Laudanum

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Laudanum
Combination of
Morphine morphinan
Codeine morphinan
Thebaine morphinan
Papaverine benzylisoquinoline
Clinical data
Pregnancy
category
  • US: C (Risk not ruled out)
Dependence
liability		 Extremely high
Routes of
administration		 oral, buccal/sublingual
Legal status
Legal status
Identifiers
ATC code A07DA02 (WHO)
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Laudanum (pronounced /ˈlɔːd(ə)nəm/) (also known as Tincture of Opium) is an alcoholic herbal preparation containing approximately 10% powdered opium (the equivalent of 1% morphine).[1] It is reddish-brown in color and extremely bitter to the taste. Laudanum contains almost all of the opium alkaloids, including morphine and codeine. A potent narcotic by virtue of its high morphine concentration, laudanum was historically used to treat a variety of ailments, but its principal use was as an analgesic and cough suppressant. Until the early 20th century, laudanum was sold without a prescription and was a constituent of many patent medicines. Today, laudanum is strictly regulated and controlled throughout the world.

Most frequently, laudanum is processed to remove all or most of the narcotine present as it can be a violent emetic and does not add appreciably to the analgesic or anti-propulsive properties of opium; the resulting drug is called Denarcotised Tincture of Opium or Deodourised Tincture of Opium (DTO).

Laudanum remains available by prescription in the United States and the United Kingdom, although today the drug's therapeutic indications are generally confined to controlling diarrhea, alleviating pain, and easing withdrawal symptoms in infants who were born to mothers addicted to heroin or other opioids.

While the terms laudanum and tincture of opium are generally interchangeable, in contemporary medical practice, the latter is used almost exclusively.

File:Laudanum.jpeg
Bottle of Laudanum/Opium Tincture. Note the bright red "POISON" warning box on the label given the potency of the drug and potential for overdose.

History

Paracelsus, born Phillippus Aureolus Theophrastus Bombastus von Hohenheim (1493–1541) in Salzburg, Austria, a 16th century Swiss-German alchemist, discovered that the alkaloids in opium are far more soluble in alcohol than water. Having experimented with various opium concoctions, Paracelsus came across a specific tincture of opium that was of considerable use in reducing pain. He called this preparation laudanum, derived from the Latin verb laudare, to praise.[2] Initially, the term "laudanum" referred to any combination of opium and alcohol. Indeed, Paracelsus' laudanum was strikingly different from the standard laudanum of the 17th century and beyond. His preparation contained opium, crushed pearls, musk, amber, and other substances.[3] One researcher has documented that "Laudanum, as listed in the London Pharmacoepoeia (1618), was a pill made from opium, saffron, castor, ambergris, musk and nutmeg."[4]

Laudanum remained largely unknown until the 1660s when an English physician named Thomas Sydenham (1624–1689) compounded a proprietary opium tincture that he also named laudanum, although it differed substantially from the laudanum of Paracelsus. In 1676 Sydenham published a seminal work, Medical Observations Concerning the History and Cure of Acute Diseases, in which he promoted his brand of opium tincture, and advocated its use for a range of medical conditions.[3] By the 18th century, the medicinal properties of opium and laudanum were well-known. Several physicians, including John Jones, John Brown, and George Young, the latter of whom published a comprehensive medical text entitled Treatise on Opium extolled the virtues of laudanum and recommended the drug for practically every ailment.[2] "Opium, and after 1820, morphine, was mixed with everything imaginable: mercury, hashish, cayenne pepper, ether, chloroform, belladonna, whiskey, wine and brandy."[5]

As one researcher has noted: "To understand the popularity of a medicine that eased--even if only temporarily--coughing, diarrhoea and pain, one only has to consider the living conditions at the time." In the 1850s, "cholera and dysentery regularly ripped through communities, its victims often dying from debilitating diarrhoea," and dropsy, consumption, ague and rheumatism were all too common.[6]

By the 19th century, laudanum was used in many patent medicines to "relieve pain... to produce sleep... to allay irritation... to check excessive secretions... to support the system... [and] as a soporific".[7][8] The limited pharmacopoeia of the day meant that opium derivatives were among the most efficacious of available treatments, so laudanum was widely prescribed for ailments from colds to meningitis to cardiac diseases, in both adults and children. Laudanum was used during the yellow fever epidemic. Innumerable Victorian women were prescribed the drug for relief of menstrual cramps and vague aches. Nurses also spoon-fed laudanum to infants. The Romantic and Victorian eras were marked by the widespread use of laudanum in Europe and the United States. Mary Todd Lincoln, for example, the wife of President Abraham Lincoln, was a laudanum addict, as was the English poet Samuel Taylor Coleridge, who was famously interrupted in the middle of an opium-induced writing session of Kubla Khan by a "person from Porlock", actually his physician stopping by to deliver more laudanum.[9] Initially a working class drug, laudanum was cheaper than a bottle of gin or wine, because it was treated as a medication for legal purposes and not taxed as an alcoholic beverage.

Laudanum was used in home remedies and prescriptions, as well as a single medication. For example, a 1901 medical book published for home health use gave the following two "Simple Remedy Formulas" for DYSENTERRY [sic]: (1) Thin boiled starch, 2 ounces; Laudanum, 20 drops; "Use as an injection every six to twelve hours"; (2) Tincture rhubarb, 1 ounce; Laudanum 4 drachms; "Dose: One teaspoonful every three hours." In a section entitled "Professional Prescriptions" is a formula for DIARRHOEA (ACUTE): Tincture opium, deodorized, 15 drops; Subnitrate of bismuth, 2 drachms; Simple syrup, 1/2 ounce; Chalk mixture, 1-1/2 ounces, "A teaspoonful every two or three hours to a child one year old." DIARRHOEA (CHRONIC): Aqueous extract of ergot, 20 grains; Extract of nux vomica, 5 grains; Extract of Opium, 10 grains, "Make 20 pills. Take one pill every three or four hours."[10]

The early 20th century brought increased regulation of all manner of narcotics, including laudanum, as the addictive properties of opium became more widely understood, and "patent medicines came under fire largely because of their mysterious compositions."[11] In the United States, the Pure Food and Drug Act of 1906 required that certain specified drugs, including alcohol, cocaine, heroin, morphine, and cannabis, be accurately labeled with contents and dosage. Previously many drugs had been sold as patent medicines with secret ingredients or misleading labels. Cocaine, heroin, cannabis, and other such drugs continued to be legally available without prescription as long as they were labeled. It is estimated that sale of patent medicines containing opiates decreased by 33% after labeling was mandated.[12] In 1906 in Britain and in 1908 in Canada "laws requiring disclosure of ingredients and limitation of narcotic content were instituted."[11]

The Harrison Narcotics Tax Act of 1914 restricted the manufacture and distribution of opiates, including laudanum, and coca derivatives in the United States; this was followed by France's Loi des stupefiants in 1916, and Britain's Dangerous Drugs Act in 1920.[11]

In 1929-30, Parke, Davis & Co., a major United States drug manufacturer based in Detroit, Michigan, sold "Opium, U.S.P. (Laudanum)" as Tincture No. 23 for $10.80 per pint (16 fluid ounces), and "Opium Camphorated, U.S.P. (Paregoric)" as Tincture No. 20, for $2.20 per pint. Concentrated versions were available. "Opium Camphorated, for U.S.P. Tincture: Liquid No. 338" was "exactly 8 times the strength of Tincture Opium Camphorated (Paregoric) [italics in original], U.S.P., "designed for preparing the tincture by direct dilution," and cost $7 per pint. Similarly, at a cost of $36 per pint, "Opium Concentrated, for U.S.P. Tincture: Liquid No. 336," was "four times the strength of the official tincture," and "designed for the extemporaneous preparation of the tincture."[13] The catalog also noted: "For quarter-pint bottles add 80c. per pint to the price given for pints."

Toward the middle 20th century, the use of opiates was generally limited to the treatment of pain, and opium was no longer a medically-accepted "cure-all". Further, the pharmaceutical industry began synthesizing various opioids, such as propoxyphene, oxymorphone and oxycodone. These synthetic opioids, along with codeine and morphine were preferable to laudanum since a single opioid could be prescribed for different types of pain rather than the "cocktail" of laudanum, which contains nearly all of the opium alkaloids. Consequently, laudanum became mostly obsolete as an analgesic, since its principal ingredient is morphine, which can be prescribed by itself to treat pain. There is no medical evidence that laudanum is superior to treating pain over morphine alone.

In 1970, the U.S. adopted the Uniform Controlled Substances Act, which regulated opium tincture (Laudanum) as a Schedule II substance (currently DEA #9630),[14] placing even tighter controls on the drug.

By the late 20th century, laudanum's use was almost exclusively confined to treating severe diarrhea. The current prescribing information for laudanum in the U.S. states that opium tincture's sole indication is as an antidiarrheal, although the drug is occasionally prescribed off-label for treating pain and neonatal withdrawal syndrome.

Historical varieties

Several historical varieties of laudanum exist, including Paracelsus' laudanum, Sydenham's Laudanum (also known as tinctura opii crocata), benzoic laudanum (tinctura opii benzoica),[15] and deodorized tincture of opium (the most common contemporary formulation), among others. Depending on the version, additional amounts of the substances and additional active ingredients (e.g. saffron, sugar, eugenol) are added, modifying its effects (e.g., amount of sedation, or anti-tussive properties).

There is probably no single reference that lists all the pharmaceutical variations of laudanum that were created and used in different countries during centuries since it was initially formulated. The reasons are that in addition to official variations described in pharmacoepias, pharmacists and drug manufacturers were free to alter such formulas. The alcohol content of Laudanum probably varied substantially; on the labels of turn-of-the-century bottles of Laudanum, alcoholic content is stated as 48%. In contrast, the current version of Laudanum contains about 18% alcohol.

The three variations of Laudanum listed here were used in the United States during the late 19th century and their formulas are copied from a publication of the day: (1) Sydenham's Laudanum:[16] "According to the Paris Codex this is prepared as follows: opium, 2 ounces; saffron, 1 ounce; bruised cinnamon and bruised cloves, each 1 drachm; sherry wine, 1 pint. Mix and macerate for 15 days and filter. Twenty drops are equal to one grain of opium." (2) Rousseau's Laudanum: "Dissolve 12 ounces white honey in 3 pounds warm water, and set it aside in a warm place. When fermentation begins add to it a solution of 4 ounces selected opium in 12 ounces water. Let the mixture stand for a month at a temperature of 86° Fahr.; then strain, filter, and evaporate to 10 ounces; finally strain and add 4-1/2 ounces proof alcohol. Seven drops of this preparation contain about 1 grain of opium." (3) Tincture of Opium (Laudanum), U.S.P., attributed to the United States Pharmacoepia of 1863: "Macerate 2-1/2 ounces opium, in moderately fine powder in 1 pint water for 3 days, with frequent agitation. Add 1 pint alcohol, and macerate for 3 days longer. Percolate, and displace 2 pints tincture by adding dilute alcohol in the percolator."[17]

Modern status

United States

Tincture of Opium is available by prescription in the United States. It is regulated as a Schedule II drug (No. 9639) under the Controlled Substances Act.

The only preformulated and marketed opium tincture in the United States is manufactured by Marathon Pharmaceuticals, which acquired the rights to the drug from Ranbaxy in late 2008.[18] Marathon produces a single formulation of opium tincture, which is deodorized (or denarcotized). Each mL contains 10 mg of anhydrous morphine (the equivalent of 100 mg of powdered opium), other opium alkaloids (except narcotine), and ethanol, 19%. It is available prepackaged in bottles of 4 ounces (118 mL) and 16 ounces (1 pint or 473 mL).

The cost of opium tincture today is prohibitive; the average wholesale pharmacy price for one four ounce bottle is over $750. It is unclear how this price may have changed over time, whether it is universal or different in different regions of the country. The applicability of certain kinds of health insurance may affect the retail price. For example, in 2010, the cost of a prescription for 45 mL of Tincture of Opium filled at a CVS Pharmacy in Washington, D.C., was $69. This implies a retail cost of about $180 per 4 ounces, or $45 per ounce, or $9 per teaspoon.(Pricing Information) The high price is likely due to the fact that there is only one manufacturer of this drug in the U.S. This compares with the cost of laudanum in the 19th century, which was mere pennies per ounce (historic cost of various drugs and poisons).

It is also possible to obtain laudanum in the U.S. at a compounding pharmacy. The compounding pharmacist would mix the appropriate amount of powdered opium (USP) with alcohol, as directed on the prescription. Tincture of Opium, U.S.P., is prepared from "granulated opium, 100 gm; paraffin, 50 gm; alcohol,[19] 200 cc; and water, a sufficient quantity to make about 1000 cc." To prepare Tincture of Opium, U.S.P., "Heat 500 cc of water to boiling, pour it on the granulated opium contained in a suitable vessel, and stir the mixture frequently during 24 hours. Transfer the mixture to a percolator, and, when the original menstrum has ceased to drop, continue the percolation slowly, gradually adding water until the opium is exhausted. Concentrate the percolate by evaporation in a water bath until it measures 150 cc, add the paraffin, and continue the heating until this is entirely melted. Beat the mixture thoroughly and set it aside to cool. When cool, pierce a hole through the top layer of paraffin and drain off the liquid, and wash the residual paraffin and the filter with small portions of water until the combined liquids measure 950 cc. After assaying a portion of this liquid to determine the morphine content, the volume of the finished Tincture is adjusted by the addition of a mixture of 1 volume of alcohol and 4 volumes of water, to make each 100 cc contain 1 gm of anhydrous morphine."[20]

Tincture of Opium is what is known as an "unapproved drug" by the U.S. Food and Drug Administration (FDA); the marketing and distribution of opium tincture are permitted today because opium tincture was sold prior to the Federal Food, Drug & Cosmetic Act of 1938.[21] Given its "grandfathered" status, opium tincture has never been required to undergo the strict FDA drug review and approval process. Nevertheless, the FDA has closely monitored the labeling of opium tincture. Bottles of opium tincture are required by the FDA to bear a bright red "POISON" label given the potency of the drug and the potential for overdose (see discussion about confusion with Paregoric below).

United Kingdom

Opium tincture is available in the U.K., where it is referred to as Tincture of Opium, B.P., Laudanum, Thebaic Tincture, or Tinctura Thebaica, and "adjusted to contain 1% w/v of anhydrous morphine."[22] It is a Class A substance under the Misuse of Drugs Act of 1971. At least one manufacturer (Macfarlan Smith) still produces laudanum in the U.K. as of 2009.[23]

Pharmacology

Opium tincture is useful as an analgesic and antidiarrheal. Opium enhances the tone in the long segments of the longitudinal muscle and inhibits propulsive contraction of circular and longitudinal muscles. The pharmacological effects of opium tincture are due principally to its morphine content. The quantity of the papaverine and codeine alkaloids in opium tincture is too small to have any demonstrable central nervous system effect.[24]

Most modern formulations of opium tincture do not contain the alkaloid narcotine (also known as noscapine), which has antitussive properties. Even modest doses of narcotine can induce profound nausea and vomiting.[25] Since opium tincture is usually prescribed for its antidiarrheal and analgesic properties (rather than as an antitussive), opium tincture without narcotine is generally preferred. This "de-narcotized" or "deodorized" opium tincture is formulated using a petroleum distillate to remove the narcotine.[24]

Oral doses of opium tincture are rapidly absorbed in the gastrointestinal tract and metabolized in the liver. Peak plasma concentrations of the morphine content are reached in about one hour, and nearly 75% of the morphine content of the opium tincture is excreted in the urine within 48 hours after oral administration.

Indications and dosage

Diarrhea

Opium tincture is indicated for the treatment of severe fulminant diarrhea that does not respond to mainline therapy or modalities [disambiguation needed File:InterlanguageLinks-Asset-Pencil-Hover.gif].[24] The recommended dose is 0.6 mL (6 mg or 10 minims) by mouth four times a day.[24] Refractory cases (such as diarrhea resulting from the complications of AIDS) may require higher than normal dosing. In terminal diseases, there is no ceiling dose for opium tincture; the dose is increased slowly until diarrhea is controlled.[26]

Neonatal Abstinence Syndrome (NAS)

Opium tincture is used to treat neonatal abstinence syndrome (NAS) when diluted 1:25 (one part opium tincture to 25 parts water).[27] The recommended dose is 0.2 mL of the diluted solution under the tongue every three hours, which may be increased by 0.05 mL every three hours until no objective signs of withdrawal are observed.[27] In no event, however, should the dose exceed 0.7 mL every three hours.[27] The opium tincture is gradually tapered over a 3-5 week period, at which point the newborn should be completely free of withdrawal symptoms.[27]

Pain

Opium tincture is useful for the treatment of pain owing to its high concentration of morphine. (The amount of codeine in the tincture is negligible and does not have any appreciable analgesic effect). The dose is generally the same as that for morphine in opioid-naïve patients, titrated upward as needed. The usual starting dose in adults is 1.5 mL by mouth every 3 to 4 hours, representing the equivalent of 15 mg (0.23 grains, or nearly 1/4 grain) of morphine base per dose. Patients already tolerant to opioids may require higher starting doses. There is a danger of overdose in treating pain with opium tincture; see below. Since morphine and codeine are available alone in various forms, and are easier to dose and are much cheaper, opium tincture is rarely prescribed for pain in contemporary medicine. Tincture of Opium, U.S.P., contains 17% to 19% alcohol, by volume.

A brief uptick in the use of laudanum occurred in the middle of the current decade when a crop failure and other problems caused the shortage of multi-purpose soluble tablets of morphine, used at highest volume in recent times as an oral, sublingual, or buccally-administered analgesic.

Dosage

Care and caution should always be taken in administering doses of Tincture of Opium, such as the use of a dosage syringe or other suitable measurement device, and to note that the dosages in this article refer to Apothecaries weight and fluid measure. In particular, "the difference between a minim and a drop should be borne in mind when figuring doses. A minim is always a sixtieth part of a fuidrachm regardless of the character of the substance, while a drop varies from a forty-fifth to a two-hundred-and-fiftieth part, according to the surface tension of the fluid."[28] Tincture of Opium (Laudanum) and Camphorated Tincture of Opium (Paregoric) each have 50.9 drops per gram; 50.0 drops per cc; 185.0 drops per fluid drachm; and 3.10 drops per minim."[29] The importance of these distinctions are evident in view of the dangers of erroneously relying upon more general descriptions of Apothecaries fluid measure, which typically list 60 minims per fluid dram, and 8 fluid drams per fluid ounce (480 minims).[30]

Hazards

Potency of laudanum

Opium tincture is one of the most potent oral formulations of morphine available by prescription. Accidental or deliberate overdose is common with opium tincture given the highly-concentrated nature of the solution. Overdose and death may occur with a single oral dose of between 100 – 150 mg of morphine in a healthy adult who is not habituated to opiates.[31][32] This represents the equivalent of between two to three teaspoons of opium tincture. Prudent medical judgment necessitates toward dispensing very small quantities of opium tincture in small dropper bottles or in pre-filled syringes to reduce the risk of intentional or accidental overdose.[33]

Danger of confusion with paregoric

In the United States, opium tincture contains 10 mg per mL of anhydrous morphine. By contrast, opium tincture's weaker cousin, paregoric, also confusingly known as "camphorated tincture of opium", is 1/25th the strength of opium tincture, containing only 0.4 mg of morphine per mL. A 25-fold morphine overdose may occur if opium tincture is used where paregoric is indicated. Opium tincture is almost always dosed in drops, or fractions of a mL, or less commonly, in minims, while paregoric is dosed in teaspoons or tablespoons. Thus, an order for opium tincture containing directions in teaspoons is almost certainly in error. To avoid this potentially fatal outcome, the term "camphorated tincture of opium" is avoided in place of paregoric since the former can easily be mistaken for opium tincture.[34]

The FDA has worked with the manufacturers of opium tincture and paregoric to address this problem via product labeling. In 2005, labels for opium tincture began to bear the "POISON" warning, as well as the concentration of morphine (10 mg/mL) in large text beneath the words "Opium Tincture". The FDA has also alerted pharmacists and other medical practitioners about the dangers of confusing these drugs, and has recommended that opium tincture not be stocked as a standard item (i.e., that it should not be "on the shelf"), that opium tincture be dispensed in oral syringes, and that pharmacy software alert the dispenser if unusually large doses of opium tincture appear to be indicated.[35]

Despite the FDA's efforts over the past few years, the confusion persists, with often deadly results.[33] The Institute for Safe Medical Practices recommends that opium tincture not be stocked at all in a pharmacy's inventory, and that "It may be time to relegate opium tincture and paregoric to the museum of outmoded opioid therapy."[34] Despite the risk of confusion, opium tincture, like many end-stage medications, is indispensable for intractable diarrhea for terminally ill patients, such as those suffering from AIDS and cancer.[26] However, a search of FDA's website does not reveal any efforts at this time to ban opium tincture or restrict its use; in fact, the FDA has a web page devoted to patient and practitioner education about opium tincture and paregoric.(See FDA Patient Education Webcast on Confusion between Opium Tincture and Paregoric)

Misinterpretation of "DTO"

"DTO" is an abbreviation for Deodorized Tincture of Opium. However, DTO is sometimes also erroneously employed to abbreviate "diluted tincture of opium", a 1:25 mixture of opium tincture to water prescribed to treat withdrawal symptoms in newborns whose mothers were using opiates while pregnant. The United States Pharmacopeia and FDA recommend that practitioners refrain from using DTO in prescriptions given this potential for confusion. In cases where pharmacists have misinterpreted DTO to mean "deodorized tincture of opium" when "diluted tincture of opium" was meant, infants have received a massive 25-fold overdose of morphine, sometimes resulting in fatalities.[34]

Side effects

Adverse effects of laudanum are generally the same as with morphine, and include euphoria, dysphoria, pruritis, constipation, reduced tidal volume, respiratory depression, as well as psychological dependence, physical dependence, miosis, and xerostomia. Overdose can result in severe respiratory depression or collapse and death. The ethanol component can also induce adverse effects at higher doses; the side effects are the same as with alcohol.

Long-term use of laudanum in nonterminal diseases is discouraged due to the possibility of tolerance and addiction. Long-term use can also lead to abnormal liver function tests; specifically, prolonged morphine use can increase ALT and AST blood serum levels.

Treatment for overdose

Opioid antagonists (such as Narcan (naloxone) or naltrexone) are the first-line agents employed to reverse opioid intoxication.

See also

References

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  1. ↑ Also labeled Tr. Opii, Tinctura Opii Deodorati, Tincture of Deodorized Opium, Opii tinctura. Tincture of Opium, U.S.P, "yields, from each 100 cc, not less than 0.95 gm and not more than 1.05 gm of anhydrous morphine." Source: The Pharmacopoeia of the United States of America. 10th Decennial revision (U.S.P. X). Philadelphia: J. B. Lippincott Company, 1925 (Official from January 1, 1926), page 400.
  2. ↑ 2.0 2.1 Strathern, Paul. "A Tradition is Born". A Brief History of Medicine. Retrieved 2009-01-16. 
  3. ↑ 3.0 3.1 Davenport-Hines, Richard. "Early History". The Pursuit of Oblivion. Retrieved 2009-01-16. 
  4. ↑ In the Arms of Morpheus: The Tragic History of Laudanum, Morphine, and Patent Medicines," by Barbara Hodgson. Buffalo, New York: Firefly Books, 2001, page 45.
  5. ↑ In the Arms of Morpheus: The Tragic History of Laudanum, Morphine, and Patent Medicines," by Barbara Hodgson. Buffalo, New York: Firefly Books, 2001, page 104.
  6. ↑ In the Arms of Morpheus: The Tragic History of Laudanum, Morphine, and Patent Medicines," by Barbara Hodgson. Buffalo, New York: Firefly Books, 2001, pages 44-49.
  7. ↑ Potter, Sam'l O. L. "Opium". A Compend of Materia Medica, Therapeutics, and Prescription Writing. Retrieved 2007-10-13. 
  8. ↑ Licit & Illicit Drugs, by Edward M. Brecher and the Editors of Consumer Reports. Boston: Little, Brown and Company, 1972. See Chapter 1, "Nineteenth-century America--a 'dope fiend's paradise'", pages 3-7.
  9. ↑ See Dr. Anne Beidler's The Addiction of Mary Todd Lincoln <http://lincoln.coffeetownpress.com/>
  10. ↑ Medicology or Home Encyclopedia of Health, by Joseph G. Richardson. New York, Philadelphia and London: University Medical Society, 1901, pages 1276 and 1282.
  11. ↑ 11.0 11.1 11.2 In the Arms of Morpheus: The Tragic History of Laudanum, Morphine, and Patent Medicines," by Barbara Hodgson. Buffalo, New York: Firefly Books, 2001, page 126.
  12. ↑ Musto, David F. (1999 (3rd edition)). The American Disease: Origins of Narcotic Control. Oxford University Press. ISBN 0195125096. http://books.google.com/?id=7VrQy2d8PxYC.
  13. ↑ 1929-1930 Physicians' Catalog of the Pharmaceutical and Biological Products of Parke, Davis & Company, pages 87-88.
  14. ↑ http://www.justice.gov/dea/pubs/scheduling.html, visited July 31, 2010). Also under Schedule II are opium extracts, opium fluidextract, opium poppy (Papaver somniferum), granulated opium, powdered opium, and raw or gum opium, each with an individual DEA number.
  15. ↑ Belgische Farmacopee, 5de uitgave, 1966; part 3.
  16. ↑ Thomas Sydenham, an English physician, formulated this version of Laudanum in the 1660s.
  17. ↑ Encyclopedia of Practical Receipts and Processes, by William B. Dick. Fifth edition. New York: Dick & Fitzgerald, Publishers, 1890, pages 416, 447 and 472.
  18. ↑ "Opium Tincture Now Available from Marathon Pharma". Marathon Pharmaceuticals, 2008. Retrieved 2008-10-28. 
  19. ↑ Refers to 190 proof alcohol (95% alcohol by volume).
  20. ↑ Source: The Pharmacopoeia of the United States of America. 10th Decennial revision (U.S.P. X). Philadelphia: J. B. Lippincott Company, 1925 (Official from January 1, 1926), pages 400-401.
  21. ↑ "Unapproved Drugs, What's the Big Deal?" (PDF). International Journal of Pharmaceutical Compounding, Winter 2006. Retrieved 2009-01-03. 
  22. ↑ The Extra Pharmacopeia Martindale. Vol. 1, 24th edition. London: The Pharmaceutical Press, 1958, page 924.
  23. ↑ "Macfarlan Smith Product List of Controlled Drugs". Johnson Matthey Website. Retrieved 2009-01-28. 
  24. ↑ 24.0 24.1 24.2 24.3 "Opium Tincture Prescribing Information" (PDF). Marathon Pharmaceuticals, 2009. Retrieved 2009-01-03. 
  25. ↑ Principles of Pharmacy, entry on Tincture of Deodorized Opium. W.B. Saunders Company, 1917. Retrieved 2008-01-27. 
  26. ↑ 26.0 26.1 End of Life Care for Patients with AIDS. McGraw Hill, 2006. Retrieved 2009-01-30. 
  27. ↑ 27.0 27.1 27.2 27.3 Neonatal Withdrawal Syndromes. McGraw Hill, 2006. Retrieved 2009-01-30. 
  28. ↑ The Art of Compounding, by Wilbur S. Scoville and Justin L. Powers. 6th edition. Philadelphia: P. Blakiston's Son & Co., Inc., 1937, page 16. The normal drop counter "shall have an exit with an external diameter of 3 millimeters, and shall discharge drops of distilled water at 15°C, of such a size that 20 drops shall weigh 1 gram."
  29. ↑ The Art of Compounding, by Wilbur S. Scoville and Justin L. Powers. 6th edition. Philadelphia: P. Blakiston's Son & Co., Inc., 1937, page 18.
  30. ↑ Arithmetic of Pharmacy, by A. B. Stevens. 6th edition, revised and enlarged by Charles H. Stocking and Justin L. Powers. New York: D. Van Nostrand Company, Inc., 1926, page 2.
  31. ↑ "Material Safety Data Sheet for Morphine Sulfate". Mallinckrodt Pharmaceuticals. Retrieved 2009-01-16. 
  32. ↑ Medical Toxicology, Toxic Dose of Morphine (p. 929). Wolter Kluwer Health. Retrieved 2009-03-06. 
  33. ↑ 33.0 33.1 "Recurring Confusion Between Opium Tincture and Paregoric; "Dispense opium tincture only in small dropper bottles or oral syringes"". Pharmacy Times. Retrieved 2009-01-30. 
  34. ↑ 34.0 34.1 34.2 "Hazard Alert! Recurring Confusion Between Tincture of Opium and Paregoric". Institute for Safe Medication Practices. Retrieved 2007-10-13. 
  35. ↑ "More Confusion Between Opium Tinctures". Institute for Safe Medication Practices. Retrieved 2009-01-17. 
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