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morphine (morphine sulfate [MS], MS Contin, Roxanol, Oramorph SR, Kadian, Avinza, DepoDur, Duromorph)

Tradenames: MS Contin, Roxanol. (morphine sulfate) DEA-controlled substance: class 2 Indications: 1) treatment of mild to moderate acute & chronic pain 2) surgery - preoperative pain & postoperative pain control - cesarean section [10] 3) pulmonary edema 4) acute myocardial infarction 5) pain control & adjunct for sedation in the ICU 6) dyspnea management in palliative care 7) neonatal abstinence syndrome [10] Contraindications: - use with or within 14 days of discontinuing a monoamine oxidase inhibitor - avoid use in the setting of renal failure [8] - hydromorphone is an effective alternative [8] Dosage: - 0.1 mg/kg up to 2-4 mg increments IV. - 0.1-0.2 mg/kg up to 15 mg IM every 4 hours. - IV drip requires less morphine than IV push to achieve desired anesthesia. - stop IV infusion if urine output ceases; use IV push PRN [6] parenteral/oral potency: 3/1 [6] conversion of IV to oral morphine, use parenteral/oral potency ratio of 3/1 [6] breakthrough doses (see Immediate release below) calculate the total 24 hour oral morphine used (sustained release + immediate release) & prescribe this as sustained release for chronic pain, start with 30-50% of 24 hour morphine dose as sustained release, plus immediate release PRN for breakthrough pain [8] maximum dose 90 mg/day for chronic pain (not cancer pain) [11] Injection: 2 mg/mL, 4 mg/mL, 8 mg/mL, 10 mg/mL (1 mL) 15 mg/mL (1 mL, 20 mL), 25 mg/mL (20 mL) Injection: (preservative-free) 0.5 mg/mL, 1 mg/mL (10 mL) DepoDur: extended-release liposome epidural injection Sustained-release: MS Contin (morphine SA): 15-30 mg PO every 8-12 hours. Tabs: 15, 30 & 60 mg. Also works given rectally [7] Kadian: sustained-release form suitable for administration via G-tube Avinza: sustained-release capsule [7]; QD dosing Capsules: 30, 60, 90, 120 mg. - Do NOT crush, chew or dissolve; - potentially fatal release of morphine - may sprinkle beads on applesauce, but - do NOT chew beads Immediate release: (MS IR) - 15-30 mg PO every 4 hours PRN for breakthrough pain - breakthrough doses should be ~10% of total daily dose or 1/3-1/4 the single sustained-release dose of morphine PO - as often as hourly (GRS) [6] - every 3-4 hours (NEJM) [12] Tabs: 15 & 30 mg. Elixir: - 10-30 mg PO every 4 hours. 20 mg/mL. Tradename: Roxanol. (sublingual) Pharmacokinetics: 1) variable absorption depending upon dose & form 2) peak respiratory depression effects a) at 7 min following IV administration b) at 90 min following SC administration 3) metabolized by the liver to morphine-6-glucuronide (active) & morphine-3-glucuronide (inactive) 4) morphine glucuronides eliminated in the urine 5) accumulation of glucuronide metablites with renal failure or in elderly patients taking high doses for prolonged periods Form/route peak duration tablets/oral solution 1 h 4-5 h extended-release tablets 1 h 8-12 h suppository 10-60 min 3-7 h subcutaneous injection 50-90 min 4-5 h intramuscular injection 30-60 min 4-5 h intravenous injection 20 min 4-5 h Dosage adjustment in renal failure: - metabolized by liver, but one of two major metabolites morphine-6-glucuronide is active - a dosage of 30 mg BID with eGFR if 43 mL/min ok per VAMC pharmacy in opioid-tolerant patient - switch to hydromorphone if evidence of morphine-6-glucuronide neurotoxicity in patients with renal insufficiency Adverse effects: 1) common (> 10%) - weakness, pain at site of injection, nausea/vomiting, hypotension, dry mouth, dizziness, constipation, histamine release - if hypotension develops, administer fluids as 1st line 2) less common (1-10%) - restlessness, anorexia, headache, GI irritation, false sense of well being, visual disturbance, biliary spasm, decreased urination, trembling, paralytic ileus, confusion, shortness of breath, respiratory depression 3) uncommon (< 1%) - insomnia, ureteral spasms, muscle rigidity, depression, hallucinations, paradoxical CNS stimulation, peripheral vasodilation, pruritus, miosis, increased intracranial pressure 4) other - respiratory depression: dose & tolerance dependent - rarely occurs in patients actively in pain [8] - sedation, drowsiness improves with continued use - rash/itching (uncommon) - usually the 1st 5-7 days - due to histamine release - not considered an allergic reaction - no evidence itching improves with continued use (no reference provided) - management - diphenhydramine (Benadryl) PRN - hydroxyzine (Atarax) PRN - nausea/vomiting - usually the 1st 5-7 days, susequently tolerance develops - due to CTZ stimulation or vestibular toxicity - management - prochlorperazine (Compazine) for CTZ stimulation - meclizine for vestibular toxicity - tolerance & dependence (physical &/or psychological) - constipation - stool softener (docusate) with initiation of therapy - laxatives PRN - tolerance to constipation does not develop - myoclonic reactions, hyperreflexia: - due to accumulation of morphine-6-glucuronide - may be accompanied by aggressive behavior - management: - hydration with normal saline to increase clearance of morphine-6-glucuronide - clonazepam PRN - change to another opiate (i.e. oxycodone, hydromorphone if renal insufficiency) - convert 50% of the dose/day [6] - urinary retention with epidural/intrathecal route - overdose: - pulmonary edema - most common complication - occurs within hours of overdose - resolves in 24-48 hours - aspiration pneumonia - management: - airway support - IV administration of naloxone - 2 mg (0.01 mg/kg in children) - may repeat up to a total of 10 mg Drug interactions: 1) may enhance respiratory depression, hypotension, & sedation caused by central nervous system depressants (e.g, sedatives, hypnotics, tranquilizers, anesthetics, antiemetics, phenothiazines, benzodiazepines etc) 2) drugs with opioid antagonist activity (e.g., pentazocine, butorphanol, naloxone etc) may block morphine's analgesic effect or precipitate withdrawal symptoms 3) cimetidine may decrease the rate of metabolism of morphine 4) concomitant use with or within 14 days of discontinuing a monoamine oxidase inhibitor may result in anxiety, confusion, respiratory depression, or coma 5) may also enhance the respiratory depression or neuromuscular blockade caused by skeletal muscle relaxants 6) morphine can reduce the efficacy of diuretics by causing urinary retention, especially in men with BPH, & by causing antidiuretic hormone release 7) drugs with anticholinergic activity may enhance morphine- induced urinary retention or constipation 8) morphine levels may be increased significantly by p-glycoprotein inhibitors (e.g., diltiazem, verapamil, clarithromycin, etc) Laboratory: 1) specimen: a) serum, plasma (heparin, EDTA), urine b) glassware should be silanized prior to use c) stable for 9 months at -20 degrees C 2) methods: a) serum/plasma: GLC, HPLC, RIA, EIA, GC-MS, fluorometry b) urine: FPIA 3) interferences: -> RIA & EIA lack specificity 1] cross reactivity with morphine-3-glucuronide 2] ingestion of large amounts of poppy seeds may produce positive results in immunoassays 4) labs with Loincs - morphine in specimen - morphine in hair - morphine in body fluid - morphine in CSF - morphine in gastric fluid - morphine in meconium - morphine in saliva - morphine in serum/plasma/blood - morphine in serum/plasma - morphine in urine - morphine free in body fluid - morphine free in bile - morphine free in blood - morphine free in CSF - morphine free in gastric fluid - morphine free in serum/plasma - morphine free in stool - morphine free in urine - morphine free in vitreous fluid Mechanism of action: 1) morphine is the standard against which new analgesics are compared. 2) mu (++), delta (+) & kappa (+) agonist 3) alters perception of pain at the level of the spinal cord & higher levels of the CNS 4) alters emotional response to pain 5) cough suppressant effects are due to direct action on the cough centers in the medulla 6) antimotility effects are due to increased bowel tone to the point of spasm 7) venodilator

Interactions

drug interactions drug adverse effects (more general classes)

Specific

aerosolized morphine (nebulized morphine)

General

morphinan opiate opioid receptor agonist (narcotic)

Properties

MISC-INFO: elimination route LIVER 1/2life 1.8-4.2 HOURS therapeutic-range 10-80 NG/ML toxic-range >200 NG/ML protein-binding 35% elimination by hemodialysis - pregnancy-category C safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 8th ed. Gilman et al, eds. Permagon Press/McGraw Hill pg 489
  2. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Clinical Guide to Laboratory Tests, NW Tietz (ed) 3rd ed, WB Saunders, Philadelpha 1995
  5. Prescriber's Letter 9(5):27 2002
  6. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004, 7th edition 2010
  7. Prescriber's Letter 13(10): 2006 Alternative or 'Off-label' Routes of Drug Administration Detail-Document#: 221012 (subscription needed) http://www.prescribersletter.com
  8. Medical Knowledge Self Assessment Program (MKSAP) 16, 17. American College of Physicians, Philadelphia 2012, 2015
  9. Swetz KM, Kamal AH. In the clinic. Palliative care. Ann Intern Med. 2012 Feb 7;156(3) PMID: 22312158
  10. Deprecated Reference
  11. Anello J, Feinberg B, Heinegg J et al New Guidelines and Recommendations Guideline on oioid administration by Veterans Affaris and U.S. Department of Defense http://reference.medscape.com/features/slideshow/guidelines/2017/april
  12. NEJM Knowledge+