Morphine

By MelanieDrugs

Also known as

Kadian, avinza, MS contin, morf, morpho, M.S., miss emma, mister blue, monf, dover’s powder, paregoric, laudanum, MST, zomorph, sevredol, morphgesic, MXL, oramorph, duramorph, M, monkey, roxanol, white stuff, TNT, tango and cash, dance fever, murder 8, gorilla

Classification

Opioid, narcotic analgesic

Overview

Morphine is an opiate that comes from the opium poppy, and is in fact the ‘daddy’ of the family of substances that come from this plant (others include codeine, papaverine, thebaine etc.) 1. The principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle. In January, 2017, morphine was approved for the treatment of chronic pain 2.

Medical usage

Pain relief for moderate to severe pain 3.

What does it look like?

Either blue or white tablets, capsules or ampules 1.

Source

The primary active agent of opium. Little illicit morphine finds its way into Britain, but what is found on the illicit market in this country has probably been diverted from the pharmaceutical industry, pharmacies, or GPs prescriptions 3.

Street price

Oramorph oral solution, 10mg/5mL syrup/liquid ranges between £2 and £8 4. Zomorph, 10mg pill £2 4.

Why take it?

Sought after effects

  • very effective painkiller (often the only effective pain relief for chronic pain syndromes),
  • wide range of formulations available 1,
  • euphoria,
  • relaxation,
  • decreased anxiety 3.

Undesired effects

  • large dose usually required,
  • short-acting,
  • very ‘prickly’ when injected,
  • dose increases usually required (variable ‘ceiling’ dose),
  • doctors often reluctant to prescribe 1,
  • sweating,
  • nausea,
  • vomiting,
  • drowsiness,
  • respiratory depression,
  • constipation 3.

Dosage

Abuse

  • threshold < 10 mg,
  • light 10 – 15 mg 5, 5 – 10 mgs 6.
  • common 15 – 20 mgs 5, 6.
  • strong 20 – 30 mgs 5, 30 mgs + 6.
  • heavy 30 mg + 5.

What are the different forms?

Morphine comes as tablets, capsules, granules (that you dissolve in water to make a drink), a liquid that you swallow, suppositories, injection 7.

How long do its effects last?

Onset of effects

  • oral (immediate release) – 10 – 30 minutes 5, 6.
  • oral (extended release) – 40 – 80 minutes,
  • insufflated – 10 – 30 minutes,
  • rectal – 10 – 30 minutes,
  • intravenous/intramuscular injection – 0 – 1 minutes 6.

Come up

  • oral – 20 – 40 minutes 5.

Peak

  • oral – 2 – 3 hours 5.

Offset

  • oral – 1 – 2 hours 5.

Duration of effects

  • oral (immediate release) – 4 – 6 hours 5, 6.
  • oral (extended release) – 4 – 10 hours,
  • insufflated – 4 – 5 hours,
  • rectal – 3 – 4 hours,
  • intravenous/intramuscular injection – 1 – 12 hours 6

After-effects

  • oral (immediate release) – 1 – 12 hours 5, 6.
  • oral (extended release) – 1 – 12 hours,
  • insufflated – 1 – 12 hours,
  • rectal – 1 – 12 hours,
  • intravenous/intramuscular injection – 1 – 12 hours 6.

Pharmacology

Endogenous opioids include endorphins, enkephalins and dynorphins. Morphine appears to mimic and amplify the action of endorphins, which act to reduce physical pain, causing sleepiness, and provoke feelings of pleasure. They can be released in response to pain and external stimuli, such as sex and exercise. It crosses the blood-brain barrier less efficiently than heroin, which is synthesised from morphine.

It interacts predominantly with the μ-opioid receptor. These μ-binding sites are discretely distributed in the human brain, gut and spinal cord.

Morphine is an opioid receptor agonist – its main effect is binding to and activating the μ-opioid receptors in the CNS. 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. It also has a complex relationship with the way humans process and respond to emotional affect. The drug is a very potent modulating agent for psychic pain and trauma, and it is widely believed that this explains its huge appeal to people who have been victims of abuse and neglect, particularly in early life.

Morphine is also a κ-opioid and δ-opioid receptor agonist, κ-opioid’s action is associated with analgesia, miosis and psychotomimetic. δ-opioid is thought to play a general role in analgesia.

Sigma (σ) receptors were once considered to be opioid receptors due to the alleviating or suppressing coughing actions of many opioid drugs being mediated via σ receptors, however they are now not usually classified with the opioid receptors. Although morphine does not bind to the σ-receptor, it has been shown that σ-agonists, antagonise morphine analgesia, and σ-antagonists enhance morphine analgesia, suggesting some interaction between morphine and the σ-opioid receptor.

More recently scientists have suggested that another receptor, now known as the nociceptin receptor or OLR-1 (opiate-like receptor) is more important to our understanding of how these drugs work 1.

Morphine exerts its effects by binding to and activating the μ-opioid receptor as an agonist. This occurs due to the way in which opioids functionally mimic the body’s natural endorphins. Endorphins are responsible for analgesia, sleepiness, and feelings of pleasure and enjoyment. They can be released in response to pain, strenuous exercise, orgasm, or excitement. This mimicking of natural endorphins results in the drug’s euphoric, analgesic, and anxiolytic effects.

These appear to stem from the way in which opioids mimic endogenous endorphins. Endorphins are responsible for analgesia, causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or excitement. This mimicking of natural endorphins results in the drug’s effects.

Morphine is produced by the human body in small amounts and acts as an immunomodulator. Endogenous morphine binds preferentially to the μ3 opioid receptor 8, 5.

Pharmacodynamics

Morphine is a narcotic pain management agent indicated for the relief of pain in patients who require opioid analgesics for more than a few days. Morphine interacts predominantly with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve. In clinical settings, morphine exerts its principal pharmacological effect on the CNS and gastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation. Morphine appears to increase the patient’s tolerance for pain and to decrease discomfort, although the presence of the pain itself may still be recognised. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Opioids also produce respiratory depression by direct action on brain stem respiratory centres 2.

Absorption

Bioavailability is approximately 30% 2.

Metabolism

Primarily hepatic (90%), converted to dihydromorphinone and normorphine. Also converted to morphine-3-glucuronide (M3G) and morphine-6-glucuronide. Virtually all morphine is converted to glucuronide metabolites; only a small fraction (less than 5%) of absorbed morphine is demethylated 2.

Half-life

2 – 4 hours 2.

Elimination

A small amount of glucuronide conjugates are excreted in bile, with minor enterohepatic recycling. Seven to 10% of administered morphine sulphate is excreted in the faeces 2.

Lethal dosage

LD50 = 461 mg/kg (rat, oral), 600 mg/kg (mouse, oral) 2.

Toxicity

Human lethal dose by ingestion is 120 – 250 mg of morphine sulphate 2.

Mechanism of action

The precise mechanism of the analgesic action of morphine is unknown. However, specific CNS opiate receptors have been identified and likely play a role in the expression of analgesic effects. Morphine first acts on the mu-opioid receptors. The mechanism of respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centres to increases in carbon dioxide tension and to electrical stimulation. It has been shown that morphine binds to and inhibits GABA inhibitory interneurons. These interneurons normally inhibit the descending pain inhibition pathway. So, without the inhibitory signals, pain modulation can proceed downstream 2.

Mode of use

Orally but sometimes the tablets are crushed and injected. Morphine sulphate is injected 3.

Signs of usage

  • drowsiness,
  • constipation,
  • slowed breathing 9.

Effects

Physical effects

  • physical euphoria,
  • pupil constriction,
  • skin flushing,
  • appetite suppression,
  • cough suppression,
  • orgasm suppression,
  • pain relief,
  • respiratory depression,
  • sedation,
  • constipation,
  • difficulty urinating,
  • itchiness,
  • nausea 5.

Cognitive effects

  • cognitive euphoria,
  • compulsive redosing,
  • dream potentiation,
  • anxiety suppression,
  • decreased libido 5.

Visual effects

  • internal hallucinations 5.

Minor effects

More common
  • constipation,
  • cramps,
  • drowsiness,
  • false or unusual sense of well-being,
  • relaxed and calm feeling,
  • sleepiness or unusual drowsiness,
  • weight loss 10.
Less common
  • absent, missed, or irregular menstrual periods,
  • agitation,
  • bad, unusual, or unpleasant (after) taste,
  • change in vision,
  • depression,
  • dry mouth,
  • face is warm or hot to touch,
  • floating feeling,
  • halos around lights,
  • heartburn or indigestion,
  • loss in sexual ability, desire, drive, or performance,
  • muscle stiffness or tightness,
  • night blindness,
  • over-bright appearance of lights,
  • problems with muscle control,
  • redness of the skin,
  • skin rash,
  • stomach discomfort or upset,
  • trouble sleeping,
  • uncontrolled eye movements 10.
Incidence not known
  • abnormal dreams,
  • change in walking and balance,
  • change or problem with discharge of semen,
  • clumsiness or unsteadiness,
  • confusion as to time, place, or person,
  • delusions,
  • dementia,
  • feeling of constant movement of self or surroundings,
  • general feeling of discomfort or illness,
  • holding false beliefs that cannot be changed by fact,
  • problems with memory,
  • seeing, hearing, or feeling things that are not there,
  • sensation of spinning,
  • unusual excitement, nervousness, or restlessness 10.

Major effects

Less common
  • abdominal or stomach pain,
  • blurred vision,
  • bulging soft spot on the head of an infant,
  • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings,
  • change in the ability to see colours, especially blue or yellow,
  • chest pain or discomfort,
  • confusion,
  • cough,
  • decreased urination,
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position,
  • facial oedema,
  • fainting,
  • fast, pounding, or irregular heartbeat or pulse,
  • headache,
  • hives, itching, or skin rash,
  • increased sweating,
  • loss of appetite,
  • nausea or vomiting,
  • nervousness,
  • pounding in the ears,
  • severe constipation,
  • severe vomiting,
  • shakiness in the legs, arms, hands, or feet,
  • slow heartbeat,
  • sweating or chills 10.
Incidence not known
  • black, tarry stools,
  • cold, clammy skin,
  • cyanosis,
  • feeling of warmth or heat,
  • flushing or redness of the skin, especially on the face and neck,
  • irregular, fast or slow, or shallow breathing,
  • lightheadedness,
  • loss of consciousness,
  • low blood pressure or pulse,
  • painful urination,
  • pale skin,
  • pinpoint red spots on the skin
  • pounding in the ears,
  • shakiness and unsteady walk,
  • unsteadiness, trembling, or other problems with muscle control or coordination,
  • unusual bleeding or bruising,
  • very slow heartbeat 10.

Abuse

  • shallow breathing in which the chest barely moves, and only a few breaths are taken each minute,
  • feeling faint or dizzy,
  • confusion,
  • low blood pressure, especially when a person is also taking other medications,
  • a severe drop in blood pressure,
  • constricted pupils,
  • loss of normal muscle tension,
  • cardiac arrest,
  • cold and clammy skin,
  • circulatory collapse,
  • coma 11.

Positive

  • euphoria,
  • pain relief,
  • elevated mood,
  • overall feeling of contentedness 12.

Neutral

  • itching 12.

Negative

  • nausea,
  • constipation,
  • CNS depression,
  • drowsiness,
  • hot/cold flashes or flushes,
  • dizziness,
  • vomiting,
  • urinary retention,
  • potential psychosis from heavy use 12.

Overdose

  • constricted, pinpoint, or small pupils (black part of the eye),
  • decreased awareness or responsiveness,
  • extreme drowsiness,
  • fever,
  • increased blood pressure,
  • increased thirst,
  • lower back or side pain,
  • muscle cramps or spasms,
  • muscle pain or stiffness,
  • no muscle tone or movement,
  • oedema,
  • severe sleepiness,
  • weight gain 10.

Risks

Short-term

  • Tolerance, overdose 3.

Long-term

  • Dependence 3.

Interactions

Dangerous

  • Ketamine – Both substances bring a risk of vomiting and unconsciousness. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position.
  • MXE – This combination can potentiate the effects of the opioid.
  • DXM – CNS depression, difficult breathing, heart issues, hepatoxic, just very unsafe combination all around. Additionally if one takes dxm, their tolerance of opiates goes down slightly, thus causing additional synergistic effects.
  • Cocaine – Stimulants increase respiration rate allowing a higher dose of opiates. If the stimulant wears off first then the opiate may overcome the patient and cause respiratory arrest.
  • Alcohol – Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. Place affected patients in the recovery position to prevent vomit aspiration from excess. Memory blackouts are likely.
  • GBL / GHB – The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position.
  • Tramadol – Concomitant use of tramadol increases the seizure risk in patients taking other opioids. These agents are often individually epileptogenic and may have additive effects on seizure threshold during coadministration. Central nervous system- and/or respiratory-depressant effects may be additively or synergistically present.
  • Benzodiazepines – Central nervous system and/or respiratory-depressant effects may be additively or synergistically present. The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Blackouts/memory loss likely 6.

Caution

  • PCP – PCP can reduce opioid tolerance, increasing the risk of overdose.
  • Nitrous oxide – Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are likely.
  • Amphetamines – Stimulants increase respiration rate allowing a higher dose of opiates. If the stimulant wears off first then the opiate may overcome the patient and cause respiratory arrest.
  • MAOIs – Coadministration of monoamine oxidase inhibitors (MAOIs) with certain opioids has been associated with rare reports of severe and fatal adverse reactions. There appear to be two types of interaction, an excitatory and a depressive one. Symptoms of the excitatory reaction may include agitation, headache, diaphoresis, hyperpyrexia, flushing, shivering, myoclonus, rigidity, tremor, diarrhea, hypertension, tachycardia, seizures, and coma. Death has occurred in some cases 6.

Legality

Morphine is a class A drug, it is only legal for a person to possess morphine if it has been prescribed for that individual. The maximum sentence for unlawful possession is 7 years imprisonment and/or a fine. The maximum sentence for supplying is life imprisonment and/or a fine 13.

Harm reduction

Morphine is not licenced for the treatment of addiction but is used for that purpose in the UK and some other jurisdictions. The half-life of morphine is short and morphine usually needs to be taken four hourly. There are slow release formulations available which address this problem but as ever with short acting opiate agonists dose levels are problematic. Many prescribers are nervous about exceeding the dose levels cited in the British National Formulary which refer, for drugs under the ‘Analgesic’ heading, to pain relief. Although many patients are seeking relief from chronic pain they are unlikely to have the same expectations of their medication as users with a background of heroin dependence whose histories, motivations and needs can be extremely complex. The DOH guidelines produced for GP’s (and all doctors) say methadone and morphine are dose equivalent at 1mg: 1mg, but this ignores the fact that the half-life of morphine is about 1/8th of that of methadone. This means to reach a meaningful dose equivalent you would need to multiply morphine dose by about 8. (‘The Handbook of Clinical Drug Data’ suggests 1mg of methadone = 10mg of morphine over 24hrs). This means that someone on 100mg of methadone will require something like 800 – 1000 mgs of morphine a day. A figure that frightens prescribers as it seems like a colossal amount of a drug with ‘clear abuse potential’. This stated however, in a market dominated by other licit and illicit opiates/opioids, the role of morphine itself, is decidedly subsidiary 1.

Paraphernalia

If injected – needle and syringe, water, matches or lighter, spoon, tourniquet, swabs 3.

Detox

Prescription opioid addiction treatment is derived from the same concepts as heroin addiction treatment, utilising medications and behavioural therapies to treat an individual’s symptoms. Methadone is a popular choice for treating withdrawal or helping an individual stay maintained during treatment, but buprenorphine can also be helpful. Behavioural therapies can help patients reduce their chances of relapse by changing the way they think about their substance abuse, teaching them to recognise triggers, and teaching them to cope with cravings 14.

History

In 1803, the German pharmacist F.W. Serturner isolated and described the principal alkaloid in opium, which he named morphium after Morpheus, the Greek god of dreams. The invention of the syringe and the discovery of other alkaloids of opium soon followed: codeine in 1832 and papaverine in 1848. By the 1850’s, the medicinal use of pure alkaloids, rather than crude opium preparations, was common in Europe. C.R. Wright first synthesised heroin from morphine in 1879, 20 years before Bayer announced its commercial product. In the United States, opium preparations became widely available in the 19th century and morphine was used extensively as a painkiller for wounded soldiers during the Civil War. The inevitable result was morphine addiction, contemporarily called the Soldier’s sickness/disease or morphinism. William Halsted (1852 – 1922), a co-founder of the Johns Hopkins medical school and the finest surgeon of his day, was a life-long ‘morphinist’ 1.

Morphine was first isolated between 1803 and 1805 by Friedrich Sertürner. This is generally believed to be the first isolation of an active ingredient from a plant. Merck began marketing it commercially in 1827. Morphine was more widely used after the invention of the hypodermic syringe in 1853 – 1855. Sertürner originally named the substance morphium after the Greek god of dreams, Morpheus, for its tendency to cause sleep 5.

Sometime around 1803 and 1804, Friedrich Wilhelm Adam Serturner (1783 – 1841), a pharmacist’s assistant, first isolated morphine as the “sleep-inducing principle” in opium (cf. Papaver somniferum, opium alkaloids). This achievement was the most important “quantum leap” in the history of pharmacology and represents the beginning of the true chemical investigation of plants. Today, the Serturner Medal is still awarded for exceptional work in pharmaceutics. Morphine may also be present in Papaver decaisnei Hochst., Papaver dubium 1. [syn. Papaver modestum Jordan, Papaver obtusifolium Desf.], and Papaver hybridum 1. (Slavik and Slavikova 1980). Whether morphine occurs in Argemone mexicana and other Papaver species (Papaver spp.) is doubtful, while the idea that hops (Humulus lupulus) contains morphine is a figment of someone’s imagination. Tiny traces of the substance have been found in hay and lettuce (cf. Lactuca virosa) (Amann and Zenk 1996, 19). Morphine has also been detected in the skin of Bufo marinus toads (cf. bufotenine) (Amann and Zenk 1996, 18). Since the time when morphine was first detected in breast milk, cow’s milk, and human cerebrospinal fluid, it has been known that it is a natural endogenous neurotransmitter in higher vertebrates, including humans (Amann and Zenk 1996; Cardinale et al. 1987; Hazum et al. 1981).

During the Golden Twenties, the use of morphine in Berlin society circles was depicted in numerous pictures and illustrations (e.g., by Paul Kamm) that appeared in magazines. These illustrations played a great role in creating the stereotype of the “Morphinist” (cf. Papaver somniferum), who also became the object of literary treatments (Bulgaka 1971; Mac From 1931). Even the life story of the man who first discovered the substance, Friedrich Wilhelm Sertiirner, became the subject of a novel (Schumann-Ingolstadt n.d.). Heroin, a derivative of morphine, has also inspired a rich body of literature. One of the first of these was the novel Heroin, by Rudolf Brunngraber (1952), which dealt with the role of heroin in Egypt during the Golden Twenties. Morphine was and still is a popular inebriant in the music scene (particularly that of jazz and rock). “Sister Morphine,” a song by the Rolling Stones (Sticky Fingers, Virgin Records, 1971), is arguably the most famous hymn to the drug. Morphine, a crossover band that mixes elements of cool jazz and modern rock, took its name from the alkaloid, and one of its albums is titled Cure for Pain (Rykodisc, 1993) 12.

Morphine (named after Morpheus, the Greek god of dreams) was isolated from opium in 1803 by the German pharmacist F. W. Serturner. Other alkaloids in opium, such as codeine, were subsequently isolated and, in 1843, Alexander Woodin invented the hypodermic needle. By the 1850s pure alkaloids were being used medically rather than the less effective opium preparations which had dominated before.

During the Crimean War (1851 – 1856) and the American Civil War (1861 – 1865) troops had free access to morphine and opium which they carried to give assistance to wounded colleagues on the battlefield. Opiate addiction grew and became known as the soldiers sickness and the army disease.

After the war some medical professionals even encouraged the addicted soldiers to buy their own needles so that they could continue to inject themselves at home. Estimates suggest that by 1920 there were 264,000 opiate addicts in the US.

Across the Atlantic, in 1898 a new opiate drug was being synthesised at St Mary’s Hospital in London. This new drug was said to be a safe, non-addictive painkiller and to provide a means of treating morphine addiction. It was given a name to reflect everyone’s belief that it was to be a miraculous and heroic new drug – heroin. Sadly, as we now know, heroin turned out to be far from non-addictive 15.

Footnotes:

1

Morphine, 2017, http://www.release.org.uk/drugs/morphine

2

Morphine, 2017, https://www.drugbank.ca/drugs/DB00295

3

Morphine, 2012, http://www.dan247.org.uk/Drug_Morphine.asp

4

Latest street prices for prescription medicines, 2017, http://streetrx.com/uk

5

Morphine, 2017, https://psychonautwiki.org/wiki/Morphine

6

Morphine, 2016, http://drugs.tripsit.me/morphine

7

Morphine, 2017, https://beta.nhs.uk/medicines/morphine/

8

Stefano, G. B. and Goumon, Y. and Casares, F. and Cadet, P. and Fricchione, G. L. and Rialas, C. and Peter, D. and Sonetti, D. and Guarna, M. and Welters, I. D. and Bianchi, E., Endogenous morphine, Trends in Neurosciences, 2000, 23, 9, 436-442, https://www.ncbi.nlm.nih.gov/pubmed/10941194

9

Morphine, 2017, http://drugfree.org/drug/morphine/

10

Morphine, 2017, https://www.drugs.com/morphine.html

11

Morphine Addiction And The Morphine High, 2017, https://www.blvdcenters.org/morphine-rehab-treatment-centers/morphine-addiction-morphine-high

12

Morphine, 2017, https://wiki.tripsit.me/wiki/Morphine

13

Morphine, 2015, https://homehealth-uk.com/morphine/

14

Morphine (An Overview Of Abuse, Addiction, Signs, Symptoms, Treatment), 2017, https://www.addictions.com/morphine-an-overview-of-abuse-addiction-signs-symptoms-treatment/

15

Morphine, 2017, http://www.drugwise.org.uk/morphine/