opium

Morphine: a drug of natural origin

Morphine is the reference drug for the therapy of severe and chronic pain, obtained from opium, a latex extracted from poppy capsules. An overview of the effects of morphine in our body, the extraction process and the main drugs available derived from morphine.

The term opioid applies to any substance, whether endogenous or of synthetic origin, which produces a morphine-like effect. In fact, in our organism there are naturally present substances that cause a pain-relieving effect similar to morphine, released by specialized cells, such as neurons. These substances were first discovered in the 1970s by researchers Hughes and Kosterlitz, who isolated and identified the structures of two endogenous pentapeptides:met-enkephalin is leu-enkephalin. The discovery of enkephalins was soon followed by the identification of other endogenous substances, such as endorphins, dynorphins is endomorphins.

All these biological neurotransmitters, as well as morphine and derived drugs, perform their function in the body by specifically binding and activating the so-called opioid receptors. To distinguish them they have been divided into three main groups:

- Mu (m);

- Delta (d);

- Kappa (k).

The presence of receptor subtypes is not excluded and the fourth member of the opioid family, the NOP receptor, has recently been discovered.

All types of receptors are found in the spinal cord, brain and digestive system and each plays a role in mediating pain, inducing euphoria, causing constipation and many other functions.

Table 1 describes the main actions performed by the receptors when activated by opioid drugs or by endogenous peptides and the intensity of the effect caused by the activation of the specific receptor.

 Mu (noun)Delta (d)Kappa (k)
Analgesia (pain relieving effect)
Supraspinal+++--
Spinal++++-
Peripheral++-++
Respiratory depression+++++-
Pupillary constriction (miosis)++-+
Reduced gastrointestinal motility+++++
Euphoria+++--
Dysphoria--+++
Sedation++-++
Physical addiction+++-+

It is important to emphasize that different endogenous drugs and peptides have different affinities for individual receptors, for example morphine and heroin bind more m-receptors, while the drug pentazocine, an opioid pain reliever drug, performs its function by binding the k-receptors. , which however also mediate delirium and apathetic hallucination, important side effects.

Natural derivation of morphine

Morphine is the gold standard for pain therapy. It is a substance with a very complex chemical structure, of natural origin, is isolated from a mixture of substances known as opium.

The use of plants or plant extracts for therapeutic purposes is as old as man, and herbal medicine and folk medicine, both ancient and modern, are at the origin of many therapies. Opium in particular has been extracted since ancient times from the immature capsules of the poppy variety Papaver somniferum, furthermore, the synthesis in the laboratory would be too expensive.

The writings of Theophrastus, philosopher and botanist of ancient Greece, disciple of Aristotle, document the use of opium in medicine as early as 200 BC It is known to historians and anthropologists that the Sumerians used opium as early as 3500 BC and who handed down this custom to the Egyptians who made use of it for its hypnotic properties; the use of opium as a narcotic and as a narcotic spread in Europe, particularly in Great Britain, starting from the 17th century, and consumed as a hydroalcoholic tincture called laudanum.

Thomas Sydenham (1624 - 1689), the English doctor who laid the foundations of clinical methodology, still remarks in the 17th century that "without opium I would not have practiced medicine", while the English writer Thomas de Quincey (1785 - 1859 ) described in the book “Confessions of an Opium Smoker” the sensations experienced when using it as an inhaled drug.

Twenty-five compounds called alkaloids have been isolated from opium, due to their structure and chemical properties, but only morphine, its methyl ether codeine and papaverine are of practical clinical interest.

The first to isolate morphine from opium was the German pharmacist Friedrich SertĂĽrner (1783 - 1841) in 1803, at the age of only twenty. The name morphine was given by SertĂĽrner referring the hypnotic properties of the compound to the Greek deity Morpheus, god of sleep.

Historically, opioid analgesics were called narcotic analgesics. Literally narcotic analgesic means that the substance causes sleep or loss of awareness in conjunction with its analgesic effect. The term narcotic has been associated with the addictive properties of opioids and other agents that depress the nervous system. The term analgesics refers to agents that relieve pain. Acute pain of severe intensity or chronic pain is currently effectively treated with opioid-type agents.

Papaver somniferum

The plant is probably native to the north-eastern regions of the Mediterranean, where opium was initially produced. Today it is cultivated in many countries of the world and the cultivation of poppy for the production of opium and its alkaloids is controlled by theInternational Narcotics Control Board of the United Nations. Turkey, Iran and India are the most important licensed opium producers.

However, in many countries there is the problem of illegal opium production, particularly in the so-called region ofgolden triangle (Burma, Thailand, Laos) and of the golden sickle (Pakistan, Afghanistan and India). Opium is also produced in China and Korea, where it is used in traditional medicine.

Opium collection and preparation: the latex is harvested when the immature bulb reaches the size of about 4 centimeters in diameter, and the color of the plant is changing from green to yellow.

The bulbs are engraved with a knife and the cut can be made along the circumference of the capsule or vertically.

When the cut is made, the latex, which immediately comes out, is very liquid and must not be collected. The latex, which is white, quickly congeals in the air and becomes brownish. The day following the engraving, the opium is harvested with an iron spatula or knife.

Each capsule can be scored 8-10 times and approximately 20,000 capsules are required to obtain 1 kg of opium. When harvesting, the climate should be dry and warm. Rain in the period between opium cutting and harvesting would ruin the harvest. As the latex is collected, first small clusters are formed, then loaves that dry in the air (the water content is reduced by 20%). After 1-2 months from the harvest, the product is given its definitive commercial form, wrapped in poppy leaves and dried in the shade, then exported (Table 2).

OpiumPackaging formWeight% of morphine
Turkish (or Smyrna)Cubes (10-13 cm on each side)2 kg12-15%
Yugoslav (or Serbian or Thessaloniki)Flat or ovoid0.2 kg16-17%
Indian (or Benares)Squared (wrapped in white wax paper)5 kg8-13%
PersianSticks (10 cm long and wrapped in red paper)0.3 kg5-10%
Egyptian (or Thebaic)Round masses (8-10 cm in diameter)Different weight3-7%
ChineseDifferent shapeDifferent weight3-5%

IN-DEPTH PHARMACOLOGY

Main opioid drugs

There morphine it is the opioid drug of choice and is the progenitor of all its synthetic and semi-synthetic derivatives. The daily dosage may vary in relation to the route of administration and the duration of its use; generally for the parenteral route the dosage is 10/20 mg per day, while for the oral route the dosage increases since the oral bioavailability is 6 times lower than for the parenteral route.

There codeine is another widely used opioid drug, it is available for example in the well-known specialty Tachidol® in combination with paracetamol for the synergistic pain-relieving effect. The 10% of the administered codeine is transformed into morphine by the metabolism of our body, however the codeine shows one sixth of the pain relieving effect of morphine overall.

L'oxycodone is another very popular opioid drug, and is well suited for oral administration; two well-known medical specialties based on oxycodone are Oxicontin® and Depalgos®, the latter associated with paracetamol. Oxycodone is used against severe pain, it is a very powerful drug, its effect is 10 times higher than that of morphine.

A very powerful opioid drug is instead the fentanyl, used in pain therapy in patients with terminal illnesses, or against severe pain; it can be administered transdermally (through the skin) following the application of a special patch, the specialty is known by the name Durogesic®; the potency of fentanyl is 30/40 times that of morphine.

L'heroin it is a synthetic derivative of morphine, present in small percentages in the mixture of substances that make up opium; it is sadly known for its use as a narcotic, for the harmful effects caused to the organism and for the withdrawal syndromes induced by acute suspension; it is also known by the name of diacetylmorphine or diamorphine, very similar in structure and effect to morphine; addiction to heroin is identical to that of morphine, but is established more quickly and with much lower amounts of the substance. In the past it has been used as a pain reliever drug, but the rapid addiction that develops after the first use has caused it to be suspended from the market.

Methadone is buprenorphine they are synthetic drugs used for heroin detoxification, in fact they are very suitable for oral administration; methadone and buprenorphine occupy the opioid receptor for a long time as a heroin antagonist and prevent its binding following subsequent ingestions; they are administered daily at gradually lower doses, until complete suspension. They cause less euphoria than heroin and morphine

The dextromethorphan it is a drug derived from structural modifications of morphine, which cause the loss of affinity for opioid receptors, while maintaining a certain antitussive activity; it is a very popular drug, and is found in pharmacies as an over-the-counter drug, an example is syrup Bronchenolo®. Also the active ingredient loperamide it is a non-narcotic opioid derivative, as it is unable to bind opioid receptors located in the central nervous system. It carries out its activity by activating the opioid receptors placed in the digestive system, in particular it is used as an antidiarrheal in the specialty Imodium®.

Finally the naloxone is the useful antidote against acute opioid poisoning, available under the trade name Narcan®, a drug that all pharmacies must keep by law. Naloxone binds opioid receptors, displacing heroin or morphine in severe intoxication, but does not cause any morphine-like effects. Acute opioid poisoning causes severe respiratory depression, which if left untreated can lead to death. Narcan-Neonatal® hospital medicine specialty based on reduced dose naloxone is also available, for administration in infants born to drug addicted mothers with breathing difficulties.

Effects of morphine on the central nervous system

- Analgesia: morphine is effective against most types of acute and chronic pain, but is much less useful in neuropathic pain syndromes. Morphine also reduces the emotional component of pain.

- Euphoria: Morphine induces a sense of happiness and well-being by reducing the agitation and anxiety associated with painful illnesses or injuries.

- Respiratory depression: normal analgesic doses of morphine cause respiratory depression, with an increase in the concentration of CO2 in arterial blood; morphine activates the opioid m-receptors present in the brain bulb, in the center of the breath, causing depression. Respiratory depression is certainly the most dangerous side effect of these drugs and occurs at therapeutic doses. This effect is the most common cause of death from acute opioid intoxication.

- Nausea and vomiting: these effects occur in about 40% of patients administered morphine, and are apparently not separable from the analgesic effect. Nausea and vomiting are usually transient and disappear upon repeated administration.

- Pupillary constriction: myosis is mediated by the stimulation of the mek receptors present in the oculomotor nucleus. Pinpoint pupils are a characteristic diagnosis for opioid overdose.

Effects of morphine in the digestive system

- Gastrointestinal motility: morphine reduces the motility of many parts of the gastrointestinal system, causing constipation which can also be serious and dangerous for the patient. The noticeable increase in gastric emptying time can greatly delay the absorption of other drugs.

- Increased biliary pressure: the pressure in the biliary tract increases due to the contraction of the gallbladder and the constriction of the biliary sphincter. Opioids should not be given to patients suffering from pain caused by biliary colic.

Other effects of morphine

- Release of histamine: morphine causes the release of histamine by mast cells; this release may cause local effects such as itching, hives at the injection site, or systemic effects such as bronchoconstriction and hypotension. Morphine should not be given to patients with asthma.

- Immunosuppression: the immune system becomes depressed following abuse, making the body more likely to get infections.

Addiction, tolerance, dependence: tolerance to opioids, or the increase in the dose necessary to produce a given pharmacological effect, develops over a few days of use. Physical dependence, on the other hand, refers to a state in which drug withdrawal causes adverse physiological effects such as withdrawal syndrome. These phenomena reach a certain severity if opioids are administered for more than a few days. However, they should not be confused with addiction, in which physical dependence is much more pronounced and psychological dependence or "strong desire" is the main driving force.

Related article: Pain

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