Morphine, formerly known as morphium, is an opiate found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (Papaver somniferum). It is mainly used as an analgesic (pain medication). There are multiple methods used to administer morphine: oral; sublingual; via inhalation; injection into a muscle, injection under the skin, or injection into the spinal cord area; transdermal; intravenously; or via rectal suppository. It acts directly on the central nervous system (CNS) to induce analgesia 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 and chronic pain and is frequently used for pain from myocardial infarction, kidney stones, and during labor. 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, euphoria, nausea, dizziness, sweating, and constipation. Potentially serious side effects of morphine include decreased respiratory effort, vomiting, and low blood pressure. Morphine is highly addictive and prone to abuse. If one's dose is reduced after long-term use, opioid withdrawal symptoms may occur. Caution is advised for the use of morphine during pregnancy or breastfeeding, as it may affect the health of the baby.
Morphine was first isolated in 1804 by German pharmacist Friedrich Sertürner. 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 in 18531855. Sertürner originally named the substance morphium, after the Greek god of dreams, Morpheus, as it has a tendency to cause sleep.
The primary source of morphine is isolation from poppy straw of the opium poppy. 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. About 70% of morphine is used to make other opioids such as hydromorphone, oxymorphone, and heroin. It is a Schedule II drug 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. In 2023, it was the 156th most commonly prescribed medication in the United States, with more than 3million prescriptions. It is available as a generic medication.
Medical uses Pain Morphine is used primarily to treat both acute and chronic severe pain. 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 myocardial infarction 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. However, a 2006 review found little evidence to support this practice.
A 2016 Cochrane review concluded that morphine is effective in relieving cancer pain.
Shortness of breath Morphine is beneficial in reducing the symptom of shortness of breath due to both cancer 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, Poland, and Canada for persons with opioid addiction who cannot tolerate either methadone or buprenorphine.
Contraindications Relative contraindications to morphine include: Respiratory depression when appropriate equipment is not available. Although it has previously been thought that morphine was contraindicated in acute pancreatitis, a review of the literature shows no evidence for this.
Adverse effects
Constipation Like loperamide and other opioids, morphine acts on the myenteric plexus 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 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. This effect was shown in animals when a nitric oxide precursor, L-arginine, reversed morphine-induced changes in gut motility.
Hormone imbalance
Clinical studies consistently conclude that morphine, like other opioids, often causes hypogonadism and hormone imbalances 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. 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 and bone fracture 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 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 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 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 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, chronic pain, 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 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).
Reinforcement disorders
Addiction
Morphine is a highly addictive substance. In a controlled study comparing the physiological and subjective effects of heroin and morphine in individuals formerly addicted to opioids, subjects showed no preference for one drug over the other. Equipotent, injected doses had comparable action courses, with heroin crossing the blood–brain barrier slightly quicker. No difference in subjects' self-rated feelings of euphoria, ambition, nervousness, relaxation, or drowsiness was observed. 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, 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, 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 subjective effects, which is what the addicted individuals are seeking.
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), 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).
Dependence and 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 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 Stage II, 14 h to 18 h 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) Stage III, 16 h to 24 h after last dose: Increase in all of the above, dilated pupils, piloerection (goose bumps), muscle twitches, hot flashes, cold flashes, aching bones and muscles, loss of appetite, 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, loose stool, insomnia, elevation of blood pressure, fever, increase in frequency of breathing and tidal volume, tachycardia (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, and other blood changes