Tramadol

# 1) Receptor-level action → clinical effects

**Primary (dual mechanism):**

* **Weak μ-opioid receptor agonist.** Parent drug = weak; **O-desmethyltramadol (M1)** (via **CYP2D6**) = much **stronger μ agonist** → main opioid effect.

* **Monoamine reuptake inhibition (SNRI):** inhibits **serotonin (5-HT)** and **noradrenaline** reuptake in the dorsal horn → descending inhibitory pain pathway activation.

**Other effects / receptors (minor):**

* Very weak **NMDA modulation** described; not clinically dominant.

**Clinical effects from the above:**

* **Analgesia** (moderate) with **opioid-sparing** properties.

* **Less respiratory depression** than pure μ-agonists at usual doses—but still possible (esp. ultrarapid CYP2D6 metabolisers or with other sedatives).

* **Seizure threshold lowered** (monoaminergic component).

* **Serotonergic effects** → risk of **serotonin syndrome** with SSRIs/SNRIs/MAOIs/linezolid/triptans.

* **Nausea, dizziness**, sweating; **less constipation** than morphine but still present.

---

# 2) Vial strength, preparation & basic pharmacokinetics (+ disadvantages)

**Forms:**

* **IV/IM**: 50 mg/mL (1 mL amp).

* **PO**: 50 mg immediate-release (IR); 100/150/200 mg extended-release (ER).

**PK (adult):**

* **Onset:** PO 30–60 min (peak 2–3 h); IV 5–10 min.

* **Duration:** ~6 h (IR).

* **Metabolism:** hepatic **CYP2D6 → M1 (active)**; **CYP3A4/2B6** → N-desmethyl (inactive).

* **Elimination:** renal (parent + metabolites).

* **Half-life:** parent ~6 h; **M1 ~7–9 h** (prolonged in renal impairment).

**Disadvantages from PK/PD:**

* **High inter-patient variability** (CYP2D6 phenotype).

* **Seizure risk**, **serotonin toxicity** potential.

* Accumulates in **renal**/severe **hepatic** impairment → prolonged sedation, respiratory depression.

* **Not reliable** for severe acute pain; ceiling effect.

---

# 3) Practical dosing

## A. Peri-operative / ward analgesia (adult)

* **PO IR:** **50–100 mg** q6h PRN (usual max **400 mg/day**).

* **PO ER:** **100 mg once daily**, titrate by 100 mg every 3–7 days to **200–300 mg/day** (follow local max).

* **IV:** **50–100 mg** slow IV over ≥2–3 min, q6h PRN (avoid rapid pushes).

* **Post-anaesthetic shivering (alternative to pethidine):** **0.5–1 mg/kg IV** slowly (common practice).

## B. ICU

* **Not a first-line ICU analgesic** (variable effect, interactions).

* Consider **enteral tramadol** for step-down analgesia when extubating or reducing strong opioids: **50–100 mg PO q6–8h** (reduce in renal/hepatic impairment).

* **Avoid continuous IV infusions.**

---

# 4) Special populations — dosing cautions

### Pregnancy

* Short courses may be used if benefits outweigh risks. **Chronic use** near term → neonatal respiratory depression/withdrawal. Prefer alternatives where possible.

### Lactation

* **Avoid**: risk of neonatal sedation/apnoea—especially if mother is a **CYP2D6 ultrarapid metaboliser** (higher M1 in milk).

### Hepatic impairment

* **Reduce dose/extend interval.** Severe hepatic failure: **50 mg PO/IV q12h** (or avoid); ER not recommended.

### Renal impairment

* **CrCl <30 mL/min:** **50–100 mg q12h**; **max 200 mg/day**. Avoid ER formulations. Monitor for accumulation.

### Obesity

* Dose clinically (no clear TBW scaling benefit). Start low; titrate to effect (sedation risk with co-depressants).

### Paediatrics

* **Contraindicated <12 years.**

* **Avoid 12–18 years** after **tonsillectomy/adenoidectomy** or in **OSA/obesity** (ultrarapid CYP2D6 → life-threatening respiratory depression).

* If used where allowed: specialist dosing only, with close monitoring.

---

# 5) Drug interactions (clinically key)

* **Serotonergic agents** (**SSRIs/SNRIs/TCAs/MAOIs/linezolid/methylene blue/triptans**): ↑ **serotonin syndrome** risk → agitation, clonus, hyperreflexia, hyperthermia; **avoid MAOIs within 14 days**.

* **CYP2D6 inhibitors** (fluoxetine, paroxetine, bupropion, quinidine, duloxetine): ↓ M1 formation → **less analgesia** but **more serotonergic AEs**.

* **CYP3A4 inhibitors/inducers** (azoles, macrolides, protease inhibitors, rifampicin, carbamazepine): alter tramadol levels → monitor/titrate.

* **Seizure threshold-lowering drugs** (bupropion, clozapine, tramadol itself, TCAs): additive **seizure risk**.

* **CNS depressants** (benzos, opioids, alcohol, propofol): additive sedation/respiratory depression.

---

# 6) Significant complications & management

| Complication                   | Mechanism / Features                                                         | What to do                                                                                                             |

| ------------------------------ | ---------------------------------------------------------------------------- | ---------------------------------------------------------------------------------------------------------------------- |

| **Serotonin syndrome**         | SNRI effect + serotonergic co-meds                                           | Stop serotonergic agents, supportive care, **benzodiazepines**, active cooling; **cyproheptadine** if moderate–severe. |

| **Seizures**                   | Lowers threshold; higher risk with high doses/renal failure/CYP interactions | Airway, **benzodiazepine** IV, correct electrolytes; avoid further tramadol.                                           |

| **Respiratory depression**     | μ-agonism (notable in ultrarapid CYP2D6, co-depressants)                     | Airway/ventilation; **naloxone** titration (small increments; risk of precipitating pain/sympathetic surge).           |

| **Hypoglycaemia (rare)**       | Proposed insulin modulation                                                  | Monitor glucose in unexplained diaphoresis/confusion.                                                                  |

| **Hyponatraemia/SIADH (rare)** | Serotonergic effect                                                          | Check Na⁺ if confusion/seizure; fluid management per SIADH.                                                            |

| **Nausea, dizziness**          | Central effects                                                              | Ondansetron/metoclopramide; slow position changes.                                                                     |

---

## Pocket viva line

*Tramadol provides **dual-mechanism** analgesia (weak **μ-agonist** + **SNRI**). It has **variable efficacy** (CYP2D6 dependent), **less respiratory depression** than strong opioids at modest doses, but carries **seizure** and **serotonin-syndrome** risks and **accumulates** in renal/hepatic impairment. Typical adult dosing: **50–100 mg PO/IV q6h** (max **400 mg/day**; reduce to **200 mg/day** if **CrCl <30**).*

Remifentanil

1) Receptor-level action → clinical effects

Primary:

μ-opioid receptor full agonist, ultra–short acting.

Same receptor subtype profile as fentanyl 

(μ₁ → analgesia, μ₂ → respiratory depression, bradycardia, rigidity).

Unique feature:

Rapid hydrolysis by non-specific plasma and tissue esterases. 

Hence, independent of liver or renal function → predictable and context-insensitive offset.

Other receptor effects (minor):

* Weak δ and κ agonism (minimal clinical effect).

* No histamine release → stable haemodynamics.

Clinical effects derived from above

* CNS: profound, titratable analgesia and hypnosis supplement; rapid recovery after discontinuation.

* CVS: dose-dependent bradycardia and hypotension (from vagal tone and reduced sympathetic drive).

* Respiratory: potent depression and apnoea at high doses.

* No residual analgesia after infusion stops → requires overlap with longer-acting analgesic.

* No histamine release or direct myocardial depression — excellent for cardiac surgery and TIVA.

---

2) Vial strength, preparation & basic pharmacokinetics (+ disadvantages)

Formulation

* Powder vials 1 mg, 2 mg, or 5 mg; reconstitute with saline → 50 mcg/mL or 20–25 mcg/mL for infusion.

Pharmacokinetics

* Onset:30–60 seconds.

* Peak effect: 1–2 minutes.

* Steady state: within 3–5 minutes of infusion start.

* Context-sensitive half-time: ~3–5 minutes regardless of infusion duration (key advantage).

* Metabolism: by non-specific esterases in blood & tissues (not pseudocholinesterase).

* Elimination: inactive remifentanil acid via urine.

Disadvantages:

1. No residual analgesia → abrupt pain surge if not bridged.

2. Rigidity and bradycardia if bolused rapidly.

3. Costly compared to other opioids.

4. Requires continuous infusion for effect.

---

3) Practical dosing

A. Anaesthesia (cardiac / general)

Induction & maintenance

* Bolus:

- avoid rapid large boluses;

- if required, ≤ 0.5–1 mcg/kg slowly over 60–90 s.

* Infusion:

- Induction: 0.5–1 mcg/kg/min for intubation (combined with hypnotic).

- Maintenance: 0.05–2 mcg/kg/min

- (typical 0.1–0.3 mcg/kg/min in cardiac surgery).

- Titrate to surgical stimulus; taper before end to prevent abrupt awakening pain.

**TIVA protocols:

- Commonly combined with propofol 50–150 mcg/kg/min, producing smooth, titratable anaesthesia.

- For off-pump CABG or minimally invasive cardiac surgery: start low (0.05–0.15 mcg/kg/min) and titrate to haemodynamic response.

**Extubation or emergence:

- Gradually wean over 10–15 min while introducing morphine/fentanyl for postoperative analgesia.

---

B. ICU Analgosedation

Indications:

short-term analgesia during ventilator support when rapid offset needed (e.g., after cardiac surgery).

* Loading dose:

avoid bolus; start infusion directly.

* Infusion:

0.05–0.2 mcg/kg/min (3–12 mcg/kg/h).

* For longer sedation (>24 h): taper slowly to avoid withdrawal and bridge with longer opioid.

* Contraindicated for prolonged sedation (>48–72 h) due to tolerance and hyperalgesia risk.

---

4) Special populations — dosing cautions

Pregnancy

* Crosses placenta → neonatal respiratory depression; not preferred for labour analgesia.

* Acceptable for induction in cardiac/obstetric anaesthesia if benefit outweighs risk (short half-life useful).

Lactation

* Negligible transfer; safe for short procedures.

Hepatic impairment

* No adjustment needed — metabolism independent of liver function.

Renal impairment

* No adjustment needed— inactive metabolite, rapid clearance. Ideal in renal failure.

Obesity

* Dose by Ideal or Adjusted Body Weight (not Total BW); avoid overshoot due to high potency.

Paediatrics

* Bolus:0.5–1 mcg/kg IV slowly.

* Infusion: 0.05–0.3 mcg/kg/min.

* Neonates: higher clearance variability; titrate carefully.

---

5) Drug interactions (clinically key)

1. CNS depressants 

(propofol, volatile agents, benzos): synergistic → reduce doses of both.

2. Neuromuscular blockers:

may mask chest wall rigidity; slow titration preferred.

3. β-blockers / calcium channel blockers:

additive bradycardia & hypotension → start low, titrate cautiously.

4. MAOIs / SSRIs:

rare serotonin toxicity risk.

5. Nitrous oxide / volatiles:

potentiate analgesia; lower infusion requirement.

---

6) Significant complications & management

1. Respiratory depression / apnoea

- Due to Potent μ₂ effect; rapid onset

🟢 Airway/ventilation support;

🟢 titrate down; 

🟢 naloxone (40–80 mcg IV q2 min)

2. Bradycardia / asystole

- Due to High vagal tone, esp. in β-blocked cardiac patients 

🟢 Atropine 0.3–0.6 mg IV or glycopyrrolate; 

🟢 small adrenaline if severe.

3. Chest wall rigidity

- Due to Rapid bolus

🟢 Prevent by slow administration or pre-muscle relaxant.

4. Acute tolerance / hyperalgesia

- Due to NMDA activation with prolonged infusion

🟢 Taper gradually, 

🟢 co-administer low-dose ketamine or morphine transition.

5. Rebound pain on cessation 

- No residual effect

                  

🟢 Overlap with longer-acting opioid 20–30 min before stopping. 

---

Pocket viva line

Remifentanil is an ultra–short acting μ-opioid agonist metabolised by non-specific esterases, giving a context-insensitive half-life (~3–5 min).

It provides intense, titratable analgesia with rapid recovery, minimal accumulation, and is ideal for cardiac anaesthesia and short ICU sedation.

Induction 0.5–1 mcg/kg/min; maintenance 0.05–0.3 mcg/kg/min; ICU 0.05–0.2 mcg/kg/min. 

Must bridge with a longer opioid before stopping.

Fentanyl

1) Receptor-level action → clinical effects

Primary:

μ-opioid receptor full agonist (synthetic phenylpiperidine derivative).

High affinity for μ₁ (analgesia, euphoria, respiratory depression) 

μ₂(respiratory depression, constipation, bradycardia).

Minimal κ-activity (less dysphoria than morphine).

Potency: ~100× morphine.

Other receptor effects (minor):

1. Inhibits substance P release in dorsal horn → spinal analgesia.

2. No histamine release → haemodynamic stability.

3. Mild vagal stimulation → bradycardia.

Clinical effects derived from above:

* CNS: profound analgesia, sedation, blunted stress response.

* CVS: Stable MAP (no histamine vasodilation) but bradycardia from vagal tone; minimal myocardial depression — ideal for cardiac surgery.

* Respiratory: potent dose-dependent depression and chest wall rigidity with rapid large doses.

* GI: constipation, nausea, decreased motility.

* Pupil: miosis.

* No amnesia — combine with hypnotic.

---

2) Vial strength, preparation & basic pharmacokinetics (+ disadvantages)

Vials/amps: 

50 mcg/mL (2 mL, 10 mL) common; 2500 mcg/50 mL for infusion (50 mcg/mL).

Pharmacokinetics

* Onset: 1–2 min (very lipid-soluble, rapid BBB entry).

* Peak: 3–5 min.

* Duration: 30–60 min after bolus (redistribution).

* Metabolism: hepatic CYP3A4 N-dealkylation → inactive norfentanyl.

* Elimination: renal excretion of metabolites; elimination t½ = 3–4 h.

* Context-sensitive t½: short initially but lengthens steeply with prolonged infusion (hours → days).

Disadvantages

1. Accumulation with prolonged infusions → delayed awakening.

2. Chest wall rigidity with large rapid IV doses.

3. Requires ventilatory support in almost all anaesthetic doses.

4. No amnesia → needs hypnotic/benzodiazepine adjunct.

---

3) Practical dosing

A. Anaesthesia (Cardiac / General)

* Premedication: 

25–100 mcg IV (analgesia, blunting laryngoscopy).

* Induction (cardiac):

 5–20 mcg/kg IV (often 5–10 mcg/kg; up to 30–50 mcg/kg in classical “high-dose opioid” cardiac technique).

* Maintenance:

1–5 mcg/kg IV boluses or infusion 1–5 mcg/kg/h titrated to surgical stimulation.

* Combine with benzodiazepine or propofol for hypnosis.

B. ICU / Analgosedation

Indications: 

ventilated patient analgesia, adjunct to sedation, haemodynamically unstable or renally impaired patients (preferred over morphine).

* Bolus:

25–100 mcg IV q30 min PRN.

* Infusion:

1–2 mcg/kg/h (range 0.5–5 mcg/kg/h).

* In renal failure: safe—no active metabolites.

* Convert to intermittent boluses or enteral opioid once stable.

---

4) Special populations — dosing cautions

Pregnancy

* Crosses placenta → neonatal respiratory depression after maternal dosing near delivery.

* Acceptable for cardiac/obstetric anaesthesia when benefit outweighs risk; ensure neonatal resuscitation readiness.

Lactation

* Excreted in breast milk in small amounts; short-term peri-operative use acceptable; monitor infant for sedation/apnoea.

Hepatic impairment

* Metabolised hepatically → reduce dose and titrate slowly.

* Prolonged effect possible in severe liver failure.

Renal impairment

* No active metabolites; safe choice in renal dysfunction (unlike morphine).

* May still accumulate with prolonged high-dose infusion—titrate by effect.

Obesity

* Highly lipophilic → rapid redistribution into fat → accumulation.

* Bolus dose on Lean/Adjusted BW, infusion titrated to effect.

Paediatrics

* Premed:

1–2 mcg/kg IV/IM.

* Induction:

2–10 mcg/kg IV.

* Maintenance:

1–5 mcg/kg/h.

* Neonates/infants: longer elimination t½ → lower maintenance rates.

--

5) Drug interactions (clinically key)

1. CNS depressants

(propofol, benzos, volatiles): additive respiratory/CVS depression → titrate carefully.

2. MAOIs / SSRIs / SNRIs / TCAs:

theoretical serotonin syndrome risk (rare).

3. CYP3A4 inhibitors

(azole antifungals, macrolides, protease inhibitors, diltiazem/verapamil, grapefruit): ↓ clearance → prolonged/apnoea.

4. CYP3A4 inducers

(rifampicin, phenytoin, carbamazepine): ↑ clearance → shorter duration.

5. Muscle relaxants:

additive chest rigidity; avoid rapid co-administration without neuromuscular blocker ready.

---

6) Significant complications & management

1. Respiratory depression / apnoea

- Due to brainstem μ₂ depression 

* Support airway,

* ventilation, 

* naloxone 40–80 mcg IV q2 min; may need infusion (≈ 60 % of total reversal dose / h). 

2. Chest wall rigidity

- Due to central dopamine-dependent μ effect after rapid large dose

* Prevent with slow injection or give muscle relaxant; 

* if it occurs, suxamethonium 1 mg/kg or naloxone.

3. Bradycardia

- Due to vagal stimulation

* Atropine 0.3–0.6 mg IV or glycopyrrolate; 

*if severe, small epinephrine bolus.            

                         

4. Nausea / vomiting     

       

- Due to CTZ stimulation                                            

* Ondansetron/metoclopramide.                                                                                           

5. Tolerance & dependence

- Due to chronic use.

* Gradual wean; 

* multimodal analgesia. 

.                                                                              

---

Pocket viva line

Fentanyl is a potent μ-opioid agonist (~100× morphine) providing rapid, haemodynamically stable analgesia ideal for cardiac anaesthesia. 

It causes dose-dependent respiratory depression, bradycardia, and chest wall rigidity with large rapid doses.

Induction 5–20 mcg/kg IV; ICU infusion 1–2 mcg/kg/h; safe in renal failure but accumulates with prolonged use.

Morphine

# 1) Receptor-level action → clinical effects

**Primary:** **μ-opioid receptor agonist** (full agonist)

* Acts on **μ₁** → analgesia, euphoria, respiratory depression

* **μ₂** → respiratory depression, constipation, bradycardia, physical dependence

* **κ-receptor:** weak agonism → some spinal analgesia, dysphoria

* **δ-receptor:** minor contribution to analgesia, tolerance

**Other sites of action:**

* **Brainstem respiratory centre:** ↓ CO₂ responsiveness → respiratory depression

* **Medullary cough centre:** suppression → antitussive

* **GI μ-receptors:** ↓ peristalsis + ↑ sphincter tone → constipation, biliary colic

* **Vagal nuclei / histamine release:** bradycardia + hypotension

* **Pupil:** parasympathetic stimulation → miosis (“pin-point pupils”)

**Clinical effects from above**

* Profound **analgesia & sedation**, **euphoria**, **respiratory depression**, **miosis**, **constipation**, **urinary retention**, **pruritus**, **nausea/vomiting** (via CTZ stimulation), **histamine-induced hypotension**, **tolerance & dependence** with chronic exposure.

---

# 2) Vial strength, preparation & basic pharmacokinetics (+ disadvantages)

**Vials/amps:** 10 mg/mL (1 mL amp), occasionally 15 mg/mL or 30 mg/mL; dilute to convenient concentration for infusion (e.g. 50 mg in 50 mL = 1 mg/mL).

**PK**

* **Onset:** 2–5 min IV  (peak ≈ 20 min) **Duration:** 3–4 h (analgesia)

* **Distribution:** large Vd, crosses BBB slowly (slower onset vs fentanyl)

* **Metabolism:** hepatic glucuronidation → **M3G** (inactive + neuro-excitant) & **M6G** (active, potent analgesic)

* **Elimination:** renal (major), biliary (minor) t½ ≈ 2 – 4 h (prolonged in renal failure)

**Disadvantages**

* **Slow onset/offset**, **histamine-mediated hypotension**, **accumulation** in renal failure (M6G) → delayed respiratory depression, **nausea/pruritus**, **constipation**.

---

# 3) Practical dosing

## A. Anaesthesia / Peri-operative

* **Premed / analgesic supplement:** 2–5 mg IV slowly (0.05–0.1 mg/kg).

* **Induction adjunct:** 0.1–0.2 mg/kg IV (rare now; use fentanyl/remifentanil instead for cardiac cases).

* **Epidural/Intrathecal:** preservative-free morphine (0.1–0.2 mg intrathecal or 2–5 mg epidural).

## B. ICU (analgesia ± sedation)

**Indications:** long-acting analgesia in intubated or post-cardiac-surgery patients when renal function normal and haemodynamics stable.

* **Bolus:** 1–4 mg IV q5–10 min to effect.

* **Infusion:** **0.5–2 mg/h** (≈ 7–30 mcg/kg/h), titrate to comfort/vent synchrony.

* Convert to enteral/PRN once stable.

* Avoid or greatly reduce if **eGFR < 30 mL/min/1.73 m²**.

**Neuraxial post-op infusions:** 0.1–0.2 mg morphine with local anaesthetic per mL in epidural at 2–6 mL/h (per local protocol).

---

# 4) Special populations — dosing cautions

### Pregnancy

* Crosses placenta → fetal/neonatal respiratory depression & withdrawal with chronic use.

* **Short-term use in labour or cardiac emergencies** acceptable under obstetric guidance.

* Avoid prolonged high-dose use before delivery.

### Lactation

* Appears in milk; after a **single low dose**, generally safe.

* **Chronic or high-dose maternal use** may sedate infant → monitor or pause breastfeeding for 24 h if multiple doses given.

### Hepatic impairment

* Metabolism slowed → longer effect; dose ↓ and interval ↑.

* In severe hepatic failure, avoid repeated high boluses.

### Renal impairment

* **Major caution.** M6G & M3G accumulate → delayed, prolonged respiratory depression or agitation/myoclonus.

* Prefer **fentanyl or remifentanil** if eGFR < 30.

* If unavoidable: halve bolus & extend interval; avoid infusion.

### Obesity

* Hydrophilic → distributes mainly in lean tissue.

* **Dose on Lean/Adjusted BW** to prevent accumulation; monitor sedation closely.

### Paediatrics

* **IV bolus:** 0.05–0.1 mg/kg q2–4 h prn.

* **IM:** 0.1–0.2 mg/kg q2–4 h prn.

* **Neonates:** start 0.025–0.05 mg/kg; immature clearance → titrate slowly.

* Avoid infusions in neonates unless strictly monitored.

---

# 5) Drug interactions (clinically key)

* **CNS depressants** (opioids, benzos, propofol, volatile agents, alcohol): synergistic → respiratory depression → use lower doses & monitor capnography.

* **MAOIs / SSRIs / TCAs:** risk of serotonin toxicity (rare) → avoid concurrent MAOIs within 14 days.

* **Antihypertensives / nitrates:** additive hypotension.

* **Anticholinergics:** enhanced constipation & urinary retention.

* **Partial agonist-antagonists** (buprenorphine, nalbuphine): may antagonise morphine analgesia.

* **Cimetidine:** ↓ hepatic clearance → ↑ levels.

---

# 6) Significant complications & management

| Complication                  | Mechanism / Notes                                                           | Management                                                                                                                       |

| ----------------------------- | --------------------------------------------------------------------------- | -------------------------------------------------------------------------------------------------------------------------------- |

| **Respiratory depression**    | ↓ brainstem CO₂ sensitivity; may appear > 2 h post-dose (esp renal failure) | Airway support, naloxone (40–80 mcg IV q2 min to effect, then infusion ~ 60% of effective bolus per h); monitor for re-sedation. |

| **Hypotension / bradycardia** | Histamine release + vagal tone                                              | Fluids, antihistamines, vasopressor if needed.                                                                                   |

| **Nausea / vomiting**         | CTZ stimulation                                                             | Ondansetron / metoclopramide.                                                                                                    |

| **Pruritus**                  | Histamine ± central effect                                                  | Antihistamines / low-dose naloxone infusion (0.25 mcg/kg/h).                                                                     |

| **Constipation**              | μ gut inhibition                                                            | Stool softeners / laxatives from day 1.                                                                                          |

| **Urinary retention**         | Sphincter ↑ tone                                                            | Bladder scan + catheter if symptomatic.                                                                                          |

| **Dependence & withdrawal**   | Chronic exposure                                                            | Taper slowly if > 5–7 days use.                                                                                                  |

---

## Pocket viva line

*Morphine is a **μ-opioid receptor agonist** providing potent analgesia and sedation but causes **respiratory depression, histamine-mediated hypotension, constipation, and metabolite accumulation** in renal failure.

IV 2–5 mg slowly or infusion 0.5–2 mg/h in ICU; avoid continuous use if eGFR < 30. Monitor for delayed respiratory depression and manage with naloxone if required.*