Morphine
Systematic (IUPAC) name
(5α,6α)-7,8-didehydro-
4,5-epoxy-17-methylmorphinan-3,6-diol
Clinical data
Trade names Mscontin, Oramorph, Sevredol (morphine as a sulfate)
AHFS/Drugs.com
Pregnancy cat.
Legal status
High
Routes Inhalation (smoking), insufflation (snorting), oral, rectal, subcutaneous (SC), intramuscular (IM), intravenous (IV), epidural, and intrathecal (IT)
Pharmacokinetic data
Bioavailability 20–40% (oral), 36–71% (rectally),[1] 100% (IV/IM)
Protein binding 30–40%
Metabolism Hepatic 90%
Half-life 2–3 h
Excretion Renal 90%, biliary 10%
Identifiers
CAS number  YesY
64-31-3 (neutral sulfate),
52-26-6 (hydrochloride)
ATC code N02
PubChem
IUPHAR ligand
DrugBank
ChemSpider  YesY
UNII  YesY
KEGG  YesY
ChEBI  YesY
ChEMBL  YesY
Chemical data
Formula C17H19NO3 
Mol. mass 285.34
Physical data
Solubility in water HCl & sulf.: 60 mg/mL (20 °C)
 YesY   

Morphine (INN) () (sold under nearly a hundred trade names) is an opioid analgesic drug, and the main psychoactive chemical in opium. In clinical medicine, morphine is regarded as the gold standard of analgesics used to relieve intense pain. Like other opioids, such as oxycodone, hydromorphone, and diacetylmorphine (heroin), morphine acts directly on the central nervous system (CNS) to relieve pain.

Morphine has a high potential for addiction; tolerance and psychological dependence develop rapidly, although physiological dependence may take several months to develop. Tolerance to respiratory depression and euphoria develops more rapidly than tolerance to analgesia, and many chronic pain patients are therefore maintained on a stable dose for years. However, its effects can also reverse fairly rapidly, worsening pain through hyperalgesia.

Morphine is the most abundant opiate found in opium, the dried health system.[3]

Medical uses

Morphine is primarily used to treat both acute and chronic severe pain. It is also used for pain due to myocardial infarction and for labor pains.[4] However, concerns exist that morphine may increase mortality in the setting of non ST elevation myocardial infarction.[5] Morphine has also traditionally been used in the treatment of acute pulmonary edema.[4] A 2006 review, though, found little evidence to support this practice.[6]

Immediate-release morphine is beneficial in reducing the symptom of acute shortness of breath due to both cancer and noncancer causes.[7][8] 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.[9][10]

Its duration of analgesia is about 3–4 hours when administered via the intravenous, subcutaneous, or intramuscular routes and 3–6 hours when given by mouth.[11] Morphine is also used in slow-release formulations for opiate substitution therapy (OST) in Austria, Bulgaria, and Slovenia, for addicts who cannot tolerate the side effects of using either methadone or buprenorphine, or for addicts who are "not held" by buprenorphine or methadone.[12]

Side effects

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.[13] This effect was shown in animals when a nitric oxide precursor, L-Arginine, reversed morphine-induced changes in gut motility.[14]

Addiction

Morphine is a potentially highly addictive substance. It can cause psychological dependence and physical dependence as well as tolerance. In the presence of pain and the other disorders for which morphine is indicated, a combination of psychological and physiological factors tend to prevent true addiction from developing, although physical dependence and tolerance will develop with protracted opioid therapy.

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.[15] 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.[15] 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.[16]

Other studies, such as the Rat Park experiments, suggest that morphine is less physically addictive than others suggest, and most studies on morphine addiction show that "severely distressed animals, like severely distressed people, will relieve their distress pharmacologically if they can."[17] In these studies, rats with a morphine "addiction" overcome their addiction when placed in decent living environments with enough space, good food, companionship, areas for exercise, and areas for privacy. More recent research has shown that an enriched environment may decrease morphine addiction in mice.[18]

Tolerance

Tolerance to the analgesic effects of morphine is fairly rapid. 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),[19] μ-opioid receptor internalization and/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.[20]) 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.

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, they are:

  • Stage I, 6 to 14 hours after last dose: Drug craving, anxiety, irritability, perspiration, and mild to moderate dysphoria
  • Stage II, 14 to 18 hours after last dose: Yawning, heavy perspiration, mild depression, lacrimation, crying, runny nose, dysphoria, also intensification of the above symptoms, "yen sleep" (a waking trance-like state)
  • Stage III, 16 to 24 hours after last dose: Rhinorrhea (runny nose) and increase in other of the above, dilated pupils, piloerection (goose bumps - giving the name 'cold turkey'), muscle twitches, hot flashes, cold flashes, aching bones and muscles, loss of appetite, and the beginning of intestinal cramping
  • 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
  • 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 to an hour or less, weight loss of 2 to 5 kg per 24 hours, increased white cell count, and other blood changes
  • 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

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.[21]

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 ome 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,[22] 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"[16]) and excessive sweating are also characteristic symptoms.[23] 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.[24][25]

The psychological dependence associated with morphine [27]

Hormone imbalance

Clinical studies consistently conclude, like other opioids, morphine often causes hypogonadism and hormone imbalances in chronic users of both genders. This side effect is dose-dependent and occurs in both therapeutic and recreational users. Morphine can interfere with menstruation in women by suppressing levels of luteinizing hormone. Many studies suggest the majority (perhaps as much as 90%) of chronic opioid users have opioid-induced hypogonadism. This effect may cause the increased likelihood of osteoporosis and bone fracture observed in chronic morphine users. Studies suggest the effect is temporary. As of 2013, the effect of low-dose or acute use of morphine on the endocrine system is unclear.[28][29]

Overdose

A large overdose can cause asphyxia and death by respiratory depression if the person does not receive medical attention immediately.[30] Overdose treatment includes the administration of naloxone. The latter completely reverses morphine's effects, but precipitates immediate onset of withdrawal in opiate-addicted subjects. Multiple doses may be needed.[30]

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.[31]

Contraindications

These conditions are relative contraindications for morphine:

Although it has previously been thought that morphine was contraindicated in acute pancreatitis, a review of the literature shows no evidence for this.[33]

Pharmacodynamics

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 receptor heteromer.[34][35] 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.[36]

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.[36] 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,[37] suggesting some interaction between morphine and the σ-opioid receptor.

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.[38]