Morphine

Historical Background

Morphine was first isolated in the early 19th century by Friedrich Sertürner, a German pharmacist. Named after Morpheus, the Greek god of dreams, morphine quickly became a staple in medical practice due to its powerful analgesic properties. It was widely used during the American Civil War and other conflicts to treat soldiers' injuries, which unfortunately led to widespread addiction, known as "soldier's disease."

Medical Uses

Morphine is primarily used in the medical field for:

Pain Management: It is prescribed for acute and chronic pain, especially in cases of cancer, myocardial infarction, and post-surgical recovery.
Palliative Care: Morphine is a key component in palliative care, providing comfort to patients with terminal illnesses.
Anesthesia: It is sometimes used as a pre-anesthetic medication to relieve pain and anxiety before surgery.

Mechanism of Action

Morphine works by binding to opioid receptors in the brain and spinal cord. These receptors are part of the central nervous system and are responsible for transmitting pain signals. By binding to these receptors, morphine effectively blocks the transmission of pain signals, providing relief to the patient. The primary receptors involved are the mu-opioid receptors, which are also responsible for the drug's euphoric effects.

Side Effects and Risks

While morphine is effective in pain management, it comes with a range of side effects and risks:

Common Side Effects: These include drowsiness, constipation, nausea, vomiting, and dizziness.
Respiratory Depression: One of the most serious risks is respiratory depression, where breathing becomes shallow or stops altogether.
Addiction and Dependence: Morphine has a high potential for addiction and dependence, leading to misuse and abuse.
Tolerance: Over time, patients may develop a tolerance, requiring higher doses to achieve the same level of pain relief.

Considerations and Precautions

When prescribing or using morphine, several considerations must be taken into account:

Dosage: It is crucial to follow the prescribed dosage to minimize the risk of addiction and side effects.
Patient History: A thorough patient history should be reviewed to assess the risk of addiction or adverse reactions.
Monitoring: Patients on morphine should be closely monitored for signs of respiratory depression and other side effects.
Alternative Treatments: Consideration of alternative pain management strategies may be necessary for patients with a history of substance abuse.

Legal and Ethical Aspects

Morphine is classified as a Schedule II controlled substance in the United States, indicating a high potential for abuse but also recognized medical uses. This classification necessitates strict regulations on its prescription and distribution. Healthcare providers must balance the ethical responsibility of managing pain with the potential for abuse and addiction.

Articles/Studies

Repeated Morphine Prolongs Postoperative Pain in Male Rats.

Morphine-alcohol treatment impairs cognitive functions and increases neuro-inflammatory responses in the medial prefrontal cortex of juvenile male rats

Can a poisonous sea snail replace morphine?

Sulforaphane alleviates hyperalgesia and enhances analgesic potency of morphine in rats with cancer-induced bone pain.

Prevention of Morphine Tolerance & Dependence

Risks

Alternatives to Morphine & Ways to Lower Dosage

IV Morphine is 3 times as potent as oral morphine

Wikipedia:

Morphine is a pain medication of the opiate type which is found naturally in a number of plants and animals.^[5][7] It acts directly on the central nervous system (CNS) to decrease the feeling of pain. It can be taken for both acute pain and chronic pain. Morphine is frequently used for pain from myocardial infarction and during labour. It can be given by mouth, by injection into a muscle, by injecting under the skin, intravenously, into the space around the spinal cord, or rectally.^[5] Maximum effect is around 20 min when given intravenously and 60 min when given by mouth while duration of effect is between three and 7 h. Long-acting formulations also exist.

Potentially serious side effects include a decreased respiratory effort and low blood pressure. Morphine has a high potential for addiction and abuse. If the dose is reduced after long-term use, withdrawal may occur. Common side effects include drowsiness, vomiting, and constipation. Caution is advised when used during pregnancy or breast feeding, as morphine will affect the baby.^[5]

Morphine was first isolated between 1803 and 1805 by Friedrich Sertürner.^[8] This is generally believed to be the first isolation of an active ingredient from a plant.^[9] Merck began marketing it commercially in 1827.^[8] Morphine was more widely used after the invention of the hypodermic syringe in 1853–1855.^[8][10] Sertürner originally named the substance morphium after the Greek god of dreams, Morpheus, as it has a tendency to cause sleep.^[10][11]

The primary source of morphine is isolation from poppy straw of the opium poppy.^[12] In 2013, an estimated 523,000 kilograms of morphine were produced.^[13] About 45 000 kg were used directly for pain, an increase over the last twenty years of four times.^[13]Most use for this purpose was in the developed world.^[13] About 70% of morphine is used to make other opioids such as hydromorphone, oxymorphone, and heroin.^[13][14][15] It is a Schedule II drug in the United States,^[14] Class A in the United Kingdom,^[16] and Schedule I in Canada.^[17] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.^[18] Morphine is sold under many trade names.^[1]

Medical uses

Pain

Morphine is used primarily to treat both acute and chronic severe pain. It is also used for pain due to myocardial infarction and for labor pains.^[19] Its duration of analgesia is about three to seven hours.^[5][6]

However, concerns exist that morphine may increase mortality in the setting of non ST elevation myocardial infarction.^[20] Morphine has also traditionally been used in the treatment of acute pulmonary edema.^[19] A 2006 review, though, found little evidence to support this practice.^[21] A 2016 Cochrane review concluded that morphine is effective in relieving cancer pain. Side-effects of nausea and constipation are rarely severe enough to warrant stopping treatment.^[22]

Shortness of breath

Immediate-release morphine is beneficial in reducing the symptom of shortness of breath due to both cancer and noncancer causes.^[23][24] 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.^[25][26]

Opioid use disorder

Morphine is also available as a slow-release formulation for opiate substitution therapy (OST) in Austria, Bulgaria, and Slovenia, for addicts who cannot tolerate either methadone or buprenorphine.^[27]

Contraindications

Relative contraindications to morphine include:

respiratory depression when appropriate equipment is not available^[5]
Although it has previously been thought that morphine was contraindicated in acute pancreatitis, a review of the literature shows no evidence for this.^[28]

Adverse effects

Common and short term

Itch^[29]
Nausea^[29]
Vomiting^[29]
Constipation^[29]
Drowsiness^[29]
dry mouth^[29]

Other

Opioid dependence
Dizziness
Decreased sex drive
impaired sexual function
Decreased testosterone levels
Depression
Immunodeficiency
opioid-induced abnormal pain sensitivity
Irregular menstruation
Increased risk of falls
Slowed breathing

A localized reaction to intravenous morphine caused by histamine release in the veins

Constipation

Like loperamide and other opioids, morphine acts on the myenteric plexus in the intestinal tract, reducing gut motility, 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 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 generation.^[30] This effect was shown in animals when a nitric oxide precursor, L-arginine, reversed morphine-induced changes in gut motility.^[31]

Hormone imbalance

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 central nervous system depressant. 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 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),^[34] though no studies have shown a correlation between morphine and gross motor abilities.

In terms of cognitive abilities, one study has shown that morphine may have a negative impact on anterograde and retrograde memory,^[35]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 and cognition. It is likely that the effects of morphine will be more pronounced in opioid-naive subjects than chronic opioid users.

In chronic opioid users, such as those on Chronic Opioid Analgesic Therapy (COAT) for managing severe, chronic pain, behavioural testing has shown normal functioning on perception, cognition, coordination and behaviour in most cases. One 2000 study^[36] 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 speed of responding for successful performance (e.g., Rey Complex Figure Test) but made more errors than controls. COAT patients showed no deficits in visual-spatial perception and organization (as shown in the WAIS-R 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, cognitive, or neuropsychological functioning.

Reinforcement disorders

Addiction

Before the Morphine by Santiago Rusiñol

Morphine is a highly addictive substance. In controlled studies comparing the physiological and subjective effects of heroin 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 no difference in subjects' self-rated feelings of euphoria, ambition, nervousness, relaxation, drowsiness, or sleepiness.^[37] 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 hydromorphone, fentanyl, oxycodone, and pethidine/meperidine, 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 were also much more likely to produce euphoria and other positive subjective effects when compared to these other opioids.^[37] The choice of heroin and morphine over other opioids by former drug addicts may also be because heroin (also known as morphine diacetate, diamorphine, or diacetyl morphine) is an ester of morphine and a morphine prodrug, essentially meaning they are identical drugs in vivo. Heroin is converted to morphine before binding to the opioid receptors in the brain and spinal cord, where morphine causes the subjective effects, which is what the addicted individuals are seeking.^[38]

Tolerance

Several hypotheses are given about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization),^[39] μ-opioid receptor internalization or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.^[40]) CCK might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, have been shown to slow the development of tolerance to morphine.

Dependence and withdrawal

See also: Opioid dependence and Opioid withdrawal

Cessation of dosing with morphine creates the prototypical opioid withdrawal syndrome, which, unlike that of barbiturates, benzodiazepines, alcohol, or sedative-hypnotics, is not fatal by itself in neurologically healthy patients without heart or lung problems.

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^[by ^whom?], they are:

Stage I, 6 to 14 hours after last dose: Drug craving, anxiety, irritability, perspiration, and mild to moderate dysphoria^[citation ^needed]
Stage II, 14 to 18 hours after last dose: Yawning, heavy perspiration, mild depression, lacrimation, crying, headaches, runny nose, dysphoria, also intensification of the above symptoms, "yen sleep" (a waking trance-like state) ^{[clarification} ^needed]
Stage III, 16 to 24 hours after last dose: Rhinorrhea (runny nose) and increase in other of the above, dilated pupils, piloerection (goose bumps – a purported origin of the phrase, 'cold turkey,' but in fact the phrase originated outside of drug treatment),^[41] muscle twitches, hot flashes, cold flashes, aching bones and muscles, loss of appetite, and the beginning of intestinal cramping^[citation ^needed]
Stage IV, 24 to 36 hours after last dose: Increase in all of the above including severe cramping and involuntary leg movements ("kicking the habit" also called restless leg syndrome), loose stool, insomnia, elevation of blood pressure, moderate elevation in body temperature, increase in frequency of breathing and tidal volume, tachycardia (elevated pulse), restlessness, nausea^[citation ^needed]
Stage V, 36 to 72 hours after last dose: Increase in the above, fetal position, vomiting, free and frequent liquid diarrhea, which sometimes can accelerate the time of passage of food from mouth to out of system, weight loss of 2 to 5 kg per 24 hours, increased white cell count, and other blood changes^[citation ^needed]
Stage VI, after completion of above: Recovery of appetite and normal bowel function, beginning of transition to postacute and chronic symptoms that are mainly psychological, but may also include increased sensitivity to pain, hypertension, colitis or other gastrointestinal afflictions related to motility, and problems with weight control in either direction^[citation ^needed]

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.^[42]

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 6–12 hours) after the last administration. Early symptoms include watery eyes, insomnia, diarrhea, runny nose, yawning, dysphoria, sweating, and in some cases a strong drug craving. Severe headache, restlessness, irritability, 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 very common. During the acute withdrawal period, systolic and diastolic blood pressures increase, usually beyond premorphine levels, and heart rate increases,^[43] which have potential to cause a heart attack, blood clot, or stroke.

Chills or cold flashes with goose bumps ("cold turkey") alternating with flushing (hot flashes), kicking movements of the legs ("kicking the habit"^[38]) and excessive sweating are also characteristic symptoms.^[44] 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 and 96 hours after the last dose and subside after about 8 to 12 days. Sudden withdrawal by heavily dependent users who are in poor health is very rarely fatal. Morphine withdrawal is considered less dangerous than alcohol, barbiturate, or benzodiazepine withdrawal.^[45][46]

The psychological dependence associated with morphine addiction is complex and protracted. Long after the physical need for morphine has passed, the addict 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 very long and painful process.^{[47][unreliable} ^medical ^source] Addicts often suffer severe depression, anxiety, insomnia, mood swings, amnesia (forgetfulness), low self-esteem, confusion, paranoia, and other psychological disorders. 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 to morphine's addictive and reinforcing nature is its relapse rate. Abusers of morphine (and heroin) have one of the highest relapse rates among all drug users, ranging up to 98% in the estimation of some medical experts.^[48]

Overdose

A large overdose can cause asphyxia and death by respiratory depression if the person does not receive medical attention immediately.^[49] Overdose treatment includes the administration of naloxone. The latter completely reverses morphine's effects, but may result in immediate onset of withdrawal in opiate-addicted subjects. Multiple doses may be needed.^[49]

The minimum lethal dose is 200 mg, but in case of hypersensitivity, 60 mg can bring sudden death. In serious drug dependency (high tolerance), 2000–3000 mg per day can be tolerated.^[50]

Pharmacology

Pharmacodynamics

Main article: Opioid receptor

This section's factual accuracy may be compromised due to out-of-date information. Please update this article to reflect recent events or newly available information. (July 2014)

Endogenous opioids include endorphins, enkephalins, dynorphins, and even morphine itself. Morphine appears to mimic endorphins. Endorphins, a contraction of the term endogenous morphines, are responsible for analgesia (reducing pain), causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or excitement.

Morphine is the prototype narcotic drug and is the standard against which all other opioids are tested. It interacts predominantly with the μ–δ-opioid (Mu-Delta) receptor heteromer.^[51][52] The μ-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve.^[53]

Morphine is a phenanthrene opioid receptor agonist – its main effect is binding to and activating the μ-opioid receptors in the central nervous system. In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation. Activation of the μ-opioid receptors is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is a rapid-acting narcotic, and it is known to bind very strongly to the μ-opioid receptors, and for this reason, it often has a higher incidence of euphoria/dysphoria, respiratory depression, sedation, pruritus, tolerance, and physical and psychological dependence when compared to other opioids at equianalgesic doses. Morphine is also a κ-opioid and δ-opioid receptor agonist, κ-opioid's action is associated with spinal analgesia, miosis (pinpoint pupils) and psychotomimetic effects. δ-Opioid is thought to play a role in analgesia.^[53] Although morphine does not bind to the σ-receptor, it has been shown that σ-agonists, such as (+)-pentazocine, inhibit morphine analgesia, and σ-antagonists enhance morphine analgesia,^[54] suggesting downstream involvement of the σ-receptor in the actions of morphine.

The effects of morphine can be countered with opioid antagonists such as naloxone and naltrexone; the development of tolerance to morphine may be inhibited by NMDA antagonists such as ketamine or dextromethorphan.^[55] 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, ketobemidone, piritramide, and methadone 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.

Gene expression

Studies have shown that morphine can alter the expression of a number of genes. A single injection of morphine has been shown to alter the expression of two major groups of genes, for proteins involved in mitochondrial respiration and for cytoskeleton-related proteins.^[56]

Effects on the immune system

Morphine has long been known to act on receptors expressed on cells of the central nervous system resulting in pain relief and analgesia. In the 1970s and '80s, evidence suggesting that opioid drug addicts show increased risk of infection (such as increased pneumonia, tuberculosis, and HIV/AIDS) led scientists to believe that morphine may also affect the immune system. This possibility increased interest in the effect of chronic morphine use on the immune system.

The first step of 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, part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producing cytokines, 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 (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).^[57]

This regulation of cytokines appear 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), which is activated through the ligand LPS (lipopolysaccharide). This causes the p38 MAPK to be phosphorylated. 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 then treated with LPS, the production of cytokines is different. Once treated with morphine, the p38 MAPK does not produce IL-10, instead favoring 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 and other cytokines. Since cytokines are produced as part of the immediate immunological response (inflammation), 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 hind-paw incision, pain thresholds and cytokine production were measured. Normally, cytokine production in and around the wounded area increases in order to fight infection and control healing (and, possibly, to control pain), but pre-incisional morphine administration (0.1–10.0 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.^[58]

Pharmacokinetics

Absorption and metabolism

Morphine can be taken orally, sublingually, bucally, rectally, subcutaneously, intranasally, intravenously, intrathecally or epidurally and inhaled via a nebulizer. As a recreational drug, it is becoming more common to inhale ("Chasing the Dragon"), but, for medical purposes, intravenous (IV) injection is the most common method of administration. Morphine is subject to extensive first-pass metabolism (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.^[59] Morphine is metabolised primarily in the liver and approximately 87% of a dose of morphine is excreted in the urine within 72 h of administration. Morphine is metabolized primarily into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G)^[60] via glucuronidation 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.^[61] 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.^[61] Morphine may also be metabolized into small amounts of normorphine, codeine, and hydromorphone. Metabolism rate is determined by gender, age, diet, genetic makeup, disease state (if any), and use of other medications. The elimination 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 blood–brain barrier, but, because of poor lipid solubility, protein binding, rapid conjugation with glucuronic acid and ionization, it does not cross easily. Diacetylmorphine, which is derived from morphine, crosses the blood–brain barrier more easily, making it more potent.^[62]

Extended-release

Main article: Extended-release morphine

There are extended-release formulations of orally administered morphine whose effect last longer, which can be given once per day. Brand names for this formulation of morphine include Avinza,^[63] Kadian,^[63] MS Contin^[63] and Dolcontin.^[64] For constant pain, the relieving effect of extended-release morphine given once (for Kadian)^[65] or twice (for MS Contin)^[65] every 24 hours is roughly the same as multiple administrations of immediate release (or "regular") morphine.^[66] 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.^[66]

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. Chromatography can be used to test for each of these substances individually. Some testing procedures hydrolyze 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 (SPE) and detected using liquid chromatography-mass spectrometry (LC-MS).

Ingestion of codeine or food containing poppy seeds can cause false positives.^[67]

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.^[68] A 2009 review determined that, when the analyte is morphine and the limit of detection is 1 ng/ml, a 20 mg intravenous (IV) dose of morphine is detectable for 12–24 hours. A limit of detection of 0.6 ng/ml had similar results.^[69]

Natural occurrence

Chemistry

Chemical structure of morphine. The benzylisoquinoline backbone is shown in green.

Same structure with correct 3D configuration; backbone in blue.

Morphine is a benzylisoquinoline alkaloid with two additional ring closures. It has:

A rigid pentacyclic structure consisting of a benzene ring (A), two partially unsaturated cyclohexane rings (B and C), a piperidine ring (D) and a tetrahydrofuran ring (E). Rings A, B and C are the phenanthrene ring system. This ring system has little conformational flexibility.
Two hydroxyl functional groups: a C3-phenolic OH (pKa 9.9) and a C6-allylic OH,
An ether linkage between C4 and C5,
Unsaturation between C7 and C8,
A basic, tertiary amine function at position 17,
5 centers of chirality (C5, C6, C9, C13 and C14) with morphine exhibiting a high degree of stereoselectivity of analgesic action.^[79]

Most of the licit morphine produced is used to make codeine by methylation. It is also a precursor for many drugs including heroin (3,6-diacetylmorphine), hydromorphone (dihydromorphinone), and oxymorphone (14-hydroxydihydromorphinone); many morphine derivatives can also be manufactured using thebaine or codeine as a starting material. 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 with a 6-methylene group produces a compound some 1,443 times more potent than morphine, stronger than the Bentley compounds such as etorphine (M99, the Immobilon tranquilliser dart) by some measures.

The structure-activity relationship of morphine has been extensively studied. 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 naloxone (Narcan), naltrexone (Trexan), diprenorphine (M5050, the reversing agent for the Immobilon dart) and nalorphine (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 are devoid of narcotic effects.

Morphine and most of its derivatives do not exhibit optical isomerism, although some more distant relatives like the morphinan series (levorphanol, dextorphan and the racemic parent chemical dromoran) do, and as noted above stereoselectivity in vivo is an important issue.

Morphine-derived agonist–antagonist drugs have also been developed. Elements of the morphine structure have been used to create completely synthetic drugs such as the morphinan family (levorphanol, dextromethorphan and others) and other groups that have many 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.

Most semi-synthetic opioids, both of the morphine and codeine 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; 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.

Structure and propertiesMolarmass	Structure and propertiesMolarmass	Structure and propertiesMolarmass	Structure and propertiesMolarmass	Structure and propertiesMolarmass	Structure and propertiesMolarmass	Structure and propertiesMolarmass	Structure and propertiesMolarmass
^[80]	285.338 g/molIndexofrefraction	285.338 g/molIndexofrefraction	285.338 g/molIndexofrefraction	285.338 g/molIndexofrefraction	285.338 g/molIndexofrefraction	285.338 g/molIndexofrefraction	285.338 g/molIndexofrefraction
, nD	?	?	?	?	?	?	?
Acidity (pKa)^[80]		Step 1: 8.21at25°CStep2			: 9.85at20°CSolubility
^[80]	0.15 g/L at 20 °CMeltingpoint	0.15 g/L at 20 °CMeltingpoint	0.15 g/L at 20 °CMeltingpoint	0.15 g/L at 20 °CMeltingpoint	0.15 g/L at 20 °CMeltingpoint	0.15 g/L at 20 °CMeltingpoint	0.15 g/L at 20 °CMeltingpoint
^[80]	255 °CBoilingpoint	255 °CBoilingpoint	255 °CBoilingpoint	255 °CBoilingpoint	255 °CBoilingpoint	255 °CBoilingpoint	255 °CBoilingpoint
^[80]	190 °C sublimes	190 °C sublimes	190 °C sublimes	190 °C sublimes	190 °C sublimes	190 °C sublimes	190 °C sublimes

Both morphine and its hydrated form, C17H19NO3H2O, are sparingly soluble in water. In five liters of water, only one gram of the hydrate will dissolve. 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 to make them suitable for injection.^[81]

A number of 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, which is another name for heroin, is a Schedule I controlled substance, so it is not used clinically in the United States; it is a sanctioned medication in the United Kingdom and in Canada and some countries in Continental Europe, its use being particularly common (nearly to the degree of the hydrochloride salt) in the United Kingdom. Morphine meconate is a major form of the alkaloid in the poppy, as is morphine pectinate, nitrate, sulphate, 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; multiple barbiturate 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. Morphine valerate produced industrially was one ingredient of a medication available for both oral and parenteral administration popular many years ago in Europe and elsewhere called Trivalin (not to be confused with the current, unrelated herbal preparation of the same name), which also included the valerates of caffeine and cocaine, with a version containing codeine valerate as a fourth ingredient being distributed under the name Tetravalin.

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.

The salts listed by the United States Drug Enforcement Administration for reporting purposes, in addition to a few others, are as follows:

[show]Select forms of morphine as 'morphiniums' or N-protonated cations of morphine, i.e. ionic salts & chemical form with freebase conversion ratios:

Synthesis

Main article: Morphine total synthesis

The first morphine total synthesis, devised by Marshall D. Gates, Jr. in 1952, remains a widely used example of total synthesis.^[82] Several other syntheses were reported, notably by the research groups of Rice,^[83] Evans,^[84] Fuchs,^[85] Parker,^[86] Overman,^[87] Mulzer-Trauner,^[88] White,^[89] Taber,^[90] Trost,^[91] Fukuyama,^[92] Guillou,^[93] and Stork.^[94] It is "highly unlikely" that a chemical synthesis will ever be able to compete with the cost of producing morphine from the opium poppy.^[95]

Production

First generation production of Alkaloids from licit latex-derived opium

In the opium poppy, the alkaloids are bound to meconic acid. 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 is performed in many steps (one amount of crushed plant is extracted at least six to ten times, so practically every alkaloid 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.^[citation ^needed] 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.^[citation ^needed]

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.^[citation ^needed]

Opium poppy contains at least 50 different alkaloids, but most of them are of very low concentration. Morphine is the principal alkaloid in raw opium and constitutes roughly 8–19% of opium by dry weight (depending on growing conditions).^[62] Some purpose-developed strains of poppy now produce opium that is up to 26% morphine by weight.^[citation ^needed] 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.^[citation ^needed] The Norman strain of P. Somniferum, also developed in Tasmania, produces down to 0.04% morphine but with much higher amounts of thebaine and oripavine, which can be used to synthesise semi-synthetic opioids as well as other drugs like stimulants, emetics, opioid antagonists, anticholinergics, and smooth-muscle agents.^[citation ^needed]

In the 1950s and 1960s, Hungary 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 2 acres (8,100 m2). It is also legal to sell dried poppy 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, codeine, 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 actually 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.

Precursor to other opioids

Pharmaceutical

Morphine is a precursor in the manufacture in a large number of opioids such as dihydromorphine, hydromorphone, hydrocodone, and oxycodone as well as codeine, which itself has a large family of semi-synthetic derivatives. Morphine is commonly treated with acetic anhydride and ignited to yield heroin.^[96] Throughout Europe there is growing acceptance within the medical community of the use of slow release oral morphine as a substitution treatment alternative to methadone and buprenorphine for patients not able to tolerate the side-effects of buprenorphine and methadone. Slow-release oral morphine has been in widespread use for opiate maintenance therapy in Austria, Bulgaria, and Slovakia for many years and it is available on a small scale in many other countries including the UK. The long-acting nature of slow-release morphine mimics that of buprenorphine because the sustained blood levels are relatively flat so there is no "high" per se that a patient would feel but rather a sustained feeling of wellness and avoidance of withdrawal symptoms. For patients sensitive to the side-effects that in part may be a result of the unnatural pharmacological actions of buprenorphine and methadone, slow-release oral morphine formulations offer a promising future for use managing opiate addiction. The pharmacology of heroin and morphine is identical except the two acetyl groups increase the lipid solubility of the heroin molecule, causing heroin to cross the blood–brain barrier and enter the brain more rapidly in injection. Once in the brain, these acetyl groups are removed to yield morphine, which causes the subjective effects of heroin. Thus, heroin may be thought of as a more rapidly acting form of morphine.^[97]

Illicit

Illicit morphine is rarely produced from codeine found in over-the-counter cough and pain medicines. This demethylation reaction is often performed using pyridine and hydrochloric acid.^[98]

Another source of illicit morphine comes from the extraction of morphine from extended-release morphine products, such as MS-Contin. Morphine can be extracted from these products with simple extraction techniques to yield a morphine solution that can be injected.^[99] As an alternative, the tablets can be crushed and snorted, injected or swallowed, although this provides much less euphoria but retains some of the extended-release effect, and the extended-release property is why MS-Contin is used in some countries alongside methadone, dihydrocodeine, buprenorphine, dihydroetorphine, piritramide, levo-alpha-acetylmethadol (LAAM), and special 24-hour formulations of hydromorphone for maintenance and detoxification of those physically dependent on opioids.

Another means of using or misusing morphine is to use chemical reactions to turn it into heroin or another stronger opioid. Morphine can, using a technique reported in New Zealand (where the initial precursor is codeine) and elsewhere known as home-bake, be turned into what is usually a mixture of morphine, heroin, 3-monoacetylmorphine, 6-monoacetylmorphine, and codeine derivatives like acetylcodeine if the process is using morphine made from demethylating codeine.

Since heroin is one of a series of 3,6 diesters of morphine, it is possible to convert morphine to nicomorphine (Vilan) using nicotinic anhydride, dipropanoylmorphine with propionic anhydride, dibutanoylmorphine and disalicyloylmorphine with the respective acid anhydrides. Glacial acetic acid can be used to obtain a mixture high in 6-monoacetylmorphine, niacin (vitamin B3) in some form would be precursor to 6-nicotinylmorphine, salicylic acid may yield the salicyoyl analogue of 6-MAM, and so on.

The clandestine conversion of morphine to ketones of the hydromorphone class or other derivatives like dihydromorphine (Paramorfan), desomorphine (Permonid), metopon, etc. and codeine to hydrocodone (Dicodid), dihydrocodeine (Paracodin), etc. is more involved, time-consuming, requires lab equipment of various types, and usually requires expensive catalysts and large amounts of morphine at the outset and is less common but still has been discovered by authorities in various ways during the last 20 years or so. Dihydromorphine can be acetylated into another 3,6 morphine diester, namely diacetyldihydromorphine (Paralaudin), and hydrocodone into the bacon.