laudanum

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.

Laudanum (pronounced /ˈlɔːd(ə)nəm/) (laudanum liquidum simplex), also known as opium tincture or thebaic tincture is an alcoholic herbal preparation containing approximately 10% opium and 1% morphine (the equivalent of 100 mg of opium/10 mg of morphine per mL). It is made by combining ethanol with opium latex or powder. 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 antitussive. Until the early 20th century, laudanum was sold without a prescription and was a constituent of many patent medicines. Today, the manufacture, distribution and use of laudanum are strictly regulated. Contrary to popular belief, laudanum is available by prescription in the United States and the United Kingdom, although the drug's medicinal uses 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.

History

Paracelsus, 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.^[1] 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 adulterants.^[2]

Laudanum remained largely unknown until the 1660s when an English physician named Thomas Sydenham 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.^[2] 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.^[1]

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".^[3] 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.^[4] 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.

The early 20th century brought increased regulation of all manner of narcotics, including laudanum, as the addictive properties of opium became more widely understood. In the United States, the Harrison Narcotics Tax Act of 1914 restricted the manufacture and distribution of opiates, including laudanum, and coca derivatives. 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. Further, laudanum contains a significant amount of alcohol, which can contribute to respiratory depression.

In 1970, the U.S. adopted the Uniform Controlled Substances Act, which regulated opium tincture as a Schedule II narcotic, 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),^[5] 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).

Modern status

United States

Opium tincture is available by prescription in the United States. It is regulated as a Schedule II drug under the Controlled Substances Act (by virtue of its containing powdered opium, which is specifically listed as a Schedule II substance (no. 9639)).

The only preformulated and marketed opium tincture in the U.S. is manufactured by Marathon Pharmaceuticals, which acquired the rights to the drug from Ranbaxy in late 2008.^[6] 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 480 mL). The cost of opium tincture today is prohibitive; the average wholesale pharmacy price for one four ounce bottle is over $660 -- the equivalent of nearly $28 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. However, it may be preferable to obtain the prepackaged opium tincture since powdered opium, USP, is not deodorized or denarcotized, and it is uncertain whether a compounding pharmacy would have the necessary chemicals to deodorize or denarcotize the tincture.

Opium tincture 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.^[7] 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. 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.^[8]

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 papaverine and codeine alkaloids in opium tincture are too small to have any demonstrable central nervous system effects.^[9]

Most modern formulations of opium tincture do not contain the alkaloid narcotine, which has anti-tussive properties. Even modest doses of narcotine (also known as noscapine) can induce profound nausea and vomiting.^[10] Since opium tincture is usually prescribed for its antidiarrheal and analgesic properties (rather than as an anti-tussive), deodorized opium tincture is preferred. Opium tincture is denarcotized/deodorized via a petroleum distillate.^[9]

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.^[9] The usual dose of opium tincture to treat diarrhea is 0.6 mL (or 10 minims) by mouth four times a day.^[9] 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.^[11]

Neonatal Withdrawal Syndrome

Opium tincture may be used for the treatment of neonatal withdrawal syndrome when diluted 1:25 (one part opium tincture to 25 parts water).^[12] The usual dose is 0.2 mL under the tongue every three hours, which may be increased by 0.05 mL every three hours until withdrawal symptoms are brought under control.^[12] In no event, however, should the dose exceed 0.7 mL every three hours.^[12] The opium tincture is gradually tapered over a 3-5 week period, at which point the newborn should be completely free of withdrawal symptoms.^[12]

Severe Pain

By virtue of its high morphine content, opium tincture is useful for the treatment of pain. The dose of opium tincture for pain is generally the same as for morphine in opioid-naïve patients, titrated upward as needed to control the pain. A usual starting dose in adults is 1.5mL every 3 to 4 hours, representing the equivalent of 15mg of morphine per dose. Patients already habituated to opioids may require higher starting doses. There is a danger of overdose in treating pain with opium tincture; see below. Morphine or codeine may be preferred to opium tincture, since neither contains alcohol.

Hazards

Potency of Laudanum

Opium tincture is one of the most potent oral formulations of morphine available by prescription. Accidental or deliberate overdose is not uncommon 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.^[13][14] This represents the equivalent of between two to three teaspoons of opium tincture. Prudent medical judgment militates 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.^[15]

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.^[16] 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.^[17] Despite the FDA's efforts over the past few years, the confusion persists, with often deadly results.^[15] 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."^[16] 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.^[11] 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 are addicted to opiates. 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 instead of diluted tincture of opium, infants have received a massive 25-fold overdose of morphine, occasionally resulting in fatalities ^[16]

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

Aggressive treatment is required in suspected overdose; death can occur within hours of ingestion of large quantities of laudanum. As little as one teaspoon has resulted in death from morphine intoxication. Opioid antagonists (such as Narcan (naloxone) or naltrexone) are the first-line agents employed to reverse opioid intoxication; it should be borne in mind that repeated doses of antagonists may be required because the duration of action of the laudanum may be longer than the antagonists; close observation of the patient over at least 12 hours is required. Opioid antagonists should be used with extreme caution in patients who have become physically dependent on opium tincture as the antagonists may precipitate an immediate abstinence syndrome; doses of the antagonist must be titrated slowly to avoid withdrawal symptoms.

See also

• Paregoric
• Poppy tea
• Thomas Sydenham

References

External links

• Merck Prescribing Information for Laudanum/Opium Tincture. Includes detailed dosage information.