn DOWN pain signals
• The patient still has the injury, but the brain does not receive the alarm as loudly
• Result: Pain relief (analgesia) = patient can function, breathe, sleep, heal

---

SECTION 2: BUILD THE FOUNDATION

Part A: Normal Pain Physiology - How Pain Works

TISSUE INJURY (fire starts)
        ↓
NOCICEPTORS activated (smoke detectors go off)
        ↓
Pain signal travels up peripheral nerve (alarm travels through wires)
        ↓
Enters spinal cord at dorsal horn (reaches the main junction box)
        ↓
Signal crosses to other side and travels up spinothalamic tract
        ↓
Reaches thalamus (relay station - like a switchboard)
        ↓
Reaches cortex (brain's awareness center - the control room)
        ↓
Pain is PERCEIVED (alarm heard and understood)

---

Part B: The Body's Own Built-In Pain Relief System

---

Part C: Opioid Receptors - The Locks

---

Part D: How Opioid Receptors Work at the Cell Level

Morphine arrives → binds to μ receptor on neuron surface
        ↓
Receptor changes shape → activates G-protein (Gi/Go type - inhibitory)
        ↓
G-protein does THREE things simultaneously:
        |
        ├──→ INHIBITS adenylyl cyclase → Less cAMP made
        |    (cAMP is a "go signal" for the cell - less cAMP = cell slows down)
        |
        ├──→ OPENS K+ channels → Potassium flows OUT of cell
        |    (this hyperpolarizes the cell = harder to fire = neuron quieted)
        |
        └──→ CLOSES Ca2+ channels → Less calcium enters cell
             (calcium is needed to release neurotransmitters - 
             less Ca2+ = less Substance P and glutamate released)

---

Part E: Where Opioids Act - Multiple Levels

• Immune cells in inflamed tissue release β-endorphin
• Opioid receptors on peripheral sensory nerve terminals are activated
• Result: Reduced peripheral sensitization, less pain signal generated

• Opioids inhibit pre-synaptic neurons: less Substance P and glutamate released
• Opioids inhibit post-synaptic neurons: less transmission to brain
• This is the main analgesic site for spinal/epidural opioids

• Periaqueductal Gray (PAG) in the midbrain - major site
• Rostral Ventromedial Medulla (RVM)
• Locus Coeruleus
• Opioids activate DESCENDING INHIBITORY pathways from here
• These descending pathways use serotonin and norepinephrine to further reduce pain transmission in the spinal cord

---

SECTION 3: DRUG CLASS FRAMEWORK

Classification of Opioids

OPIOIDS
   │
   ├── NATURAL (from opium poppy, Papaver somniferum)
   │       Morphine, Codeine
   │
   ├── SEMISYNTHETIC (natural opioid + chemical modification)
   │       Heroin (diacetylmorphine), Oxycodone, Hydromorphone,
   │       Buprenorphine, Naloxone, Naltrexone
   │
   └── SYNTHETIC (entirely made in lab)
           Fentanyl, Methadone, Meperidine (pethidine),
           Tramadol, Tapentadol, Remifentanil, Alfentanil

---

INDIVIDUAL DRUG PROFILES

---

1. MORPHINE - The Prototype

• Oral bioavailability is LOW (20-30%) due to extensive first-pass metabolism in the liver
• Given orally, intravenously (IV), subcutaneously (SC), intramuscularly (IM), epidurally, intrathecally
• IV and SC give the most reliable response
• Least lipophilic of the common opioids → crosses blood-brain barrier (BBB) SLOWLY
• Metabolized in liver by glucuronyl transferase enzyme (glucuronidation)
• Two main metabolites:
  • Morphine-6-glucuronide (M6G): MORE potent than morphine as an analgesic - accumulates in renal failure and can cause prolonged toxicity
  • Morphine-3-glucuronide (M3G): NO analgesic activity - may cause neuro-excitatory effects (hyperalgesia, allodynia, myoclonus)
• Excreted in urine (kidneys)
• Duration of action: 4-5 hours (systemic); longer epidurally

• Severe acute pain (post-surgical, trauma, MI)
• Cancer pain
• Pulmonary edema (acute left heart failure) - reduces preload, reduces anxiety, reduces dyspnea
• As a pre-anesthetic medication
• Dyspnea in terminally ill patients

• Head injury (raises ICP, causes CO₂ retention → further raises ICP, miosis masks neurological signs)
• Acute bronchial asthma / COPD (respiratory depression)
• Hepatic or renal failure (metabolite accumulation)
• Biliary colic (use pethidine)
• Concurrent MAO inhibitors (risk of serotonin syndrome with some opioids)

---

2. CODEINE

• CYP2D6 is highly polymorphic - different people have different genetic variants:
  • Poor metabolizers (10% of Caucasians, 1% of Asians): Cannot convert codeine → morphine. Codeine gives them NO pain relief but full adverse effects
  • Ultra-rapid metabolizers (1-7% of Caucasians, 29% of North Africans): Convert codeine too fast → dangerously high morphine levels → toxicity, even death
• This genetic variation makes codeine unpredictable and risky in some populations
• Codeine is BLACK BOX WARNING in breastfeeding mothers (ultra-rapid metabolizers can have high morphine in breast milk → infant death)

• Mild-to-moderate pain (usually in combination with paracetamol/NSAIDs)
• Cough suppressant (antitussive) - acts centrally on cough center in medulla
• Diarrhea

---

3. FENTANYL

• It crosses the BBB VERY FAST → rapid onset
• Rapid redistribution from brain to fat and muscle → short duration despite being extremely potent
• It does not cause histamine release (unlike morphine) → less cardiovascular effects

• IV (intraoperative analgesia/anesthesia - most common surgical use)
• Transdermal patch (Duragesic) - for chronic severe pain (cancer); takes 12-24 hours to reach therapeutic levels, lasts 72 hours
• Transmucosal (buccal, sublingual lollipop) - for breakthrough cancer pain
• Intranasal

• Onset IV: 1-2 minutes
• Duration IV bolus: 30-60 minutes (due to redistribution, not metabolism)
• Metabolism: liver (CYP3A4) → inactive metabolites (no active metabolites like morphine)
• Excreted: urine and feces

• Intraoperative analgesia and anesthesia induction
• Sedation in ICU
• Chronic cancer pain (transdermal patch)
• Acute pain in emergency settings

---

4. MEPERIDINE (PETHIDINE)

• Has atropine-like (antimuscarinic) activity → causes tachycardia and dry mouth (unlike morphine which causes bradycardia)
• Does NOT cause miosis as strongly as morphine
• Does NOT constipate as much as morphine (weaker GI effects)
• NO constriction of sphincter of Oddi → preferred for biliary colic and pancreatitis
• Does NOT cause bronchoconstriction → safer in asthma

• Meperidine is metabolized to normeperidine in the liver
• Normeperidine has a long half-life (15-20 hours)
• Normeperidine is a CNS STIMULANT → causes tremors, myoclonus, agitation, and SEIZURES
• Accumulates in renal failure and elderly patients
• Therefore meperidine should NOT be used for chronic pain or in renal failure

• Acute severe pain
• Biliary colic, pancreatitis
• Shivering after anesthesia (unique property - acts on κ receptors in the hypothalamus to reduce shivering threshold)
• Labor analgesia (but fetal respiratory depression still occurs)

---

5. METHADONE

1. Long and highly variable half-life: 15-60 hours (sometimes up to 120 hours). This makes dosing complex but allows once-daily oral dosing for addiction maintenance.
2. NMDA receptor antagonist: In addition to μ agonism, methadone also BLOCKS NMDA receptors (the same receptor that ketamine blocks). This:
   • Makes it useful for neuropathic pain (which involves NMDA receptor sensitization)
   • Reduces opioid tolerance (NMDA antagonism counteracts tolerance mechanisms)
   • Reduces opioid-induced hyperalgesia
3. No active metabolites → safer in renal failure than morphine
4. QT prolongation: Methadone blocks hERG potassium channels in the heart → prolongs QT interval → risk of torsades de pointes. Must monitor ECG.
5. High oral bioavailability: Nearly 80% - excellent oral absorption.

• Chronic severe pain (especially neuropathic pain)
• Opioid use disorder (addiction maintenance therapy) - daily oral dose suppresses cravings and withdrawal
• Detoxification from opioids

---

6. BUPRENORPHINE

• This is VERY important clinically
• At high doses, buprenorphine does NOT continue to increase respiratory depression the way morphine does
• This makes it much SAFER in overdose compared to full agonists
• However, the ceiling effect on analgesia also means it may not provide sufficient pain relief in very severe pain

• Buprenorphine binds μ receptors with VERY HIGH affinity
• It can DISPLACE morphine from receptors (if given after morphine)
• BUT naloxone cannot easily displace buprenorphine - so buprenorphine overdose requires LARGE DOSES of naloxone and prolonged infusion

• Sublingual/buccal (Subutex): Well absorbed sublingually; bypasses first-pass metabolism (oral bioavailability is poor)
• Transdermal patch (Butrans): For chronic pain
• Buprenorphine + Naloxone (Suboxone sublingual film): Naloxone is added as an abuse deterrent. When taken sublingually (as intended), naloxone is not absorbed. But if someone injects it to get high, the naloxone is absorbed and precipitates withdrawal.

• Opioid use disorder treatment (maintenance, detox)
• Moderate-to-severe chronic pain
• Safer alternative for patients at risk of respiratory depression (obese patients, COPD, sleep apnea)
• Opioid-induced hyperalgesia - rotating to buprenorphine may resolve this

---

7. TRAMADOL

1. Weak μ receptor agonist (about 1/6000th the potency of morphine at the receptor level, but analgesic potency ~1/10th morphine)
2. Inhibits reuptake of serotonin AND norepinephrine from synapses (like an antidepressant/SNRI)

• Neuropathic pain (where the norepinephrine/serotonin component helps)
• Fibromyalgia

• Lower risk of respiratory depression than morphine
• LOWERS seizure threshold → can cause seizures (especially in overdose or in epilepsy patients)
• Serotonin syndrome risk - especially with other serotonergic drugs (SSRIs, MAOIs, SNRIs)
• Less constipation than morphine
• Nausea, dizziness common

---

8. TAPENTADOL

1. Moderate μ receptor agonist (stronger than tramadol's opioid component)
2. Norepinephrine reuptake inhibitor (NO serotonin reuptake inhibition)

• No serotonin syndrome risk
• No active metabolite conversion needed (no CYP2D6 issue)
• Better tolerated (less nausea, vomiting)

---

OPIOID ANTAGONISTS

9. NALOXONE

• Can be given IV, IM, SC, intranasal
• Onset IV: within 2 minutes
• Duration: ONLY 30-90 minutes - much shorter than most opioids
• This is CRITICAL: A patient who received naloxone for heroin overdose may "wake up" and then fall unconscious again as the naloxone wears off but heroin is still in the system. They need monitoring and possibly repeated doses or a naloxone infusion.

• Opioid overdose reversal - the primary use; classic presentation is coma + respiratory depression + pinpoint pupils
• Diagnosis of opioid dependence (precipitates acute withdrawal in dependent patients)
• Combined with buprenorphine (Suboxone) as abuse deterrent
• Combined with oral opioids (Targinact = oxycodone + naloxone) to reduce constipation (naloxone absorbed locally in gut, reversed in liver - reduces gut opioid effects without affecting systemic analgesia)

• 0.4-2 mg IV, repeat every 2-3 minutes as needed
• For fentanyl overdose, may need much higher and repeated doses
• For buprenorphine overdose - very large doses needed (buprenorphine sticks to the receptor so tightly)

---

10. NALTREXONE

• Oral route (unlike naloxone which is poorly oral due to first-pass metabolism)
• Duration: 24 hours oral; 30 days IM (Vivitrol)
• Good oral bioavailability

• Opioid use disorder - maintenance therapy. Patient is first detoxed, then started on naltrexone. Any opioid they take will have NO effect (blocked). This removes the reward of using opioids.
• Alcohol use disorder - reduces craving for alcohol (endogenous opioid system is involved in alcohol reward)
• Rapid opioid detoxification (combined with clonidine)

• Hepatotoxicity at high doses - monitor LFTs
• Nausea, vivid nightmares
• Can precipitate severe withdrawal if patient is still opioid-dependent (must wait 7-10 days after last opioid before starting)

---

PENTAZOCINE (Mixed Agonist/Antagonist)

• Agonist at κ receptors → analgesia, sedation, dysphoria, hallucinations
• Weak antagonist/partial agonist at μ receptors

• Produces dysphoria and psychotomimetic effects (due to κ agonism) more than euphoria
• Lower abuse potential than morphine (dysphoria is unpleasant, not rewarding)
• Can precipitate withdrawal in opioid-dependent patients (because it partially blocks μ receptors)
• Does NOT cause as much respiratory depression as morphine (κ agonism can even antagonize μ-mediated respiratory depression)
• Increases blood pressure and heart rate (unlike morphine) - mechanism not fully clear
• Was commonly combined with antihistamine (tripelennamine) - "Ts and Blues" - a street drug combination

---

SECTION 4: TEACH USING ANALOGIES

Imagine your body has three types of "pain dimmer switches" on the walls of your nerve cells. Morphine is a master key that reaches into all three switches but works best on the "mu switch." When it turns the mu switch off, the lights (pain signals) go dim. The more morphine, the dimmer the lights. But the same switch also controls the breathing machinery - so if you turn it off too much, the breathing machinery dims along with the pain.

A full agonist (morphine) is like pressing an elevator button all the way down to the floor you want - it goes all the way. A partial agonist (buprenorphine) is like the button that only goes halfway - no matter how hard you press it, the elevator only goes halfway. So buprenorphine can only partially activate the receptor no matter what dose you give.

Naloxone is like a security guard who grabs a fake key (morphine) and pulls it out of the lock, then stands in the doorway so nothing else can get in. The receptor is now blocked but not activated.

Meperidine is like a nice employee who does their job (pain relief), but secretly has an evil twin brother (normeperidine) who is always born in the liver and has completely opposite behavior - instead of quieting things down, the evil twin causes seizures and excitation.

Codeine is like an encrypted message. When you give it to the body, the liver needs to DECODE it (using CYP2D6) to get the actual message (morphine). If you don't have the right decoder (poor metabolizer), the message never gets read. If your decoder works too fast (ultra-rapid metabolizer), too many messages flood the system at once.

Imagine a nightclub with opioid receptors as speakers. When morphine arrives (loud music), the bouncers at first are excited. But if you play the same loud music every night for weeks, the bouncers start wearing earplugs (receptors desensitize), removing speakers (receptor downregulation), and the same music no longer sounds as loud. You need louder music (higher dose) to get the same effect. That's tolerance.

M6G is morphine's hardworking child - even more potent than the parent. M3G is morphine's troublesome sibling - no pain relief, but causes agitation and makes you more sensitive to pain (antianalgesic). In renal failure, both children accumulate - the good (M6G → excess sedation/respiratory depression) and the bad (M3G → neuroexcitation).

---

SECTION 5: STEP-BY-STEP CLINICAL REASONING

Case 1: Post-Operative Severe Pain

• Acute, nociceptive (tissue damage from surgery)
• Short-term requirement
• Need for reliable, fast-acting relief

• IV morphine or IV fentanyl are first-line for severe acute surgical pain
• Both are full μ agonists
• IV route gives immediate, reliable effect (bypasses first-pass metabolism, reliably absorbed)

• IV morphine: Well-established, cheap, longer duration (3-4h), good for moderate-severe pain
• IV fentanyl: Faster onset (1-2 min), shorter duration, no histamine release (better if patient has asthma), no active metabolites (better if patient has renal issues)
• For this patient with no co-morbidities: Morphine 2-5 mg IV, titrated to effect, is appropriate

• If patient has COPD or obstructive sleep apnea → minimize dose, monitor closely; fentanyl's shorter duration may be safer
• If patient has renal failure → avoid morphine (M6G accumulates) → use fentanyl or hydromorphone instead
• If patient has allergy to morphine → fentanyl or hydromorphone
• If patient has biliary surgery → pethidine might be preferred (no sphincter of Oddi spasm)

• Respiratory depression → monitor respiratory rate and SpO₂, have naloxone ready
• Nausea → prescribe antiemetic (ondansetron or metoclopramide)
• Constipation → prescribe senna or lactulose from day 1
• Urinary retention → monitor urine output; catheter if needed
• Over-sedation → regular sedation scoring

---

Case 2: Opioid Overdose in the Emergency Department

1. Coma / unconsciousness (CNS depression)
2. Respiratory depression (rate < 12/min, shallow breathing)
3. Miosis (pinpoint pupils)

• Airway first: Jaw thrust, chin lift, bag-valve-mask ventilation if needed
• Naloxone 0.4-2 mg IV - titrate carefully (don't want to precipitate severe withdrawal in a dependent patient)
• If no IV access: Intranasal naloxone 4 mg (Narcan nasal spray)
• Repeat every 2-3 minutes if no response (up to 10 mg)

• Set up a naloxone INFUSION (2/3 of the effective reversal dose per hour)
• Patient needs at least 12-24 hours monitoring in hospital

• Much harder to reverse - buprenorphine's very high affinity means standard doses of naloxone are insufficient
• Need very high doses of naloxone (up to 10-20 mg) over hours
• Respiratory support (mechanical ventilation) may be needed

• You have precipitated acute opioid withdrawal
• The patient was likely opioid dependent
• Withdrawal itself is NOT immediately life-threatening (unlike alcohol withdrawal)
• Manage symptomatically: clonidine (for sympathetic hyperactivity), antiemetics, antidiarrheals

---

Case 3: Cancer Patient with Chronic Severe Pain

• YES - high-dose opioids paradoxically INCREASE pain sensitivity over time
• Mechanism: NMDA receptor activation, central sensitization, accumulation of M3G (morphine's antianalgesic metabolite)
• The drug that was supposed to reduce pain is now worsening it

• Opioid rotation - switch to a different opioid (this often resolves OIH)
• Consider methadone - its NMDA antagonism helps with hyperalgesia AND neuropathic components
• Consider buprenorphine - partial agonism may reset the system

STEP 1: Mild pain → Non-opioids (paracetamol, NSAIDs)
STEP 2: Moderate pain → Weak opioids (codeine, tramadol) ± non-opioids
STEP 3: Severe pain → Strong opioids (morphine, fentanyl, oxycodone) ± non-opioids

---

SECTION 6: MEMORY TOOLS

Mnemonic 1: OPIOID ADVERSE EFFECTS - "RCCM-PLUS"

---

Mnemonic 2: OPIOID OVERDOSE TRIAD - "CMR"

---

Mnemonic 3: MORPHINE METABOLITES

---

Mnemonic 4: MEPERIDINE - "MEPERIDINE HAS A CATCH"

---

Mnemonic 5: Opioid Receptors - "MKD-SAD"

---

Drug Comparison Table

---

WHO Pain Ladder - Visual

       ↑ PAIN SEVERITY
       │
STEP 3 │  STRONG OPIOIDS (morphine, fentanyl, oxycodone)
       │  ± non-opioids ± adjuvants
       │
STEP 2 │  WEAK OPIOIDS (codeine, tramadol)
       │  ± non-opioids ± adjuvants
       │
STEP 1 │  NON-OPIOIDS (paracetamol, NSAIDs, aspirin)
       │  ± adjuvants
       └────────────────────────────────────────────>

---

SECTION 7: EXAMINER'S CORNER

Most Tested Facts in MBBS Examinations

1. Morphine's active metabolites: M6G (analgesic, accumulates in renal failure) and M3G (neuroexcitatory, no analgesia)
2. Meperidine's toxic metabolite: Normeperidine → seizures
3. Meperidine + MAO inhibitors = DEADLY (serotonin syndrome)
4. Drug of choice for biliary colic: Meperidine (pethidine) - because it does NOT cause sphincter of Oddi spasm
5. Drug of choice for opioid overdose: Naloxone
6. Buprenorphine ceiling effect: Ceiling on respiratory depression, makes it safer
7. Codeine is a prodrug: Converted to morphine by CYP2D6
8. Fentanyl potency: 100x more potent than morphine
9. Methadone special properties: NMDA antagonist + QT prolongation
10. Tolerance does NOT develop to: Miosis and constipation
11. Opioid overdose classic triad: Coma + miosis + respiratory depression
12. Naloxone duration is SHORTER than most opioids → re-dosing often needed

---

Most Likely Essay Questions

1. "Describe the pharmacology of morphine with special reference to its mechanism of action, pharmacokinetics, adverse effects, and therapeutic uses."
2. "What is tolerance? Describe the mechanism of opioid tolerance and physical dependence. How is opioid withdrawal managed?"
3. "Classify opioid analgesics. Compare and contrast the pharmacology of morphine, pethidine (meperidine), and fentanyl."
4. "Describe the pharmacological basis of treating opioid overdose. What are the complications of naloxone administration?"
5. "Write short notes on: Buprenorphine in opioid use disorder / Methadone's special pharmacological properties / Opioid rotation."

---

Most Likely Viva Questions

• "What is the antidote for morphine poisoning? Why must you keep the patient for 24 hours even after they respond to naloxone?"
• "Why is pethidine preferred over morphine in biliary colic?"
• "Why does tolerance develop to morphine's analgesic effects but not to constipation?"
• "What are the active metabolites of morphine? What happens in renal failure?"
• "What is physical dependence? Is it the same as addiction?"
• "Explain the mechanism of respiratory depression by opioids."
• "What is opioid-induced hyperalgesia?"
• "Why is buprenorphine used in addiction treatment?"
• "What is the Suboxone formulation and what is the rationale for combining buprenorphine with naloxone?"

---

Most Likely MCQs (with answers)

---

Common Examination Traps

1. Trap: "Morphine is the drug of choice for ALL pain." Reality: Morphine is contraindicated in biliary colic (use meperidine), head injury, bronchial asthma, renal failure (M6G accumulates), and labor (fetal respiratory depression).
2. Trap: "Naloxone can be given orally." Reality: Naloxone has extensive first-pass metabolism → almost no systemic effect when swallowed. Only when injected does it work systemically. (Exception: the Targinact formulation where local gut effect is the intended action.)
3. Trap: "Tolerance develops to all opioid effects." Reality: Tolerance does NOT develop to miosis or constipation. These remain throughout treatment.
4. Trap: "Buprenorphine is less effective than morphine because it is a partial agonist." Reality: In practice, buprenorphine can provide excellent analgesia for moderate-to-severe pain. Its partial agonism is a safety feature, not a weakness.
5. Trap: "All opioids release histamine." Reality: Fentanyl, alfentanil, remifentanil, sufentanil do NOT cause histamine release. Morphine and meperidine do.
6. Trap: "Meperidine is the drug of choice for chronic pain." Reality: Meperidine is NOT suitable for chronic use. Normeperidine accumulates → neurotoxicity. Meperidine is for short-term acute pain only.
7. Trap: "Starting a patient on a fentanyl patch is appropriate for new opioid users." Reality: Fentanyl patches are only for opioid-TOLERANT patients. Using in opioid-naïve patients can cause fatal respiratory depression.

---

SECTION 8: TOLERANCE, DEPENDENCE, AND OPIOID USE DISORDER

Definitions (Know the Difference)

Why Tolerance Develops (Mechanism)

Repeated opioid receptor activation
              ↓
G-protein-coupled receptor kinase (GRK) phosphorylates receptor
              ↓
β-arrestin recruited → uncouples G-protein from receptor
              ↓
Receptor internalized (removed from cell surface) = downregulation
              ↓
Fewer functional receptors available
              ↓
Same dose → less effect → need higher dose = TOLERANCE

• cAMP pathway adapts (superactivation of adenylyl cyclase - this is also responsible for withdrawal symptoms when drug is stopped)
• NMDA receptor upregulation (counteracts opioid inhibitory effects)
• Changes in gene expression

Opioid Withdrawal Syndrome

• Short-acting opioids (heroin, morphine): Begins 8-24 hours after last dose; peaks 36-72 hours; resolves 5-7 days
• Long-acting opioids (methadone): Begins 36-48 hours; peaks 72 hours; may last weeks

Management of Opioid Withdrawal

1. Methadone maintenance: Replace short-acting opioid with long-acting oral methadone; gradual dose tapering
2. Buprenorphine/naloxone: Effective at reducing withdrawal and cravings; started when patient is in mild-moderate withdrawal (COWS score)
3. Clonidine: Alpha-2 agonist → reduces sympathetic hyperactivity (tachycardia, sweating, anxiety, diarrhea) - does NOT reduce craving or opioid-specific symptoms fully
4. Symptomatic treatment: Antidiarrheals, antiemetics, NSAIDs for muscle pain, benzodiazepines for sleep

---

SECTION 9: HIGH-YIELD REVISION SHEET

ONE-PAGE EMERGENCY REVIEW

• μ (mu) = Morphine's main receptor → analgesia + ALL major side effects
• κ (kappa) = Dysphoria, sedation, hallucinations (pentazocine acts here)
• δ (delta) = Modulation, enkephalins

• Gold standard full μ agonist
• Low oral bioavailability (first-pass)
• Metabolites: M6G (active, analgesic) → accumulates in RENAL FAILURE; M3G (no analgesia, neuroexcitation)
• NEVER use in: Head injury, asthma, biliary colic, renal failure, labor

• Preferred: Biliary colic, pancreatitis (no sphincter of Oddi spasm)
• AVOID: Renal failure, epilepsy, chronic use
• DEADLY: + MAO inhibitors (serotonin syndrome)
• Toxic metabolite: Normeperidine → SEIZURES

• Develops to: Analgesia, euphoria, sedation, respiratory depression, emesis
• DOES NOT DEVELOP to: Constipation, miosis

---

SECTION 10: SELF-ASSESSMENT

---

---

---

---

1. Highly variable and prolonged half-life (15-60 hours, sometimes up to 120 hours) - allows once-daily dosing but makes titration complex and risky.
2. NMDA receptor antagonism in addition to μ agonism - this counteracts opioid tolerance and makes it effective for neuropathic pain.
3. No active metabolites - safer than morphine in renal impairment.
4. QT interval prolongation - blocks cardiac hERG potassium channels, risk of torsades de pointes, requires ECG monitoring.
5. High oral bioavailability (~80%) - excellent oral absorption, unlike morphine.
6. Used in opioid addiction maintenance - once daily oral dosing, prevents withdrawal and blocks opioid "high" if other opioids are used concurrently.
7. Effective for opioid-induced hyperalgesia - NMDA antagonism reduces central sensitization.

---

1. Neuromuscular abnormalities: Myoclonus, hyperreflexia, incoordination, clonus (especially ankle clonus), tremors
2. Autonomic instability: Tachycardia, hypertension, hyperthermia, diaphoresis, diarrhea
3. Mental status changes: Agitation, confusion, restlessness

---

---

• Reduces the sensitivity of the medullary respiratory center to rising CO₂ levels (normally CO₂ drives breathing; opioids blunt this response)
• Reduces hypoxic drive
• Causes a decrease in respiratory rate and tidal volume
• Can cause apnea at high doses

---

---

• Increase the buprenorphine dose (it still provides some analgesia as a partial agonist)
• Transition off buprenorphine to a full agonist before elective surgery
• Use non-opioid analgesics adjunctively

---

• Euphoria, elevated mood, talkativeness, flushed face, restlessness
• Hallucinations and mania in some cases; convulsions in children/neonates
• May be absent if a very large dose is taken (goes directly to stage 2)

• Drowsiness, giddiness, headache, nausea, vomiting
• Pruritus (histamine release)
• Pupils contracted (miosis), conjunctival congestion, cyanosis of face/lips
• Pulse and BP initially normal

• Unconsciousness, unresponsiveness
• Pinpoint pupils (diagnostic sign)
• Declining BP, feeble pulse
• Cold, clammy skin, facial pallor
• Flaccid muscles
• Death from respiratory failure (medullary respiratory center depression)

1. Airway, Breathing, Circulation (ABC) - maintain ventilation with bag-mask or intubation
2. Specific antidote: Naloxone 0.4-2 mg IV repeated every 2-3 min as needed; set up infusion
3. Activated charcoal if oral ingestion and patient is awake/airway protected
4. Gastric lavage if within 1-2 hours of oral ingestion (protect airway first)
5. Supportive care: IV fluids, treatment of hypotension
6. Monitor for at least 4-6 hours after apparent recovery
7. Marquis test (forensic): morphine + reagent (formaldehyde + H₂SO₄) → purple-red color

---

---

What This Note Covers

• Morphine (prototype, M6G/M3G metabolites)
• Codeine (prodrug, CYP2D6 genetics)
• Fentanyl (100x morphine, transdermal patch)
• Meperidine (biliary colic, normeperidine seizures, MAO inhibitor danger)
• Methadone (NMDA antagonism, QT, addiction treatment)
• Buprenorphine (partial agonist, ceiling effect, Suboxone)
• Tramadol (dual mechanism, serotonin syndrome risk)
• Naloxone/Naltrexone (antagonists, overdose reversal, addiction treatment)
• Pentazocine (mixed agonist/antagonist)