Morphine: Clarke's Analysis of Drugs and Poisons Página 1 de 6

Printed from: Clarke's Analysis of Drugs and Poisons, London: Pharmaceutical Press. Electronic version, 2005.
Morphine Narcotic Analgesic

Synonym. Morphia
(5α,6α)-7,8-Didehydro–4,5–epoxy–17–methylmorphinan–3,6–diol monohydrate
C17H19NO3,H2O = 303.4
CAS—57–27–2 (anhydrous); 6009–81–0 (monohydrate)

The principal alkaloid of opium. A white crystalline powder or colourless or white acicular crystals. M.p. 254° to 256°, with
decomposition.

Soluble 1 in 5000 of water, 1 in 210 of ethanol, 1 in 1220 of chloroform, and 1 in 125 of glycerol; practically insoluble in
ether. Note that the solubility can vary according to the method of preparation and the crystalline state.

Morphine Acetate

C17H19NO3,C2H4O2,3H2O = 399.4
CAS—596–15–6 (anhydrous); 5974–11–8 (trihydrate)

A white amorphous or crystalline powder.

Soluble 1 in 2.25 of water, 1 in 22 of ethanol, 1 in 4.75 of chloroform, and 1 in 4.5 of glycerol; practically insoluble in ether.

Morphine Hydrochloride

C17H19NO3,HCl,3H2O = 375.8
CAS—52–26–6 (anhydrous); 6055–06–7 (trihydrate)

Colourless silky crystals or crystalline powder, or cubical white masses. A solution in water is laevorotatory.

Soluble 1 in 17.5 of water and 1 in 100 of ethanol; slowly soluble in glycerol; practically insoluble in chloroform and ether.

Morphine Sulfate

Proprietary names. Astramorph; Duramorph; Infumorph; Kadian; Moraxen; Morcap; MS Contin(us); MSIR; MST-Continus;
MXL; Oramorph; RMS; Roxanol; Sevredol; Zomorph.
(C17H19NO3)2,H2SO4,5H2O = 758.8
CAS—64–31–3 (anhydrous); 6211–15–0 (pentahydrate)

White, acicular crystals, cubical masses, or crystalline powder. When exposed to air it gradually loses water of crystallisation.
It darkens on prolonged exposure to light. M.p. 250°, with decomposition (anhydrous form). A solution in water is

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laevorotatory.

Soluble 1 in 15.5 of water and 1 in 1000 of ethanol; practically insoluble in chloroform and ether.

Morphine Tartrate
Proprietary name. It is an ingredient of Cyclimorph.
(C17H19NO3)2,C4H6O6,3H2O = 774.8
CAS—302–31–8 (anhydrous); 6032–59–3 (trihydrate)

Minute, colourless, acicular, efflorescent crystals.

Soluble 1 in 11 of water and 1 in 1000 of ethanol; practically insoluble in chloroform, ether, and carbon disulfide.

Dissociation Constant. pKa8.0, 9.9 (20°).

Partition Coefficient. Log P(octanol/pH 7.4), –0.1.

Colour Tests. Ferric Chloride—blue; Liebermann's Test—black; Mandelin's Test—blue–grey; Marquis Test—violet.

Thin–layer Chromatography. System TA—Rf 37; system TB—Rf 00; system TC—Rf 09; system TE—Rf 20; system
TL—Rf 01; system TAE—Rf 18; system TAF—Rf 23; system TAJ—Rf 00; system TAK—Rf 00; system TAL—Rf 15.
(Dragendorff spray, positive; acidified iodoplatinate solution, positive; Marquis reagent, violet.)

Gas Chromatography. System GA—morphine RI 2445, morphine-AC2 (diamorphine) RI 2615, morphine-PFP2 RI 2360,
morphine-TMS2 RI 2560, morphine-TFA2 RI 2250, M (nor-) RI 2459, M (nor-)-AC3 RI 2955, M (nor-)-PFP2 RI 2440, M
(nor-) PFP3 RI 2405, M (nor-)-TMS3 RI 2605, codeine RI 2375, norcodeine RI 2388; system GB—morphine RI 2564,
morphine-AC2 (diamorphine) RI 2769, morphine-TMS2 RI 2602, codeine RI 2511, norcodeine RI 2535; system GC—
morphine RI 2542, codeine RI 2681; system GM—morphine, not eluted. Column: 5% phenyl methyl siloxane capillary
(30 m × 0.25 mm i.d., 0.25 μm film thickness). Column temperature: 150°, 1 min; increased to 250° at 40°/min, held for
21.5 min. Carrier gas: helium, 1.5 mL/min flow rate. MS detection. Retention time: 5.84 min. [B. Fryirs et al.,J. Chromatogr.
B Biomed. Sci. Appl.,1997, 6931, 51–57.] Column: HP-5 capillary 95% dimethylsiloxane, 5% diphenylsiloxane
(25 m × 0.25 mm i.d., 0.25 μm film thickness). Column temperature: 120°; held 2 min; increased to 280° at 20°/min; held
10 min. Carrier gas helium: 1 mL/min flow rate. MS detection. Retention time: 12.88 min. [F. Pragst et al.,J. Anal.
Toxicol.,1999, 23, 168–171.]

High Performance Liquid Chromatography. System HA—morphine k 3.8 (tailing peak), codeine k 4.8 (tailing peak),
morphine N-oxide k 3.2 (tailing peak), norcodeine k 3.1 (tailing peak), normorphine k 2.9 (tailing peak); system HC—
morphine k 1.30, codeine k 1.21, morphine–3–glucuronide k 1.56, norcodeine k 3.51, normorphine k 3.92; system HS—k
5.16; system HX—morphine RI 200, codeine RI 266; system HY—morphine RI 182, normorphine RI 237; system HZ—
morphine retention time 1.8 min; system HAA—morphine retention time 3.3 min; system HAX—morphine retention time
5.6 min; system HAY—morphine retention time 3.2 min. Column: C18 (Nucleosil, 250 × 8.4 mm i.d., 5 μm). Mobile phase:
1% acetonitrile in TEAP buffer, 0 to 8 min; 3% acetonitrile in TEAP buffer, 8 to 23 min, 1.0 mL/min flow rate. Fluorescence
detection (λex = 245 nm, λem = 345 nm). Retention time: morphine, 6.97 min; morphine–3–glucuronide, 4.91 min; morphine–
6–glucuronide, 8.71 min. [R. Aderjan et al.,J. Anal. Toxicol.,1995, 193, 163–168.] Column: μPorasil (300 × 3.9 mm i.d.,
10 μm): pre–column, silica (15 × 3.2 mm i.d., 7 μm). Mobile phase: sodium acetate buffer (5 mM, pH 3.75): acetonitrile
(25:75), 1.2 mL/min flow rate. ECD. Retention time: 10.45 min (k, 5.04). [W. J. Liaw et al.,J. Chromatogr. B Biomed. Sci.
Appl.,1998, 7142, 237–245.] Column: Inertsil ODS-3 (150 × 3 mm i.d., 5 μm). Mobile phase: 1 mM ammonium formate
(pH 3): acetonitrile (maintained at 5% for 5 min, increased to 20% in 5 min, held 5 min), 0.4 mL/min flow rate. MS detection.
Retention time: morphine, 2.7 min; morphine–3–glucuronide, 2.2 min; morphine–6–glucuronide, 4.3 min. [A. Dienes-Nagy et
al.,J. Chromatogr. A,1999, 854(1–2), 109–118.]

Ultraviolet Spectrum. Aqueous acid—285 (A11=52a); aqueous alkali—298 nm (A11=92a).

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Infra–red Spectrum. Principal peaks at wavenumbers 805, 1243, 1118, 945, 1086, 833 cm−1 (Nujol).

Mass Spectrum. Principal ions at m/z 285, 162, 42, 215, 286, 124, 44, 284; codeine 299, 42, 162, 124, 229, 59, 300, 69;
norcodeine 285, 81, 215, 148, 286, 164, 110, 115; normorphine 271, 81, 150, 201, 148, 110, 272, 82.

Quantification
GAS CHROMATOGRAPHY. In postmortem tissues: limit of detection 50 μg/L in blood, 300 ng/g in kidney and liver, 500 μg/L in
urine, FID—G. R. Nakamura and E. L. Way,Anal. Chem.,1975, 47, 775–778. In whole blood: limit of detection 1 μg/L,
ECD—S. Felby,Forensic Sci. Int.,1979, 13, 145–150. In raw opium and opium preparations—D. C. Garratt et al.,Analyst,

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Lond.,1978, 103, 268–283. In urine: NPD, FID—T. Vu-Duc and A. Vernay,Biomed. Chromatogr.,1990, 42, 65–69. In blood:
morphine and other opioids, limit of quantification 10 μg/L, electron–ionisation detection—S. Mykkanen et al.,J. Anal.
Toxicol.,2000, 24, 122–126. In postmortem bone and bone marrow: FID—N. Raikos et al.,Forensic Sci. Int.,2001, 123, 140–
141.
GAS CHROMATOGRAPHY–MASS SPECTROMETRY. In CSF, urine, and vitreous humor: limit of quantification 1 μg/L—F. Pragst et
al.,J. Anal. Toxicol.,1999, 233, 168–172. In serum and urine: limit of quantification 5.7 ng/L and 0.71 ng/L, respectively—U.
Hofmann et al.,J. Chromatogr. B Biomed. Sci. Appl.,1999, 727, 81–88. In urine: limit of quantification 25 μg/L and limit of
detection 10 μg/L—R. Meatherall,J. Anal. Toxicol.,1999, 233, 177–186. In hair: limit of quantification is 0.5 mg/g—K. M.
Hold et al.,J. Chromatogr. Sci.,1998, 363, 125–130. In plasma: limit of quantification 0.75 μg/L and estimated limit of
detection is 0.2 μg/L—B. Fryirs et al.,J. Chromatogr. B Biomed. Sci. Appl.,1997, 6931, 51–57. In urine: limit of detection is
2.0 μg/L and limit of quantification 10.0 μg/L—C. L. O’Neal and A. Poklis,J. Anal. Toxicol.,1997, 216, 427–432. In hair:
limit of detection 0.1 μg/g, using a 30–mg hair sample, SIM—P. Kintz and P. Mangin,Forens. Sci. Int.,1995, 732, 93–100. In
plasma or whole blood: morphine and other opioids, limit of detection <5 μg/L—A. Geier et al.,Int. J. Legal Med.,1996, 109,
80–83. In hair: morphine and other opioids, limits of detection 0.12 to 0.28 μg/L—Y. Gaillard and G. Pepin,Forensic Sci.
Int.,1997, 86, 49–59. In urine: morphine and other opioids—L. A. Broussard et al.,Clin. Chem.,1997, 43, 1029–1032; M.
Cremese et al.,J. Forensic Sci.,1998, 43, 1220–1224. In hair: morphine and other opioids—S. Pichini et al.,J. Anal.
Toxicol.,1999, 23, 343–348. In plasma: limit of quantification about 0.8 μg/L—H. J. Leis et al.,J. Chromatogr. B Biomed. Sci.
Appl.,2000, 744, 113–119. In urine: morphine and other drugs of abuse—S. P. Vorce et al.,J. Anal. Toxicol.,2000, 24, 595–
601. In urine: morphine and other drugs of abuse, limits of detection 3 to 12 μg/L—V. Karacic and L. Skender,Arh. Hig.
Rada. Toksikol.,2000, 51, 389–400. In hair: morphine, codeine, and cocaine—W. E. Brewer et al.,Anal. Chem.,2001, 73,
2371–2376. In serum, saliva, or hair: morphine and other opioids—W. Piekoszewski et al.,Przegl. Lek.,2001, 58, 287–289. In
plasma: limit of quantification 0.38 μg/L—H. J. Leis et al.,Rapid Commun. Mass Spectrom.,2002, 16, 646–649. In plasma:
morphine glucuronides—H. J. Leis et al.,J. Mass Spectrom.,2002, 37, 395–400. In hair or oral fluid: morphine and other
opioids—J. Jones et al.,J. Anal. Toxicol.,2002, 26, 171–175. In hair: morphine and other opioids—M. Montagna et
al.,Forensic Sci. Int.,2002, 128, 79–83. In urine: morphine and other opioids—C. Meadway et al.,Forensic Sci. Int.,2002, 127,
136–141.
HIGH PERFORMANCE LIQUID CHROMATOGRAPHY. In plasma: limit of detection is 0.1 μg/L, ECD—W. J. Liaw et al.,J.
Chromatogr. B Biomed. Sci. Appl.,1998, 7142, 237–245. In serum: limit of detection 5 μg/L, fluorescence detection—R.
Aderjan et al.,J. Anal. Toxicol.,1995, 193, 163–168. In plasma: limit of detection is 1 μg/L morphine, ECD—P. P. Rop et
al.,J. Chromatogr. B Biomed. Sci. Appl.,1994, 6612, 245–253. In urine: limit of detection 50 μg/L, UV and ECD—J.
Gerostamoulos et al.,J. Chromatogr.,1993, 6171, 152–156. In plasma: limit of quantification 10 μg/L, fluorescence
detection—D. A. Barrett et al.,J. Chromatogr.,1991, 5661, 135–145. In plasma: morphine and its glucuronides, limits of
detection about 5 to 10 μg/L, fluorescence detection—R. Hartley et al.,Biomed. Chromatogr.,1993, 7, 34–37. In plasma:
morphine and its metabolites, limit of quantification for morphine 1 μg/L, diode–array detection—D. Weilbo et al.,J.
Chromatogr.,1993, 615, 164–168. In urine: morphine and other opioids, limit of detection for morphine 50 μg/L, UV and
electrochemical detection—J. Gerostamoulos et al.,J. Chromatogr.,1993, 617, 152–156. In plasma and CSF: morphine and its
glucuronides, limit of detection for morphine in plasma 6.1 μg/L, electrochemical detection—A. W. Wright et al.,Ther. Drug
Monit.,1994, 16, 200–208; A. W. Wright et al.,Ther. Drug Monit.,1998, 20, 218. In blood or bile: morphine and codeine, limit
of quantification in blood 100 μg/L, UV and fluorescence detection—K. L. Crump et al.,J. Anal. Toxicol.,1994, 18, 208–212.
In plasma: morphine and its glucuronides, limit of detection for morphine 1 μg/L, fluorescence detection—J. Huwyler et al.,J.
Chromatogr.,1995, 674 B Biomed. Appl., 57–63; Y. Rotshteyn and B. Weingarten,Ther. Drug Monit.,1996, 18, 179–188. In
plasma: endogenous morphine, electrochemical detection—Y. Liu et al.,Life Sci.,1997, 60, 237–243. In blood: morphine and
its glucuronides, fluorescence detection—J. Beike et al.,Int. J. Legal Med.,1997, 110, 226–229. In plasma: morphine and
codeine, limit of quantification 50 μg/L, UV detection—M. Freiermuth and J. C. Plasse,J. Pharm. Biomed. Anal.,1997, 15,
759–764. In plasma: fluorescence detection—S. Emara,Biomed. Chromatogr.,1998, 12, 15–20. In plasma: morphine and its
glucuronides, electrochemical detection—A. W. Wright and M. T. Smith,Ther. Drug Monit.,1998, 20, 215–218. In urine:
electrochemical detection—B. A. Rashid et al.,J. Chromatogr. A,1998, 797, 245–250. In blood: morphine and its
glucuronides, limit of detection 3 ng/g, fluorescence detection—J. Beike et al.,J. Chromatogr. B Biomed. Sci. Appl.,1999,
726, 111–119. In plasma: morphine and its glucuronides, limit of detection for morphine 0.1 μg/L, electrochemical and
fluorescence detection—Q. C. Meng et al.,J. Chromatogr. B Biomed. Sci. Appl.,2000, 742, 115–123. In plasma: morphine and
its glucuronides, limits of detection 0.5 μg/L and 10 μg/L respectively, UV detection—K. Ary and K. Rona,J. Pharm.

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Biomed. Anal.,2001, 26, 179–187.

HIGH PERFORMANCE LIQUID CHROMATOGRAPHY–MASS SPECTROMETRY. In serum: morphine and its glucuronides, limit of
quantification for morphine 10 μg/L—R. Pacifini et al.,J. Chromatogr.,1995, 664 B Biomed. Appl., 329–334. In serum:
morphine and its glucuronides, limit of quantification for morphine about 0.8 μg/L—N. Tyrefors et al.,J. Chromatogr.
A,1996, 729, 279–285. In serum, urine, or CSF: morphine and its metabolites, limit of quantification for morphine in serum or
CSF 0.4 μg/L and in urine 3.0 μg/L—G. Schanzle et al.,J. Chromatogr. B Biomed. Sci. Appl.,1999, 721, 55–65. In serum:
morphine and its glucuronides, limit of quantification for morphine 1 μg/L—M. Blanchet et al.,J. Chromatogr. A,1999, 854,
93–108. In plasma: morphine and its glucuronides—M. H. Slawson et al.,J. Anal. Toxicol.,1999, 23, 468–473.In blood: limit
of quantification is 0.5 μg/L for morphine, 1.0 μg/L for its 6–glucuronide metabolite and 5 μg/L for the 3–glucuronide—A.
Dienes-Nagy et al.,J. Chromatogr. A,1999, 854(1–2), 109–118. In serum: limit of quantification is 4.0 μg/L—P. Zuccaro et
al.,J. Anal. Toxicol.,1997, 214, 268–277. In blood, CSF fluid, serum, urine, and vitreous humour: 1 μg/L morphine, 5 μg/L for
the 3–glucuronide and the 6–glucuronide metabolite—M. J. Bogusz et al.,J. Chromatogr. B Biomed. Sci. Appl.,1997, 703(1–
2), 115–127.
NOTE. For a study of monitoring opiate use in substance abuse treatment patients with sweat and urine drug testing, see M.
A. Huestis et al.,J. Anal. Toxicol.,2000, 24, 509–521.

Disposition in the Body. Rapidly absorbed after subcutaneous, IV, or IM administration. Absorption after oral
administration is variable and there is considerable first–pass metabolism. Enterohepatic circulation may occur. It is widely
distributed, mainly in kidneys, liver, lungs, and spleen with lower concentrations in the brain and muscles, but does not
accumulate in the tissues. Morphine crosses the blood–brain barrier and the placenta; it is found in breast milk and sweat.
Approx. 90% of a dose is metabolised after administration. The major metabolic reaction is conjugation to form morphine–3-
and 6–glucuronides; morphine 6–glucuronide probably contributes to the analgesic effect, but the 3–glucuronide may
antagonise analgesia. Other reactions include N-demethylation, O-methylation, and N-oxide formation and other active
metabolites include normorphine, codeine, and morphine ethereal sulfate. After a parenteral dose, up to 90% is excreted in the
urine in 24 h, including about 10% of the dose as free morphine, 65 to 70% as conjugated morphine, up to 10% as morphine–
3–ethereal sulfate, 1% as normorphine, and 3% as normorphine glucuronide. After an oral dose, about 60% is excreted in the
urine in 24 h, and about 3% of the dose is excreted as free morphine in 48 h. The urinary excretion of morphine appears to be
pH-dependent to some extent; as the urine becomes more acid, excretion of free morphine rises, and as the urine becomes
more alkaline excretion of the glucuronide conjugate rises. Up to about 10% of a dose may be excreted in the bile.Morphine is
the major active metabolite of diamorphine, and is also a metabolite of codeine.

NOTE. Morphine may be slowly converted to pseudomorphine in cadavers and can be found as such on exhumation.
THERAPEUTIC CONCENTRATION. In plasma, usually in the range 0.01 to 0.07 mg/L.
4 healthy volunteers, aged 19 to 34 years, were administered 3 consecutive doses of 2.2, 4.4, and 8.8 mg morphine sulfate
pentahydrate at 40–min intervals via an aerosol delivery system. Plasma morphine concentrations were proportional to the
dose in this study. Additionally, 6 volunteers were administered 4.4 mg aerosolised morphine sulfate over a 2.1–min period
on 3 occasions and IV infusions of 2 mg and 4 mg morphine sulfate over 3 min. The mean peak plasma morphine
concentration for the aerosol dose was 0.109 mg/L (0.039 to 0.398) at 2.7 min, 0.165 mg/L for the 2 mg IV dose at 3.0 min,
and 0.273 mg/L for the 4 mg IV dose at 3.2 min. [M. E. Ward et al.,Clin. Pharmacol. Ther.,1997, 626, 596–609.]

12 patients with post–hepatic cirrhosis (mean age, 40.3 years; range, 35 to 45 years) and 10 healthy volunteers (mean, 39.3
years old) were administered 30 mg controlled–release morphine. The peak serum concentration was 0.035 mg/L in the
cirrhotic patients and 0.013 mg/L in the healthy observed at 174.0 min and 142.5 min, respectively. [H. I. Kotb et al.,Br. J.
Anaesth.,1997, 796, 804–806.]

31 new–born infants (gestational age, 24 to 41 weeks) on ventilation were administered 140 μg/kg for 1 hour followed by
20 μg/kg/h, for 2 to 4 days. The mean serum morphine concentration during the constant infusion was 0.105 mg/L observed at
2 h. The mean steady state concentration was 0.167 mg/L which was achieved between 24 and 48 h of infusion. Steady–state
concentrations of morphine–6–glucuronide and morphine–3–glucuronide were not reached within 60 h. [E. Saarenmaa et
al.,Clin. Pharmacol. Ther.,2000, 682, 160–166.]

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In 10 patients receiving oral morphine as either a once–a–day extended–release formulation or a twice–a–day extended–
release formulation for 7 days, plasma concentrations 30 min post–dose were reported as follows (mg/L):

Twice daily Once daily

Morphine 0.011 0.017

Morphine–3–glucuronide 0.592 0.709

Morphine–6–glucuronide 0.086 0.092

(normalised to a total daily dose of 100 mg). [R. K. Portenoy et al.,Pain Symptom Manage.,2002, 23, 292–300.]

In 8 patients receiving morphine, 60 to 3000 mg daily via chronic (8 to 160 days) subcutaneous infusion, for severe cancer
pain, the normalised plasma concentrations of morphine, morphine–6–glucuronide, and morphine–3–glucuronide were 0.3 to
0.8 μg/L, 1.0 to 3.1 μg/L, and 6.8 to 24.3 μg/L, respectively. [A. Vermeire et al.,Eur. J. Clin. Pharmacol.,1998, 53, 325–330.]

TOXICITY. The estimated minimum oral lethal dose for adults is 200 mg but addicts may be able to tolerate up to 10 times as
much. Morphine is initially eliminated from the blood fairly quickly and blood concentrations are difficult to interpret,
especially as toxic effects depend on the degree of tolerance that has been acquired.
An 8–year–old girl accidentally ingested morphine before going to bed and was found dead the next morning. Following a
tonsillectomy, she was prescribed pethidine syrup at a dose of 100 mg every 4 h but the pharmacist accidentally dispensed
Roxanol containing 20 mg/mL morphine sulfate. The girl took 1 to 2 teaspoons as prescribed. The blood morphine
concentration was 0.128 mg/L, bile, 135 mg/L, and morphine was found in the stomach contents at a concentration of
16 mg/L (a total amount of 2.3 mg). The cause of death was determined as morphine poisoning which resulted in respiratory
depression. [A. Poklis et al.,Forens. Sci. Int.,1995, 761, 55–59.]

A 46–year–old woman who was admitted to hospital in a coma with severe respiratory failure later developed cardiovascular
instability and convulsions but recovered sufficiently 2 days later to communicate in writing that she had ingested a large
quantity of controlled–release morphine tablets. 60 hours after the presumed intake, the plasma concentrations of morphine,
morphine–3–glucuronide, and morphine–6–glucuronide were 0.655, 6.504 and 1.157 mg/L, respectively; urinary recovery of
morphine and its metabolites amounted to 6.8 mmol, equivalent to an oral intake of at least 2500 mg. [D. Westerling et
al.,Acta Anaesthesiol. Scand.,1998, 42, 586–589.]

BIOAVAILABILITY. About 20 to 30%.

HALF–LIFE. Plasma half–life, about 2 to 3 h.
VOLUME OF DISTRIBUTION. About 3 to 5 L/kg.
CLEARANCE. Plasma clearance, about 15 to 20 mL/min/kg; mean total body clearance for new–born infants (24 to 41 weeks'
gestation age), 2.4 (range, 0.8 to 6.4) mL/min/kg.
PROTEIN BINDING. In plasma, 20 to 35%.
NOTE. For a review of the metabolism of morphine, see L. L. Christrup, Acta Anaesthesiol. Scand., 1997, 41, 116–122 and
for a review of the pharmacokinetics of sustained–release morphine, see G. K. Gourlay,Clin. Pharmacokinet.,1998, 35, 173–
190.

Dose. 5 to 20 mg of morphine hydrochloride, sulfate, or tartrate, by mouth or parenterally, every 4 h.

© Pharmaceutical Press 2005

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