Morphine, formerly also called morphia, is an

opiate An opiate is an alkaloid substance derived from opium (or poppy straw). It differs from the similar term ''opioid'' in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain ( ...

that is found naturally in

opium Opium (also known as poppy tears, or Lachryma papaveris) is the dried latex obtained from the seed Capsule (fruit), capsules of the opium poppy ''Papaver somniferum''. Approximately 12 percent of opium is made up of the analgesic alkaloid mor ...

, a dark brown resin produced by drying the latex of opium poppies (''

Papaver somniferum ''Papaver somniferum'', commonly known as the opium poppy or breadseed poppy, is a species of flowering plant in the family Papaveraceae. It is the species of plant from which both opium and poppy seeds are derived and is also a valuable orname ...

''). It is mainly used as an

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

(pain medication). There are multiple methods used to administer morphine: oral;

sublingual Sublingual (List of abbreviations used in medical prescriptions, abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through Tissue (biology), t ...

; via inhalation;

injection into a muscle Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...

injection under the skin Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, colle ...

, or injection into the

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...

area;

transdermal Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery. The drug is administered in the form of a patch or ointm ...

; or via

rectal The rectum (: rectums or recta) is the final straight portion of the large intestine in humans and some other mammals, and the Gastrointestinal tract, gut in others. Before expulsion through the anus or cloaca, the rectum stores the feces te ...

suppository A suppository is a dosage form used to deliver pharmaceutical drug, medications by insertion into a body orifice (any opening in the body), where it dissolves or melts to exert local or systemic effects. There are three types of suppositories, eac ...

. It acts directly on the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

(CNS) to induce

analgesia Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...

and alter perception and emotional response to pain. Physical and psychological dependence and tolerance may develop with repeated administration. It can be taken for both

acute pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...

and

chronic pain Chronic pain is pain that persists or recurs for longer than 3 months.https://icd.who.int/browse/2025-01/mms/en#1581976053 It is also known as gradual burning pain, electrical pain, throbbing pain, and nauseating pain. This type of pain is in cont ...

and is frequently used for pain from

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

kidney stone Kidney stone disease (known as nephrolithiasis, renal calculus disease, or urolithiasis) is a crystallopathy and occurs when there are too many minerals in the urine and not enough liquid or hydration. This imbalance causes tiny pieces of cr ...

s, and during

labor Labour or labor may refer to: * Childbirth, the delivery of a baby * Labour (human activity), or work ** Manual labour, physical work ** Wage labour, a socioeconomic relationship between a worker and an employer ** Organized labour and the labour ...

. Its maximum effect is reached after about 20 minutes when administered intravenously and 60 minutes when administered by mouth, while the duration of its effect is 3–7 hours. Long-acting formulations of morphine are sold under the brand names MS Contin and Kadian, among others. Generic long-acting formulations are also available. Common side effects of morphine include

drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

sweating Perspiration, also known as sweat, is the fluid secreted by sweat glands in the skin of mammals. Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distributed over much of the ...

, and

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

. Potentially serious

side effects In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...

of morphine include decreased respiratory effort,

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

, and

low blood pressure Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

. Morphine is highly

addictive Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

and prone to

abuse Abuse is the act of improper usage or treatment of a person or thing, often to unfairly or improperly gain benefit. Abuse can come in many forms, such as: physical or verbal maltreatment, injury, assault, violation, rape, unjust practices, ...

. If one's dose is reduced after long-term use,

opioid withdrawal Opioid withdrawal is a set of symptoms arising from the sudden cessation or reduction of opioids where previous usage has been heavy and prolonged. Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs syndrome, naus ...

symptoms may occur. Caution is advised for the use of morphine during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

, as it may affect the health of the baby. Morphine was first isolated in 1804 by German pharmacist

Friedrich Sertürner Friedrich Wilhelm Adam Sertürner (; 19 June 1783 – 20 February 1841) was a German pharmacist and a pioneer of alkaloid chemistry. He is best known for his discovery of morphine, which he isolated from opium in 1804, and for conducting tests, ...

. This is believed to be the first isolation of a medicinal alkaloid from a plant. Merck began marketing it commercially in 1827. Morphine was more widely used after the invention of the

hypodermic syringe A syringe is a simple reciprocating pump consisting of a plunger (though in modern syringes, it is actually a piston) that fits tightly within a cylindrical tube called a barrel. The plunger can be linearly pulled and pushed along the insid ...

in 18531855. Sertürner originally named the substance ''morphium'', after the Greek god of dreams,

Morpheus Morpheus ('Fashioner', derived from the meaning 'form, shape') is a god associated with sleep and dreams. In Ovid's ''Metamorphoses'' he is the son of Somnus (Sleep, the Roman counterpart of Hypnos) and appears in dreams in human form. From the ...

, as it has a tendency to cause sleep. The primary source of morphine is isolation from

poppy straw Poppy straw (also known as opium straw, mowed opium straw, crushed poppy capsule, poppy chaff, or poppy husk) is derived from opium poppies (''Papaver somniferum'') that are harvested when fully mature and dried by mechanical means. Opium poppy s ...

of the

opium poppy ''Papaver somniferum'', commonly known as the opium poppy or breadseed poppy, is a species of flowering plant in the family Papaveraceae. It is the species of plant from which both opium and poppy seeds are derived and is also a valuable orname ...

. In 2013, approximately 523 tons of morphine were produced. Approximately 45 tons were used directly for pain, an increase of 400% over the last twenty years. Most use for this purpose was in the

developed world A developed country, or advanced country, is a sovereign state that has a high quality of life, developed economy, and advanced technological infrastructure relative to other less industrialized nations. Most commonly, the criteria for eval ...

. About 70% of morphine is used to make other

opioids Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

such as

hydromorphone Hydromorphone, also known as dihydromorphinone, and sold under the brand name Dilaudid among others, is a morphinan opioid used to treat moderate to severe pain. Typically, long-term use is only recommended for pain due to cancer. It may b ...

oxymorphone Oxymorphone (sold under the brand names Numorphan and Opana among others) is a highly potent opioid analgesic indicated for treatment of severe pain. Pain relief after injection begins after about 5–10 minutes; after oral administration it ...

, and

heroin Heroin, also known as diacetylmorphine and diamorphine among other names, is a morphinan opioid substance synthesized from the Opium, dried latex of the Papaver somniferum, opium poppy; it is mainly used as a recreational drug for its eupho ...

. It is a

Schedule II drug The Controlled Substances Act (CSA) is the statute establishing federal U.S. drug policy under which the manufacture, importation, possession, use, and distribution of certain substances is regulated. It was passed by the 91st United States ...

in the United States, Class A in the United Kingdom, and Schedule I in Canada. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. In 2022, it was the 139th most commonly prescribed medication in the United States, with more than 4million prescriptions. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

Medical uses

Pain

Morphine is used primarily to treat both acute and chronic severe

pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...

. Its duration of analgesia is about three to seven hours. Side effects of nausea and constipation are rarely severe enough to warrant stopping treatment. It is used for pain due to

and for labor pains. However, concerns exist that morphine may increase mortality in the event of non ST elevation myocardial infarction. Morphine has also traditionally been used in the treatment of

acute pulmonary edema Pulmonary edema (British English: oedema), also known as pulmonary congestion, is excessive fluid accumulation in the tissue or air spaces (usually alveoli) of the lungs. This leads to impaired gas exchange, most often leading to shortness ...

. However, a 2006 review found little evidence to support this practice. A 2016 Cochrane review concluded that morphine is effective in relieving

cancer pain Pain in cancer may arise from a tumor compressing or infiltrating nearby body parts; from treatments and diagnostic procedures; or from skin, nerve and other changes caused by a hormone imbalance or immune response. Most chronic (long-lasting) pai ...

Shortness of breath

Morphine is beneficial in reducing the symptom of

shortness of breath Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that con ...

due to both

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

and non-cancer causes. In the setting of breathlessness at rest or on minimal exertion from conditions such as advanced cancer or end-stage cardiorespiratory diseases, regular, low-dose sustained-release morphine significantly reduces breathlessness safely, with its benefits maintained over time.

Opioid use disorder

Morphine is used in a slow-release formulation for opiate substitution therapy (OST) in Austria, Germany, Bulgaria, Slovenia, and Canada for persons with

opioid addiction Opioids are a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, including pain relief. Th ...

who cannot tolerate either

methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid used medically to treat chronic pain and opioid use disorder. Prescribed for daily use, the medicine relieves cravings and opioid withdrawal sym ...

buprenorphine Buprenorphine, sold under the brand name Subutex among others, is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection (intravenous a ...

. File:GT-Capros-Morphinsulfat-2018.jpg, Two capsules (5 mg & 10 mg) of morphine sulfate extended-release File:Morphine 1mL Vial.jpg, 1 milliliter ampoule containing 10 mg of morphine

Contraindications

Relative

contraindication In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...

s to morphine include: *

respiratory depression Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...

when appropriate equipment is not available. * Although it has previously been thought that morphine was contraindicated in

acute pancreatitis Acute pancreatitis (AP) is a sudden inflammation of the pancreas. Causes include a gallstone impacted in the common bile duct or the pancreatic duct, heavy alcohol use, systemic disease, trauma, elevated calcium levels, hypertriglyceridemia (w ...

, a review of the literature shows no evidence for this.

Adverse effects

Constipation

loperamide Loperamide, sold under the brand name Imodium, among others,Drugs.co Page accessed 4 September 2015 is a medication of the opioid receptor agonist class used to decrease the frequency of diarrhea. It is often used for this purpose in irritable ...

and other opioids, morphine acts on the

myenteric plexus The myenteric plexus (or Auerbach's plexus) provides motor innervation to both layers of the muscular layer of the gut, having both parasympathetic and sympathetic input (although present ganglion cell bodies belong to parasympathetic innervatio ...

in the intestinal tract, reducing gut motility, and causing constipation. The gastrointestinal effects of morphine are mediated primarily by μ-opioid receptors in the bowel. By inhibiting gastric emptying and reducing propulsive

peristalsis Peristalsis ( , ) is a type of intestinal motility, characterized by symmetry in biology#Radial symmetry, radially symmetrical contraction and relaxation of muscles that propagate in a wave down a tube, in an wikt:anterograde, anterograde dir ...

of the intestine, morphine decreases the rate of intestinal transit. Reduction in gut secretion and increased intestinal fluid absorption also contribute to the constipating effect. Opioids also may act on the gut indirectly through tonic gut spasms after inhibition of

nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...

generation. This effect was shown in animals when a nitric oxide precursor,

L-arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the ...

, reversed morphine-induced changes in gut motility.

Hormone imbalance

Clinical studies consistently conclude that morphine, like other opioids, often causes

hypogonadism Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...

and

hormone imbalance Endocrine diseases are disorders of the endocrine system. The branch of medicine associated with endocrine disorders is known as endocrinology. Types of disease Broadly speaking, endocrine disorders may be subdivided into three groups: # Endocri ...

s in chronic users of both sexes. This side effect is dose-dependent and occurs in both therapeutic and recreational users. Morphine can interfere with menstruation by suppressing levels of

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...

. Multiple studies suggest the majority (perhaps as many as 90%) of chronic opioid users have opioid-induced hypogonadism. This effect may cause the increased likelihood of

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...

and

bone fracture A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of any bone in the body. In more severe cases, the bone may be broken into several fragments, known as a ''c ...

observed in chronic morphine users. Studies suggest the effect is temporary. , the effect of low-dose or acute use of morphine on the endocrine system is unclear.

Effects on human performance

Most reviews conclude that opioids produce minimal impairment of human performance on tests of sensory, motor, or attentional abilities. However, recent studies have been able to show some impairments caused by morphine, which is not surprising, given that morphine is a

depressant Depressants, also known as central nervous system depressants, or colloquially known as "downers", are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various ...

. Morphine has resulted in impaired functioning on critical flicker frequency (a measure of overall CNS arousal) and impaired performance on the Maddox wing test (a measure of the deviation of the visual axes of the eyes). Few studies have investigated the effects of morphine on motor abilities; a high dose of morphine can impair finger tapping and the ability to maintain a low constant level of isometric force (i.e. fine motor control is impaired), though no studies have shown a correlation between morphine and gross motor abilities. In terms of

cognitive Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

abilities, one study has shown that morphine may negatively impact anterograde and retrograde memory, but these effects are minimal and transient. Overall, it seems that acute doses of opioids in non-tolerant subjects produce minor effects in some sensory and motor abilities, and perhaps also in

attention Attention or focus, is the concentration of awareness on some phenomenon to the exclusion of other stimuli. It is the selective concentration on discrete information, either subjectively or objectively. William James (1890) wrote that "Atte ...

and cognition. The effects of morphine will likely be more pronounced in opioid-naive subjects than in chronic opioid users. In chronic opioid users, such as those on Chronic Opioid Analgesic Therapy (COAT) for managing severe,

, behavioural testing has shown normal functioning on perception, cognition, coordination, and behaviour in most cases. One 2000 study analysed COAT patients to determine whether they were able to safely operate a motor vehicle. The findings from this study suggest that stable opioid use does not significantly impair abilities inherent in driving (this includes physical, cognitive, and perceptual skills). COAT patients showed rapid completion of tasks that require the speed of responding for successful performance (e.g.,

Rey Complex Figure Rey or REY may refer to: *Rey (given name), a given name *Rey (surname), a surname * Rey Skywalker, a character in the ''Star Wars'' films *Rey, Iran, a city in Iran * Ray County, in Tehran Province of Iran * ''Rey'' (film), a 2015 Indian film *Th ...

Test) but made more errors than controls. COAT patients showed no deficits in visual-spatial perception and organization (as shown in the

WAIS-R The Wechsler Adult Intelligence Scale (WAIS) is an IQ test designed to measure intelligence and cognitive ability in adults and older adolescents. For children between the ages of 6 and 16, Wechsler Intelligence Scale for Children (WISC) is commo ...

Block Design Test) but did show impaired immediate and short-term visual memory (as shown on the Rey Complex Figure Test – Recall). These patients showed no impairments in higher-order cognitive abilities (i.e., planning). COAT patients appeared to have difficulty following instructions and showed a propensity toward impulsive behaviour, yet this did not reach statistical significance. It is important to note that this study reveals that COAT patients have no domain-specific deficits, which supports the notion that chronic opioid use has minor effects on psychomotor,

, or

neuropsychological Neuropsychology is a branch of psychology concerned with how a person's cognition and behavior are related to the brain and the rest of the nervous system. Professionals in this branch of psychology focus on how injuries or illnesses of the brai ...

functioning.

Reinforcement disorders

Addiction

Morphine is a highly

substance. Multiple studies, including one by ''The Lancet'', ranked morphine/heroin as the #1 most addictive substance, followed by

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

at #2,

nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...

#3,

barbiturates Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as ...

at #4, and

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

at #5. In controlled studies comparing the physiological and subjective effects of

and morphine in individuals formerly addicted to opiates, subjects showed no preference for one drug over the other. Equipotent, injected doses had comparable action courses, with heroin crossing the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

slightly quicker. No difference in subjects' self-rated feelings of

, ambition, nervousness, relaxation, or drowsiness. Short-term addiction studies by the same researchers demonstrated that tolerance developed at a similar rate to both heroin and morphine. When compared to the opioids

fentanyl Fentanyl is a highly potent synthetic piperidine opioid primarily used as an analgesic (pain medication). It is 30 to 50 times more Potency (pharmacology), potent than heroin and 50 to 100 times more potent than morphine. Its primary Medici ...

oxycodone Oxycodone, sold under the brand name Roxicodone and OxyContin (which is the extended-release form) among others, is a semi-synthetic opioid used medically for the treatment of moderate to severe pain. It is highly addictive and is a commonly ...

, and

pethidine Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a fully synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Ot ...

, former addicts showed a strong preference for heroin and morphine, suggesting that heroin and morphine are particularly susceptible to abuse and addiction. Morphine and heroin also produced higher rates of euphoria and other positive subjective effects when compared to these other opioids. The choice of heroin and morphine over other opioids by former drug addicts may also be because heroin is an ester of morphine and morphine

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

, essentially meaning they are identical drugs ''in vivo''. Heroin is converted to morphine before binding to the

opioid receptor Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostati ...

s in the brain and spinal cord, where morphine causes subjective effects, which is what the addicted individuals are seeking.

Tolerance

Several hypotheses are given about how tolerance develops, including opioid receptor

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

(which would change the receptor conformation), functional decoupling of receptors from

G-proteins G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their ...

(leading to receptor desensitization), μ-opioid receptor internalization or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the

cAMP Camp may refer to: Areas of confinement, imprisonment, or for execution * Concentration camp, an internment camp for political prisoners or politically targeted demographics, such as members of national or minority ethnic groups * Extermination ...

pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt).

Dependence and withdrawal

Cessation of dosing with morphine creates the prototypical opioid withdrawal syndrome, which, unlike that of

benzodiazepines Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat co ...

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

, or

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

-hypnotics, is not fatal by itself in otherwise healthy people. Acute morphine withdrawal, along with that of any other opioid, proceeds through a number of stages. Other opioids differ in the intensity and length of each, and weak opioids and mixed agonist-antagonists may have acute withdrawal syndromes that do not reach the highest level. As commonly cited, they are: * Stage I, 6 h to 14 h after last dose: Drug craving, anxiety, irritability, perspiration, and mild to moderate

dysphoria Dysphoria (; ) is a profound state of unease or dissatisfaction. It is the semantic opposite of euphoria. In a psychiatric context, dysphoria may accompany depression, anxiety, or agitation. In psychiatry Intense states of distress and uneas ...

* Stage II, 14 h to 18 h after last dose:

Yawn A yawn is a reflex in vertebrate animals characterized by a long inspiratory phase with gradual mouth gaping, followed by a brief climax (or acme) with muscle stretching, and a rapid expiratory phase with muscle relaxation, which typically last ...

ing, heavy

perspiration Perspiration, also known as sweat, is the fluid secreted by sweat glands in the skin of mammals. Two types of sweat glands can be found in humans: eccrine glands and Apocrine sweat gland, apocrine glands. The eccrine sweat glands are distribu ...

, mild depression,

lacrimation Tears are a clear liquid secreted by the lacrimal glands (tear gland) found in the eyes of all land mammals. Tears are made up of water, electrolytes, proteins, lipids, and mucins that form layers on the surface of eyes. The different types of ...

crying Crying is the dropping of tears (or welling of tears in the eyes) in response to an emotional state or physical pain. Emotions that can lead to crying include sadness, anger, joy, and fear. Crying can also be caused by relief from a period ...

, headaches, runny nose, dysphoria, also intensification of the above symptoms, "yen sleep" (a waking trance-like state) * Stage III, 16 h to 24 h after last dose: Increase in all of the above,

dilated pupils Mydriasis is the dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, trauma, or the use of certain types of drugs. It may also b ...

piloerection Goose bumps, goosebumps or goose pimples are the bumps on a person's skin at the base of body hairs which may involuntarily develop when a person is tickled, cold or experiencing strong emotions such as fear, euphoria or sexual arousal. The f ...

(goose bumps), muscle twitches,

hot flash Hot flushes are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and may typically last from t ...

es, cold flashes, aching bones and muscles,

loss of appetite Anorexia is a medical term for a loss of appetite. While the term outside of the scientific literature is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while o ...

, and the beginning of intestinal cramping * Stage IV, 24 h to 36 h after last dose: Increase in all of the above including severe cramping,

restless legs syndrome Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporaril ...

(RLS), loose stool,

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

, elevation of blood pressure,

fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...

, increase in frequency of breathing and tidal volume,

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...

(elevated pulse), restlessness, nausea * Stage V, 36 h to 72 h after last dose: Increase in all of the above, fetal position, vomiting, free and frequent liquid diarrhea, weight loss of 2 kg to 5 kg per 24 h, increased

white cell count A complete blood count (CBC), also known as a full blood count (FBC) or full haemogram (FHG), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, ...

, and other blood changes * Stage VI, after completion of above: Recovery of appetite and normal bowel function, beginning of transition to post-acute withdrawal symptoms that are mainly psychological, but may also include increased sensitivity to pain,

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

colitis Colitis is swelling or inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and ...

or other gastrointestinal afflictions related to motility, and problems with weight control in either direction In advanced stages of withdrawal, ultrasonographic evidence of pancreatitis has been demonstrated in some patients and is presumably attributed to spasm of the pancreatic

sphincter of Oddi The sphincter of Oddi (SO) (also hepatopancreatic sphincter or Glisson's sphincter), is a sphincter, a muscular valve that, in humans and some animals, controls the flow of bile and pancreatic juice out of the gallbladder and pancreas respective ...

. The withdrawal symptoms associated with morphine addiction are usually experienced shortly before the time of the next scheduled dose, sometimes within as early as a few hours (usually 6 h to 12 h) after the last administration. Early symptoms include watery eyes, insomnia, diarrhea, runny nose, yawning,

, sweating, and, in some cases, a strong drug craving. Severe headache, restlessness,

irritability Irritability is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimul ...

, loss of appetite, body aches, severe abdominal pain, nausea and vomiting, tremors, and even stronger and more intense drug craving appear as the syndrome progresses. Severe depression and vomiting are common. During the acute withdrawal period, systolic and diastolic blood pressures increase, usually beyond premorphine levels, and heart rate increases, which have potential to cause a heart attack, blood clot, or stroke. Chills or cold flashes with goose bumps alternating with flushing (hot flashes), kicking movements of the legs, and excessive sweating are also characteristic symptoms. Severe pains in the bones and muscles of the back and extremities occur, as do muscle spasms. At any point during this process, a suitable narcotic can be administered that will dramatically reverse the withdrawal symptoms. Major withdrawal symptoms peak between 48 h and 96 h after the last dose and subside after about 8 to 12 days. Sudden discontinuation of morphine by heavily

dependent A dependant (US spelling: dependent) is a person who relies on another as a primary source of income and usually assistance with activities of daily living Activities of daily living (ADLs) is a term used in healthcare to refer to an individ ...

users who are in poor health is rarely fatal. Morphine withdrawal is considered less dangerous than alcohol, barbiturate, or benzodiazepine withdrawal. The psychological dependence associated with morphine

addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

is complex and protracted. Long after the physical need for morphine has passed, addicts will usually continue to think and talk about the use of morphine (or other drugs) and feel strange or overwhelmed coping with daily activities without being under the influence of morphine. Psychological withdrawal from morphine is usually a long and painful process. Addicts often experience severe depression, anxiety, insomnia, mood swings, forgetfulness, low

self-esteem Self-esteem is confidence in one's own worth, abilities, or morals. Self-esteem encompasses beliefs about oneself (for example, "I am loved", "I am worthy") as well as emotional states, such as triumph, despair, pride, and shame. Smith and Macki ...

confusion In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"

paranoia Paranoia is an instinct or thought process that is believed to be heavily influenced by anxiety, suspicion, or fear, often to the point of delusion and irrationality. Paranoid thinking typically includes persecutory beliefs, or beliefs of co ...

, and other psychological problems. Without intervention, the syndrome will run its course, and most of the overt physical symptoms will disappear within 7 to 10 days including psychological dependence. A high probability of relapse exists after morphine withdrawal when neither the physical environment nor the behavioral motivators that contributed to the abuse have been altered. Testimony of morphine's addictive and reinforcing nature is its relapse rate. Users of morphine have one of the highest relapse rates among all drug users, ranging up to 98% in the estimation of some medical experts.

Toxicity

A large

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

can cause

asphyxia Asphyxia or asphyxiation is a condition of deficient supply of oxygen to the body which arises from abnormal breathing. Asphyxia causes generalized hypoxia, which affects all the tissues and organs, some more rapidly than others. There are m ...

and death by respiratory depression if the person does not receive medical attention immediately. Overdose treatment includes the administration of

naloxone Naloxone, sold under the brand name Narcan among others, is an opioid antagonist, a medication used to reverse or reduce the effects of opioids. For example, it is used to restore breathing after an opioid overdose. Effects begin within two ...

. The latter completely reverses morphine's effects but may result in the immediate onset of withdrawal in opiate-addicted subjects. Multiple doses may be needed as the duration of action of morphine is longer than that of naloxone.

Pharmacology

Pharmacodynamics

Due to its long history and established use as a pain medication, this compound has become the benchmark to which all other opioids are compared. It interacts predominantly with the μ–δ-opioid (Mu-Delta) receptor heteromer. The μ-binding sites are discretely distributed in the

human brain The human brain is the central organ (anatomy), organ of the nervous system, and with the spinal cord, comprises the central nervous system. It consists of the cerebrum, the brainstem and the cerebellum. The brain controls most of the activi ...

, with high densities in the posterior

amygdala The amygdala (; : amygdalae or amygdalas; also '; Latin from Greek language, Greek, , ', 'almond', 'tonsil') is a paired nucleus (neuroanatomy), nuclear complex present in the Cerebral hemisphere, cerebral hemispheres of vertebrates. It is c ...

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...

, nucleus caudatus,

putamen The putamen (; from Latin, meaning "nutshell") is a subcortical nucleus (neuroanatomy), nucleus with a rounded structure, in the basal ganglia nuclear group. It is located at the base of the forebrain and above the midbrain. The putamen and c ...

, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (

substantia gelatinosa The apex of the posterior grey column, one of the three grey columns of the spinal cord, is capped by a V-shaped or crescentic mass of translucent, gelatinous neuroglia, termed the substantia gelatinosa of Rolando (or SGR) (or gelatinous substanc ...

) of the spinal cord and in the spinal nucleus of the

trigeminal nerve In neuroanatomy, the trigeminal nerve (literal translation, lit. ''triplet'' nerve), also known as the fifth cranial nerve, cranial nerve V, or simply CN V, is a cranial nerve responsible for Sense, sensation in the face and motor functions ...

. Morphine is a

phenanthrene Phenanthrene is a polycyclic aromatic hydrocarbon (PAH) with formula C14H10, consisting of three fused benzene rings. It is a colorless, crystal-like solid, but can also appear yellow. Phenanthrene is used to make dyes, plastics, pesticides, expl ...

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

– its main effect is binding to and activating the

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...

(MOR) in the

. Its

intrinsic activity Intrinsic activity (IA) and efficacy (Emax) refer to the relative ability of a drug- receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind ...

at the MOR is heavily dependent on the

assay An assay is an investigative (analytic) procedure in laboratory medicine, mining, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity ...

and tissue being tested; in some situations it is a

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...

while in others it can be a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

or even

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

. Its primary actions of therapeutic value are analgesia and sedation. Activation of the MOR is associated with analgesia, sedation,

, physical dependence, and

. Morphine is also a

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four re ...

(KOR) and

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi alpha subunit, Gi/G0 and has enkephalins as it ...

(DOR) agonist. Activation of the KOR is associated with spinal analgesia,

miosis Miosis, or myosis (), is excessive constriction of the pupil.Farlex medical dictionary
citing: ...

(pinpoint pupils), and

psychotomimetic A drug with psychotomimetic (also known as psychomimetic or psychotogenic) actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to only hallucinations. Psychotomimesis is the onset of psychotic symptoms followi ...

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. The effects of morphine can be countered with

opioid receptor antagonist An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors. Naloxone and naltrexone are commonly used opioid antagonist drugs which are competitive antagonists that bind to the ...

s such as

and

naltrexone Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol use or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been ...

; the development of tolerance to morphine may be inhibited by

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to receptor antagonist, antagonize, or inhibit the action of, the NMDA, ''N''-Methyl-D-aspartate receptor (NMDA receptor, NMDAR). They are commonly used as anesthetics for humans and anima ...

s such as

ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...

dextromethorphan Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...

, and

memantine Memantine, sold under the brand name Namenda among others, is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizz ...

. The rotation of morphine with chemically dissimilar opioids in the long-term treatment of pain will slow down the growth of tolerance in the longer run, particularly agents known to have significantly incomplete cross-tolerance with morphine such as

levorphanol Levorphanol (brand name Levo-Dromoran) is an opioid medication used to treat moderate to severe pain. It is the levorotatory enantiomer of the compound racemorphan. Its dextrorotatory counterpart is dextrorphan. It was first described in Ge ...

ketobemidone Ketobemidone, sold under the brand name Ketogan (a mixture of ketobemidone and Spasmolytic A29) among others, is a powerful synthetic opioid painkiller. Its effectiveness against pain is in the same range as morphine, and it also has some NMDA- ...

, piritramide, and

and its derivatives; all of these drugs also have NMDA antagonist properties. It is believed that the strong opioid with the most incomplete cross-tolerance with morphine is either methadone or dextromoramide. Morphine_Ampoule_For_Veterinary_Use

Analgesia creation

Morphine creates analgesia through the activation of a specific group of neurons in the

rostral ventromedial medulla The rostral ventromedial medulla (RVM), or ventromedial nucleus of the spinal cord, is a group of neurons located close to the midline on the floor of the medulla oblongata. The rostral ventromedial medulla sends descending inhibitory and excita ...

, called the "morphine ensemble." This ensemble includes glutamatergic neurons that project to the spinal cord, known as RVM^BDNF neurons. These neurons connect to inhibitory neurons in the spinal cord, called SC^Gal neurons, which release the neurotransmitter GABA and the neuropeptide

galanin Galanin is a neuropeptide encoded by the ''GAL'' gene, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors. Much of galanin's functio ...

. The inhibition of SC^Gal neurons is crucial for morphine's pain-relieving effects. Additionally, the neurotrophic factor

BDNF Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...

, produced within the RVM^BDNF neurons, is required for morphine's action. Increasing BDNF levels enhances morphine's analgesic effects, even at lower doses.

Gene expression

Studies have shown that morphine can alter the expression of several

genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. A single injection of morphine has been shown to alter the expression of two major groups of genes, for proteins involved in

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

l respiration and for

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

-related proteins.

Effects on the immune system

Morphine has long been known to act on receptors expressed in cells of the

resulting in pain relief and

. In the 1970s and '80s, evidence suggesting that people addicted to opioids show an increased risk of infection (such as increased

pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...

tuberculosis Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption, is a contagious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can al ...

, and

HIV/AIDS The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...

) led scientists to believe that morphine may also affect the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

. This possibility increased interest in the effect of chronic morphine use on the immune system. The first step in determining that morphine may affect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system. One study successfully showed that

dendritic cells A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...

, part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producing

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

s, which are the tools for communication in the immune system. This same study showed that dendritic cells chronically treated with morphine during their differentiation produce more

interleukin-12 Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, helper T cells and human B- lymphoblastoid cells ( NC-37) in response to antigenic stimulation. IL-12 belongs to the family of i ...

(IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and less interleukin-10 (IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection). This regulation of cytokines appears to occur via the p38 MAPKs (mitogen-activated protein kinase)-dependent pathway. Usually, the p38 within the dendritic cell expresses

TLR 4 Toll-like receptor 4 (TLR4), also designated as CD284 (cluster of differentiation 284), is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approx ...

(toll-like receptor 4), which is activated through the ligand LPS (

lipopolysaccharide Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...

). This causes the p38 MAPK to be

phosphorylated In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

. This phosphorylation activates the p38 MAPK to begin producing IL-10 and IL-12. When the dendritic cells are chronically exposed to morphine during their differentiation process and then treated with LPS, the production of cytokines is different. Once treated with morphine, the p38 MAPK does not produce IL-10, instead favoring the production of IL-12. The exact mechanism through which the production of one cytokine is increased in favor over another is not known. Most likely, the morphine causes increased phosphorylation of the p38 MAPK. Transcriptional level interactions between IL-10 and IL-12 may further increase the production of IL-12 once IL-10 is not being produced. This increased production of IL-12 causes increased T-cell immune response. Further studies on the effects of morphine on the immune system have shown that morphine influences the production of

neutrophils Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different ...

and other

cytokines Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

. Since cytokines are produced as part of the immediate immunological response (

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

), it has been suggested that they may also influence pain. In this way, cytokines may be a logical target for analgesic development. Recently, one study has used an animal model (hind-paw incision) to observe the effects of morphine administration on the acute immunological response. Following the hind-paw incision, pain thresholds and cytokine production were measured. Normally, cytokine production in and around the wounded area increases to fight

infection An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...

and control healing (and, possibly, to control pain), but pre-incisional morphine administration (0.1 mg/kg to 10.0 mg/kg) reduced the number of cytokines found around the wound in a dose-dependent manner. The authors suggest that morphine administration in the acute post-injury period may reduce resistance to infection and may impair the healing of the wound.

Pharmacokinetics

Absorption and metabolism

Morphine can be taken

orally The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or oral ...

sublingually Sublingual (abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through tissues under the tongue. Many drugs are absorbed through sublingual a ...

, bucally,

rectally The rectum (: rectums or recta) is the final straight portion of the large intestine in humans and some other mammals, and the gut in others. Before expulsion through the anus or cloaca, the rectum stores the feces temporarily. The adult hu ...

subcutaneously The subcutaneous tissue (), also called the hypodermis, hypoderm (), subcutis, or superficial fascia, is the lowermost layer of the integumentary system in vertebrates. The types of cells found in the layer are fibroblasts, adipose cells, and m ...

intranasally Nasal administration, popularly known as snorting, is a route of administration in which drugs are insufflated through the nose. It can be a form of either topical administration or systemic administration, as the drugs thus locally delivered ca ...

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

ly,

intrathecal Intrathecal administration is a route of administration for drugs via an injection into the spinal canal, or into the subarachnoid space (sin. ''intrathecal space'') so that it reaches the cerebrospinal fluid (CSF). It is useful in several applic ...

ly or

epidural Epidural administration (from Ancient Greek ἐπί, "upon" + '' dura mater'') is a method of medication administration in which a medicine is injected into the epidural space around the spinal cord. The epidural route is used by physicians ...

ly and inhaled via a nebulizer. As a recreational drug, it is becoming more common to inhale ("

Chasing the Dragon "Chasing the dragon" (CTD) (), or "foily" in Australian English, refers to inhaling the vapor of a powdered psychoactive drug off a heated sheet of aluminium foil. The moving vapor is chased after with a tube (often rolled foil) through which th ...

"), but, for medical purposes, intravenous (IV) injection is the most common method of administration. Morphine is subject to extensive

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

(a large proportion is broken down in the liver), so, if taken orally, only 40% to 50% of the dose reaches the central nervous system. Resultant plasma levels after subcutaneous (SC), intramuscular (IM), and IV injection are all comparable. After IM or SC injections, morphine plasma levels peak in approximately 20 min, and, after oral administration, levels peak in approximately 30 min. Morphine is

metabolised Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

primarily in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and approximately 87% of a dose of morphine is excreted in the

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

within 72 h of administration. Morphine is metabolized primarily into

morphine-3-glucuronide Morphine-3-glucuronide is a metabolite of morphine produced by UGT2B7. It is not active as an opioid agonist, but does have some action as a convulsant, which does not appear to be mediated through opioid receptors, but rather through interacti ...

(M3G) and

morphine-6-glucuronide Morphine-6-glucuronide (M6G) is a major active metabolite of morphine. M6G is formed from morphine by the enzyme UGT2B7. It has analgesic effects roughly half that of morphine. M6G can accumulate to toxic levels in kidney failure. History of di ...

(M6G) via

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

by phase II metabolism enzyme UDP-glucuronosyl transferase-2B7 (UGT2B7). About 60% of morphine is converted to M3G, and 6% to 10% is converted to M6G. Not only does the metabolism occur in the liver but it may also take place in the brain and the kidneys. M3G does not undergo opioid receptor binding and has no analgesic effect. M6G binds to μ-receptors and is half as potent an analgesic as morphine in humans. Morphine may also be metabolized into small amounts of

normorphine Normorphine is an opiate analogue, the N-demethylated derivative of morphine, that was first described in the 1950s when a large group of N-substituted morphine analogues were characterized for activity. The compound has relatively little opioid ...

codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically use ...

, and

. Metabolism rate is determined by gender, age, diet, genetic makeup, disease state (if any), and use of other medications. The elimination

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...

of morphine is approximately 120 min, though there may be slight differences between men and women. Morphine can be stored in fat, and, thus, can be detectable even after death. Morphine can cross the

, but, because of poor lipid solubility, protein binding, rapid conjugation with glucuronic acid, and ionization, it does not cross easily.

Heroin Heroin, also known as diacetylmorphine and diamorphine among other names, is a morphinan opioid substance synthesized from the Opium, dried latex of the Papaver somniferum, opium poppy; it is mainly used as a recreational drug for its eupho ...

, which is derived from morphine, crosses the blood-brain barrier more easily, making it more potent.Jenkins AJ (2008) Pharmacokinetics of specific drugs. In Karch SB (''Ed''), ''Pharmacokinetics and pharmacodynamics of abused drugs''. CRC Press: Boca Raton.

Extended-release

There are

extended-release Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers a drug with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release R, XR, XLdosage) or to a spe ...

formulations of orally administered morphine whose effect lasts longer, which can be given once per day. Brand names for this formulation of morphine include Avinza, Kadian, MS Contin, Dolcontin, and DepoDur. Last reviewed on 18 November 2015 For constant pain, the relieving effect of extended-release morphine given once (for Kadian) or twice (for MS Contin) every 24 hours is roughly the same as multiple administrations of ''immediate release'' (or "regular") morphine. Extended-release morphine can be administered together with "rescue doses" of immediate-release morphine as needed in case of breakthrough pain, each generally consisting of 5% to 15% of the 24-hour extended-release dosage.

Detection in body fluids

Morphine and its major metabolites, morphine-3-glucuronide, and morphine-6-glucuronide, can be detected in blood, plasma, hair, and urine using an

immunoassay An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoassay ...

Chromatography In chemical analysis, chromatography is a laboratory technique for the Separation process, separation of a mixture into its components. The mixture is dissolved in a fluid solvent (gas or liquid) called the ''mobile phase'', which carries it ...

can be used to test for each of these substances individually. Some testing procedures

hydrolyze Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

metabolic products into morphine before the immunoassay, which must be considered when comparing morphine levels in separately published results. Morphine can also be isolated from whole blood samples by

solid phase extraction Solid-phase extraction (SPE) is a solid-liquid extractive technique, by which compounds that are dissolved or suspended in a liquid mixture are separated, isolated or purified, from other compounds in this mixture, according to their physical and ...

(SPE) and detected using

liquid chromatography-mass spectrometry Liquid is a state of matter with a definite volume but no fixed shape. Liquids adapt to the shape of their container and are nearly incompressible, maintaining their volume even under pressure. The density of a liquid is usually close to that ...

(LC-MS). Ingestion of codeine or food containing poppy seeds can cause false positives. A 1999 review estimated that relatively low doses of heroin (which metabolizes immediately into morphine) are detectable by standard urine tests for 1–1.5 days after use. A 2009 review determined that, when the

analyte An analyte, component (in clinical chemistry), titrand (in titrations), or chemical species is a substance or chemical constituent that is of interest in an analytical procedure. The remainder of the sample is called the matrix. The procedure ...

is morphine and the

limit of detection The limit of detection (LOD or LoD) is the lowest signal, or the lowest corresponding quantity to be determined (or extracted) from the signal, that can be observed with a sufficient degree of confidence or statistical significance. However, the ...

is 1ng/ml, a 20mg intravenous (IV) dose of morphine is detectable for 12–24 hours. A limit of detection of 0.6ng/ml had similar results.

Chirality and biological activity

Morphine is a pentacyclic 3°amine (alkaloid) with 5 stereogenic centers and exists in 32 stereoisomeric forms. But the desired analgesic activity resides exclusively in the natural product, the (-)-enantiomer with the configuration (5R,6S,9R,13S,14R).

Natural occurrence

Morphine is the most abundant opiate found in

, the dried

latex Latex is an emulsion (stable dispersion) of polymer microparticles in water. Latices are found in nature, but synthetic latices are common as well. In nature, latex is found as a wikt:milky, milky fluid, which is present in 10% of all floweri ...

extracted by shallowly scoring the unripe seedpods of the ''

'' poppy. Morphine is generally 8–14% of the dry weight of opium. Przemko and Norman cultivars of the opium poppy, are used to produce two other alkaloids,

thebaine Thebaine (paramorphine), also known as codeine methyl enol ether, is an opiate alkaloid, its name coming from the Greek Θῆβαι, '' Thēbai'' (Thebes), an ancient city in Upper Egypt. A minor constituent of opium, thebaine is chemically simi ...

and

oripavine Oripavine is an opioid and the major metabolite of thebaine. It is the precursor to the semi-synthetic compounds etorphine and buprenorphine. Although this chemical compound has analgesic potency comparable to morphine, it is not used clinica ...

, which are used in the manufacture of semi-synthetic and synthetic opioids like

and

etorphine Etorphine (M99) is a semi-synthetic opioid possessing an analgesic potency approximately 1,000–3,000 times that of morphine. It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather the re ...

. '' P. bracteatum'' does not contain morphine or

, or other narcotic

-type, alkaloids. This species is rather a source of

. Occurrence of morphine in other Papaverales and

Papaveraceae The Papaveraceae, informally known as the poppy family, are an economically important family (biology), family of about 42 genera and approximately 775 known species of flowering plants in the order Ranunculales. The family is cosmopolitan dis ...

, as well as in some species of

hops Hops are the flowers (also called seed cones or strobiles) of the hop plant ''Humulus lupulus'', a member of the Cannabaceae family of flowering plants. They are used primarily as a bittering, flavouring, and stability agent in beer, to whic ...

and

mulberry ''Morus'', a genus of flowering plants in the family Moraceae, consists of 19 species of deciduous trees commonly known as mulberries, growing wild and under cultivation in many temperate world regions. Generally, the genus has 64 subordinat ...

trees has not been confirmed. Morphine is produced most predominantly early in the life cycle of the plant. Past the optimum point for extraction, various processes in the plant produce codeine,

, and in some cases negligible amounts of

dihydromorphine Dihydromorphine (Paramorfan, Paramorphan) is a semi-synthetic opioid structurally related to and derived from morphine. The 7,8-double bond in morphine is reduced to a single bond to get dihydromorphine. Dihydromorphine is a moderately strong a ...

dihydrocodeine Dihydrocodeine is a semi- synthetic opioid analgesic prescribed for pain or severe dyspnea, or as an antitussive, either alone or compounded with paracetamol (acetaminophen) (as in co-dydramol) or aspirin. It was developed in Germany in 190 ...

, tetrahydro-thebaine, and

hydrocodone Hydrocodone, also known as dihydrocodeinone, is a semi-synthetic opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically, it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone fo ...

(these compounds are rather synthesized from thebaine and oripavine). In the brains of mammals, morphine is detectable in trace steady-state concentrations. The human body also produces

endorphins Endorphins (contracted from endogenous morphine) are peptides produced in the brain that block the perception of pain and increase feelings of wellbeing. They are produced and stored in the pituitary gland of the brain. Endorphins are endogeno ...

, which are chemically related

endogenous opioid Opioid peptides or opiate peptides are peptides that bind to opioid receptors in the brain; opiates and opioids mimic the effect of these peptides. Such peptides may be produced by the body itself, for example endorphins. The effects of these p ...

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

s that function as

neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...

s and have similar effects to morphine.

Human biosynthesis

Morphine is an

in humans. Various human cells are capable of synthesizing and releasing it, including

white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

s. The primary biosynthetic pathway for morphine in humans consists of Morphine biosynthesis in humans

L-tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...

→ ''para''-tyramine or

L-DOPA -DOPA, also known as -3,4-dihydroxyphenylalanine and used medically as levodopa, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DO ...

→

Dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

:L-tyrosine → L-DOPA → 3,4-dihydroxyphenylacetaldehyde (DOPAL) :Dopamine + DOPAL → (''S'')-norlaudanosoline →→→ (''S'')-

reticuline Reticuline is an alkaloid found in opium and a variety of plants including ''Lindera aggregata'', ''Annona squamosa'', and ''Ocotea#Selected species, Ocotea fasciculata'' (also known as ''Ocotea duckei''). Experiments in rodents suggest reticuli ...

→

1,2-dehydroreticulinium Onekama ( ) is a village in Manistee County in the U.S. state of Michigan. The population was 399 at the 2020 census. The village is located on the northeast shore of Portage Lake and is surrounded by Onekama Township. The town's name is deriv ...

→ (''R'')-reticuline →

salutaridine Salutaridine, also known as floripavine, is an alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be ...

→ salutaridinol →

→ neopinone → codeinone →

→ morphine The intermediate (''S'')-norlaudanosoline (also known as tetrahydropapaveroline) is synthesized through the addition of DOPAL and dopamine.

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...

, a

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

isoenzyme is involved in two steps along the biosynthetic pathway, catalyzing both the biosynthesis of dopamine from tyramine and of morphine from codeine. Urinary concentrations of endogenous codeine and morphine have been found to significantly increase in individuals taking

for the treatment of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

Biosynthesis in the opium poppy

Biosynthesis of morphine in the

begins with two tyrosine derivatives,

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

and 4-hydroxyphenylacetaldehyde. Condensation of these precursors yields the primary intermediate higenamine (norcoclaurine). Subsequent action of four enzymes yields the tetrahydroisoquinoline

, which is converted into

, and

. The enzymes involved in this process are the

salutaridine synthase In enzymology, a salutaridine synthase () is an enzyme that catalyzes the chemical reaction :(R)-reticuline + NADPH + H+ + O2 \rightleftharpoons salutaridine + NADP+ + 2 H2O The 4 substrates of this enzyme are (R)-reticuline, NADPH, H+, and ...

, salutaridine:NADPH 7-oxidoreductase and the codeinone reductase. Researchers are attempting to reproduce the biosynthetic pathway that produces morphine in

genetically engineered Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including th ...

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...

. In June 2015 the ''S''-reticuline could be produced from sugar and ''R''-reticuline could be converted to morphine, but the intermediate reaction could not be performed. In August 2015 the first complete synthesis of thebaine and hydrocodone in yeast was reported, but the process would need to be 100,000 times more productive to be suitable for commercial use.

Chemistry

Elements of the morphine structure have been used to create completely synthetic drugs such as the

morphinan Morphinan is the prototype chemical structure of a large chemical class of psychoactive drugs, consisting of opiate analgesics, cough suppressants, and dissociative hallucinogens, among others. Typical examples include compounds such as morphine, ...

family (

and others) and other groups that have multiple members with morphine-like qualities. The modification of morphine and the aforementioned synthetics has also given rise to non-narcotic drugs with other uses such as emetics, stimulants, antitussives, anticholinergics, muscle relaxants, local anaesthetics, general anaesthetics, and others. Morphine-derived

agonist–antagonist In pharmacology the term agonist-antagonist or mixed agonist/antagonist is used to refer to a drug which under some conditions behaves as an agonist (a substance that fully activates the receptor that it binds to) while under other conditions, beh ...

drugs have also been developed.

Structure description

Benzylisoquinoline structure in Morphine

Morphine is a

benzylisoquinoline Substitution of the heterocycle isoquinoline at the C1 position by a benzyl group provides 1‑benzylisoquinoline, the most widely examined of the numerous benzylisoquinoline structural isomers. The 1-benzylisoquinoline moiety can be identified w ...

alkaloid with two additional ring closures. As Jack DeRuiter of the Department of Drug Discovery and Development (formerly, Pharmacal Sciences), Harrison School of Pharmacy, Auburn University stated in his Fall 2000 course notes for that earlier department's "Principles of Drug Action 2" course, "Examination of the morphine molecule reveals the following structural features important to its pharmacological profile... Morphine and most of its derivatives do not exhibit optical isomerism, although some more distant relatives like the morphinan series (levorphanol, dextrorphan, and the racemic parent chemical racemorphan) do, and as noted above stereoselectivity in vivo is an important issue.

Uses and derivatives

Most of the licit morphine produced is used to make

by methylation. It is also a precursor for a number of drugs including

(3,6-diacetylmorphine),

(dihydromorphinone), and

(14-hydroxydihydromorphinone). Most semi-synthetic opioids, both of the morphine and

subgroups, are created by modifying one or more of the following: * Halogenating or making other modifications at positions 1 or 2 on the morphine carbon skeleton. * The methyl group that makes morphine into codeine can be removed or added back, or replaced with another functional group like ethyl and others to make codeine analogues of morphine-derived drugs and vice versa. Codeine analogues of morphine-based drugs often serve as prodrugs of the stronger drug, as in codeine and morphine, hydrocodone and hydromorphone, oxycodone and oxymorphone, nicocodeine and nicomorphine, dihydrocodeine and dihydromorphine, etc. * Saturating, opening, or other changes to the bond between positions 7 and 8, as well as adding, removing, or modifying functional groups to these positions; saturating, reducing, eliminating, or otherwise modifying the 7–8 bond and attaching a functional group at 14 yields

hydromorphinol Hydromorphinol (RAM-320, 14-hydroxydihydromorphine), is an opiate analogue that is a derivative of morphine, where the 14-position has been hydroxylated and the 7,8- double bond saturated. It has similar effects to morphine such as sedation, anal ...

; the oxidation of the hydroxyl group to a carbonyl and changing the 7–8 bond to single from double changes codeine into oxycodone. * Attachment, removal, or modification of functional groups to positions 3 or 6 (dihydrocodeine and related, hydrocodone, nicomorphine); in the case of moving the methyl functional group from position 3 to 6, codeine becomes heterocodeine, which is 72 times stronger, and therefore six times stronger than morphine * Attachment of functional groups or other modification at position 14 (oxymorphone, oxycodone, naloxone) * Modifications at positions 2, 4, 5, or 17, usually along with other changes to the molecule elsewhere on the morphine skeleton. Often this is done with drugs produced by catalytic reduction, hydrogenation, oxidation, or the like, producing strong derivatives of morphine and codeine. Many morphine derivatives can also be manufactured using

or codeine as a starting material. Replacement of the ''N''-methyl group of morphine with an ''N''-phenylethyl group results in a product that is 18 times more powerful than morphine in its opiate agonist potency. Combining this modification with the replacement of the 6-

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

with a 6-

methylene group A methylene group is any part of a molecule that consists of two hydrogen atoms bound to a carbon Carbon () is a chemical element; it has chemical symbol, symbol C and atomic number 6. It is nonmetallic and tetravalence, tetravalent—m ...

produces a compound some 1,443 times more potent than morphine, stronger than the

Bentley compounds Bentley Motors Limited is a British designer, manufacturer and marketer of luxury cars and SUVs. Headquartered in Crewe, England, the company was founded by W. O. Bentley (1888–1971) in 1919 in Cricklewood, North London, and became wide ...

such as

(M99, the Immobilon tranquilliser dart) by some measures. Closely related to morphine are the opioids morphine-''N''-oxide (genomorphine), which is a pharmaceutical that is no longer in common use; and pseudomorphine, an alkaloid that exists in opium, form as degradation products of morphine. As a result of the extensive study and use of this molecule, more than 250 morphine derivatives (also counting codeine and related drugs) have been developed since the last quarter of the 19th century. These drugs range from 25% the analgesic strength of codeine (or slightly more than 2% of the strength of morphine) to several thousand times the strength of morphine, to powerful opioid antagonists, including

(Narcan),

(Trexan),

diprenorphine Diprenorphine (brand name Revivon; former developmental code name M5050), also known as diprenorfin, is a non-selective, high-affinity, weak partial agonist of the μ- (MOR), κ- (KOR), and δ-opioid receptor (DOR) (with equal affinity) which ...

(M5050, the reversing agent for the Immobilon dart) and

nalorphine Nalorphine (; also known as ''N''-allylnormorphine; brand names Lethidrone and Nalline) is a mixed opioid agonist–antagonist with opioid antagonist and analgesic properties. It was introduced in 1954 and was used as an antidote to reverse ...

(Nalline). Some opioid agonist-antagonists, partial agonists, and inverse agonists are also derived from morphine. The receptor-activation profile of the semi-synthetic morphine derivatives varies widely and some, like

apomorphine Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antago ...

are devoid of narcotic effects.

Chemical salts of Morphine

Both morphine and its hydrated form are sparingly soluble in water. For this reason, pharmaceutical companies produce sulfate and hydrochloride salts of the drug, both of which are over 300 times more water-soluble than their parent molecule. Whereas the pH of a saturated morphine hydrate solution is 8.5, the salts are acidic. Since they derive from a strong acid but weak base, they are both at about pH = 5; as a consequence, the morphine salts are mixed with small amounts of

NaOH Sodium hydroxide, also known as lye and caustic soda, is an inorganic compound with the formula . It is a white solid ionic compound consisting of sodium cations and hydroxide anions . Sodium hydroxide is a highly corrosive base and alkali t ...

to make them suitable for injection. Many salts of morphine are used, with the most common in current clinical use being the hydrochloride, sulfate, tartrate, and citrate; less commonly methobromide, hydrobromide, hydroiodide, lactate, chloride, and bitartrate and the others listed below. Morphine diacetate (heroin) is not a salt, but rather a further derivative, see above. Morphine meconate is a major form of the alkaloid in the poppy, as is morphine pectinate, nitrate, sulfate, and some others. Like codeine, dihydrocodeine and other (especially older) opiates, morphine has been used as the salicylate salt by some suppliers and can be easily compounded, imparting the therapeutic advantage of both the opioid and the

NSAID Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...

; multiple

barbiturate Barbiturates are a class of depressant, depressant drugs that are chemically derived from barbituric acid. They are effective when used medication, medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological a ...

salts of morphine were also used in the past, as was/is morphine valerate, the salt of the acid being the active principle of valerian. Calcium morphenate is the intermediate in various latex and poppy-straw methods of morphine production, more rarely sodium morphenate takes its place. Morphine ascorbate and other salts such as the tannate, citrate, and acetate, phosphate, valerate and others may be present in poppy tea depending on the method of preparation. The salts listed by the

United States Drug Enforcement Administration The Drug Enforcement Administration (DEA) is a Federal law enforcement in the United States, United States federal law enforcement agency under the U.S. Department of Justice tasked with combating illicit Illegal drug trade, drug trafficking a ...

for reporting purposes, in addition to a few others, are as follows:

Production

In the

, the alkaloids are bound to

meconic acid Meconic acid, also known as acidum meconicum and poppy acid, is a chemical substance found in certain plants of the poppy family, Papaveraceae, such as ''Papaver somniferum'' (opium poppy) and '' Papaver bracteatum''. Meconic acid constitutes abo ...

. The method is to extract from the crushed plant with diluted sulfuric acid, which is a stronger acid than meconic acid, but not so strong to react with alkaloid molecules. The

extraction Extraction may refer to: Science and technology Biology and medicine * Comedo extraction, a method of acne treatment * Dental extraction, the surgical removal of a tooth from the mouth Computing and information science * Data extraction, the ...

is performed in multiple steps (one amount of crushed plant is extracted at least six to ten times, so practically every

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

goes into the solution). From the solution obtained at the last extraction step, the alkaloids are precipitated by either ammonium hydroxide or sodium carbonate. The last step is purifying and separating morphine from other opium alkaloids. The somewhat similar Gregory process was developed in the United Kingdom during the Second World War, which begins with stewing the entire plant, in most cases save the roots and leaves, in plain or mildly acidified water, then proceeding through steps of concentration, extraction, and purification of alkaloids. Other methods of processing "poppy straw" (i.e., dried pods and stalks) use steam, one or more of several types of alcohol, or other organic solvents. The poppy straw methods predominate in Continental Europe and the British Commonwealth, with the latex method in most common use in India. The latex method can involve either vertical or horizontal slicing of the unripe pods with a two-to five-bladed knife with a guard developed specifically for this purpose to the depth of a fraction of a millimetre and scoring of the pods can be done up to five times. An alternative latex method sometimes used in China in the past is to cut off the poppy heads, run a large needle through them, and collect the dried latex 24 to 48 hours later. In India, opium harvested by licensed poppy farmers is dehydrated to uniform levels of hydration at government processing centers and then sold to pharmaceutical companies that extract morphine from the opium. However, in Turkey and Tasmania, morphine is obtained by harvesting and processing the fully mature dry seed pods with attached stalks, called ''poppy straw''. In Turkey, a water extraction process is used, while in Tasmania, a solvent extraction process is used. Opium poppy contains at least 50 different alkaloids, but most of them are of low concentration. Morphine is the principal alkaloid in raw opium and constitutes roughly 8–19% of

by dry weight (depending on growing conditions). Some purpose-developed strains of poppy now produce opium that is up to 26% morphine by weight. A rough rule of thumb to determine the morphine content of pulverised dried poppy straw is to divide the percentage expected for the strain or crop via the latex method by eight or an empirically determined factor, which is often in the range of 5 to 15. The Norman strain of ''P. somniferum'', also developed in

Tasmania Tasmania (; palawa kani: ''Lutruwita'') is an island States and territories of Australia, state of Australia. It is located to the south of the Mainland Australia, Australian mainland, and is separated from it by the Bass Strait. The sta ...

, produces down to 0.04% morphine but with much higher amounts of

and

, which can be used to synthesise semi-synthetic opioids as well as other drugs like stimulants, emetics, opioid antagonists, anticholinergics, and smooth-muscle agents. In the 1950s and 1960s,

Hungary Hungary is a landlocked country in Central Europe. Spanning much of the Pannonian Basin, Carpathian Basin, it is bordered by Slovakia to the north, Ukraine to the northeast, Romania to the east and southeast, Serbia to the south, Croatia and ...

supplied nearly 60% of Europe's total medication-purpose morphine production. To this day, poppy farming is legal in Hungary, but poppy farms are limited by law to . It is also legal to sell dried poppies in flower shops for use in floral arrangements. It was announced in 1973 that a team at the National Institutes of Health in the United States had developed a method for total synthesis of morphine,

, and thebaine using coal tar as a starting material. A shortage in codeine-hydrocodone class cough suppressants (all of which can be made from morphine in one or more steps, as well as from codeine or thebaine) was the initial reason for the research. Most morphine produced for pharmaceutical use around the world is converted into codeine as the concentration of the latter in both raw opium and poppy straw is much lower than that of morphine; in most countries, the usage of codeine (both as end-product and precursor) is at least equal or greater than that of morphine on a weight basis.

Chemical synthesis

The first morphine total synthesis, devised by Marshall D. Gates, Jr. in 1952, remains a widely used example of total synthesis. Several other syntheses were reported, notably by the research groups of Rice, Evans, Fuchs, Parker, Overman, Mulzer-Trauner, White, Taber, Trost, Fukuyama, Guillou, and Stork. Because of the stereochemical complexity and consequent synthetic challenge presented by this Polycyclic compound, polycyclic structure, Michael Freemantle has expressed the view that it is "highly unlikely" that a chemical synthesis will ever be cost-effective such that it could compete with the cost of producing morphine from the opium poppy.

GMO synthesis

Research

Thebaine has been produced by GMO ''E. coli''.

Precursor to other opioids

Pharmaceutical

Morphine is a precursor in the manufacture of several opioids such as

, and

as well as

, which itself has a large family of semi-synthetic derivatives.

Illicit

Illicit morphine is produced, though rarely, from codeine found in over-the-counter cough and pain medicines. Another illicit source is morphine extracted from extended-release morphine products. Chemical reactions can then be used to convert morphine, dihydromorphine, and hydrocodone into

or other opioids [e.g., diacetyldihydromorphine (Paralaudin), and thebacon]. Other clandestine conversions—of morphine, into ketones of the hydromorphone class, or other derivatives like

(Paramorfan), desomorphine (Permonid), metopon, etc., and of codeine into

(Dicodid),

(Paracodin), etc. —require greater expertise, and types and quantities of chemicals and equipment that are more difficult to source, and so are more rarely used, illicitly (but cases have been recorded).

History

The earliest known reference to morphine can be traced back to Theophrastus in the 3rd century BC, however, possible references to morphine may go as far back as 2100 BC as Sumerian clay tablets which records lists of medical prescriptions including opium-based cures. An opium-based elixir has been ascribed to Alchemy, alchemists of Byzantine Empire, Byzantine times, but the specific formula was lost during the Ottoman conquest of Constantinople (Istanbul). Around 1522, Paracelsus made reference to an opium-based elixir that he called ''laudanum'' from the Latin word ''laudāre'', meaning "to praise". He described it as a potent painkiller but recommended that it be used sparingly. The recipe given differs substantially from that of modern-day laudanum. Morphine was discovered as the first active alkaloid extracted from the

plant in December 1804 in Paderborn, Germany, Paderborn by German pharmacist

. In 1817, Sertürner reported experiments in which he administered morphine to himself, three young boys, three dogs, and a mouse; all four people almost died. Sertürner originally named the substance ''morphium'' after the Greek god of dreams,

, as it has a tendency to cause sleep. Sertürner's morphium was six times stronger than opium. He hypothesized that, because lower doses of the drug were needed, it would be less addictive. However, Sertürner became addicted to the drug, warning that "I consider it my duty to attract attention to the terrible effects of this new substance I called morphium in order that calamity may be averted." The drug was first marketed to the general public by Sertürner and Company in 1817 as a analgesic, pain medication, and also as a treatment for opium and alcohol addiction. It was first used as a poison in 1822 when Edme Castaing of France was convicted of murdering a patient. Commercial production began in Darmstadt, Germany, in 1827 by the pharmacy that became the pharmaceutical company Merck, with morphine sales being a large part of their early growth. In the 1850s, Alexander Wood (physician), Alexander Wood reported that he had injected morphine into his wife Rebecca as an experiment; the myth goes that this killed her because of respiratory depression, but she outlived her husband by ten years. Later it was found that morphine was more addictive than either alcohol or opium, and its extensive use during the American Civil War allegedly resulted in over 400,000 people with the "soldier's disease" of morphine addiction. This idea has been a subject of controversy, as there have been suggestions that such a disease was in fact a fabrication; the first documented use of the phrase "soldier's disease" was in 1915. Diacetylmorphine (better known as

) was synthesized from morphine in 1874 and brought to market by Bayer in 1898. Heroin is approximately 1.5 to 2 times more potent than morphine weight for weight. Due to the lipophilicity, lipid solubility of diacetylmorphine, it can cross the

faster than morphine, subsequently increasing the reinforcing component of addiction. Using a variety of subjective and objective measures, one study estimated the relative potency of heroin to morphine administered intravenously to post-addicts to be 1.80–2.66 mg of morphine sulfate to 1 mg of diamorphine hydrochloride (heroin). Morphine became a controlled substance in the US under the Harrison Narcotics Tax Act of 1914, and possession without a prescription in the US is a criminal offense. Morphine was the most commonly abused narcotic analgesic in the world until heroin was synthesized and came into use. In general, until the synthesis of

(), the dihydromorphinone class of opioids (1920s), and

(1916) and similar drugs, there were no other drugs in the same efficacy range as opium, morphine, and heroin, with synthetics still several years away (

was invented in Germany in 1937) and opioid agonists among the semi-synthetics were analogues and derivatives of codeine such as

(Paracodin), ethylmorphine (Dionine), and benzylmorphine (Peronine). Even today, morphine is the most sought-after prescription narcotic by heroin addicts when heroin is scarce, all other things being equal; local conditions and user preference may cause

, high-dose oxycodone, or

as well as dextromoramide in specific instances such as 1970s Australia, to top that particular list. The stop-gap drugs used by the largest absolute number of heroin addicts is probably codeine, with significant use also of

, poppy straw derivatives like poppy pod and poppy seed tea, propoxyphene, and tramadol. The structural formula of morphine was determined by 1925 by Robert Robinson (organic chemist), Robert Robinson. At least three methods of total synthesis of morphine from starting materials such as coal tar and petroleum distillates have been patented, the first of which was announced in 1952, by Marshall D. Gates, Jr. at the University of Rochester. Still, the vast majority of morphine is derived from the opium poppy by either the traditional method of gathering latex from the scored, unripe pods of the poppy, or processes using poppy straw, the dried pods and stems of the plant, the most widespread of which was invented in Hungary in 1925 and announced in 1930 by Hungarian pharmacologist János Kabay. In 2003, there was a discovery of endogenous morphine occurring naturally in the human body. Thirty years of speculation were made on this subject because there was a receptor that, it appeared, reacted only to morphine: the μ-opioid receptor, μ₃-opioid receptor in human tissue. Human cells that form in reaction to cancerous neuroblastoma cells have been found to contain trace amounts of endogenous morphine.

Society and culture

Legal status

* In Australia, morphine is classified as a Standard for the Uniform Scheduling of Drugs and Poisons#Schedule 8 Controlled Drug (Possession without authority illegal), Schedule 8 drug under the variously titled State and Territory Poisons Acts. * In Canada, morphine is classified as a Controlled Drugs and Substances Act#Schedule I, Schedule I drug under the Controlled Drugs and Substances Act. * In France, morphine is in the strictest schedule of controlled substances, based upon the December 1970 French controlled substances law. * In Germany, morphine is a ''verkehrsfähiges und verschreibungsfähiges Betäubungsmittel'' listed under ''Anlage III'' (the equivalent of CSA Schedule II) of the Betäubungsmittelgesetz. * In Switzerland, morphine is scheduled similarly to Germany's legal classification of the drug. * In Japan, morphine is classified as a narcotic under the :ja:麻薬及び向精神薬取締法, Narcotics and Psychotropics Control Act (, ''mayaku oyobi kōseishinyaku torishimarihō''). * In the Netherlands, morphine is classified as a List 1 drug under the Opium Law. * In New Zealand, morphine is classified as a Class B drug under the Misuse of Drugs Act 1975. * In the United Kingdom, morphine is listed as a Class A drug under the Misuse of Drugs Act 1971 and a Schedule 2 Controlled Drug under the Misuse of Drugs Regulations 2001. * In the United States, morphine is classified as a Controlled Substances Act#Schedule II controlled substances, Schedule II controlled substance under the Controlled Substances Act under main Administrative Controlled Substances Code Number 9300. Morphine pharmaceuticals are subject to annual manufacturing quotas; in 2017 these quotas were 35.0 tonnes of production for sale, and 27.3 tonnes of production as an intermediate, or chemical precursor, for conversion into other drugs. Morphine produced for use in extremely dilute formulations is excluded from the manufacturing quota. * United Nations, Internationally (UN), morphine is a Schedule I drug under the Single Convention on Narcotic Drugs.

Non-medical use

The euphoria, comprehensive alleviation of distress and therefore all aspects of suffering, promotion of sociability and empathy, "body high", and anxiolysis provided by narcotic drugs including opioids can cause the use of high doses in the absence of pain for a protracted period, which can impart a craving for the drug in the user. As the prototype of the entire opioid class of drugs, morphine has properties that may lead to its misuse. Morphine addiction is the model upon which the current perception of addiction is based. Animal and human studies and clinical experience back up the contention that morphine is one of the most euphoric drugs known, and via all but the IV route heroin and morphine cannot be distinguished according to studies because heroin is a prodrug for the delivery of systemic morphine. Chemical changes to the morphine molecule yield other euphorigenics such as

(Dilaudid, Hydal), and

(Numorphan, Opana), as well as the latter three's methylated equivalents

, and oxycodone, respectively; in addition to heroin, there are dipropanoylmorphine, diacetyldihydromorphine, and other members of the 3,6 morphine diester category like nicomorphine and other similar semi-synthetic opiates like desomorphine,

, etc. used clinically in a number of countries of the world but also produced illicitly in rare instances. In general, non-medical use of morphine entails taking more than prescribed or outside of medical supervision, injecting oral formulations, mixing it with unapproved potentiators such as alcohol, cocaine, and the like, or defeating the extended-release mechanism by chewing the tablets or turning into a powder for snorting or preparing injectables. The latter method can be as time-consuming and involved as traditional methods of smoking opium. This and the fact that the liver destroys a large percentage of the drug on the first pass impacts the demand side of the equation for clandestine re-sellers, as some customers are not needle users and may have been disappointed with ingesting the drug orally. As morphine is generally as hard or harder to divert than

in a lot of cases, morphine in any form is uncommon on the street, although ampoules and phials of morphine injection, pure pharmaceutical morphine powder, and soluble multi-purpose tablets are popular where available. Morphine is also available in a paste that is used in the production of heroin, which can be smoked by itself or turned into a soluble salt and injected; the same goes for the penultimate products of the Kompot (Polish Heroin) and black tar processes. Poppy straw as well as opium can yield morphine of purity levels ranging from poppy tea to near-pharmaceutical-grade morphine by itself or with all of the more than 50 other alkaloids. It also is the active narcotic ingredient in opium and all of its forms, derivatives, and analogues as well as forming from the breakdown of heroin and otherwise present in multiple batches of illicit heroin as the result of incomplete acetylation.

Names

Morphine is marketing, marketed under multiple different brand names in various parts of the world. It was formerly called Morphia in British English. Informal names for morphine include: Cube Juice, Dope, Dreamer, Emsel, First Line, God's Drug, Hard Stuff, Hocus, Hows, Lydia, Lydic, M, Miss Emma, Mister Blue, Monkey, Morf, Morph, Morphide, Morphie, Morpho, Mother, MS, Ms. Emma, Mud, New Jack Swing (if mixed with

), Sister, Tab, Unkie, Unkie White, and Stuff. MS Contin tablets are known as misties, and the 100 mg extended-release tablets as greys and blockbusters. The "speedball (drug), speedball" can use morphine as the opioid component, which is combined with cocaine, amphetamines, methylphenidate, or similar drugs. "Blue Velvet" is a combination of morphine with the antihistamine tripelennamine (Pyrabenzamine, PBZ, Pelamine) taken by injection.

Access in developing countries

Although morphine is cheap, people in poorer countries often do not have access to it. According to a 2005 estimate by the International Narcotics Control Board, six countries (Australia, Canada, France, Germany, the United Kingdom, and the United States) consume 79% of the world's morphine. The less affluent countries, accounting for 80% of the world's population, consumed only about 6% of the global morphine supply. Some countries import virtually no morphine, and in others the drug is rarely available even for relieving severe pain while dying. Experts in pain management attribute the under-distribution of morphine to an unwarranted fear of the drug's potential for addiction and abuse. While morphine is clearly addictive, Western doctors believe it is worthwhile to use the drug and then wean the patient off when the treatment is over.

Veterinary use

Morphine is a common perioperative analgesic in small animal veterinary medicine due to morphine's low cost and multiple routes of administration. Morphine has been used in cats and dogs since the late 19th century. Morphine can be used in dogs, cats, and horses. In horses usage is less common due to concerns over gastrointestinal ileus and neurological effects. Lower doses such as 0.1–0.2mg/kg given epidurally do not result in these adverse effects. Opioids in general are uncommon for livestock due to regulations around their usage. Morphine can be used for surgery in pigs, cattle, goats, and llamas.

References

External links

* * {{Authority control Morphine, World Health Organization essential medicines Wikipedia medicine articles ready to translate 1804 in science