Overview of CAS 57-27-2

Client Email Product
Also known as: Morphia, Morphinum, Morphium, Morphina, Morphin, (-)-morphine
Molecular Formula
Molecular Weight
285.34  g/mol
InChI Key

Morphine is an Opioid Agonist. The mechanism of action of morphine is as a Full Opioid Agonist.
1 2D Structure


2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
2.1.2 InChI
2.1.3 InChI Key
2.1.4 Canonical SMILES
2.1.5 Isomeric SMILES
2.2 Other Identifiers
2.2.1 UNII
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Chloride, Morphine

2. Contin, Ms

3. Duramorph

4. Morphia

5. Morphine Chloride

6. Morphine Sulfate

7. Morphine Sulfate (2:1), Anhydrous

8. Morphine Sulfate (2:1), Pentahydrate

9. Ms Contin

10. Oramorph Sr

11. Sdz 202 250

12. Sdz 202-250

13. Sdz 202250

14. Sdz202 250

15. Sdz202-250

16. Sdz202250

17. Sulfate, Morphine

2.3.2 Depositor-Supplied Synonyms

1. Morphia

2. Morphinum

3. Morphium

4. Morphina

5. Morphin

6. (-)-morphine

7. Duromorph

8. Ms Contin

9. Depodur

10. Meconium

11. Morphinism

12. Moscontin

13. Ospalivina

14. Morfina

15. L-morphine

16. Dulcontin

17. Nepenthe

18. Roxanol

19. Kadian

20. 57-27-2

21. Morphine Sulfate

22. Infumorph

23. Dreamer

24. Morpho

25. Avinza

26. Hocus

27. Unkie

28. Cube Juice

29. Hard Stuff

30. Oramorph Sr

31. Statex Sr

32. M-eslon

33. Ms Emma

34. Morphin [german]

35. Morfina [italian]

36. Duramorph

37. Morphina [italian]

38. Morphine [ban]

39. Astramorph Pf

40. Duramorph Pf

41. Ccris 5762

42. Dolcontin

43. Hsdb 2134

44. (5r,6s,9r,13s,14r)-4,5-epoxy-n-methyl-7-morphinen-3,6-diol

45. Unii-76i7g6d29c

46. D-(-)-morphine

47. Chebi:17303

48. Chembl70

49. Einecs 200-320-2

50. 4,5alpha-epoxy-17-methyl-7-morphinen-3,6alpha-diol

51. 7,8-didehydro-4,5-epoxy-17-methyl-morphinan-3,6-diol

52. (7r,7as,12bs)-3-methyl-2,3,4,4a,7,7a-hexahydro-1h-4,12-methano[1]benzofuro[3,2-e]isoquinoline-7,9-diol

53. Dea No. 9300

54. 76i7g6d29c

55. (5alpha,6alpha)-17-methyl-7,8-didehydro-4,5-epoxymorphinan-3,6-diol

56. Morphine (ban)

57. Morphine Forte

58. Rms

59. Morphine H.p

60. (5alpha,6alpha)-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol

61. Morphinan-3,6-alpha-diol, 7,8-didehydro-4,5-alpha-epoxy-17-methyl-

62. Morphine Extra-forte

63. Morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-methyl-, (5alpha,6alpha)-

64. 9h-9,9c-iminoethanophenanthro(4,5-bcd)furan-3,5-diol, 4a,5,7a,8-tetrahydro-12-methyl-

65. Methyl[?]diol

66. Aguettant

67. Dinamorf

68. Sevredol

69. Dimorf

70. Moi

71. Epimorph

72. Morphitec

73. Oramorph

74. Rescudose

75. Statex Drops

76. Oms Concentrate

77. Rms Uniserts

78. Roxanol Ud

79. (morphine)

80. Substitol (tn)

81. Mscontin, Oramorph

82. (4r,4ar,7s,7ar,12bs)-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol

83. (-)-(etorphine)

84. Msir

85. Roxanol 100

86. (-)morphine Sulfate

87. Morfina Dosa (tn)

88. Sdz202-250

89. Nsc11441

90. Sdz 202-250

91. Ms/l

92. Ms/s

93. Epitope Id:116646

94. Morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-methyl- (5alpha,6alpha)-

95. Schembl2997

96. M.o.s

97. Bidd:gt0147

98. Gtpl1627

99. Dtxsid9023336

100. Morphine 0.1 Mg/ml In Methanol

101. Morphine 1.0 Mg/ml In Methanol

102. Bqjcrhhnabkaku-kbqpjgbksa-n

103. Zinc3812983

104. Bdbm50000092

105. Akos015966554

106. Db00295

107. An-23579

108. An-23737

109. Ls-91748

110. C01516

111. D08233

112. 7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol

113. Unii-1m5vy6itrt Component Bqjcrhhnabkaku-kbqpjgbksa-n

114. 17-methyl-7,8-didehydro-4,5alpha-epoxymorphinan-3,6alpha-diol

115. 7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol(morphine)

116. (5a,6a)-7,8-didehydro-4,5-epoxy-17-methylmorphinian-3,6-diol

117. (5alpha,6alpha)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol

118. (5alpha,6beta)-17-methyl-7,8-didehydro-4,5-epoxymorphinan-3,6-diol

119. 3-(4-hydroxy-phenyl)-1-propyl-piperidine-3-carboxylic Acid Ethyl Ester

120. 6-tert-butyl-3-methyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine

121. (-)(5.alpha.,6.alpha.)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol

122. Morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-methyl- (5..alpha.,6.alpha.)-

123. Morphine Solution, 1.0 Mg/ml In Methanol, Ampule Of 1 Ml, Certified Reference Material

124. (1s,5r,13r,14s)-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol

125. (1s,5r,13r,14s,17r)-4-methyl-12-oxa-4-azapentacyclo[;{1,13}.0;{5,17}.0;{7,18}]octadeca-7(18),8,10,15-tetraene-10,14-diol

126. (1s,5r,13r,14s,17r)-4-methyl-12-oxa-4-azapentacyclo[^{1,13}.0^{5,17}.0^{7,18}]octadeca-7,9,11(18),15-tetraene-10,14-diol

127. (morphine) 4-methyl-(1s,5r,13r,14s,17r)-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol

128. 2-{4-[2,4-diamino-6-pteridinylmethyl(methyl)amino]phenylcarboxamido}pentanedioic Acid(morphine)

129. 4-methyl-(1s,5r,13r,14s,17r)-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol

130. 4-methyl-(1s,5r,13r,14s,17r)-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol ; Hydrochloride

131. 4-methyl-(1s,5r,13r,14s,17r)-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol ;sulphate Salt(morphine)

132. 4-methyl-(1s,5r,13r,14s,17r)-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol((morphine))

133. 4-methyl-(1s,5r,13r,14s,17r)-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol(morphine Sulfate)

134. 4-methyl-(1s,5r,13r,14s,17r)-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol(morphine)

135. 4-methyl-(1s,5r,13r,14s,17r)-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol(morphine)(hcl)

136. 4-methyl-(1s,5r,13r,14s,17r)-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol,sulfate(morphinesulfate)

137. 4-methyl-(1s,5r,13r,14s,17r)-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diolmorphine

138. 4-methyl-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol

139. 4-methyl-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol (morphine)

140. 4-methyl-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol(morphine)

141. 6,11-dimethyl-3-(3-methyl-but-2-enyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ol(morphine)

142. 9h-9,9c-iminoethanophenanthro(4,5-bcd)furan-3,5-diol, 4alpha,5,7alpha,8-tetrahydro-12-methyl-

143. Morphine, (5a,6a)-7,8-didehydro-4,5-epoxy-17-methylmorphinian-3,6-diol, Morphium, Morphia, Dolcontin, Duromorph, Morphina, Nepenthe

144. Morphine;4-methyl-(1s,5r,13r,14s,17r)-12-oxa-4-azapentacyclo[,13.05,17.07,18]octadeca-7(18),8,10,15-tetraene-10,14-diol

2.4 Create Date
3 Chemical and Physical Properties
Molecular Weight 285.34 g/mol
Molecular Formula C17H19NO3
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count4
Rotatable Bond Count0
Exact Mass285.136493 g/mol
Monoisotopic Mass285.136493 g/mol
Topological Polar Surface Area52.9 A^2
Heavy Atom Count21
Formal Charge0
Isotope Atom Count0
Defined Atom Stereocenter Count5
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Therapeutic Uses

Analgesics, Opioid; Narcotics

National Library of Medicine's Medical Subject Headings. Morphine. Online file (MeSH, 2016). Available from, as of August 12, 2016:

/CLINICAL TRIALS/ is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Morphine is included in the database.

NIH/NLM; ClinicalTrials.Gov. Available from, as of March 17, 2016:

The primary objective was to determine whether oral morphine sulfate contributed to decreased length of stay, both in the hospital and neonatal intensive care unit (NICU), when compared to oral methadone for the treatment of neonatal abstinence syndrome (NAS). Secondary objectives included evaluation of NAS scores, opioid requirements, use of adjuvant therapy, and total cost of hospital stay. An equal number of neonates who received oral morphine sulfate and oral methadone as treatment for NAS were identified. Inclusion criteria included in utero exposure to opioids as determined by maternal history, toxicology reports during pregnancy or at the time of delivery, or infant urine toxicology reports and symptoms of NAS requiring pharmacological treatment. Exclusion criteria included neonates transferred to or from another facility during treatment, neonates discharged on NAS treatment, and neonates diagnosed with iatrogenic NAS due to postnatal exposure to opioids. Twenty six neonates met inclusion criteria. Statistically significant decreases in length of hospital and NICU stay, length of treatment, maximum opioid requirements, and total cost were found when neonates treated for NAS with oral morphine sulfate were compared to those treated with oral methadone. No statistically significant differences in average maximum NAS score or use of adjuvant therapy were found between the two groups. Oral morphine sulfate reduced length of NICU and hospital stay, length of treatment, and total cost of treatment for neonates treated for NAS.

Young ME et al; Am J Health Syst Pharm 72 (23 Suppl 3): S162-7 (2015) PMID:26582303

We have conducted a meta-analysis of the clinical effects of morphine and hydromorphone to compare their benefit in analgesia. Embase and Medline were searched with an end-date of June 2009 for randomized, controlled trials or observational studies that addressed comparative analgesic and side-effects or particular side-effects. Two researchers independently identified included studies and extracted the data. Estimates of opioid effects were combined by using a random-effects model. Meta-analysis of eight studies suggested that hydromorphone (494 patients) provides slightly better (P=0.012) clinical analgesia than morphine (510 patients). The effect-size was small (Cohen's d=0.266) and disappeared when one study was removed, although the advantage of hydromorphone was more evident in studies of better quality (Jadad's rating). Side-effects were similar, for example, nausea (P=0.383, nine studies, 456 patients receiving hydromorphone and 460 morphine); vomiting (P=0.306, six studies, 246 patients receiving hydromorphone and 239 morphine); or itching (P=0.249, eight studies, 405 patients receiving hydromorphone, 410 morphine). This suggests some advantage of hydromorphone over morphine for analgesia. Additional potential clinical pharmacological advantages with regard to side-effects, such as safety in renal failure or during acute analgesia titration, are based on limited evidence and require substantiation by further studies.

Felden L et al; Br J Anaesth 107 (3): 319-28 (2011) PMID:21841049

Morphine sulfate is a strong analgesia used to relieve severe, acute pain or moderate to severe, chronic pain (e.g, in terminally ill patients). The drug is also used parenterally as a supplement for analgesia during labor.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2229

Chronic epidural or intrathecal administration of highly concentrated injections (i.e., Infumorph) via continuous, controlled microinfusion for the management of chronic intractable pain has been designated an orphan use by the US FDA.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2229

Morphine is the drug of choice in relieving pain of myocardial infarction.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2229

IV: Relief of severe pain (eg, pain of myocardial infarction (MI), severe injuries, severe chronic pain associated with terminal cancer after all non-narcotic analgesics have failed); used preoperatively to sedate the patient and allay apprehension, facilitate anesthesia induction, and reduce anesthetic dosage; control postoperative pain; relieve anxiety and reduce left ventricular work by reducing preload pressure; treatment of dyspnea associated with acute left ventricular failure and pulmonary edema; produce anesthesia for open-heart surgery.

Drug Facts and Comparisons 2015. Clinical Drug Information, LLC St. Louis, MO 2015, p. 1361

Morphine is used in patients with acute pulmonary edema for its cardiovascular effects and to allay anxiety. Morphine should not be used in the treatment of pulmonary edema resulting from a chemical respiratory irritant.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2230

THERAP CAT (VET): Analgesic (narcotic), preanesthetic, antitussive, antiperstaltic.

O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1167

4.2 Drug Warning

The U.S. Food and Drug Administration (FDA) is warning about several safety issues with the entire class of opioid pain medicines. These safety risks are potentially harmful interactions with numerous other medications, problems with the adrenal glands, and decreased sex hormone levels. We are requiring changes to the labels of all opioid drugs to warn about these risks. Opioids can interact with antidepressants and migraine medicines to cause a serious central nervous system reaction called serotonin syndrome, in which high levels of the chemical serotonin build up in the brain and cause toxicity. Taking opioids may lead to a rare, but serious condition in which the adrenal glands do not produce adequate amounts of the hormone cortisol. Cortisol helps the body respond to stress. Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as reduced interest in sex, impotence, or infertility.

FDA; FDA Drug Safety Communication: FDA Warns About Several Safety Issues with Opioid Pain Medicines; Requires Label Changes (March 22, 2016). Available from, as of March 22, 2016:

In a continuing effort to educate prescribers and patients about the potential risks related to opioid use, the U.S. Food and Drug Administration today announced required class-wide safety labeling changes for immediate-release (IR) opioid pain medications. Among the changes, the FDA is requiring a new boxed warning about the serious risks of misuse, abuse, addiction, overdose and death. Today's actions are among a number of steps the agency recently outlined in a plan to reassess its approach to opioid medications. The plan is focused on policies aimed at reversing the epidemic, while still providing patients in pain access to effective relief.

FDA; FDA News Release: FDA Announces Enhanced Warnings for Immediate-Release Opioid Pain Medications Related to Risks of Misuse, Abuse, Addiction, Overdose and Death (March 22, 2016). Available from, as of March 22, 2016

CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016; This guideline provides recommendations for primary care clinicians who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. The guideline addresses 1) when to initiate or continue opioids for chronic pain; 2) opioid selection, dosage, duration, follow-up, and discontinuation; and 3) assessing risk and addressing harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, and recommendations are made on the basis of a systematic review of the scientific evidence while considering benefits and harms, values and preferences, and resource allocation. CDC obtained input from experts, stakeholders, the public, peer reviewers, and a federally chartered advisory committee. It is important that patients receive appropriate pain treatment with careful consideration of the benefits and risks of treatment options. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death.

Dowell D et al; Morbidity and Mortality Weekly Report (MMWR) 65 (1):1-49 (2016); Available from, as of March 22, 2016:

Caution should be taken to avoid the use of morphine preparations with preservatives in intrathecal or epidural use.

Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 768

Morphine should be used with caution in patients with toxic psychoses.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2233

In patients with myocardial infarction, morphine causes a decrease in systemic vascular resistance which may result in a transient fall in systemic arterial pressure leading to severe hypotension; however, this usually is not a particular threat to supine patients.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2233

Morphine sulfate extended-release capsules contain fumaric acid. ... Dosages exceeding 1.6 g daily ... contain a quantity of fumaric acid that may be associated with serious renal toxicity.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2233

The most serious adverse effect of morphine is respiratory depression.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2233

Epidural and intrathecal administration of morphine are also frequently associated with pruritus, which is dose related but not confined to the site of administration. Urinary retention, which may persist for 10-20 hours after administration, has occurred in about 90% of males who received the drug epidurally or intrathecally and less frequently in females. ... Caution should be exercised when epidural morphine therapy is undertaken in patients with reduced metabolic clearance and those with renal and/or hepatic dysfunction since accumulation (over several days) of high systemic concentrations of the drug may occur in such patients. Lumbar puncture-type headache occurs in many patients for several days after intrathecal catheter implantation but generally responds to bedrest and/or other conventional therapy. Peripheral edema, including unexplained genital swelling in males, also has occurred following infusion-device implantation surgery.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2233

Epidural or intrathecal injection of morphine sulfate is contraindicated in patients whose concomitant drug therapy or medical condition would contraindicate administration of the drug by these routes, such as when infection is present at the injection site or the patient has uncontrolled bleeding diathesis or is receiving anticoagulants.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2233

Several manufacturers recommend that morphine sulfate not be used in patients with known or suspected paralytic ileus.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2233

Morphine may cause severe hypotension in patients whose ability to maintain blood pressure has been compromised by blood volume depletion or concomitant use of certain drugs (e.g., general anesthetics, phenothiazines).

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2233

Serious adverse events and deaths have occurred as a result of inadvertant overdosage of concentrated morphine sulfate oral solutions.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2233

Opiate agonists generally should not be used in premature neonates since the drugs reportedly cross the immature blood-brain barrier more readily than they do the mature barrier and thereby produce disproportionate respiratory depression. ... The manufacturers state that commercially available strengths of morphine sulfate extended-release capsules are not appropriate for children and that the contents of the capsules should not be sprinkled onto applesauce for administration to children.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2234

While ... clinical experience generally has not revealed age-related differences in safety or response to the drug, care should be taken in dosage selection in geriatric patients. Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, some manufacturers suggest that patients in this age group receive initial dosages of morphine sulfate as extended-release preparations in the lower end of the usual range.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2234

Although safe use of morphine has been established during labor, use of opiate agonists generally should be avoided during labor when delivery of a premature neonate is anticipated. ... Because maternally administered opiate agonists are readily distributed into fetal circulation, an opiate antagonist and resuscitative equipment for reversal of opiate-induced respiratory depression should be readily available when the drugs are used during labor and delivery. Epidurally and intrathecally administered morphine also is readily distributed into fetal circulation and may result in respiratory depression in the neonate. ... Morphine sulfate extended-release liposomal injection should not be used during labor and/or vaginal delivery. ... Highly concentrated morphine injections intended for administration via controlled-microinfusion devices are too potent for routine obstetric use; such injection should only be used in pregnant women when no other means for controlling pain is available and facilities to manage delivery and provide prenatal care for opiate toxicity and dependence in the neonate are readily accessible.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2234

Morphine should be used with caution in nursing women, since the drug has been reported to distribute into milk. Although clinically important concentrations of the drug probably are not present in milk following usual therapeutic dosages of the drug, the possibility that clinically important concentrations may be present should be considered especially when higher than usual dosages of the drug are used and in patients who have a history of opiate agonist abuse.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2234

4.3 Minimum/Potential Fatal Human Dose

The mean morphine blood level in 10 fatalities was 0.2 to 2.3 ug/g. After an overdose of morphine sulfate, a 14-year-old girl had a plasma morphine concentration of 0.5 ug/mL. She developed an atypical leukoencephalopathy.

Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 769

Morphine leads to death in amounts of 0.15-0.2 g (sc) or 0.3-0.4g (oral) in adults. Babies and young children are much more susceptible, and death has been observed at doses of 30 mg.

Harvey, A.L. (ed.). Natural and Synthetic Neurotoxins. London, England: Academic Press 1993., p. 263

Toxic morphine blood concentration: 10-100 ug/dL; Lethal morphine blood concentration: > 400 ug/dL /From table/

Gossel, T.A., J.D. Bricker. Principles of Clinical Toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 1994., p. 421

4.4 Drug Indication

Morphine is used for the management of chronic moderate-to-severe pain.[A176050] Opioids, including morphine, can manage pain effectively when used for a short amount of time. The use of opioids for longer periods needs to be monitored as they can develop a physical dependence, addiction disorder and drug abuse.[L5728]

FDA Label

5 Pharmacology and Biochemistry
5.1 Pharmacology

The binding of morphine in the opioid receptors blocks the transmission of nociceptive signals, it activates the signaling of pain-modulating neurons in the spinal cord and inhibits the transmission from primary afferent nociceptors to the dorsal horn sensory projection cells.[A176035] The onset of action is of 6-30 minutes.[A176035] The excess in the consumption of morphine and opioids, in general, can produce changes in the synaptic neuroplasticity mainly in the postsynaptic sites, dendritic terminals and modifications in the density.[A176056] Analysis of intravenous morphine showed that the attenuation of pain and analgesic effect was sex-dependent. The potency of the morphine effect is of around half in men when compared to the effect in women, as observed with an EC50 of 76 and 33 ng/ml respectively. As well, the effect of the active metabolite of morphine, morphine-6-glucuronide, was only about 22 times less potent than the morphine when analyzed in pupil constriction.[A176116]

Morphine is an opiate alkaloid isolated from the plant Papaver somniferum and produced synthetically. Morphine binds to and activates specific opiate receptors (delta, mu and kappa), each of which are involved in controlling different brain functions. In the central nervous and gastrointestinal systems, this agent exhibits widespread effects including analgesia, anxiolysis, euphoria, sedation, respiratory depression, and gastrointestinal system smooth muscle contraction. (NCI04)

5.2 MeSH Pharmacological Classification


Agents that induce NARCOSIS. Narcotics include agents that cause somnolence or induced sleep (STUPOR); natural or synthetic derivatives of OPIUM or MORPHINE or any substance that has such effects. They are potent inducers of ANALGESIA and OPIOID-RELATED DISORDERS. (See all compounds classified as Narcotics.)

Analgesics, Opioid

Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS. (See all compounds classified as Analgesics, Opioid.)

5.3 FDA Pharmacological Classification
5.3.1 Active Moiety


5.3.2 FDA UNII


5.3.3 Pharmacological Classes

Mechanisms of Action [MoA]

Full Opioid Agonists

Established Pharmacologic Class [EPC]

Opioid Agonist

5.4 ATC Code

N - Nervous system

N02 - Analgesics

N02A - Opioids

N02AA - Natural opium alkaloids

N02AA01 - Morphine

5.5 Absorption, Distribution and Excretion


Morphine presents an almost complete absorption mainly done in an alkaline environment in the upper intestine as well as in the rectal mucosa.[A176119] Morphine presents significant first-pass metabolism and thus, oral doses are required to be six times bigger than parenteral administration in order to achieve the same analgesic effect. The steady-state concentration of morphine is achieved after 24-48 hours of initial administration,[A176035] and a peak plasma concentration of 283 nmol/L can range from 15 min when administered parentally to 90 min when administered orally.[A176122, A176164] The AUC of morphine is reported to be in the range of 225-290 nmol.h/L with a bioavailability that can range from 80-100% depending on the route of administration.[A176164]

Route of Elimination

The elimination of morphine and its metabolites is mainly done by the urine from which only 2-10% of the dose corresponds to the unchanged form.[A176059] However, right after oral administration, there is extensive presystemic elimination through the passage across the bowel wall and through the liver. From the elimination route, about 70-80% of the administered dose is excreted after 48 hours.[A176119]

Volume of Distribution

Morphine presents a significantly low transfer between plasma and the effect site.[A176116] The reported volume of distribution of morphine is 5.31 L/kg while for morphine-6-glucuronide is of 3.61 L/kg.[A176119]


The apparent clearance of morphine administered intravenously and subcutaneously is of 1600 ml/min.[A176164]

Morphine crosses the placenta at term. ... Pregnant patients in labor clear the parent compound almost twice as fast. Infants younger than 1 month of age have prolonged half-life of morphine compared to older children. The clearance of morphine approaches adult values in the second month of life. The milk to plasma ratio of morphine is 2.5:1. Although significant infant plasma levels may develop, breast-feeding can usually be performed safely. A breast-feeding infant may absorb 0.8% to 12% of the maternal dose.

Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 768

Morphine sulfate is variably absorbed from the GI tract. Food may increase the extent of GI absorption of morphine sulfate administered as conventional preparations. Food may decrease the rate of absorption of morphine sulfate administered as extended-release capsules; however, the extent of absorption of the drug does not appear to be affected.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2234

Following administration of single 10-mg doses of morphine sulfate as an oral solution or rectal suppository in one study in a limited number of patients with pain associated with cancer, absorption of the drug from the rectal suppository was greater than that from the oral solution over a 4.5-hour period after administration. Oral bioavailability and average plasma concentrations at steady state reportedly are similar following oral administration of morphine sulfate as conventional or extended-release preparations. However, lower peak and higher trough plasma concentrations of morphine may occur with administration of some extended-release tablets and capsules compared with conventional morphine sulfate formulations. In patient-controlled analgesia studies, the minimum analgesic plasma concentration of morphine was determined to be 20-40 ng/mL.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2234

Peak analgesia occurs within 60 minutes following oral administration of conventional preparations of the drug, and analgesia occurs within 20-60 minutes after rectal administration. Peak analgesia occurs within 50-90 minutes following subcutaneous injection, 30-60 minutes after IM injection, and 20 minutes after IV injection. Analgesia may be maintained up to 7 hours. Following IM administration of morphine sulfate, maximal respiratory depression occurs within 30 minutes. Maximal respiratory depression following IV and subcutaneous injection occurs within 7 minutes and 90 minutes, respectively. Sensitivity of the respiratory center returns to normal within 2-3 hours, but respiratory minute volume may remain below normal for 4-5 hours.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2234

Because of the blood-brain barrier, when morphine sulfate is injected into peripheral circulation (e.g., via IV injection), systemic plasma concentrations of the drug remain higher than the corresponding CNS concentration. Morphine sulfate is absorbed slowly into systemic circulation following intrathecal administration, accounting for the prolonged duration of action by this route. Systemic absorption following epidural administration of conventional morphine sulfate injection is rapid, with plasma concentration-time profiles reportedly resembling closely those attained after IV or IM administration of the drug; however, CSF morphine concentrations exceed those in plasma within 15 minutes after epidural injection of a single 2-mg dose and are detectable for up to 20 hours after administration. Area under the plasma concentration-time curve (AUC) is similar following epidural administration of equivalent single doses of morphine sulfate as conventional injection or extended-release liposomal injection, but peak plasma concentrations achieved with the extended-release liposomal formulation are about 30% of those achieved with the conventional injection. Following epidural injection of the extended-release liposomal formulation, absorption of morphine into the intrathecal space relative to absorption into systemic circulation has not been determined.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2234

Time to peak plasma concentration following either intrathecal or epidural morphine sulfate administration is similar /to CSF/, approximately 5-10 minutes. Following administration of morphine sulfate extended-release liposomal injection into the epidural space, morphine sulfate is released from the multivesicular liposomes over time; following epidural administration of the extended-release liposomal preparation, time to peak plasma concentrations is about 1 hour. The time to peak plasma concentration following oral administration of morphine sulfate extended-release capsules every 24 hours was 10.3 hours compared with 4.4 hours for morphine sulfate extended-release tablets administered every 12 hours.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2234

Following IV administration, morphine has an apparent volume of distribution ranging from 1-4.7 L/kg. Protein binding is reported to be 36% and muscle tissue binding reported to be 54%. Following epidural administration as the conventional injection, the absorption half-life of morphine across the dura is approximately 22 minutes. Following intrathecal administration of morphine, there is a rapid initial distribution phase lasting approximately 15-30 minutes; the disposition period of the drug in CSF from 15 minutes to approximately 6 hours following intrathecal administration appears to represent a combination of the distribution and elimination phases. Approximately 4% of an epidurally injected dose of conventional morphine sulfate injection distributes into CSF. Distribution across the dura is slow, with peak CSF concentrations occurring 60-90 minutes after an epidural dose. The apparent volume of distribution of morphine in the intrathecal space is about 22 mL (range: 14-30 mL).

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2235

Up to 2-12% of an administered dose of morphine is eliminated unchanged in the urine. About 90% of total urinary excretion occurs within 24 hours after the last dose is given. Approximately 7-10% of a dose of morphine is excreted in feces with a large portion of this excreted via bile.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2235

After subcutaneous or intramuscular injection morphine is readily absorbed into the blood. ... Morphine is distributed throughout the body but mainly in the kidneys, liver, lungs and spleen, with lower concentrations in the brain and muscles. ... Morphine diffuses across the placenta and traces also appear in milk and sweat.

SWEETMAN, S.C. (ed.) Martindale-The Complete Drug Reference. 36th ed. London: The Pharmaceutical Press, 2009., p. 88

In general, the opioids are mostly absorbed from the GI tract ... . About one-third of morphine in the plasma is protein-bound after a therapeutic dose. Morphine itself does not persist in tissues, and 24 hours after the last dose, tissue concentrations are low. ... Morphine is eliminated by glomerular filtration, primarily as morphine-3-glucuronide; 90% of the total excretion takes place during the first day. Very little morphine is excreted unchanged. Enterohepatic circulation of morphine and its glucuronides occurs, which accounts for the presence of small amounts of morphine in feces and urine for several days after the last dose.

Brunton, L. Chabner, B, Knollman, B. Goodman and Gillman's The Pharmaceutical Basis of Therapeutics, Twelth Edition, McGraw Hill Medical, New York, NY. 2011, p. 499

Opiates are an important drug class in drug testing programs. Ingestion of poppy seeds containing morphine and codeine can yield positive opiate tests and mislead result interpretation in forensic and clinical settings. Multiple publications evaluated urine opiate concentrations following poppy seed ingestion, but only two addressed oral fluid (OF) results; neither provided the ingested morphine and codeine dosage. We administered two 45 g raw poppy seed doses, each containing 15.7 mg morphine and 3.1 mg codeine, 8 hr apart to 17 healthy adults. All OF specimens were screened by on-site OF immunoassay Draeger DrugTest 5000, and confirmed with OF collected with Oral-Eze device and quantified by liquid chromatography-tandem mass spectrometry (1 ug/L morphine and codeine limits of quantification). Specimens (n=459) were collected before and up to 32 hr after the first dose. All specimens screened positive 0.5 hr after dosing and remained positive for 0.5-13 hr at Draeger 20 ug/L morphine cut-off. Maximum OF morphine and codeine concentrations (Cmax ) were 177 and 32.6 ug/L, with times to Cmax (Tmax) of 0.5-1 hr and 0.5-2.5 hr post-dose, respectively. Windows of detection after the second dose extended at least 24 hr for morphine and to 18 hr for codeine. After both doses, the last morphine positive OF result was 1 hr with 40 ug/L 2004 proposed US Substance Abuse and Mental Health Services Administration cut-off, and 0.5 hr with 95 ug/L cut-off, recently recommended by the Driving under the Influence of Drugs and Medicines project. Positive OF morphine results are possible 0.5-1 hr after ingestion of 15.7 mg of morphine in raw poppy seeds, depending on the cut-off employed.

Concheiro M et al; Drug Test Anal 7 (7): 586-91 (2015) PMID:25345619 Full text:

To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2) to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety. This open label, dose escalation, four-sequence study was conducted in 10 healthy males. Three escalating doses of morphine hydrochloride (10 mg, 15 mg and 20 mg) were administered 20 cm from the anal verge. A 2 mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid chromatographic method. Modeling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction. A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6 hr, clearance 78 L/hr [relative standard error (RSE) 12%] and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side effects were observed. A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses were safe and well tolerated.

Brokjer A et al; Eur J Pharm Sci 68: 78-86 (2015) PMID:25486331

Currently, the majority of the surgical procedures performed in pediatric hospitals are done on a day care basis, with post-operative pain being managed by caregivers at home. Pain after discharge of these post-operative children has historically been managed with oral codeine in combination with paracetamol (acetaminophen). Codeine is an opioid, which elicits its analgesic effects via metabolism to morphine and codeine-6-glucuronide. Oral morphine is a feasible alternative for outpatient analgesia; however, the pharmacokinetics of morphine after oral administration have been previously described only sparsely, and there is little information in healthy children. The clinical trial included 40 children from 2 to 6 years of age, with an American Society of Anesthesiologists physical status classification of 1 or 2, who were undergoing surgical procedures requiring opioid analgesia. Morphine was orally administered prior to surgery in one of three doses: 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg. Blood samples were collected for plasma morphine, morphine-3-glucuronide (M3G) andmorphine-6-glucuronide (M6G) concentrations at 30, 60, 90, 120, 180 and 240 min after administration. All analyses were performed with the non-linear mixed-effect modeling software NONMEM version 7.2, using the first-order conditional estimation (FOCE) method. A pharmacokinetic model was developed to simultaneously describe the plasma profiles of morphine and its metabolites M3G and M6G after a single dose of oral morphine in young children (2-6 years of age). The disposition of morphine, M3G and M6G in plasma was best described by a one-compartment model. M3G and M6G metabolite formation was best described by a delay transit compartment, indicating a delay in the appearance of these two major metabolites. This model provides a foundation on which to further evaluate the use of oral morphine and its safety in young children. Longer follow-up time for morphine oral doses and incorporation of other important covariates, such as phenotype, will add value and will help overcome the limitations of the presented population pharmacokinetic analysis.

Velez de Mendizabal N et al; Clin Pharmacokinet 54 (10): 1083-90 (2015) PMID:25773480

Although morphine is used frequently to treat pain in the intensive care unit, its pharmacokinetics has not been adequately quantified in critically ill patients. We evaluated the glucuronidation and elimination clearance of morphine in intensive care patients compared with healthy volunteers based on the morphine and morphine-3-glucuronide (M3G) concentrations. A population pharmacokinetic model with covariate analysis was developed with the nonlinear mixed-effects modeling software (NONMEM 7.3). The analysis included 3012 morphine and M3G concentrations from 135 intensive care patients (117 cardiothoracic surgery patients and 18 critically ill patients), who received continuous morphine infusions adapted to individual pain levels, and 622 morphine and M3G concentrations from a previously published study of 20 healthy volunteers, who received an IV bolus of morphine followed by a 1-hour infusion. For morphine, a 3-compartment model best described the data, whereas for M3G, a 1-compartment model fits best. In intensive care patients with a normal creatinine concentration, a decrease of 76% was estimated in M3G clearance compared with healthy subjects, conditional on the M3G volume of distribution being the same in intensive care patients and healthy volunteers. Furthermore, serum creatinine concentration was identified as a covariate for both elimination clearance of M3G in intensive care patients and unchanged morphine clearance in all patients and healthy volunteers. Under the assumptions in the model, M3G elimination was significantly decreased in intensive care patients when compared with healthy volunteers, which resulted in substantially increased M3G concentrations. Increased M3G levels were even more pronounced in patients with increased serum creatinine levels. Model-based simulations show that, because of the reduction in morphine clearance in intensive care patients with renal failure, a 33% reduction in the maintenance dose would result in morphine serum concentrations equal to those in healthy volunteers and intensive care patients with normal renal function, although M3G concentrations remain increased. Future pharmacodynamic investigations are needed to identify target concentrations in this population, after which final dosing recommendations can be made.

Ahlers SJ et al; Anesth Analg 121 (5): 1261-73 (2015) PMID:26332855

Interpretation of opiate drug test results can be challenging due to casual dietary consumption of poppy seeds, which may contain variable opiate content. Opiate concentrations in paired oral fluid (OF), collected with the Oral-Eze Oral Fluid Collection System, and urine were analyzed after ingestion of poppy seeds from the same source, consumed raw or contained in a roll. In Part 1, 12 individuals consumed equal portions of a poppy seed roll. For Part 2, the same individuals consumed an equivalent quantity of raw poppy seeds, containing ~3.2 mg of morphine and 0.6 mg of codeine. Specimens were analyzed both by enzyme immunoassay (opiates) and by GC-MS (morphine/codeine). Urinary morphine was between 155-1,408 (roll) and 294-4,213 ng/mL (raw), measured at 2, 4, 6 and 20 hr post-ingestion. Urinary codeine concentrations between 140-194 (roll) and 121-664 ng/mL (raw) were observed up to 6 hr post-ingestion. Following consumption of raw poppy seeds, OF specimens were positive, above LOQ, from 0.25 to 3.0 hr with morphine ranging from 7 to 600 ng/mL and codeine from 8 to 112 ng/mL. After poppy seed roll consumption, morphine concentrations of 7-143 ng/mL were observed up to 1.5 hr with codeine detected in only 5.5% of OF specimens and ranging from 8 to 28 ng/mL. Combined with the existing poppy seed literature, these results support previous findings and provide guidance for interpretation of OF opiate testing.

Samano KL et al; J Anal Toxicol 39 (8): 655-61 (2015) PMID:26378141 Full text:

After the ingestion of three poppy-seed bagels, the following codeine and morphine concentrations were determined in the urine: 214 ng/mL codeine and 2797 ng/mL morphine at 3 hr, and 16 ng/mL codeine and 676 ng/mL morphine at 22 hr. This work indicates that a positive finding of codeine or morphine in the urine of an individual does not necessarily indicate heroin, morphine, or codeine use.

Struempler RE; J Anal Toxicol 11 (3): 97-9 (1989)

The pharmacokinetics of intradural morphine used for major abdominal surgery were evaluated. Lumbar spinal fluid and plasma concentrations were measured at intervals after morphine 0.05 mg/kg had been injected intradurally in 21 patients scheduled for elective abdominal aortic surgery. The CSF morphine concentrations were fitted by a biexponential function. A non-compartmental model based on statistical moment theory was used for calculating the intradural morphine disposition. Mean residence time was 137 +/- 54.9 minutes, mean initial volume of distribution 15 +/- 5.49 mL, mean volume of distribution at steady-state 42 +/- 18.25 mL and mean clearance 0.34 +/- 0.18 mL/min (0.02 +/- 0.01 L/hr). The moments of the morphine concentration-time curves and the pharmacokinetic parameters varied between the patients. They were not significantly different with regard to morphine dosage, or patient sex or age. Free morphine could not be detected in plasma. Morphine-3-glucuronide appeared in plasma at 5 minutes, increased to a maximum at 240 minutes and fell below the detection limit at about 16 hours after morphine administration.

Ionescu TI et al; Clin Pharmacokinet 14: 178-86 (1988) PMID:3370903

The pharmacokinetics of intravenous morphine were determined in three groups (0 to 1/2, 2 to 4, and 6 years) of children and related to the respiratory rate, arterial PCO2, and postoperative analgesia. With respect to pharmacokinetics, children seem to mature very early, because in patients aged 5 to 6 months corresponding parameters similar to those in adults were encountered. The two youngest patients (11 days and 2.4 months) diverged clearly from the others. Their mean plasma clearance of morphine was 5.2 mL/min/kg and volume of the central compartment was 0.36 L/kg. In the other patients the clearance ranged from 25.8 to 75.6 mL/min/kg and volume of central compartment from 0.67 to 2.07 L/kg, respectively. The mean analgetic concentration of morphine was 26.2 micrograms/L in the youngest group and 3.8 micrograms/L in the other patients. The effect of morphine on respiration was similar in all groups and did not differ from that of adults. The respiratory depressant effect of morphine in the two youngest patients was not analyzed.

Olkkola KT et al; Clin Pharmacol Ther 44: 128-36 (1988) PMID:3135138

The pharmacokinetics and subjective side effects of i.v. morphine sulphate 120 micrograms kg-1 and morphine-6-glucuronide (M6G) 30 ug kg-1 were determined in six healthy volunteers, using a placebo-controlled, single-blind randomized crossover design. Five of these volunteers underwent an additional (non-randomized) study of M6G 60 ug kg-1. Subjective side effects were similar following both drugs, but of shorter duration following M6G. Morphine was not detected after administration of M6G. For M6G 30 ug kg-1 the mean (SD) volume of distribution, elimination half-life and clearance were 29.38 (18.36) liter, 2.05 (1.2) hr and 187.81 (37.41) liter hr-1, respectively. These values were not significantly different from those obtained for M6G 60 ug kg-1. In all subjects the volumes of distribution and clearances were significantly smaller for M6G than for morphine, but the elimination half-lives were similar.

Hanna MH et al: Br J Anaesth 66 (1): 103-7 (1991) PMID:1997044

5.6 Metabolism/Metabolites

Around 90% of morphine is glucuronidated and sulfated in position 3 and 6 by the activity of UDP-Glucuronosyltransferase-2B7 in the liver.[A176059] The glucuronide metabolites do not reach steady-state before 60 hours. From these metabolites, morphine-3-glucuronide presents lower clearance, a smaller volume of distribution and shorter half-life when compared to the most active biologically metabolite morphine-6-glucuronide.[A176035] Other than this major metabolites, some other metabolites are codeine, normorphine, and morphine ethereal sulfate.[A176119]

... patients on therapeutic codeine also test positively for morphine, because morphine is a codeine metabolite.

Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 769

/Heroin/ is converted metabolically by ester hydrolysis first to 6-monoacetylmorphine (heroin-specific metabolite) and then to morphine by hydrolysis for the second acetate ester. When the heroin base enters the body, it is fairly lipophilic, so a portion of the dose readily crosses the blood-brain barrier into the central nervous system where the hydrolysis of the two esters can take place. Morphine is less lipophilic than heroin and does not cross back across the blood-brain barrier as readily. Morphine readily undergoes the additional phase I metabolic transformation of oxidative N-demethylation by CYP2D6. Phase II (conjugation) reactions of morphine include formation of the glucuronide conjugates at the hydroxyl moieties at positions 3 and 6. The glucuronides are then excreted. Note that the aromatic ring stays intact throughout the metabolic transformations, illustrating the stability imparted by aromaticity.

Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 370

Morphine is metabolized principally in the liver and undergoes conjugation with glucuronic acid principally at the 3-hydroxyl group. Secondary conjugation also occurs at the 6-hydroxyl group to form the 6-glucuronide, which is pharmacologically active, and to a limited extent the 3,6-diglucuronide. Plasma concentrations of the 3-glucuronide, which is inactive, and the 6-glucuronide substantially exceed those of unchanged drug, and the latter metabolite appears to contribute substantially to the drug's pharmacologic activity. Elimination of the drug may be reduced substantially in neonates compared with older children and adults. Morphine is excreted in urine mainly as morphine-3-glucuronide. In addition to the 3,6-diglucuronide, other minor metabolites that have been described includes normorphine and the 3-ethereal sulfate. ... In patients with renal impairment, accumulation of morphine-6-glucuronide occurs, which can result in enhanced and prolonged opiate activity.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2235

The major pathway for the metabolism of morphine is conjugation with glucuronic acid. The two major metabolites formed are morphine-6-glucuronide and morphine-3-glucuronide. Small amounts of morphine-3,6-diglucuronide also may be formed.

Brunton, L. Chabner, B, Knollman, B. Goodman and Gillman's The Pharmaceutical Basis of Therapeutics, Twelth Edition, McGraw Hill Medical, New York, NY. 2011, p. 499

Morphine is one of several opioids used to treat chronic pain. Because of its high abuse potential, urine drug tests can confirm "consistency with prescribed medications." Hydromorphone is a recently described minor metabolite of morphine, but few data exist on the characteristics of this metabolic pathway or the relationship of morphine and hydromorphone between and within subjects. Part I of this retrospective study shows that formation of hydromorphone from morphine is concentration-dependent and possibly saturated at high concentrations of morphine. In addition, the percentage of ultra-rapid metabolizers and poor metabolizers can be determined using the lower asymptote of a sigmoidal mathematical fit and are estimated to be 0.63 and 4.0%, respectively. Expected limits of morphine and hydromorphone (as a result of morphine metabolism) concentrations in the urine were established. Part II of this study used the metabolic ratio (hydromorphone-morphine) to determine the inter-patient and intra-patient variability in morphine metabolism to hydromorphone. Metabolic ratio values varied over a large range; 25-fold and 7-fold, respectively. The expected limits established in this study can assist in assessing the cause for possible variances in metabolism, such as drug interactions. The wide variability between and within subjects may explain unpredictable, adverse effects.

Hughes MM et al; J Anal Toxicol 36 (4): 250-6 (2012) PMID:22511699

Cytochrome P450 2D6 (CYP2D6) is a member of the cytochrome P450 (CYP) superfamily involved in the biotransformation of drugs and substances of abuse encountered in clinical toxicology. Among the CYP superfamily, the CYP2D6 gene is considered as the most polymorphic as more than 105 different alleles have been identified so far. CYP2D6 genetic polymorphisms have the potential to affect the toxicity of their substrates. This review will focus specifically on CYP2D6 genetic polymorphisms and their relevance for poisoning due to amphetamines, opioid analgesics and antidepressants in humans. PubMed (up to August 2013) was searched with the following selection criteria: 'CYP2D6 AND (toxicology OR poisoning OR intoxication OR overdose)'. Of the 454 citations retrieved, only 46 papers dealt with the impact of CYP2D6 polymorphisms on poisoning due to amphetamines, opioid analgesics and antidepressants. ... Opioid analgesics. CYP2D6 ultra-rapid metabolizers are more likely to experience the adverse effects of codeine and tramadol. Opioid analgesics that do not rely on CYP2D6 for therapeutic activity, such as morphine and hydromorphone, may therefore be a better alternative to codeine and tramadol, with the limitation that these drugs have their own set of adverse reactions. ... Either poor or extensive/ultra-rapid CYP2D6 metabolizers may be exposed to toxic effects of amphetamines, opioid analgesics and antidepressants. In these three categories, the level of evidence is substance dependent, with differences within the same pharmacological class.

Haufroid V, Hantson P; Clin Toxicol (Phila) 53 (6): 501-10 (2015) PMID:25998998

Opioid analgesics are commonly prescribed for acute and chronic pain, but are subject to abuse. Consequently, toxicology testing programs are frequently implemented for both forensic and clinical applications. Understanding opioid metabolism and disposition is essential for assessing risk of toxicity and, in some cases, providing additional information regarding risk of therapeutic failure. Opioids significantly metabolized by the cytochromeP450 (CYP450) enzyme system maybe subject to drug-drug interactions, including codeine, hydrocodone, oxycodone, fentanyl, meperidine, methadone, buprenorphine, and tramadol. CYP2D6 metabolism is polymorphic, and pharmacogenetic testing has been investigated for codeine, tramadol, oxycodone, and hydrocodone. CYP2B6 pharmacogenetic testing of methadone may reduce the risk of cardiac toxicity associated with the S-enantiomer. Opioids metabolized primarily by uridine 5'-diphospho-glucuronsyltransferase (UGT) enzymes include morphine, hydromorphone, dihydrocodeine, oxymorphone, levorphanol, and tapentadol. Parent and metabolite disposition is described for blood, oral fluid, and urine. Parent drug is most commonly detected in blood and oral fluid, whereas metabolites typically predominate in urine. Oral fluid/blood ratios exceed 1 for most opioids, making this an excellent alternative matrix for testing of this drug class. Metabolites of codeine, hydrocodone, and oxycodone are commercially available, and knowledge of metabolism is necessary for correct interpretation.

DePriest AZ et al; Forensic Sci Rev 27 (2): 115-45 (2015) PMID:26227254

Large interindividual variability in morphine pharmacokinetics could contribute to variability in morphine analgesia and adverse events. Influence of weight, genetic polymorphisms, race and sex on morphine clearance and metabolite formation from 220 children undergoing outpatient adenotonsillectomy was studied. A nonlinear mixed effects model was developed in NONMEM to describe morphine and morphineglucuronide pharmacokinetics. Children with ABCC3 -211C>T polymorphism C/C genotype had significantly higher levels of morphine-6-glucuronide and morphine-3-glucuronide formation (~40%) than C/T+T/T genotypes (p < 0.05). In this extended cohort similar to our earlier report, OCT1 homozygous genotypes (n = 13, OCT1*2-*5/*2-*5) had lower morphine clearance (14%; p = 0.06), and in addition complementing lower metabolite formation (~39%) was observed. ABCB1 3435C>T TT genotype children had lower levels of morphine-3-glucuronide formation though no effect was observed on morphine and morphine-6-glucuronide pharmacokinetics. /These/ data suggest that besides bodyweight, OCT1 and ABCC3 genotypes play a significant role in the pharmacokinetics of intravenous morphine and its metabolites in children.

Venkatasubramanian R et al; Pharmacogenomics. 2014 Jul;15(10):1297-309 PMID:25155932 Full text:

Females who have developed addiction to heroin also abuse it during pregnancy. Heroin can be detected in the fetal blood-flow already an hour after maternal i.v. injection. Heroin metabolites enter the fetal blood-flow through the placental barrier by passive transport. We present a 27-year-old female in the 5th month of pregnancy that had a miscarriage. Chemo-toxicological analysis (gas chromatography with mass spectrometry--GC/MS), showed the presence of morphine in the fetal liver (31.92 ng/g), placenta (27.94 ng/g) and meconium (136.33 ng/g). The analysis did not show the presence of 6-monoacetylmorphine. In all cases when the autopsy of fetus or newborn is performed, with mother suspected as i.v. heroin abuser, chemo- toxicological placental analysis, placenta and meconium should be also done.

Srp Arh Celok Lek 142 (9-10): 610-3 (2014) PMID:25518544

The interpretation of postmortem drug levels is complicated by changes in drug blood levels in the postmortem period, a phenomena known as postmortem drug redistribution. We investigated the postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in a rabbit model. Heroin (1 mg/kg) was injected into anesthetized rabbit; after 1 hr, an auricular vein blood sample was taken and the rabbit was euthanized. Following death rabbits were placed in a supine position at room temperature and divided into three groups namely (1) immediate autopsy, (2) autopsy after 30 minutes and (3) autopsy 24 hr after death. Various samples which included femoral blood, cardiac blood, lung, liver, kidney, vitreous humor, subcutaneous and abdominal fat, liver, bone marrow and skeletal muscle were taken. The samples were analyzed with a validated LC-MS/MS method. It was observed that within minutes there was a significant increase in free morphine postmortem femoral blood concentration compared to the antemortem sample (0.01 +/- 0.01 to 0.05 +/- 0.02 mg/L).Various other changes in free morphine and metabolite concentrations were observed during the course of the experiment in various tissues. Principal component analysis was used to investigate possible correlations between free morphine in the various samples. Some correlations were observed but gave poor predictions (>20 % error) when back calculating. The results suggest that rabbits are a good model for further studies of postmortem redistribution but that further study and understanding of the phenomena is required before accurate predictions of the blood concentration at the time of death are possible.

Maskell PD et al; Int J Legal Med 130 (2): 519-31 (2016) PMID:25863436

The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 hr after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.

Elkomy MH et al; AAPS J 18 (1): 124-33 (2016) PMID:26349564 Full text:

... The potent analgesic morphine is metabolized by more than one UGT to the active metabolite morphine-6-glucuronide and to morphine-3-glucuronide, which is devoid of analgesic activity. Thus, differential induction of UGTs involved in metabolism of morphine might lead to decreased or increased analgesic effects, depending on which UGT is preferentially induced. ...

Fromm MF et al; Pain 72 (1-2): 261-7 (1997) PMID:9272811

5.7 Biological Half-Life

Morphine presents an equilibrated half-life of 2-3 hours.[A176116]

... The mean terminal half-life of morphine following epidural injection is 90 minutes (range: 39-349 minutes), which is similar to the half-life of the drug reported after IV or IM administration (1.5-4.5 hours).

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2235

CSF concentrations of morphine decline in a biphasic manner following epidural injection of conventional morphine sulfate injection, with an early distribution half-life of 1.5 hours and a terminal half-life of about 6 hours.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2235

Following epidural administration of a 10-, 15-, or 20-mg dose of morphine sulfate extended-release liposomal injection, the half-life reportedly is 16.2, 20, or 23.9 hours, respectively.

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2235

Following intrathecal administration of /morphine/, the mean reported CSF half-life is 90 minutes (range: 42-136 minutes).

American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 2235

A high correlation (r= +0.92) was observed between the degree of morphine analgesic activity and the concn of drug in rat brain. Morphine entered the brain rapidly following sc injection, and reached peak levels 30 min after dosing. Following iv injection, serum morphine levels were initially higher in dogs with hypercarbia than in dogs with normocarbia, although the elimination half-life was similar, 65 to 67 min in both cases. In hypercarbia, morphine concn in the cerebral cortex were significantly higher and the morphine half-life in brain was 6.9 hr, compared with 4.1 hr in normocarbia.

The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979., p. 28

The half-life of morphine increases from three to four hours in normal subjects to 89 to 136 hours in renal failure subjects.

Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995., p. 32-18

5.8 Mechanism of Action

It is important to consider that about 85% of the effect observed by morphine administration is due to the activity of morphine-6-glucuronide.[A176059] Morphine and its metabolites act as agonists of the mu and the kappa opioid receptors which derive later into analgesia.[A176035] The mu-opioid receptor is a key part of the effect of morphine in the ventral tegmental area which reinforces the effects of morphine. However, in studies with delta opioid receptor knock-out mice, it was reported a reduction in the rewarding effect of morphine suggesting that the rewarding effect of morphine is related to activity towards the delta opioid receptor in the nucleus accumbens.[A176050] From the three target receptors of morphine, the mu receptor is associated with the side effects of the morphine such as modifications in the respiratory system and addiction.[A176056]

Visual analysis of the direct electroencephalograph has revealed that morphine /slowed/ the predominant frequency and /increased/ high-voltage delta activity.

Khazan N; p.173-215 in Methods in Narcotics Research; Ehrempresis S, Neidle A, eds (1981) as cited in DHHS/NIDA; Research Monograph Series 52: Testing Drugs for Physical Dependence Potential and Abuse Liability p.30 (1984) DHHS Pub No. (ADM)87-1332

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