Narcotic Analgesic-Morphine

Morphine is a pain medication of the opiate family which is found naturally in a number of plants and animals. 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. It is frequently used for pain from myocardial infarction and during labor. It can be given by mouth, by injection into a muscle, by injection under the skin, intravenously, injection into the space around the spinal cord, or rectally. Maximum effect is reached after about 20 minutes when given intravenously and after 60 minutes when given by mouth, while duration of effect is 3–7 hours. Long-acting formulations also exist. Potentially serious side effects include decreased respiratory effort and low blood pressure. Morphine is addictive and prone to abuse. If the dose is reduced after long-term use, opioid withdrawal symptoms may occur. Common side effects include drowsiness, vomiting, and constipation. Caution is advised when used during pregnancy or breast feeding, as morphine may affect the baby. 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, as it has a tendency to cause sleep. 


                                   Chemical Structure of Morphine

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, a four-fold increase over the last twenty years. Most use for this purpose was in the developed world. About 70 percent 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, the most effective and safe medicines needed in a health system. Morphine is sold under many trade names.

NARCOTIC ANALGESICS: Drugs which reduce pain arising from the viscera and produce narcosis (depression of CNS) and addiction. Drugs that induce drowsiness, sleep or stupor, specially- with analgesia are called narcotic analgesics.

PROPERTIES: Highly potent analgesics, Addicting analgesics, Mainly act on CNS (depression), Produce narcosis, Used in visceral pain,No anti-inflammatory action, No anti-pyretic and anti-platelet action, Low therapeutic index


  • NATURAL (opium alkaloids): Morphine, Codeine,Thebaine
  • SEMISYNTHETIC: Oxymorphine, Hydromorphine, Apomorphine, Oxycodone,Hydrocodone,Heroine.
  • SYNTHETIC ANALGESICS: 1. Mepredine and related phenyl-piperidine- Pethidine (meperidine), α-prodine, Piminodine

2. Methadone and related drugs: Methadone, Propoxyphene

3. Benzomorphanes: Phenazocine, Pentazocine,

4. Morphinan derivatives: Levorphanol, Butorphanol

5. Narcotic antagonists: Nalorphine, Naloxone, Levorpheine

OPIUM ALKALOIDS :The word opium is derived from Greek word “opion” meaning poppy juice. Opium is derived from the dried or partly dried latex by incision from the unripe capsules of papaver somniferam (opium poppy). It has a bitter taste. Opium contains a variable mixture of more than 25 alkaloids. And the derivatives of opium alkaloids are called opiates.






Pentazocine (partial agonist)








Overall, narcotic painkillers work by reducing nerve excitability that leads to the sensation of pain. Narcotics bind to special receptors in the brain (central nervous system) and in other areas of the body (peripheral nervous system, like the gastrointestinal tract) called opioid receptors. There are four types of opioid receptors as- Mu, Delta, Kappa & Opioid Receptor Like-1 (ORL1)

These receptors either aid with the opening of potassium channels (causing hyperpolarization) or block calcium channel openings, and block the release of excitatory neurotransmitters like substance P that are involved with pain. Sometimes a painkiller drug may be referred to as a “narcotic-like” medicine, but any true narcotic medication will have action at one of the three opioid receptors. For example, tramadol is often referred to as a “narcotic-like” medication, but this is a misnomer, as it has centrally-acting analgesic action at the opioid mu receptors, blocking pain pathways. Tramadol is also thought to act via weak reuptake inhibition of norepinephrine and serotonin, and this may contribute to its pain effects. In addition, tramadol pain relief is partially blocked by the opiate antagonist naloxone in animal studies.


Receptor type

µ/ δ




Supraspinal or spinal



Respiratory depression








GIT motility




Smooth muscle spasm affects










Physical dependency





DISTRIBUTION OF OPIOID RECEPTORS IN: Dorsal horn of the spinal cord,Limbic system,Periaqueductal grey matter,Substantia gellatenosa,Spinal trigeminal nuclei,Nucleus tractus solitarius,Medial thalamic nuclei,Nuclei of some vagal response& Hypothalmicnuclei.

MORPHINE: Sir William Osler referred to morphine as God’s own medicine. The name morphine was coined after Morpheus, the “Greek god of dreams”. Chemically, it is a phenanthrene derivative, with two planar ring and two aliphatic ring structures.

Widely used analgesic for acute and chronic pain

Main site of action: CNS and GIT

Morphine antagonist: Naloxone



Hyper-polarization and inhibiting presynaptic neurons (probably by increasing K+ efflux).

Inhibiting of cell firing, and

Pre-synaptic inhibition of neurotransmitter release (partly due to hyper-polarization and partly to a reduction of the Ca++ influx into presynaptic nerve endings).

Morphine causes decrease in CAMP production by activation of opioid receptors, the functional significance of which is unclear. 



Opening of K+ channels


Inhibition of adenylyl cyclase


Reducing Ca++ influx into presynaptic nerve terminal


K+ efflux Hyper-polarisation


Decrease CAMP production


Reduce neuro-transmitter release


Presynaptic inhibition of cell firing

Development of tolerance & dependency

Cellular action



  • ON CNS Centre’s stimulated by morphine: Oculomotor nerve nucleus, Vagus nerve, Vomiting Centre (CTZ) and
  • ON CNS Centre’s depressed by morphine: Respiratory Centre, Cough Centre, Other Centres of CNS



Morphine increases the pain threshold by acting directly on the cortex by decreasing its sensitivity to incoming pain impulses.

Morphine acts on limbic system and reduces the psychic reaction (euphoria) to pain and so decrease perception of pain.

Morphine depressed the activity of pain pathway.

Morphine inhibits perception of pain in the sensory cortex and subcortical areas by hypnosis.


Reducing sensitivity of medullary respiratory center to increase plasma CO2 concentration.

Directly depressing respiratory centre in the medulla.

C. COUGH SUPPRESSION: Due to depression of cough centre in the medulla.



  • Miosis: Morphine stimulates Edinger Westphal nucleus of third cranial nerve → increase pupillary respond to light → Miosis
  • Emesis: by stimulating CTZ (chemoreceptor trigger zone) of medulla.
  • Truncal rigidity: by stimulating monosynaptic reflexes of spinal cord→ decrease thoracic compliance→ interferes with ventilation.
  • Changes the mood and causes euphoria.
  • Causes smooth muscle stimulation.

ON CVS: Orthostatic hypotension, Depress VMC (vasomotor centre) of the medulla → Decrease vasomotor tone → ↓B. P, Release histamine → vasodilation → decrease P.R → ↓B. P

ON GIT; Morphine causes constipation & analgesia which leads to neglect the urge to defection. So, used as anti-diarrheal agent.


  • Hardening of stool by decreasing all secretions and increasing absorption.
  • Decrease propulsive movements by reducing motility of GIT smooth muscles.
  • Increase the tone of pyloric and ileocecal valves (e.g. increase the tone of smooth muscle sphincter).
  • Failure to perceive sensory stimulation that elicits defection reflex.

ON KIDNEY: Release ADH → anti-diuretics →oliguria

ON BRONCHUS: Constriction of bronchial muscle increases the rate of volume respiration → Asthma.

ON BILIARY TRACT: Increase intra-biliary pressure by constricting smooth muscle of biliary tract and sphincter Oddi → spasm of biliary muscle → increase pain.

ON URINARY BLADDER: Contracts detrusor and sphincter of urinary bladder and so causes retention of urine.

ON UTERUS: Reduce uterine tone → prolong labour

ON METABOLISM: Decrease activity & muscle tone → reduce O2 consumption → hyperglycemia

ON ENDOCRINE GLANDS: Increased ADH, prolactin and growth hormones secretion but decrease the LH secretion.

ON IMMUNE SYSTEM: Morphine increases N-K cell activity, they are chemotactic to monocytes, Decrease the resistance to infection.

ON BODY TEMPERATURE: Morphine has a biphasic, dose dependent effects on body temperature.

a) At low dose: decrease body temperature.

b) At high dose: increase body temperature.

ON SKIN: Cutaneous vasodilation secondary to histamine release can result in pruritus and sweating.

ON REPRODUCTION: Morphine causes a decrease in libido, sexual drive and sexual performance.


1. CNS ACTIONS:  Depression of CNS leading to: Analgesia, Respiratory depression, Depression of cough reflex, Sedation, Stimulation of CNS leading to: Miosis, Emesis, Hyperactive spinal cord reflexes, Convulsion. 2. CHANGES OF MOOD: euphoria and dysphoria.

3. DEPENDENCE: affects other systems too. 4. SMOOTH MUSCLE STIMULATION: Gastrointestinal muscle spasm, Biliary tract spasm, Broncho spasm, Renal tract spasm 5. CVS: Orthostatic hypotension


Morphine Stimulation of opioid receptors (mainly mu) in the CNS then Hyperpolarization and inhibition of presynaptic neurons (probably by increasing K+ efflux) followed by Inhibition of cell firing by raising the threshold for pain result Elimination of pain and also allows subjects to tolerate pain.


Behavioral restlessness, tremulousness, hyperactivity (in dysphoric reaction), Respiratory depression, Nausea and vomiting, increased intracranial pressure, Postural hypotension, Constipation, Urinary retention, Itching around the nose, urticarial (more frequent with parenteral administration).


Route of Administration: I/V I/M S/C oral

(Oral morphine is subject to extensive first pass metabolism; Bioavaibility only 20%)

Distribution: 1/3rd drug is protein bound, can cross the placenta and depress the respiration of fetus at birth.

Plasma half-life: 2 hours

Duration of analgesia: 4-6 hours

Metabolism: liver (glucoronysation), kidney

Excretion: urine, bile


1. As analgesic in: Visceral pain, Acute myocardial infraction, Pain due to fracture of long bone, Burn, Terminal stage of malignancy, Pulmonary embolism, Acute pericarditis, Pleurisy with effusion, Spontaneous pneumothorax, Postoperative pain

2. To relief anxiety in serious and frightening disease, e.g. shock, hematemesis, heart failure.

3. Pre-anaesthetic medication

4. Traveler’s diarrhoea

5. Balance anaesthetic with morphine, pethidine, and fentanyl.

6. for nocturnal dyspnea in acute left ventricular failure and pulmonary edema.

7. To control acute restlessness

8. To produced euphoria in dying patient

ADVERSE EFFECT OF MORPHINE: Respiratory depression, Nausea, vomiting, Physical and psychological dependence, Miosis (pin pointed pupil), Dizziness, mental clouding and dysphoria, Constipation, Urinary retention, Biliary and urinary spasm, Allergic reaction: urticarial, skin rash, Hypotension → shock → coma

CONTRAINDICATION OF MORPHINE: Extreme of age (Below 6 years & above 60 years), Head injury and following craniotomy, Bronchial asthma & other hypoxic stages (e.g. emphysema), Undiagnosed acute abdomen and acute pancreatitis, Pregnant & lactating mother, Liver disease (e.g. cirrhosis), Intestinal obstruction, Myxoedema, Convulsive disorder, Acute alcohol intoxication, Cardiac arrhythmias, Severe inflammatory bowel disease (IBS), Prostatic hypertrophy, urethral structure etc.



MAIN FEATURES: Coma, Miosis, Extreme slowing of respiration (2-4 breath a min)

SECONDARY FEATURES: Cold clammy skin, Low body temperature, Loss of skeletal muscle tone, Absence of reflexes Cyanosis

DIAGNOSTIC FEATURES: Triad sign, Respiratory depression, Miosis, Coma, Death is due to respiratory failure.


MEASURES TO ELIMINATE MORPHINE: Stomach wash with worm water then with KMnO4, Gastric lavage, Administration of activated charcoal, use of specific antidote: Naloxone (0.4-0.8 mg) I/V repeated after every 20-30 minutes, Keep the patient awake by repeated pinching,

MEASURES TO TREAT RESPIRATORY DEPRESSIONEndotracheal intubation (if necessary), Intermittent positive pressure ventilation, O2 inhalation (if cyanosis), Coramine (respiratory stimulant): for respiratory depression,1000 ml of 5% glucose I/V (for shock), Hot bottle or blanket (to maintain body temperature),


With frequently repeated administration of therapeutic doses of morphine or its surrogates, there is a gradual loss of effectiveness (i.e. tolerance). To produce the original response, a large dose must be administered. With the development of tolerance, physical dependence occurs so that continued administration of the drug becomes necessary to prevent a characteristic withdrawal syndrome.


Chronic exposure to opioids leads to adaptive changes in the endogenous opioid system and no doubt in receptor numbers, sensitivity & cellular response. Failure to continue administering the drug results in a characteristic withdrawal or abstinence syndrome. This consists largely, the opposite of normal actions of opioids.


12-16 hours after last dose of opiate-Irritability, body shakes, Writing, jumping and signs of aggression, Sneezing, lacrimation, yawning, chills, Tachypnea(hyperventilation), Mydriasis (pupillary dilatation).

24-72 hours after last dose of opiate-Muscular aches, Blood pressure crisis, Sweating attacks (Goose-pimples),Diarrhoea, vomiting,Bladder spasms,Pain in the abdomen and limbs, Administration of an opioid at this suppresses abstinence signs and symptoms almost immediately.


* Morphine + CNS depressant: More CNS depression. CNS depressant: such as- Tricyclic antidepressant, MAO-I, Neostigmine, Chlorpromazine.

*Morphine + Rifampicin: Increase metabolism.

*Morphine + Anti-hypertensive drug: Decrease B.P.


Abuse of opioid drugs, such as morphine, is quite common as users tend to become tolerant to the effects very quickly. Increasing the dose of morphine is classed as abuse and it will only reinforce your tolerance. Once you start abusing morphine, the risk of addiction increases significantly; accidental overdose will also be much more likely as well. It is important to be alert to the signs and symptoms associated with morphine addiction and abuse because knowing what they are may help you to get your life back on track before it spirals out of control.

A large overdose can cause asphyxia and death by respiratory depression if the person does not receive medical attention immediately. 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. The minimum lethal dose of morphine sulfate is 120 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.


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, Kadian, MS Contin and Dolcontin. For constant pain, the relieving effect of extended-release morphine given once (for Kadian) or twice (for MS Contin) every 24 hours is roughly the same as multiple administrations of immediate release (or "regular") morphine. Extended-release morphine can be administered together with "rescue doses" of immediate-release morphine as needed in case of breakthrough pain, each generally consisting of 5% to 15% of the 24-hour extended-release dosage.


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.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. 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.  limit of detection of 0.6 ng/ml had similar results.



The sole source of opium is the opium poppy. The plant is believed to have evolved from a wild strain, Papaver setigerum, which grows in coastal areas of the Mediterranean Sea. Through centuries of cultivation and breeding for its opium, a species of the plant evolved that is now known as somnijerum. Today, Papaver somnijerum is the only species of Papaver which produces opium. The genus, Papaver, is the Greek word for "poppy." The species, somnijerum, is Latin for "sleep inducing."Morphine is the most abundant opiate found in opium, the dried latex extracted by shallowly scoring the unripe seedpods of the Papaver somniferum poppy. Morphine is generally 8–14% of the dry weight of opium, although specially bred cultivars reach 26% or produce little morphine at all (under 1%, perhaps down to 0.04%). The latter varieties, including the 'Przemko' and 'Norman' cultivars of the opium poppy, are used to produce two other alkaloids, thebaine and oripavine, which are used in the manufacture of semi-synthetic and synthetic opioids like oxycodone and etorphine and some other types of drugs. P. bracteatum does not contain morphine or codeine, or other narcotic phenanthrene type, alkaloids. This species is rather a source of thebaine. Occurrence of morphine in other Papaverales and Papaveraceae, as well as in some species of hops and mulberry trees has not been confirmed. Morphine is produced most predominantly early in the life cycle of the plant. Past the optimum point for extraction, various processes in the plant produce codeine, thebaine, and in some cases negligible amounts of hydromorphone, dihydromorphine, dihydrocodeine, tetrahydro-thebaine, and hydrocodone (these compounds are rather synthesized from thebaine and oripavine). In the brain of mammals, morphine is detectable in trace steady-state concentrations. The human body also produces endorphins, which are chemically related endogenous opioid peptides that function as neuropeptides and have similar effects to morphine.


Raw or cooked opium contains more than 35 different alkaloids, including morphine, which accounts for approximately ten percent of the total raw opium weight. Heroin manufacturers must first extract the morphine from the opium, before converting the morphine to heroin. The extraction is a simple process, requiring only a few chemicals and a supply of water. Morphine is usually extracted from opium in small clandestine "laboratories" which are typically set up near the opium poppy fields. Since the morphine base is about one-tenth the weight and volume of raw opium, it is desirable to reduce the opium to morphine before transporting the product from the field to a heroin laboratory. The process of extracting morphine from opium involves dissolving opium in hot water, adding lime to precipitate non-morphine alkaloids and then adding ammonium chloride to precipitate morphine from the solution. An empty oil drum and some cooking pots are needed.


The euphoria, comprehensive alleviation of distress and therefore all aspects of suffering, promotion of sociability and empathy, "body high", and anxiolysis provided by narcotic drugs including the opioids can cause the use of high doses in the absence of pain for a protracted period, which can impart a morbid craving for the drug in the user. Being the prototype of the entire opioid class of drugs means that morphine has properties that may lend it to misuse. Morphine addiction is the model upon which the current perception of addiction is based.Animal and human studies and clinical experience back up the contention that morphine is one of the most euphoric drugs known, and via all but the IV route heroin and morphine cannot be distinguished according to studies because heroin is a prodrug for the delivery of systemic morphine. Chemical changes to the morphine molecule yield other euphorigenics such as dihydromorphine, hydromorphone (Dilaudid, Hydal), and oxymorphone (Numorphan, Opana), as well as the latter three's methylated equivalents dihydrocodeine, hydrocodone, and oxycodone, respectively; in addition to heroin, there are dipropanoyl morphine, diacetyldihydromorphine, and other members of the 3,6 morphine diester category like nicomorphine and other similar semi-synthetic opiates like desomorphine, hydromorphinol, etc. used clinically in many countries of the world but in many cases also produced illicitly in rare instances.

In general, non-medical use of morphine entails taking more than prescribed or outside of medical supervision, injecting oral formulations, mixing it with unapproved potentiators such as alcohol, cocaine, and the like, or defeating the extended-release mechanism by chewing the tablets or turning into a powder for snorting or preparing injectables. The latter method can be as time-consuming and involved as traditional methods of smoking opium. This and the fact that the liver destroys a large percentage of the drug on the first pass impacts the demand side of the equation for clandestine re-sellers, as many customers are not needle users and may have been disappointed with ingesting the drug orally. As morphine is generally as hard or harder to divert than oxycodone in a lot of cases, morphine in any form is uncommon on the street, although ampoules and phials of morphine injection, pure pharmaceutical morphine powder, and soluble multi-purpose tablets are very popular where available. Morphine is also available in a paste that is used in the production of heroin, which can be smoked by itself or turned to a soluble salt and injected; the same goes for the penultimate products of the Kompot (Polish Heroin) and black tar processes. Poppy straw as well as opium can yield morphine of purity levels ranging from poppy tea to near-pharmaceutical-grade morphine by itself or with all of the more than 50 other alkaloids.


Recent statistics from the National Institute of Drug Abuse show that 1 out of 15 people who take prescription painkillers for recreational use will try heroin within 10 years. And this problem is growing - in 2004, 1.4 million people abused or were dependent on pain medications and 5 percent used heroin. By 2010, 1.9 million people abused or were dependent on pain medications and 14 percent used heroin. Heroin users are 3 times more likely to be addicted than users of prescription painkillers (54% vs. 14%). Relative to the high cost of prescription painkillers on the street, heroin is cheap - and this contributes to its increasing popularity among addicts.The crackdown on prescription narcotics, and the rescheduling of hydrocodone from CIII to the more restrictive CII, has led many to believe rescheduling may cause a spike in heroin use due to lower availability of prescription painkillers. In 2014, there were more than 914,000 reported users of heroin, an increase of 145 percent since 2007. In addition, there were over 10,500 heroin overdose deaths in 2014.

However, in a 2016 letter in the New England Journal of Medicine, experts state that the heroin epidemic is not the direct result of the crackdown on prescription painkillers like OxyContin and Vicodin. In fact, the authors state that heroin use among people who use prescription opioids for nonmedical reasons is rare, and the transition to heroin use appears to occur at a low rate. The timing of rescheduling and policy shifts do not coincide with the spikes in heroin use. Instead, increased access to heroin, a reduced price, and higher purity of heroin seem to be the major factors leading to increases in rates of heroin use.


Compiled by: Zubair Khalid Labu, Md. Mostafizur Rahaman and Md. Atikur Rahman

Sources: Internet




Zubair Khalid Labu, Md. Mostafizur Rahaman and Md. Atikur Rahman
Department of Pharmacy
World University of Bangladesh