A is for Arsenic (26 page)

Opium addiction

An addiction to opium through ingesting it is actually quite difficult to acquire. Opium with limited processing and purification represents a diluted form of its active components, and when eaten or drunk these compounds are metabolised too quickly to produce the euphoria experience by injection of the drug. So, large quantities of opium have to be consumed to produce an addiction, but when prices collapsed as they did in nineteenth-century Europe and North America many people were able to do just that. Those taking high doses may have experienced vivid, spectacular and sometimes terrifying dreams, which is perhaps why opium became popular with artists.

The isolation and increasing availability of the active principles within opium – morphine – combined with the invention of the hypodermic syringe (around 1848) led to a dramatic increase in addiction. When the drug is delivered directly into the bloodstream, the feelings of euphoria are more rapidly achieved than when it is ingested (by eating it), and there is very little time to metabolise the drug to less potent compounds. Despite increasing and occasionally very public cases of addiction, nothing was done to regulate the sale and use of opium in Britain until the 1868 Pharmacy Act. This Act limited the sale of opium and related products to licensed premises, but the laws were largely ignored until greater penalties and more serious enforcement were introduced in 1908.

Opium contains around 50 different alkaloids, only some of which are of pharmacological interest. These include morphine
and codeine; noscapine,
⁶⁸
which has cough-suppressant properties; and papavereine, a smooth muscle relaxant. Compounds extracted from poppies are classed as opiates, whereas those that produce opiate or morphine-like reactions in the body are called opioids. Opium is still part of the
British Pharmacopoeia
even today,
⁶⁹
but the number of preparations has fallen from an all-time high of 38 in 1864 to just four in 1998. Opium prescriptions are now very rare; it is the isolated and purified opiates and opioids that are used in medicine.

Morphine

Of all the alkaloids found within the poppy plant, morphine is the best known, and it has powerful pain-relieving properties. German chemist Friedrich Sertürner (1783–1841) was the first to isolate it from opium. When Sertürner was just 16 years old, he heard doctors complaining that some samples of opium were more potent than others. He reasoned that opium was an impure mixture of compounds containing perhaps one active ingredient, and the quantity of this was likely to vary. It took him several years to isolate a white crystalline solid from raw opium, and he chose to test this in powder form on himself and three friends. They experienced severe nausea, and fell asleep for 24 hours. Sertürner therefore named the compound morphine, after Morpheus, the Greek god of dreams and son of Somnus, the god (or personification) of sleep who gives his name to the opium poppy's specific name,
somniferum
. Hardly anyone paid attention to this momentous discovery at the time. Later, when suffering from severe toothache, the pain of which even opium could not relieve, Sertürner tried his white powder again, but in a smaller dose this time. He remained awake, and his toothache disappeared completely. This time the medical profession paid attention. The benefits of morphine over opium were obvious.

Codeine

More compounds have since been isolated from opium that have roles in modern medicine. Codeine, the second most abundant alkaloid in opium, was first isolated in 1832 by Pierre Jean Robiquet (1780–1840). Structurally, codeine is very similar to morphine, differing by only one methyl group (–CH
3
). Inside the body, enzymes remove the methyl group and replace it with a hydrogen atom, effectively converting codeine into morphine. Codeine therefore has moderate pain-relieving properties, but it is much less addictive.
⁷⁰
It is still used in cough syrups because it relaxes the muscles in the throat and dries up secretions. It is also used in diarrhoea remedies, because codeine slows the muscles controlling the gut (so the watery faeces cannot be so easily expelled).

Diamorphine

By the late nineteenth century the search was on for ever more potent pain relievers, and chemists in pharmaceutical laboratories tinkered with the structure of morphine to see if the drug could be improved. One successful modification was the addition of two acetyl groups (CH
3
C(O)–) to form diacetylmorphine or diamorphine. The addition of the acetyl groups increases the solubility of the molecule in fats, and enables it to cross the blood-brain barrier more easily than morphine can. Once inside the brain, enzymes quickly remove the acetyl groups, converting the diamorphine back into morphine, where it can interact directly with opioid receptors in the brain. Consequently diamorphine acts more quickly than morphine, and it is therefore far more potent. It makes you feel like a hero, so they called it heroin. Diamorphine was first made in the laboratories of the German chemical company Bayer. The chemical process to convert morphine to heroin was simple, allowing huge quantities of this powerful drug to
be produced cheaply and easily. It was released onto the market in 1898.

Initially heroin was touted as an effective and non-addictive form of morphine. It was recommended for adults and children suffering any form of pain or discomfort. Heroin is more effective at suppressing coughs, and causes less constipation in its users than morphine. It seemed an ideal drug. However, the intensity of the high and the rapidity with which it can be achieved compared to morphine makes it far more addictive. The withdrawal symptoms from the drug are also more intense than with morphine, increasing the desire for another hit. Four years after heroin's release onto the market its addictive properties had been realised, and many countries had banned it. Most countries around the world still ban the import, production and sale of heroin, as the risk of addiction is thought to far outweigh the benefits of the drug. Britain is a notable exception; it continues to prescribe the drug in palliative care, but under very strict rules and regulations. When prescribed medically the name diamorphine (or diacetylmorphine) is used; ‘heroin' is the name usually reserved for the drug when it is manufactured, transported and sold illegally. The ease of growing poppies, extracting opium, refining the morphine it contains and modifying this into heroin make it an extremely profitable street drug (the main difficulty being that you need an awful lot of raw material). One kilogram of raw opium can produce 100g of morphine or heroin
⁷¹
. It would take an annual harvest of at least 10,000 poppy plants to supply a typical heroin user for a year.

How opiates work

Once absorbed into the body, the effects of morphine, codeine and heroin are similar, as enzymes inside the body quickly
convert codeine and heroin into morphine. Heroin is inactive in the body, and must be converted into morphine and other compounds to produce an effect. Direct injection into the bloodstream is the most effective way of delivering these drugs and, using this method of administration, their effects are observable almost instantly. Ingested morphine, codeine and heroin are absorbed into the bloodstream from all parts of the gastrointestinal tract, except the mouth. The liver is the main organ of metabolism; most ingested heroin is converted into morphine in this organ within two or three minutes.

Morphine mimics endogenous (meaning ‘synthesised by the body') opioids such as endorphins (or ‘endogenous morphine'). Structurally, endorphins are very different from morphine, but the results in the body are similar. Endorphins and morphine both activate opioid receptors, inducing feelings of pain relief, sleep, pleasure and relaxation.

Opioid receptors are found in the nerve cells of the brain, spinal cord and gut. There are four main types;
d
(delta),
m
(mu),
k
(kappa) and nociception (NOP) receptors, and there are further subtypes within these groups. Interaction of morphine with
m
receptors leads to pain relief, but also euphoria and slow, shallow breathing. This interaction seems to be largely responsible for addicts' dependence on morphine. The
d
and
k
receptor interactions also produce some pain relief, and binding with
k
may be responsible for some sedative effects. NOP receptors appear to be involved in the regulation of several brain functions, instinctive and emotional responses in particular.

From a medical point of view, the most important effect produced by morphine is pain relief. Morphine is still considered to be one of the best pain-relieving medications available, and it is the gold standard to which new drugs are compared. The interaction of morphine with opioid receptors in the cerebral cortex, the higher functioning part of the brain, modifies our
perception
of pain. A person under the influence of morphine may continue to be aware of pain, but is no longer concerned about it. Morphine is most effective when given as a
subcutaneous or intravenous injection, in a dose of 10mg for 70kg of body weight; oral administration of morphine is only one-sixth as effective. Morphine is poorly soluble in water and is usually administered as a salt, often the hydrochloride or sulfate; these are colourless and odourless, but have a bitter taste.

The breakdown of morphine in the body produces compounds known as glucuronide conjugates. These are water-soluble and can be excreted in the urine or in bile. Some of these compounds also have pain-relieving properties. For example, a trial on 20 cancer patients reported that treatment with morphine-6-glucuronide gave pain relief without sedation or euphoria.

The effects of morphine generally last between three and six hours, but this varies between individuals. This relatively short time-span often means that further doses may be required to manage severe pain. After the first few doses the body begins to become accustomed to the presence of morphine, and ever-higher doses are required for effective pain relief. After daily treatment of a few weeks, a patient may need 100 times more morphine than at the start. The body adapts to the pain relief quicker than to the level of euphoria, so increasing the dosage to manage pain also increases the feelings of euphoria. This is the development of tolerance. Opioid receptors are normally stimulated by chemicals produced within the body. For the body to still respond to these endogenous compounds in the presence of morphine, more receptors must be produced. As the number of receptors rises, the same amount of morphine will no longer produce the same effect, so the dose must be increased; an ever-increasing amount of morphine is required to achieve the same initial levels of relief. The longer treatment is continued, the more likely it is that an addiction will form.

The euphoric and addictive properties of morphine are ultimately caused by the drug's effect on dopamine levels in the
brain. Opioid receptors are indirectly involved in the release of dopamine, a chemical within the body that plays an important role in feelings of well-being. The brain releases dopamine to reinforce behaviours that are important for survival and persistence of the species – eating food, for example, and sexual contact. The interaction of morphine with opioid receptors triggers other receptors to release more dopamine.

When the body has become accustomed to the presence of morphine, a sudden decrease or absence of the drug can produce withdrawal symptoms. Cells suddenly find that there are a large number of opioid receptors with little or no morphine to stimulate them. This can lead to a wide range of symptoms that include anxiety, sweating, vomiting, diarrhoea, chills (leading to goose bumps, and the origin of the phrase ‘going cold turkey'), bone pain, heart arrhythmias, depression and headaches. These symptoms, though very unpleasant and unquestionably deeply distressing, are rarely fatal. With prolonged abstinence the number of opioid receptors decreases, and after a number of weeks or months they can return to normal. An addict returning to heroin or morphine use after a prolonged absence can easily overdose by using their ‘normal' hit, because they have lost their tolerance to the drug. However, it should be said that addiction rarely occurs in medical users of morphine and related products. For example, 90 per cent of American soldiers who used heroin regularly in Vietnam did not use it again after returning home.

The interaction of morphine with opioid receptors in other parts of the body produces some of the side effects experienced by its users. Interaction with opioid receptors in the gut reduces the activity of the muscles that move food through the intestines. The result is often constipation, but a more serious consequence can be a delay in the release of drugs because of their retention in the stomach for hours longer than usual. Other common side effects include pinpoint pupils, nausea, vomiting, itching, fainting upon standing up, mental ‘clouding' and retention of urine. Some side effects of opiates and opioids can be advantageous. Morphine-like drugs, such as codeine, are still used in cough
medicines, to suppress the cough reflex, and to treat irritable bowel syndrome. But in some people the side effects can be more serious. Some individuals are allergic to morphine, and in rare cases morphine may cause mania, delirium and, rarely in adults but more commonly in infants, convulsions.