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TOXICOLOGY

Opium

The opiates are perhaps the oldest drugs known to man. The use of opium was recorded in China over two thousand years ago and was known in Mesopotamia before that. Over the centuries the crude extract derived from poppies has been widely used as a sedative. A tincture of opium called laudanum was introduced to England and was considered indispensable to medicine. It is ironic that a compound renowned for its sedative effects should have led to at least one war. In the nineteenth century, the Chinese authorities became so alarmed about the addictive properties of opium that they tried to ban all production of it. This was contrary to the interests of the British traders dealing in opium and as a result the British sent in the gunboats to reverse the Chinese decision—one of the least savoury aspects of an otherwise relatively benevolent British Empire.

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Introduction

Opium is dried extract of Poppy (Papaver somniferum), a plant with beautiful flowers, which is now legally grown only under licence from Govt. and allowed only in Rajasthan, UP, & Maharastra India.
India produces 70-80% of opium required by pharma companies of the world to manufacture Morphine, & Codeine
Poppy is also grown illegally in many countries to feed the thriving narcotic market.

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About two weeks after the petals have fallen, the pods are fully mature, as indicated by the aforementioned shape of the capsule, a change in color from grayish-green to dark green; the points of the pods crown now stand straight out or are curved upward. At this point the pods are ready to be scored (or tapped, incised or lanced). Harvesters make the incision with a a three- or four- bladed instrument (iron or glass blades bound tightly on a wooden handle), designed to make an incision of about one millimeter deep. (Too deep an incision may result in excessive spilling either into the center of the pod or to the ground; too shallow and the latex will not ooze as desired). The pods are scored two to three times each in the afternoon, causing the white latex to drip onto the surface of the pod. The opium oxidizes, darkens, and thickens overnight, and in the morning is scraped from the surface with a flat iron blade. This process is repeated over several days until each pod is depleted of its opium. Each pod may yield from 10 to 100 milligrams of opium, with an average of 80 milligrams, which is set aside in a container to dry in the sun. A typical farm will produce 3 to 9 kilograms of opium per acre.

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Plant & Its constituents

Each plant about 1 metre high with five to eight capsules (seed pods).
Dried exudate from incised unripe capsule is crude opium
Opium is dark brown, has characteristic smell and bitter taste and contains two groups of alkaloids-

Phenanthrene group: morphine, codeine and thebaine
Benzylisoquinoline group: papaverine and noscapine

Opiates- A narcotic alkaloid derived from opium
Opioids- Drugs having similar action to morphine but not derived from it
The German pharmacist Friedrich Wilhelm Adam Seturner isolated morphine from processed opium, in 1803
Morphine content in crude opium varies and may be as high as 20%. In India it is about 10%

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History

The earliest written history of humanity’s romance with the opium poppy is found in the writings of the Sumerians dating back to approximately 3300 B.C.
How the opiate content of the poppy and its psychotropic qualities were discovered is not known. We do know that the Sumerians used it for both medicinal and recreational purposes. They referred to it as hul gil, or “plant of joy”.
Poppy’s healing powers are described in the writing of the Hippocrates, who in about 400 B.C. prescribed it to patients suffering from insomnia.
The writings of Theophrastus (3rd century B.C.) are the first known written source mentioning opium. The word opium derives from the Greek word for juice of a plant, after all, opium is prepared from the juice of Papaver somniferum.

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Alexander the Great introduced opium to the people of Iran and India in 400 A.D.

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History

Galen prescribed opium & recorded the first opium overdose. Opium was part of his therapies known for centuries as “Galenicals.”
Paracelsus introduced opium known as ‘laudanum’, or ‘black drop’ in 1541.
Indian merchants had been selling opium grown in India to the Chinese for hundreds of years. The Chinese were known to cultivate opium, but Indian opium was of higher quality and potency.
Britain further enhanced opium cultivation in India and export to China which led to Opium war when Chinese banned and destroyed imported opium.

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Opium Addiction

The use of the liquid opium called laudanum and patent medicine remedies enabled Europeans and Americans to become legally addicted to products they could purchase over the counter, order through mail, or obtain by a doctor’s prescription at a drugstore.
Many of the remedies, with such brand names as ‘Mother Bailey’s Quieting Syrup’, were spoon-fed to children. Mother’s used opium based remedies to suppress coughs, cure diarrhea and to quiet the occasionally cranky child.
By 1900, China had 13.5 million officially recorded addicts consuming 39,000 metric tons of opium per year. The government reported that 27% of adult Chinese males were opium smokers
Whereas in 1995 there was only 4,000 metric tons of opium cultivated globally
In 2006 about 6100 tonnes was produced in Afghanistan alone

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Narcotic Control

Golden Triangle (Myanmar, Vietnam, Laos and Thailand). And Crescent (Afghanistan, Pakistan, Iran) are major producers, others being Mexico & Columbia
Use of the opium-laced remedies was so widespread that it became a national problem.
International effort to control trade in opium started from 1909 to 1913 was not largely successful
Harrison Narcotics Act of 17 December 1914 in USA made possession of Opium & Cocaine by unauthorised persons illegal with 5 yrs imprisonment and fine.
After World War II the United Nations took over the matter and Convention (New York, 30 March 1961) replaced all previous conventions with one for the whole world

There is a rich and longstanding literature by and about opium users. Perhaps the most famous work of this kind is Thomas De Quincey's Confessions of an English Opium Eater, a work which details both the pleasures and the dangers of the drug. Other works from nineteenth century Britain include "The Lotos-Eaters" by Alfred Lord Tennyson and (some would argue) Goblin Market by Christina Rossetti, which depicts thinly-veiled experiences of addiction and withdrawal. Samuel Taylor Coleridge's poem "Kubla Khan" is also widely considered to be a poem of the opium experience. In the twentieth century Aldous Huxley wrote about the experience of opium. In 1957 the physician Douglas Hubble wrote an article called "Opium Addiction and English Literature" that chronicles the use of opium by prominent English writers, and its influence on their works

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Plant & Its constituents

Each plant about 1 metre high with five to eight capsules (seed pods).
Dried exudate from incised unripe capsule is crude opium
Opium is dark brown, has characteristic smell and bitter taste and contains two groups of alkaloids-

Phenanthrene group: morphine, codeine and thebaine
Benzylisoquinoline group: papaverine and noscapine

Opiates- A narcotic alkaloid derived from opium
Opioids- Drugs having similar action to morphine but not derived from it
The German pharmacist Friedrich Wilhelm Adam Seturner isolated morphine from processed opium, in 1803
Morphine content in crude opium varies and may be as high as 20%. In India it is about 10%

fter full bloom, the petals drop to reveal a small, round grayish-green fruit which continues to develop into an oblate, elongated or globular capsule ( also called the seedpod, bulb or poppy head) about the size of a chicken egg. The skin of the pod encloses the ovary, the walls of which secrete the latex (opium) which collects in a network of vessels and tubes throughout the pod.

Narcotic is a sedative analgesic now banned for its addictive property.

Opium contains a complex mixture of almost twenty-five alkaloids. The principal alkaloid in the mixture, and the one responsible for analgesic activity, is morphine, named after the Roman god of sleep—Morpheus. Although pure morphine was isolated in 1803, it was not until 1833 that chemists at Macfarlane & Co. (now Macfarlane- Smith) in Edinburgh were able to isolate and purify it on a commercial scale.

Codeine is the methyl ether of morphine and is also present in opium. It isused for treating moderate pain, coughs, and diarrhoea.

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OPIUM PREPARATIONS

Raw opium is refined called ‘cooking’ before it becomes suitable for smoking
Chasing the Dragon inhaling the vapor from heated morphine, heroin, oxycodone or opium that has been placed on a piece of foil
Madak- a mixture of tobacco and opium
In form of paregoric to treat diarrhoea.
It was also used in the form of laudanum, an alcoholic tincture
Can be taken by snorting
I.V. (mainlining)
Subcutaneously (Skin popping)
Taken mixed with Cocaine(Speed balling)

Paregoric- a preparation of opium in lower concentration to that of laudanum and which also contained camphor.

Most very raw opium must be processed and refined (called "cooking") before it is suitable for smoking. The raw opium is first dissolved in water and simmered over a low heat. The brown solution is then filtered to remove the vegetable matter, soil, insect material, and other contaminants along with the polysacharrides, lipids and waxes that are components of the poppy pod. The filtrate is then evaporated slowly over a low heat. The result is a smokable form of opium with a considerably higher morphine content percentage-wise than the raw latex. This is then pressed into bricks and either transported to heroin laboratories or used as is.

The smoking of opium does not involve the pyrolysis of the material as might be imagined. Rather the prepared opium is indirectly heated to temperatures at which the active alkaloids, chiefly morphine is vaporized. In the past smokers would lie down with specially designed pipes which had long stems and a metallic receptacle. A small amount of opium up to the size of a pea would be placed in the receptacle and the material heated indirectly by means of a candle or lamp. The smoker would lie on his or her side and inhale the vaporized morphine as needed. The pipe was commonly designed in a rounded cross section, so as to enable the metallic receptacle to be rotated into the heat source and then rest back upright as required. The pea sized material could be sufficient for up to an hour of intermittent use.

Opium is more traditionally used in the form of paregoric to treat diarrhea. It was also used in the form of laudanum, an alcoholic tincture which was commonly used as a pain medication. Samuel Taylor Coleridge is famously known to have composed his incomplete poem Kubla Khan while intoxicated with laudanum.

Most opium imported into the United States is broken down into its alkaloid constituents. These alkaloids are divided into two distinct chemical classes, phenanthrenes and isoquinolines. The principal phenanthrenes are morphine, codeine, and thebaine, while the isoquinolines have no significant central nervous system effects and are not regulated under the Controlled Substances Act. Opium is also processed into heroin, also called ‘brown sugar’ and most current drug use occurs with processed derivatives rather than with raw opium.

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Claude Monet's Of Painting 1873 'wife & son’ strolling among poppies Judged the best picture for Mother’s day of 2011

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Absorption, Metabolism And Excretion

Taken orally, by smoking or by injection
Part of consumed opium conjugated in liver with glucuronic acid
Unchanged and conjugated both are excreted mainly through urine but also through excretion in, bile, stomach, intestine, colon, in milk, and also in saliva
Heroin is converted in to morphine in body by liver

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ACUTE POISONING

Symptoms of opium poisoning is that of morphine poisoning
Symptoms begin within an hour of oral intake but within minutes of parenteral
Opium depresses all centers except vomiting, occulomotor, and sweating centers
Classical triad of opium/morphine/ heroin overdose is meiosis, and respiratory depression in a patient in coma

Give Naloxone immediately

The central Respiratory depression more marked in children & old, affects rate, minute vol. & tidal air
Clinical effect of opium poisoning is manifested in three stages

�One field of study in answering these questions is learning about the opium receptor. The most logical question to ask, why would the body, which doesn't self-produce opium or opioids, respond to such drugs? In search of this question, scientists discovered the class of naturally occurring molecules in the body called endorphins. In fact, the structure of morphine, which can be representative of most opioids, is quite similar to the molecular structure of endorphins which helps explain why these molecules would bind to the same receptor. When the body experiences pain or stress, the body manufactures these chemical endorphins to relieve some of this pain and thus they were termed the "feel-good" chemicals (WWW 6). When a person exercises, or is going into labor, or doing some other stressful activity, these endorphins flood the synaptic space between nerve cells and usually inhibit neuron firing which would create the analgesic effect (WWW 6). Anyone who has experienced taking opium or morphine knows that the euphoric and analgesic effects felt by these drugs is nothing like anything felt under natural conditions and the reason is because opium is unnaturally inserted into the body and thus is in uncontrollable excess, whereas endorphin levels are highly regulated by the body (WWW 6). ��The next question to be asked is, where are these receptors located? Naloxone is a synthetic opiate receptor antagonist which binds very tightly to the receptor. By fluorescently-labeling these molecules, it was found where, in the body, these opium receptors were located (WWW 7). Thus far, research only indicates that these receptors are only found in the central nervous system and primarily in the brain (Blum & Simon, 1977). High levels of binding were found in the limbic system excluding the hippocampal regions, the locus coeruleus and the pulvinar (Blum & Simon, 1977). By using receptor binding assays and gene cloning techniques, three opiate receptor subtypes have been discovered - mu, delta, and kappa. Some opiates have specificity for certain receptor subtypes. If the exact effects of each one of these receptors can be determined, along with determining which opiates bind to which receptor, perhaps it will be possible to find or produce pain-relieving drugs that will not have the side-effects that opium or morphine produce such as depressed breathing rate or even addiction

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Stage of Excitation

The stage is of short duration in cases of overdose.
There is euphoria and increased sense of well being
Flushing of face
Constricted pupil
Emotional bonding and talkativeness
Gradually becomes restless and dysphoric
May experience hallucinations

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Stage of Stupor

Pin point pupil
Lack of attention
Giddiness and ataxia
Nausea & vomiting
Disorientation
Drowsiness goes to sleep
Stupor
Lips may be cyanosed
Constipation is a regular feature in persons taking opiates

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Stage of Narcosis

Coma
Skin cold profuse perspiration
Muscles become flaccid
Diminished and then absent reflexes
Urinary retention
Hypothermia
Hypotension
Bradycardia pulse slow and feeble
Convulsions
Respiratory depression- slow(4-6 per minute)
Non-cardiogenic pulmonary oedema
Death

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Differential Diagnosis

CerebroVascular Accident & brain injury
Poisopning by alcohol, barbiturates, CO, benzodiazepines, carbolic acid, organophosphate
Metabolic disorders like- Diabetic Uremic and hepatic coma.
CNS infections:- Meningitis, encephalitis & encephalopathy, Cerebral malaria
Others like Epileptic, & hysterical coma, heat hyperpyrexia.

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Management

Naloxone- 0.4 mg IV may be repeated every 15 minutes up to a dose of 10 mg.
2mg naloxone in IV drip given slowly
Managing respiratory depression by Oxygen/ assisted ventilation/ Endotracheal intubation and suction may be needed
Control blood pressure by fluid and vesopressors
Fluid and electrolyte balance to be maintained
Management of cardiac arrhythmia
New antidote Nalmefene/ naltrexone is considered superior to Naloxone and longer acting

risk of precipitated withdrawal symptoms (e.g. sweating, agitation, irritability, HTN); close monitoring is needed when Naloxone or Nalmefene is bing used

Dose of Nalmefene:Initial: 0.5 mg/70 kg; followed by a 2nd dose of 1 mg/70 kg after 2-5 min if needed. If no clinical response observed after total dose of 1.5 mg/kg, additional doses are unlikely to provide therapeutic effect. Opioid-dependent patients: Initial: A challenge dose of 0.1 mg/70 kg; if no withdrawal symptoms are observed in 2 min, follow the incremental dosing recommende

Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously. Naloxone hydrochloride injection may be diluted for intravenous infusion in Sodium Chloride Injection 0.9% or Dextrose Injection 5%. The addition of 2 mg of Naloxone in 500 mL of either solution provides a concentration of 0.004 mg/mL. Mixtures should be used within 24 hours An initial dose of 0.4 mg to 2 mg of Naloxone hydrochloride may be administered intravenously. If the desired degree of counteraction and improvement in respiratory functions is not obtained, it may be repeated at 2 to 3 minute intervals. If no response is observed after 10 mg of Naloxone hydrochloride have been administered, the diagnosis of narcotic-induced or partial narcotic-induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if the intravenous route is not available. Since the duration of action of some narcotics may exceed that of Naloxone, the patient should be kept under continued surveillance and repeated doses of Naloxone should be administered, as necessary.

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Management

Gastric lavage using 1 in 5000 dilution of potassium permanganate (KMnO4) as opium slowly absorbed from GIT and also secreted in stomach after parental administration
Activated charcoal a substitute for lavage
Orally magsulph 20gm or enema with 30 gm sodium sulphate in water twice daily
Whole bowel irrigation in body packers

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Management of Addiction

Highly complex problem and needs specialized treatment in de-addiction centre
Gradual reduction of dose
Improving the nutritional status
Tranquillisers
Social support and psychotherapy
There should be no scope of self medication with narcotic
Methadone used to be given to addicts as substitute but this also causes addiction.
Propranolol a betaadrenergic blocker helps in overcoming anxiety and craving for opium

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Withdrawal Syndrome

Begins within a few hours of stoppage
Headache, profuse sweating, and stomach cramps of increasing severity
Pain in bone and muscle with twitching of muscles, shivering, goose skin
Irritability, anxiety, insomnia, depressed mood
Psychological symptoms of withdrawal start getting worse after physical symptoms subside most important being craving for the drug and associated irritation and anxiety

begin within a few hours of your missed dose. Headaches, profuse sweating and stomach cramps generally increase in intensity and expand to include bone and muscle aches and pains, leg twitches when you try and rest, insomnia despite intense fatigue, and overwhelming irritability and anxiety as well as depression. Psychological opiate addiction withdrawal symptoms begin during the physical opiate addiction withdrawal symptoms but likely won’t become the primary focus of your opiate detox until after the physical symptoms have subsided. These psychological symptoms include anxiety, depression and cravings for your opiate drug of choice, and they can persist long after the physical withdrawal symptoms are under control. It’s important that you have the support of psychological professionals who specialize in substance abuse and addiction treatment in order to get the help that you need

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Fatal Dose Fatal Period

Fatal Dose

Crude Opium:- 500mg- 2gm
Morphine:- 200 -250mg orally; 80-100 mg parenterally
Heroin:- 50mg
Pethidine:- 1gm
Codeine:- 500mg-800 mg/7-14 mg / kg
Methadone 100mg

Fatal Period:- 6-12 hours

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Autopsy Findings

Emaciated body, skin loose
Injection marks, tattoos, scarring of skin
Froth from mouth and nose
Signs of asphyxia cyanosed body almost looking black
Prominent post-mortem lividity
Smell of opium in gastric content
Pulmonary oedema and congestion
Cerebral oedema
All organs congested, trachea contains frothy secretions
Blood dark and fluid
Stomach may contain opium or its smell

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Medico-legal Aspects

It s a poison of choice to commit suicide
Accidental overdose in addicts is common because tolerance is slow on effect at respiratory center but pronounced on pleasure satisfaction so the addict inadvertently takes larger dose
Homicidal rare in adults but common in infants and children
Race horse doping to improve performance.
Used as an aphrodisiac
Opioid dependence seen in persons with chronic painful conditions
Moral degradation leading to crime to procure the drug as they increasingly require higher doses

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Medico-legal Aspects

Illicit drug use and mainlining causes diseases due to infection like hepatitis, AIDS, endocarditis, pneumonia, septicemia, osteomyelitis and tetanus, thrombophlebitis.
Due to dangerous contaminants peripheral neuropathy, amblyopia, degeneration of globus pallidus, parkinsonism, and transverse myelitis

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