MORPHINE & FENTANYL

DR NIDA FATIMAJAWAHARLAL NEHRU MEDICAL

COLLEGE ALIGARH

Opioid Receptors• Mu, Delta, Kappa• All pure agonists act at Mu receptor• Opioid receptors act on –CNS: cortex, thalamus, periaquaductal

gray, spinal cord & Peripheral neurons– Inflammed tissue & Immune cells –Respiratory and GI tract

MORPHINE• Morphine - white, crystalline powder.• µ-opioid receptor agonist.

• Synonyms:• Morphine: Astramorph®, Duramorph®,

Infumorph®, Kadian®,Morphine Sulfate®, MSIR®, MS-Contin®, Oramorph SR®, Roxanol®

• Source: Morphine is a naturally occurring substance extracted from the seedpod of the poppy plant, Papavar somniferum.

• Morphine concentration in opium can range from 4-21%.

HISTORYAbout 1806, a german youth, Frederich Serturner isolated the primary active ingredient in opium.He tested the new drug on his friends at 10 times the modern recommended dose!‑Active agent was 10x more potent than opium ‑He named it morphium after morphius, the god of dreams!!!

DRUG- MORPHINE• Drug Class: Narcotic analgesic (schedule II)• prescription forms: • Injectable (0.5-25 mg/mL strength); • oral solutions (2-20 mg/mL); • immediate and controlled release tablets

and capsules (15-200 mg); and • suppositories (5-30 mg).

Pharmacokinetics• Orally -absorbed very slowly,• Extensive first pass metabolism - 20%- 40% of

bio-availability.• Duration of action – ( 3 – 6 hours)• Distribution is wide ;concentration in liver, spleen

and kidney is greater than plasma.• Morphine freely crosses placenta.• Plasma half life 3hours (1-5 hrs).• 30% is plasma protein bound

Metabolism • The primary site metabolism is liver, where

it undergoes rapid glucuronidation. • However, extrahepatic metabolism up to

30% of its total clearance.• Morphine-6-glucuronide (m6g), as potent

as morphine. M6G has a half-life of approximately 1-2 hours.

USES• Morphine is used medicinally –• Relief of moderate to severe pain in both

acute and chronic management. • pre-operative sedation and to facilitate the

induction of anesthesia.• For long-term treatment of terminally ill,

pain ridden patients

Route of Administration• Oral (capsule, syrups, tablets )• Intravenous• Intramuscular • Subcutaneous • Epidural Administration• Intrathecal administration.

Dosage • Oral: Short-acting oral dose-severe, chronic

pain in Adults: 10 to 30 mg 4 hrly. • I.M/S.C : 5 to 20 mg (usually 10 mg), 4 hrly• I.V : initial dose 4 mg to 10 mg slowly over

4-5 min 4hrly. Daily dose range 12-120mg.• Pediatric: I.V-0.025–0.1 mg/kg. S.C- 0.1-0.2mg/kg

Epidural Adult Dosage• 5 mg in lumbar region -pain relief up to 24 hrs• Incremental doses 1-2 mg. • Max 10 mg/24 hr • For continuous infusion an initial dose of 2 to 4 mg/24 hours is recommended• INTRATHECAL DOSAGE IS USUALLY

1/10 THAT OF EPIDURAL DOSAGE.

Intra-thecal Adult Dosage• A single injection of 0.2 to 1 mg pain relief

for up to 24 hours.• A constant intravenous infusion of naloxone

hydrochloride, 0.6 mg/hr, for 24 hours after intrathecal injection may be used to reduce the incidence of potential side effects.

Side effects• Miosis• Orthostatic hypotension• Respiratory depression• Pain suppression/ Pruritus• Histamine release/hormonal release• Increased intracranial tension.• Nausea • Euphoria • Sedation

Contraindications • respiratory depression, • hypersensitivity,• paralytic ileus, and delayed gastric emptying, • Obstructive airway disease, • acute hepatic disease, • MAO Inhibitor administration, • pregnancy, lactation and in children.

Interactions • Morphine will not be effective in people

taking naltrexone. • It can increase the sedative effect of alcohol,• Increase the risk of respiratory depression

when used with MAO inhibitors and cimetidine.

• It antagonises the effects of diuretics.

FENTANYL• a potent, synthetic

opioid analgesic with a rapid onset and short duration of action.

• a strong agonist at the μ-opioid receptors.

HISTORY• Fentanyl first synthesized by Paul Janssen in

1960 by assaying analogues of the structurally related drug pethidine for opioid activity.

• Historically, used to treat breakthrough pain and is commonly used in pre-procedures as a pain reliever as well as an anesthetic in combination with a benzodiazepine.

• In the mid-1990s, fentanyl was first introduced for widespread palliative use with the clinical introduction of the Duragesic patch, Actiq lollipop and Fentora buccal through, sublingual spray

FentanylOnset: 1-2 minutes IV/IO

8 minutes IM Peak: 3-5 minutes IV routeLess predictable IM routeDuration:30-60 minutes IV1-2 hours IM Duration of respiratory depressant effect of fentanyl may be longer than the analgesic effect

Metabolism • Hepatic, primarily by CYP3A4 • Metabolized to 3-glucuronide metabolites–No analgesic properties–CSF doses often exceed doses of parent

compound (rats)–Cause neuroexcitation

• 6-glucuronide has analgesic properties

Medical uses• Fentanyl has a therapeutic index of 270.• Intravenous fentanyl is often used for

anesthesia(often used along with a hypnotic agent like propofol) and analgesia.

• along with local anesthetic for neuraxial administration (epidural or intrathecal or spinal).

• In combination with benzodiazepine, like midazolam, - procedural sedation for endoscopy, cardiac catheterization, oral surgery, etc.

• Management of chronic pain including cancer pain.

• In children intranasal fentanyl is useful for the treatment of moderate and severe pain.

Fentanyl patch• Takes 12 hours for onset of analgesia• Need adequate subcutaneous tissue for

absorption• Work by slowly releasing fentanyl through the

skin into the bloodstream over 48 to 72 hours.• Takes 24 hours to reach maximum effect• Suitable for stable pain only

Patches• Durogesic/duragesic/matrifen• Dosage is based on the size of the patch.• Dosage change after six days on patch• Change patch every 72 hours• Transdermal absorption rate is constant at

a constant skin temperature

Lozenges

• Fentanyl lozenges (Actiq) are a solid formulation of fentanyl citrate as lollipop that dissolves slowly in the mouth for transmucosal absorption.

• Effective in treating breakthrough cancer pain• It is most effective within 15 minutes.

• Rate of absorption depends on:1. Body temperature, 2. skin type, 3. amount of body fat, and4. placement of the patchUnder normal circumstances, the patch will

reach its full effect within 12 to 24 hours

• About 25% of the drug is absorbed through the oral mucosa, resulting in a fast onset of action, and the rest is swallowed and absorbed in the small intestine, acting more slowly.

• extensive first-pass metabolism, leading to an oral bioavailability of about 33% and 50% when used correctly (25% via the mouth mucosa and 25% via the gut).

Adverse effects• Most common side-effects (> 10% of patients).• CVS: Bradycardia, edema• CNS: depression, confusion, dizziness,

drowsiness, fatigue, headache, sedation• Endocrine & metabolic: Dehydration• Gastrointestinal: Constipation, nausea,

vomiting, xerostomia

• Local: Application-site reaction erythema • Neuromuscular & skeletal: Chest wall

rigidity (high dose I.V.), muscle rigidity, weakness

• Ocular: Miosis• Respiratory: Dyspnea, respiratory depression • Miscellaneous: Diaphoresis

• less frequent (3 to 10% of patients)• abdominal pain, headache, fatigue, • anorexia and weight loss, dizziness, • nervousness, hallucinations, anxiety,• depression, flu-like symptoms, • dyspepsia (indigestion), • dyspnea (shortness of breath), apnea,

hypoventilation, • urinary retention

• Fentanyl -associated with aphasia• fentanyl tends to induce less nausea, as well

as less histamine mediated itching, in relation to morphine.

• Fentanyl - prolonged respiratory depression than other opioid analgesics.

Dosage Surgery: • Premedication: I.M., slow I.V.: 50-100

mcg/dose (1-2mcg/kg) 30-60 minutes prior to surgery

• Adjunct to regional anesthesia: Slow I.V.: 25-100 mcg/dose (0.5-2mcg/kg) over 1-2 minutes.

Adjunct to general anesthesia: Slow I.V.:

• Low dose: 0.5-2 mcg/kg/dose depending on the indication.

• Moderate dose: Initial: 2-20 mcg/kg/dose; Maintenance (bolus or infusion): 1-2 mcg/kg/hour.

• High dose: 20-50 mcg/kg/dose.

Pain management• Adults:• I.V.Bolus:1-2 mcg/kg or 25-100µg/dose;

infusion @ 1-2 µg/kg/hour or 25-200 µg/hr .• Severe: I.M, I.V.: 50-100 µg/dose every 1-2

hours as needed.

Patient-controlled analgesia (PCA)

• Usual concentration: 10 mcg/mL • Demand dose: Usual: 20 mcg; range: 10-50

mcg • Lockout interval: 5-8 minutes • Usual basal rate: ≤50 mcg/hour

• Critically-ill patients: • Slow I.V.: 25-35 mcg or 0.35-0.5 mcg/kg

every 30-60 minutes as needed • Continuous infusion: 50-700 mcg/hour

(based on ~70 kg patient) or 0.7-10 mcg/kg/hour

Intrathecal fentanyl• Must be preservative-free. • Single dose: 5-25 mcg/dose- relief up to 6 hours.• Continuous infusion: Not recommended• For chronic cancer pain, infusion of very small

doses may be practical (American Pain Society, 2008).

Epidural fentanyl• Must be preservative-free. • Single dose: 25-100 µg/dose-relief up to 8 hrs• Continuous infusion: 25-100 mcg/hour

• Pain relief (IV) 1–2 mcg/kg• Pain relief (Intranasal) 2 mcg/kg• Premedication 10–15 mcg/kg (Actiq PO)• Anesthetic adjunct (IV) 1–5 mcg/kg• Maintenance infusion2–4 mcg/kg/h• Main anesthetic (IV) 50–100 mcg/kg

Pediatric Dosage

Opioid withdrawal

Acute action

• Analgesia• Respiratory Depression• Euphoria• Relaxation and sleep• Tranquilization• Decreased blood pressure• Constipation• Pupillary constriction• Hypothermia• Drying of secretions• Reduced sex drive• Flushed and warm skin

Withdrawal signs• Pain and irritability• Hyperventilation• Dysphoria and depression• Restlessness and insomnia• Fearfulness and hostility• Increased blood pressure• Diarrhea• Pupillary dilation• Hyperthermia• Lacrimation, runny nose• Spontaneous ejaculation• Chilliness & “gooseflesh”

Opioid Tolerant

"Opioid-tolerant" patients-who are taking at least: • Oral morphine 60 mg/day, or • Transdermal fentanyl 25 mcg/hour, or • Oral oxycodone 30 mg/day, or • Oral hydromorphone 8 mg/day, or • Oral oxymorphone 25 mg/day, or • Equianalgesic dose of any opioid for at least 1 wk

Opioid Induced Neurotoxicity

–Neuroexcitability - agitation, confusion, myoclonus, hallucinations and seizures

• Predisposing Factors:–High opioid doses & Prolonged opioid use–Recent rapid dose escalation–Dehydration & Renal failure & Advanced age–Other psychoactive drugs

Management of OIN• Rehydration• Treat concurrent causes of delirium e.g.

UTI, pneumonia• Reduce dose if pain controlled• Switch to a different opioid

• Thanks!!!