The main opium alkaloids found in crude
Opium alkaloids, derived from crude Papaver somniferum L. plant, are potent analgesic drugs, but their use is limited because of dependence and withdrawal. Opium alkaloids activate the mesocorticolimbic dopaminergic system, which project from the ventral tegmental area to the nucleus accumbens and medial prefrontal cortex, and dopamine is critically important in opioid consumption and sustaining. The reward effect resulting from the activation of the dopaminergic system leads to continued opioid consumption and occurs opioid dependence. After the development of opioid dependence, consumption continues to avoid withdrawal syndrome. Opioid dependence is accompanied with tolerance, which requires the use of high doses to achieve the same effect. When tolerance develops, the chronic consumer continues to use opioid above known toxic doses to produce the same effect, which can result in death regardless of the type of opioid used. Raw Papaver somniferum L. has five high-density main opium alkaloids including morphine, noscapine, codeine, thebaine, and papaverine. Some of these alkaloids bind to classical opioid receptors to produce an opioid-like effect, while the other part mediates non-opioid effects. This chapter reviews the opiod history, receptors, mechanism of action, dependence, withdrawal. In addition, general information about five main opium alkaloids, their effects, uses, routes of administration, pharmacokinetics, adverse reactions, contraindications; effects on reproduction, pregnancy, and lactation were compiled.
Opium alkaloids are products obtained from the mature capsules of
Opium alkaloids were first isolated in 1803 by Parisian Derosne, and named ‘opium salt’. Friedrich Wilhem Adam Serturner described the ‘opium salt’ in detail in 1817 and named “morphine', inspired by the Morpheus (Greek god of dreams). Karl Friedrich Wilhelm Meissner first used the word ‘alkaloid’ in 1818, which we still use. Opioids were widely used for the first time in the Franco-Prussian War and the American Civil War for medical purposes. Tincture and pills were preferred for the purpose of analgesia in wounded soldiers. Repeated use caused opioid dependence on some soldiers, and this event was first described as “soldiers’ disease” .
1.2 Opioid receptors
Although morphine and other opioid alkaloids are exogenous substances, they show agonistic effect by binding to the receptors of endogenous opioids. Opioid receptors were first described by Beckett and Casy in 1954 . In 1965, Portoghese and colleagues shared their views on the existence of multiple opioid receptor types . High-affinity and stereospecific binding sites for opioid alkaloids were also found in brain in 1973 . The presence of specific opioid receptors led to the discovery of endogenous ligands. They are enkephalins , β-endorphin , and dynorphins . The classic opioid receptors, were discovered in 1976–1977 and named after the prototypic drugs or tissue used in these studies: μ (mu, for morphine), δ (delta, for deferens), and κ (kappa, for ketocyclazocine) [12, 13]. These receptors show seven transmembrane domain structures specific to G protein-coupled receptors, are induced by morphine and antagonized by naloxone, and had similar analgesic effect. In 1995, the fourth opioid receptor, which is similar in structure with and closely related to classic opioid receptors, was also discovered [14, 15]. Fourth opioid receptor initially identified as ORL1 or LY132, it was later updated to N/OFQ by taking the name of its endogenous ligands (nociceptin/ orphanin FQ) . Although the effects of N/OFQ receptor are not fully known, they do not have a similar effect on pain as classical opioid receptors, and their sensitivity to naloxone is very low. σ (sigma), ε (epsilon), and ζ (zeta) receptors and λ (lambda) site are included in other opioid receptors . The σ receptor, discovered in 1976, is not coupled to G protein, and its effects are not antagonized by naloxone [12, 18, 19]. The ε receptor is sensitive to β-endorphin . The λ site regulates cell growth and is not antagonized by naloxone [21, 22]. Further information on opioid receptors is summarized in Table 2.
|Density (avg%) ||Molecular formula||Molecular weight (g/mol)|
|Opioid receptors||μ receptor||δ receptor||κ receptor||N/OFQ receptor|
|Other names||OP3, MOP, MOPr, Mu 1||OP1, DOP, DOR, DOPr, DOR-1||OP2, KOP, KOPr, KOR-1||OP4, KOR-3, NOCIR, kappa3-related, MOR-C, nociceptin receptor ORL, XOR1, NOP-r, nociceptin/orphanin FQ, NOPr|
|Regions with high distribution||CNS||Thalamus|
Nucleus accumbens (NAc)
İnferior and superior colliculi 
Hypothalamus [23, 24]
Anterior olfactory nucleus
Ventral tegmental area (VTA)
Brain stem nuclei 
|Spinal cord||Superficial layers dorsal horn of spinal cord ||Dorsal horn |
Immune cells 
Pregnant uterus 
Gastrointestinal (GI) tract 
Immune cells 
Pregnant uterus 
GI tract 
Immune cells 
Pregnant uterus 
GI tract 
|Types of G-protein||Primary: Gi/Go|
Endomorphin-1 and -2
|Dynorphin A Dynorphin B|
|Agonists [from main opium alkaloids]||Morphine|
Immune system functions
Immune system functions
Motor and aggressive behaviours
Reinforcement and reward
Autonomic system functions
Immune system functions 
According to the studies, μ receptor was also related with addiction , modulation of dopaminergic system , learning and memory . The δ receptors along with μ receptors contribute to emotional sensitivity .
1.3 Mechanism of action
μ, δ, and κ opioid receptors are distributed in peripheral tissue as well as CNS. Stimulation of these receptors in the CNS results in analgesia, drowsiness, euphoria, a sense of detachment, respiratory depression, nausea and vomiting, depressed cough reflex, and hypothermia. When these receptors are stimulated in peripheral tissues, miosis, orthostatic hypotension, constipation, urinary retention etc. emerges.
After stimulation of these Gi/0-coupled opioid receptors, the adenylate cyclase enzyme is suppressed and the level of cyclic AMP decreases. In addition, the voltage-gated calcium channels in the axon ends or neuron soma are closed and intracellular calcium levels are reduced, potassium channels are opened and leading to an increase in potassium conductance. As a result, inhibition and hyperpolarization of neurons occurs when opioid receptors are stimulated [42, 43].
Analgesic or antinociceptive effects, which are indicated for use of opioids, develop at the level of the brain and spinal cord. At the brain level, attenuation of impulse spread is weakened and the perception of pain is inhibited, and at the spinal cord level, the transmission of pain impulses is suppressed .
1.4 Opioid dependence
Opioid dependence or addiction is a chronic, recurrent disease that changes neurotransmitter systems in the CNS and affects movement [45, 46]. Opioid dependence develops in both psychic and physical dependence. Physical opioid dependence occurs both when used for treatment and as a result of abuse. Opioid abuse is a relapsing disease with high morbidity and mortality, which is used at higher doses to produce the same effect due to tolerance. The higher the exposure time to opioids, the higher the degree of dependence and tolerance. After physical dependence develops, opioid consumption is maintained to prevent withdrawal symptoms. So the treatment is long and difficult. For this purpose, opioid agonists such as methadone, buprenorphine, an opioid antagonist naltrexone or abstinence-based treatment may be preferred. This disease, referred to as ‘opioid abuse and opioid dependence’ in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSMIV-TR), has been changed to ‘opioid use disorder’ in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) .
The estimated annual prevalence of opioids in 2010 was 0.6–0.8% of the population aged 15–64 (26 × 106 to 36 × 106). The estimated annual prevalence of opioid use is between 0.3 and 0.5% of the adult population (13 × 106 to 21 × 106 past-year users) .
The mesocorticolimbic dopaminergic system, which project from the VTA to the NAc and medial prefrontal cortex (mPFC) are critically important in opioid dependence . Opioids act on VTA and directly or indirectly cause an increase in dopamine release in NAc region . In the pathogenesis of opioid dependence, the presence of a complex mechanism including the dopaminergic system, noradrenergic, serotonergic, etc. systems should be considered .
1.5 Opioid withdrawal
Withdrawal is a condition that occurs when the use of an exogenous substance that is used for a long time and develops physical dependence is interrupted. In opioid dependence, the mesocorticolimbic dopaminergic system activates and induces dopamine release in the NAc region. The adaptive increase in dopaminergic activity in CNS in opioid dependence is suppressed during withdrawal and withdrawal symptoms appear . In addition to dopamine, different neurotransmitters and neuromodulators, such as noradrenaline, GABA, vasopressin, substance P, neuropeptide Y, and nitric oxide, are thought to play a role in the development of opioid withdrawal [53, 54, 55]. In opioid withdrawal syndrome, symptoms such as pain, insomnia, yawning, tremor, lacrimation, rhinorrhea, sweating, dehydration, goosebumps, mydriasis, restlessness, anorexia, nausea, vomiting, diarrhea, weight loss, hyperglycemia, hypotension, decrease in respiratory rate, hyperthermia and abdominal muscle cramps are seen .
2. The main opium alkaloids in raw
Papaver somniferum L.and their pharmacological properties
International Union of Pure and Applied Chemistry (IUPAC) name: (4R,4aR,7S,7aR,12bS)-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol.
|ATC Code||N-Nervous system||N02-Analgesics||N02A-Opioids||N02AA-Natural opium alkaloids||N02AA01-Morphine|
Morphine is one of the major opium alkaloids isolated from plant
Absorption of morphine is variable, an almost complete absorption mainly done in the upper intestine as well as in the rectal mucosa. Morphine presents significant first-pass metabolism and oral bioavailability within 17–33% . Morphine distributes to brain, skeletal muscle, liver, kidneys, lungs, intestinal tract, and spleen . Hepatic metabolism occurs via glucuronic acid conjugation primarily to morphine-6-glucuronide (M6G, 10–15%) and morphine-3-glucuronide (M3G, 45–55%). Other metabolites include morphine-3,6-diglucuronide, morphine-3-ethereal sulphate, normorphine, normorphine-6-glucuronide, normorphine-3-glucuronide and codeine. M6G and normorphine show active analgesic effect by binding to opioid receptors, but M6G, which is formed more than normorphine, can contribute to analgesic effect of morphine. M3G does not contribute to the analgesic effect of morphine, because it has low affinity to opioid receptors . Half-life elimination is variable according to age group: in neonates 4.5–13.3 h, in children 1–2 h, and in adults 2–4 h. Excretion occurs with urine (2–12%) and feces (7–10%).
Morphine leads to death in amounts of 0.15–0.2 g (sc) or 0.3–0.4 g (oral) in adults. Babies and young children are much more susceptible, and death has been observed at doses of 30 mg . Morphine blood concentration within 10–100 μg/dL is toxically; if it is above 400 μg/dL is lethally .
Common adverse reactions are drowsiness, headache, constipation, nausea, vomiting, urinary retention. Although less common adverse reactions, such as depression, insomnia, paresthesia, dizziness, anxiety, abnormal dreams, confusion, seizure, myoclonus, agitation, amnesia, euphoria, pain, dyspnea, hypoventilation, respiratory depression, tremor, fever, flu-like symptoms, rhinitis, edema, hypotension, syncope, palpitations, skin rash, amblyopia, blurred vision, conjunctivitis, diplopia, miosis, nystagmus, amenorrhea, impotence, gynecomastia, urinary hesitancy, diaphoresis, anorexia, biliary colic, dyspepsia, gastroesophageal reflux disease, hiccups, xerostomia, anemia, thrombocytopenia can be seen.
Contraindications are hypersensitivity to morphine, significant respiratory depression, acute or severe bronchial asthma in the absence of resuscitative equipment, GI obstruction.
IUPAC name: (3S)-6,7-dimethoxy-3-[(5R)-4-methoxy-6-methyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-5-yl]-3H-2-benzofuran-1-one.
|ATC Code||R-Respiratory system||R05-Cough and cold preparations||R05D-Cough suppressants, excl. combinations with expectorants||R05DA-Opium alkaloids and derivatives||R05DA07-Noscapine|
Noscapine, also known as narcotine, is the second opioid alkaloid according to its density in raw
Noscapine in terms of antitussive potency, onset, and duration of action is similar to codeine, one of the main opium alkaloids . Noscapine has a relatively low bioavailability due to a first-pass metabolism . Noscapine is inactivated by converting into meconin and o-demethylated metabolites. Meconin is major urinary metabolite of noscapine .
IUPAC Name: (4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ol
|ATC Code||R-Respiratory system||R05-Cough and cold preparations||R05D-Cough suppressants, excl. combinations with expectorants||R05DA-Opium alkaloids and derivatives||R05DA04-Codeine|
Codeine, a 3-methylether derivative of morphine, is the third opioid alkaloid according to its density in the raw
Absorption is rapidly in oral use and bioavailability is higher due to less first-pass metabolism (about 53%). Codeine is distributed to a variety of tissues, with priority being to the liver, spleen and kidney . Codeine-6-glucuronide, morphine, and norcodeine is formed as a result of hepatic metabolism. Morphine is then metabolized to M3G and M6G, and contributes to analgesic effects of codeine. The half-life elimination is about 3 h and excretion is mostly done through urine and with less feces.
Abnormal dreams, insomnia, depression, paresthesia, agitation, anxiety, ataxia, dizziness, disorientation, sedation, euphoria, fatigue, hallucination, headache, bradycardia, tachycardia, circulatory depression, flushing, pruritus, skin rash, urticaria, bronchospasm, dyspnea, respiratory depression, abdominal cramps, anorexia, constipation, diarrhea, nausea, urinary hesitancy, urinary retention, blurred vision, diplopia, miosis, nystagmus, laryngospasm, muscle rigidity, tremor, hypogonadism, etc. may occur due to codeine use.
Contraindications are hypersensitivity to codeine, pediatric patients <12 years of age, postoperative management in pediatric patients <18 years of age who have undergone tonsillectomy and/or adenoidectomy, significant respiratory depression, acute or severe bronchial asthma in the absence of resuscitative equipment, GI obstruction.
IUPAC Name: (4R,7aR,12bS)-7,9-dimethoxy-3-methyl-2,4,7a,13-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline.
Thebaine, also known as paramorphine, which is not used for medicinal purposes and is used for the production of other opioids, is the fourth opioid alkaloid according to its density in the raw
IUPAC name: 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline
|ATC Code||A-Alimentary tract and metabolism||A03-Drugs for functional gastrointestinal disorders||A03A-Drugs for functional gastrointestinal disorders||A03AD-Papaverine and derivatives||A03AD01-Papaverine|
|G-Genito urinary system and sex hormones||G04-Urologicals||G04B-Urologicals||G04BE-Drugs used in erectile dysfunction||G04BE02-Papaverine|
Papaverine, which has no opioid-like effect, is the fifth opioid alkaloid based on its density in the raw
Absorption is nearly total in oral use. Oral bioavailability is higher due to less first-pass metabolism (about 54%). Papaverine is distributed to a variety of tissues, with priority being to the adipose tissue and liver. 6-Desmethylpapaverine (6-DMP, major metabolite) and 4′,6-didesmethylpapaverine (4,6-DDMP) is formed as a result of hepatic metabolism . Half-life elimination is 0.5–2 h. The excretion of papaverine is through primarily urine . No information on toxic blood concentrations is available. The oral median lethal dose in rats is 360 mg/kg, unknown in humans .
Adverse reactions are flushing, hypertension, tachycardia, headache, malaise, sedation, abdominal distress, anorexia, constipation, etc.
Use in the complete AV block is contraindicated.
Although information about opium alkaloids was about 3000 BC, it was first isolated in the 1800s. Opioid-like effects occur after opioid alkaloids bind to conventional opioid receptors, such as μ, δ, and κ. In particular, as a result of the agonistic effect on μ receptors, strong analgesia, physical dependence, tolerance and increased dopaminergic activity develop in the mesocorticolimbic system responsible for dependence. Increased dopaminergic activity in the mesocorticolimbic system, is a sign of developing physical dependence, decreases in the absence of opium alkaloids, leading to withdrawal syndrome. Hypogonadism in opium alkaloids users supports the idea that it has a suppressive effect on reproduction. In addition to the risk of teratogenicity, use in both pregnancy and lactation may lead to the development of abstinence syndrome in infants.
Conflict of interest
The authors declare no conflict of interest.