Opium has been known for millennia as a pain reliever and its use for surgical analgesia has been recorded for several centuries. The Sumerian clay tablet (about 2100 BC) is the world’s oldest recorded list of medical prescriptions. The first authentic reference to the milky juice of the poppy we find by Theophrastus at the beginning of the third century BC.
In the first century the opium poppy and opium were known by Dioscorides (recommended patients should take mandrake (contains scopolamine and atropine) mixed with wine, before limb amputation), Pliny and Celsus (who suggested the use of opium before surgery) and later by Galen. The Arabic physicians used opium very extensively and about 1000 AD it was recommended by Avicenna especially in diarrhoea and diseases of the eye.
Morphine was discovered by Freidrich Wilhelm Adam Serturner (1783-1841), a 21-year-old pharmacist’s assistant; he is also known as the founder of alkaloid research. He wondered about the medicinal properties of opium, which was widely used by 18th-century physicians. In a series of experiments, performed in his spare time and published in 1806, he managed to isolate an organic alkaloid compound from the resinous gum secreted by Papaver somniferum–the opium poppy.
He found that opium with the alkaloid removed had no effect on animals, but the alkaloid itself had 10 times the power of processed opium. Sertuner named that substance morphine, after Morpheus, the Greek god of dreams, for its tendency to cause sleep.
As he predicted, chemists and physicians soon grew interested in his discoveries. Serturner’s crystallization of morphine was the first isolation of a natural plant alkaloid. It sparked the study of alkaloid chemistry and hastened the emergence of the modern pharmaceutical industry. Other researchers soon began to isolate similar alkaloids from organic substances, such as strychnine in 1817, caffeine in 1820 and nicotine in 1828. In 1831, Serturner won a lucrative prize for the discovery.
In 1818, French physician Francois Magendie published a paper that described how morphine brought pain relief and much-needed sleep to an ailing young girl. This stimulated widespread medical interest. By the mid-1820s morphine was widely available in Western Europe in standardized doses from several sources, including the Darmstadt chemical company started by Heinrich Emanuel Merck.
By the 1850s the first reliable syringes were developed, and injected morphine became a standard method of reducing pain during and after surgery. Since then, various delivery systems for morphine have been developed, including epidural injection and pumps that allow patient-controlled analgesia.
Although morphine was originally touted as a cure for pain relief, even for opium addiction, by the 1870s physicians had become increasingly aware of its own addictive properties. Ironically, C.R. Alder Wright, a chemist at a London hospital who was searching for a non-addictive alternative to morphine, came up with a more potent narcotic, diacetylmorphine, in 1874.
Heinrich Dreser, a chemist at Bayer Laboratories developed and tested Wright’s new semi-synthetic drug on animals, humans, and most notably himself. Finding that it was a powerful painkiller and appeared effective for a variety of respiratory ailments, Bayer began producing and marketing this drug as an analgesic and a ‘sedative for coughs’ in 1898. Because of its ‘heroic’ ability to relieve pain, they called it heroin.
The medical profession initially welcomed the new drug but soon recognized its addictive potential. In 1913, Bayer halted production, edited the drug out of their official company history and focused instead on marketing their second blockbuster drug, aspirin. [See picture: Opium puppy Morphine]
Simplified preparations of opium such as tinctura opii were used up to about 2000 in Denmark. A more safe and standardized effect was obtained by the pure opium and several morphine-like drugs have been synthesized to minimize adverse effects and abuse potential. NATURE Morphine is the most abundant opiate found in opium, the dried latex which is extracted from the poppy plant.
In the brain of mammals, morphine is detectable in trace steady-state concentrations. The human body also produces endorphins, which are chemically related endogenous opioid peptides that function as neuropeptides and have similar effects to morphine. Morphine is an endogenous opioid in humans that can be synthesized by and released from various human cells, including white blood cells. CYP2D6, a cytochrome P450 isoenzyme, catalyses the biosynthesis of morphine from codeine and dopamine from tyramine along the biosynthetic pathway of morphine in humans. MEDICAL USE Administration: Morphine can be given orally or parenterally, as well as epidurally or intrathecally in the spinal cord and several other routes of administration.
Pharmacological action (Absorption & Metabolism):
Morphine primarily metabolised in the liver which means, it is subjected to extensive first-pass metabolism (therefore, if it is taken orally, only 40% to 50% of the dose reaches the central nervous system).
Like other opioids bearing a hydroxyl group, morphine is conjugated to glucuronic acid and eliminated renally (about 87% of the dose of morphine is excreted in the urine within 72 h of administration). Glucuronidation of the OH-group at position 6, unlike that at position 3, does not affect affinity. The extent to which the 6-glucuronide contributes to the analgesic action remains uncertain at present. At any rate, the activity of this polar metabolite needs to be considered in renal insufficiency (lower dosage or longer dosing interval).
Absorption: Bioavailability is approximately 30%.
Pharmacodynamics: The precise mechanism of the analgesic action of morphine is unknown. However, specific CNS opiate receptors have been identified and likely play a role in the expression of analgesic effects. Morphine is a narcotic pain management agent indicated for the relief of pain in patients who require opioid analgesics for more than a few days. Morphine interacts predominantly with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve.
In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Activation of opioid receptors in the enteric nerve plexus results in inhibition of propulsive motor activity and enhancement of segmentation activity. This antidiarrheal effect was formerly induced by application of opium tincture (paregoric) containing morphine. Because of the CNS effects (sedation, respiratory depression, physical dependence), derivatives with peripheral actions have been developed.
Its primary actions of therapeutic value are analgesia and sedation. Morphine appears to increase the patient’s tolerance for pain and to decrease discomfort, although the presence of the pain itself may still be recognized. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Opioids also produce respiratory depression by direct action on brain stem respiratory centres.
The mechanism of respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centres to increases in carbon dioxide tension and to electrical stimulation. It has been shown that morphine binds to and inhibits GABA inhibitory interneurons. These interneurons normally inhibit the descending pain inhibition pathway. So, without the inhibitory signals, pain modulation can proceed downstream.
Pharmacokinetics: When morphine is given in an appropriate dose, its effect is an excellent pain relief by influencing nociceptive pathways in the CNS. In excessive doses/ overdose, it inhibits the respiratory centre and makes apnoea imminent, which may also lead to death.
Increased sensitivity of the respiratory centre to morphine is found in patients with chronic lung disease, in neonates, or during concurrent exposure to other respiratory depressant agents. Genetic anomalies of metabolism may also lead to hypersensitivity.
- Morphine is beneficial in reducing the symptom of shortness of breath due to both cancer and noncancer causes.
- Morphine is used primarily to treat both acute and chronic severe pain (labour, myocardial infarction, etc).
Adverse Effects
- Morphine reduces the intestinal tract motility by acting on the myenteric leading to constipation (it can be used as antidiarrheal drug). • Human cognitive and performance impairment (sensory, motor, or attentional abilities).
- Morphine, like other opioids, often causes hypogonadism and hormone imbalances in chronic users of both sexes (i.e. by interfering with the menstruation by suppressing levels of luteinizing hormone)
- It is highly addictive…
- Which would lead to withdrawal and dependence effects.
- It can lead to tolerance by affecting the opioid receptor internalization or receptor down-regulation, functional decoupling of receptors from G-proteins, opioid receptor phosphorylation and upregulation of the cAMP pathway.
- A large overdose can cause asphyxia and death by respiratory depression if the person does not receive immediate medical attention (Note that the overdose treatment includes the administration of naloxone). The latter completely reverses morphine’s effects but may result in immediate onset of withdrawal in opiate-addicted subjects. Multiple doses may be needed.
The minimum lethal dose of morphine sulfate is 120 mg, but in case of hypersensitivity, 60 mg can bring sudden death. In serious drug dependency (high tolerance), 2000–3000 mg per day can be tolerated. Combination therapy, innovative delivery systems and long-acting formulations may improve clinical utility.
Pharmacology [Pharmacodynamics] in Depth
Morphine is a phenanthrene opioid receptor agonist – its main effect is binding to and activating the μ-opioid receptor (MOR) in the central nervous system. Its intrinsic activity at the MOR is heavily dependent on the assay and tissue being tested; in some situations, it is a full agonist while in others it can be a partial agonist or even antagonist. In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation.
Activation of the MOR is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is also a κ-opioid receptor (KOR) and δ-opioid receptor (DOR) agonist. Activation of the KOR is associated with spinal analgesia, miosis (pinpoint pupils), and psychotomimetic effects.
- The DOR is thought to play a role in analgesia. Although morphine does not bind to the σ receptor, it has been shown that σ receptor agonists, such as (+)-pentazocine, inhibit morphine analgesia,
- And σ receptor antagonists enhance morphine analgesia, suggesting downstream involvement of the σ receptor in the actions of morphine.
Morphine antagonists and partial agonists: The effects of opioids can be abolished by the antagonists, naloxone or naltrexone, irrespective of the receptor type involved. Given by itself, neither has any effect in normal subjects; however, in opioid-dependent subjects, both precipitate acute withdrawal signs. Because of its rapid pre-systemic elimination, naloxone is only suitable for parenteral use.
- Naltrexone is metabolically more stable and is given orally. Naloxone is effective as antidote in the treatment of opioid-induced respiratory paralysis. Since it is more rapidly eliminated than most opioids, repeated doses may be needed. Naltrexone may be used as an adjunct in withdrawal therapy.
- Buprenorphine behaves like a partial agonist/antagonist at µ-receptors.
- Pentazocine is an antagonist at µ-receptors and an agonist at κ-receptors. Both are classified as “low-ceiling” opioids, because neither can elicit the maximal analgesic effect obtained with morphine or meperidine.
The antagonist action of partial agonists may result in an initial decrease in effect of a full agonist during changeover to the latter. Intoxication with buprenorphine cannot be reversed with antagonists, because the drug dissociates only very slowly from the opioid receptors and competitive occupancy of the receptors cannot be achieved as fast as the clinical situation demands.
Chemistry & Laboratory
Morphine is a benzylisoquinoline alkaloid with two additional ring closures. Most of the licit morphine produced is used to make codeine by methylation. It is also a precursor for many drugs including heroin (3,6-diacetylmorphine), hydromorphone (dihydromorphinone), and oxymorphone (14-hydroxydihydromorphinone); many morphine derivatives can also be manufactured using thebaine or codeine as a starting material.
Mice react to morphine with excitation, evident in the form of an abnormal posture of the tail and limbs. The dose dependence of this phenomenon is observed in groups of animals (e.g., 10 mice per group) injected with increasing doses of morphine. At the low dose, only the most sensitive, at increasing doses a growing proportion, all the animals are affected at the highest dose.
