Opioid AnalgesicsOpioid AnalgesicsBy Ryan RichardsBy Ryan Richards

Overview of PresentationOverview of Presentation

Pain and the Pain management Pain and the Pain management Brief History of OpiumBrief History of Opium Endogenous Opioid PeptidesEndogenous Opioid Peptides Chemical Structure and Binding Features Chemical Structure and Binding Features

of Opioid Analgesicsof Opioid Analgesics Types of Opioid ReceptorsTypes of Opioid Receptors Types of Opioid AnalgesicsTypes of Opioid Analgesics The Future of Opioid AnalgesicsThe Future of Opioid Analgesics

““The uncomfortable sensation of pain has caused man The uncomfortable sensation of pain has caused man to seek an explanation, using contemporary concepts to seek an explanation, using contemporary concepts

to find a reason for this discomfort (1).”to find a reason for this discomfort (1).”

What is Pain? What is Pain? Pain can be defined as a somatic Pain can be defined as a somatic

sensation of acute discomfort, a sensation of acute discomfort, a symptom of some physical hurt or symptom of some physical hurt or disorder, or even emotional distress.disorder, or even emotional distress.

It is a common human experience It is a common human experience therefore the idea of pain and pain therefore the idea of pain and pain management appear throughout history management appear throughout history

What is Pain?What is Pain?

Pain is a crucial aspect of the body’s Pain is a crucial aspect of the body’s defense mechanismsdefense mechanisms

Pain “is a part of a rapid warning relay Pain “is a part of a rapid warning relay instruction the motor neurons of the instruction the motor neurons of the central nervous system to minimize central nervous system to minimize detected physical harm (2).” detected physical harm (2).”

Pain can be classified into two typesPain can be classified into two types

Acute PainAcute Pain

Acute pain is short-term pain or pain with Acute pain is short-term pain or pain with an easily identifiable causean easily identifiable cause

Acute pain “is the body's warning of Acute pain “is the body's warning of present damage to tissue or disease. It is present damage to tissue or disease. It is often fast and sharp followed by aching often fast and sharp followed by aching pain. Acute pain is centralized in one pain. Acute pain is centralized in one area before becoming somewhat spread area before becoming somewhat spread out. This type of pain responds well to out. This type of pain responds well to medications (2).” medications (2).”

Chronic Pain Chronic Pain

Chronic pain is pain that last much longer than Chronic pain is pain that last much longer than pain normally would with a particular injury. pain normally would with a particular injury.

Chronic pain can be constant or intermittent Chronic pain can be constant or intermittent and is generally harder to treat than acute pain. and is generally harder to treat than acute pain.

Pain can also be grouped by its source and Pain can also be grouped by its source and related pain detecting neurons such as related pain detecting neurons such as cutaneous pain, somatic pain, visceral pain, cutaneous pain, somatic pain, visceral pain, and neuropathic pain and neuropathic pain

Opioid Analgesics can be used to treat many Opioid Analgesics can be used to treat many types of paintypes of pain

What Causes Pain?What Causes Pain?

Pain is caused by the stimulation of pain Pain is caused by the stimulation of pain receptors which are free nerve endings. receptors which are free nerve endings.

““Nocireceptors are pain receptors that Nocireceptors are pain receptors that are located outside the spinal column in are located outside the spinal column in the dorsal root ganglion and are named the dorsal root ganglion and are named based upon their appearance at their based upon their appearance at their sensory ends. These sensory endings sensory ends. These sensory endings look like the branches of small look like the branches of small bushes( 2).” bushes( 2).”

There are two types of nocireceptors There are two types of nocireceptors that mediate fast or slow pain signalsthat mediate fast or slow pain signals

The perception of pain is when these The perception of pain is when these receptors are stimulated and they receptors are stimulated and they transmit signal to the central nervous transmit signal to the central nervous system via sensory neurons in the system via sensory neurons in the spinal cord. spinal cord.

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These neurons release excitatory These neurons release excitatory neurotransmitters which relay signals neurotransmitters which relay signals from one neuron to another. from one neuron to another.

““The signals are sent to the thalamus, in The signals are sent to the thalamus, in which pain perception occurs. From the which pain perception occurs. From the thalamus, the signal travels to the thalamus, the signal travels to the somatosensory cortex in the cerebrum, at somatosensory cortex in the cerebrum, at which point the individual becomes fully which point the individual becomes fully aware of the pain (2).” aware of the pain (2).”

Pain Signaling

What is Analgesia?What is Analgesia?

Analgesia simply means the absence of pain Analgesia simply means the absence of pain without loosing consciousness. without loosing consciousness.

““The analgesia system is mediated by 3 major The analgesia system is mediated by 3 major components : the periaquaductal grey matter components : the periaquaductal grey matter (in the midbrain), the nucleus raphe magnus (in (in the midbrain), the nucleus raphe magnus (in the medulla), and the pain inhibitory neurons the medulla), and the pain inhibitory neurons within the dorsal horns of the spinal cord, within the dorsal horns of the spinal cord, which act to inhibit pain-transmitting neurons which act to inhibit pain-transmitting neurons also located in the spinal dorsal horn. (2)”also located in the spinal dorsal horn. (2)”

These areas are the areas in which the These areas are the areas in which the chemical mechanisms of opioid analgesics will chemical mechanisms of opioid analgesics will take placetake place

Locations involved in Locations involved in Pain Signaling and Pain Signaling and

AnalgesiaAnalgesia

http://www.georgiapainphysicians.com/downloads/m1_slides/12.%20opioid%20receptors

History Of OpiumHistory Of Opium Opiates are one of the oldest types of drugs in historyOpiates are one of the oldest types of drugs in history Undisputed reference to opium found in writings Undisputed reference to opium found in writings

(Theophrastus) from the third century BC(Theophrastus) from the third century BC Use of Opium recorded in China and Mesopotamia Use of Opium recorded in China and Mesopotamia

over 2000 years agoover 2000 years ago Greeks dedicated the Opium poppy to the Gods of Greeks dedicated the Opium poppy to the Gods of

Death (Thanatos), Sleep (Hypnos), and Dreams Death (Thanatos), Sleep (Hypnos), and Dreams (Morpheus)(Morpheus)

Sixteenth Century is the first reported use of Opium for Sixteenth Century is the first reported use of Opium for its Analgesic qualitiesits Analgesic qualities

Preparations of opium in the form of elixirs became Preparations of opium in the form of elixirs became increasingly popular in the 17increasingly popular in the 17thth, 18, 18thth, and 19, and 19thth centuries centuries

By the 19By the 19thth century Opium in various forms was century Opium in various forms was considered “as legitimate as tobacco or tea (3).”considered “as legitimate as tobacco or tea (3).”

The Opium WarsThe Opium Wars

Opiates were mainly cultivated in the regions of Persia, Opiates were mainly cultivated in the regions of Persia, India, Malaysia, and China India, Malaysia, and China

As the Use of Opium became widespread its trade As the Use of Opium became widespread its trade became a major industrybecame a major industry

In the late 18In the late 18thth century the Chinese government puts a century the Chinese government puts a ban on opium because of its unwanted and addicting ban on opium because of its unwanted and addicting effectseffects

Opium use and trade remains rampant in Southern Opium use and trade remains rampant in Southern China primarily with the Dutch East Indian CompanyChina primarily with the Dutch East Indian Company

In 1840, Chinese government ceases about 3 millions In 1840, Chinese government ceases about 3 millions pounds of opium from British Merchants in an attempt pounds of opium from British Merchants in an attempt to extinguish opium tradeto extinguish opium trade

This results in a series of Wars that ended in 1860This results in a series of Wars that ended in 1860

What is an Opioid?What is an Opioid?

Opioids are drugs derived from or related to the Opioids are drugs derived from or related to the OpiumOpium

Opium is derived from the juice of the opium poppy, Opium is derived from the juice of the opium poppy, Papaver somniferumPapaver somniferum

Opium contains over twenty distinct alkaloids Opium contains over twenty distinct alkaloids (morphine was the first alkaloid of opium to be (morphine was the first alkaloid of opium to be isolated in 1806)isolated in 1806)

By the late 19By the late 19thth century use of these “pure” opium century use of these “pure” opium derivatives spread throughout the medical world, derivatives spread throughout the medical world, however, the method by which these drugs works however, the method by which these drugs works was unknown.was unknown.

Endogenous Opioid PeptidesEndogenous Opioid Peptides

It was not until the 1970’s that research allowed us to It was not until the 1970’s that research allowed us to understand how the opioid drugs work by studying the understand how the opioid drugs work by studying the endogenous opioid systemendogenous opioid system

In 1973 researchers determined the existence of opiate In 1973 researchers determined the existence of opiate binding sites in the brain through the use of binding sites in the brain through the use of radioligand-binding assays radioligand-binding assays

In 1975, an endogenous opiate-like factor called In 1975, an endogenous opiate-like factor called enkephalin was found and shortly after this two more enkephalin was found and shortly after this two more classes of endogenous opiate peptides were isolated, classes of endogenous opiate peptides were isolated, the dynophorins and the endorphins. the dynophorins and the endorphins.

Endogenous Opioid PeptidesEndogenous Opioid Peptides

““Endogenous opioid peptides are the naturally Endogenous opioid peptides are the naturally occurring ligands for opioid receptors. The term occurring ligands for opioid receptors. The term endorphin is used synonymously with endogenous endorphin is used synonymously with endogenous opioid peptides but also refers to a specific opioid peptides but also refers to a specific endogenous opioid, the Beta-endorphin (4).” endogenous opioid, the Beta-endorphin (4).”

These peptides are produced by the pituitary gland and These peptides are produced by the pituitary gland and by the hypothalamus by the hypothalamus

Opioid peptides are found in the central nervous Opioid peptides are found in the central nervous system mainly in limbic and brainstem areas system mainly in limbic and brainstem areas associated with pain reception, and the certain areas of associated with pain reception, and the certain areas of the spinal cord. Their distribution corresponds to “areas the spinal cord. Their distribution corresponds to “areas of the human brain where electrical stimulation can of the human brain where electrical stimulation can relieve pain (4).” relieve pain (4).”

Endogenous Opioid PeptidesEndogenous Opioid Peptides

These natural peptides work as ligands that interact These natural peptides work as ligands that interact with their specific receptors causing structural changes with their specific receptors causing structural changes that result in other changes in the effected neuron such that result in other changes in the effected neuron such as the opening or closing of ion gated channels or the as the opening or closing of ion gated channels or the activation or deactivation of certain enzymes. activation or deactivation of certain enzymes.

Opioid peptides work by modulating the release and Opioid peptides work by modulating the release and uptake of specific neurotrasmitters in the neurons they uptake of specific neurotrasmitters in the neurons they are found. This alteration of neurochemical balance are found. This alteration of neurochemical balance creates a vast amount of possible physiological effects, creates a vast amount of possible physiological effects, one of which is analgesia. one of which is analgesia.

All of the endogenous opioid peptides are derived from All of the endogenous opioid peptides are derived from a corresponding precursor proteins and all share a a corresponding precursor proteins and all share a common amino-terminal sequence which is called the common amino-terminal sequence which is called the “opioid motif.” “opioid motif.”

The Opioid ReceptorsThe Opioid Receptors

Shortly after the discovery and observance of Shortly after the discovery and observance of endogenous opioid peptides, multiple classes of unique endogenous opioid peptides, multiple classes of unique opioid receptors were found opioid receptors were found

There are four main opioid receptors, the mu receptor, There are four main opioid receptors, the mu receptor, the delta receptor, the kappa receptor, and the ORL-1 the delta receptor, the kappa receptor, and the ORL-1 receptor. receptor.

The sigma receptors were once thought to be opioid The sigma receptors were once thought to be opioid receptors ,however, pharmacological testing indicated receptors ,however, pharmacological testing indicated that the sigma receptors were activated by drugs that the sigma receptors were activated by drugs completely unrelated to the opioids completely unrelated to the opioids

The receptors are found on cell membranes of cells in The receptors are found on cell membranes of cells in the nervous system (neurons) and are found in unique the nervous system (neurons) and are found in unique distributions and have different effects. distributions and have different effects.

The Anatomy of a NeuronThe Anatomy of a Neuron

The The μμ-receptor-receptor Morphine and its analogues bind most strongly to this Morphine and its analogues bind most strongly to this

receptor and in fact most used opioid analgesic drugs receptor and in fact most used opioid analgesic drugs are selective for this specific receptor type. are selective for this specific receptor type.

When and opioid binds to the mu-receptor it produces When and opioid binds to the mu-receptor it produces the effects of analgesia. The mu-receptor is also the effects of analgesia. The mu-receptor is also associated with other effects such as “sedation, associated with other effects such as “sedation, reduced blood pressure, itching, nausea, euphoria, reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils) and decreased respiration, miosis (constricted pupils) and decreased bowel motility often leading to constipation decreased bowel motility often leading to constipation (5).”(5).”

When an opioid binds to the mu-receptor it induces a When an opioid binds to the mu-receptor it induces a change in shape which in turn induces a change in the change in shape which in turn induces a change in the ion channels of the associated cell membrane ion channels of the associated cell membrane

The The μμ-receptor-receptor

The mu-receptor opens up the ion channel allowing The mu-receptor opens up the ion channel allowing potassium ions to flow out of the cell causing potassium ions to flow out of the cell causing hyperpolarization of the membrane potential. This hyperpolarization of the membrane potential. This hyperpolarization causes it to become extremely hyperpolarization causes it to become extremely difficult for an action potential to be reached and difficult for an action potential to be reached and therefore the firing of the neuron become far less therefore the firing of the neuron become far less frequent and the neurons excitability decreases (3). frequent and the neurons excitability decreases (3).

The release of potassium ions also causes less The release of potassium ions also causes less calcium ions to enter the terminal end of the neuron. calcium ions to enter the terminal end of the neuron. This is where neurotransmitters are stored and as a This is where neurotransmitters are stored and as a result this significantly reduces neurotransmitter result this significantly reduces neurotransmitter release. release.

The The μμ-receptor-receptor These effects of a ligand binding to a mu-receptor These effects of a ligand binding to a mu-receptor

essentially turn off the neuron and in doing so block the essentially turn off the neuron and in doing so block the relaying of pain signals from pain receptors. relaying of pain signals from pain receptors.

They are seen in significant amounts in all areas of the They are seen in significant amounts in all areas of the central nervous system associated with pain control central nervous system associated with pain control

There are two subtypes of the mu-receptor. The There are two subtypes of the mu-receptor. The μμ1-1-receptors seem to be associated with its analgesic receptors seem to be associated with its analgesic activities and the activities and the μμ2-receptors seem to be associated 2-receptors seem to be associated with the effects of respiratory depression and with the effects of respiratory depression and constipation. constipation.

Respiratory depression is considered the deadly side Respiratory depression is considered the deadly side effect of opioid analgesic drugs. It is the cause of death effect of opioid analgesic drugs. It is the cause of death in all overdose cases. in all overdose cases.

The The κκ-receptor -receptor

The kappa receptor is very different from the The kappa receptor is very different from the mu-receptor in the fact that there are not many mu-receptor in the fact that there are not many significant agonist of the kappa receptor known significant agonist of the kappa receptor known

The kappa receptor is associated directly with The kappa receptor is associated directly with analgesia and sedation but with none of the analgesia and sedation but with none of the undesired side effects associated with the mu undesired side effects associated with the mu receptor. receptor.

Because of this, it is an area of focus in current Because of this, it is an area of focus in current research and shows promise in the research and shows promise in the development of a safer analgesic. development of a safer analgesic.

The The κκ-receptor-receptor

When and agonist or ligand binds to the kappa When and agonist or ligand binds to the kappa receptor it induces a conformational change that receptor it induces a conformational change that results directly in the closing of the calcium ion results directly in the closing of the calcium ion channels in the terminal of the neuron and the neuron channels in the terminal of the neuron and the neuron can not relay pain messages.can not relay pain messages.

Another difference between the kappa and mu Another difference between the kappa and mu receptors is that the kappa receptors only effect nerves receptors is that the kappa receptors only effect nerves that relay “pain produced by non-thermal stimuli (3),” that relay “pain produced by non-thermal stimuli (3),” and mu receptors inhibit all pain signals.and mu receptors inhibit all pain signals.

There are three subtypes of the kappa receptor There are three subtypes of the kappa receptor however the difference between these subtypes is not however the difference between these subtypes is not clearly known. clearly known.

The The δδ-receptor -receptor

The delta receptor is the strongest binding site The delta receptor is the strongest binding site of the body’s natural pain killer, the class of of the body’s natural pain killer, the class of opioid peptides called the enkephalins. opioid peptides called the enkephalins.

Morphine and other commonly used opioid Morphine and other commonly used opioid analgesics also bind to this receptor strongly analgesics also bind to this receptor strongly and act as an agonist much like they do with and act as an agonist much like they do with the mu receptor. the mu receptor.

The delta receptor is a G-protein linked The delta receptor is a G-protein linked receptor. When an agonist binds to the delta receptor. When an agonist binds to the delta receptor is induces a conformational change receptor is induces a conformational change that causes the activation of a specific G-that causes the activation of a specific G-protein. protein.

The The δδ-receptor-receptor This G-protein “inhibits the membrane This G-protein “inhibits the membrane

bound enzyme adenylate cyclase and bound enzyme adenylate cyclase and prevents the synthesis of cAMP. The prevents the synthesis of cAMP. The transmission of the pain signal requires transmission of the pain signal requires cAMP to act as a secondary messenger, cAMP to act as a secondary messenger, and so inhibition of this enzyme blocks and so inhibition of this enzyme blocks the signal ( 3).” the signal ( 3).”

The delta receptor is found in larger cells The delta receptor is found in larger cells than the other receptors and seems to be than the other receptors and seems to be important in spinal analgesia. important in spinal analgesia.

The ORL-1 receptor The ORL-1 receptor

the ORL-1 receptor or the “orphan” receptor the ORL-1 receptor or the “orphan” receptor was very recently discovered. was very recently discovered.

The natural opioid peptide that is a ligand for The natural opioid peptide that is a ligand for this receptor is nociceptin which is also called this receptor is nociceptin which is also called orphanin. orphanin.

The ORL-1 receptor is associated with many The ORL-1 receptor is associated with many different biological effects such as memory different biological effects such as memory processes, cardiovascular function, and renal processes, cardiovascular function, and renal function. function.

It is thought to have effects on dopamine levels It is thought to have effects on dopamine levels and is associated with neurotransmitter release and is associated with neurotransmitter release during anxiety. during anxiety.

Structure of OpioidsStructure of Opioids

In order to examine In order to examine important structural important structural features of Opioid features of Opioid analgesics, which are all analgesics, which are all derived from the opiate derived from the opiate structure, we will refer to structure, we will refer to the structure of the structure of morphine, the first morphine, the first identified alkaloid. identified alkaloid.

Structure of OpioidsStructure of Opioids The structure of morphine consists The structure of morphine consists

of five rings forming a T-shaped of five rings forming a T-shaped molecule molecule

The important binding groups on The important binding groups on morphine are the phenol, the morphine are the phenol, the aromatic ring, and the ionized aromatic ring, and the ionized amine. These groups are found in amine. These groups are found in all Opioid analgesics.all Opioid analgesics.

. . “A free phenol group is crucial for analgesic activity “A free phenol group is crucial for analgesic activity (3).” The aromatic ring of the opiate also seems to be (3).” The aromatic ring of the opiate also seems to be integral to its function as compounds that lack the integral to its function as compounds that lack the aromatic ring show no analgesic activity. The ionized aromatic ring show no analgesic activity. The ionized amine also plays an important role in its activity and is amine also plays an important role in its activity and is common in opioid structure. In experiments where the common in opioid structure. In experiments where the Nitrogen was replaced by a Carbon no analgesic Nitrogen was replaced by a Carbon no analgesic activity was found. It interacts with certain analgesic activity was found. It interacts with certain analgesic receptors in its ionized form. receptors in its ionized form.

Binding of OpioidsBinding of Opioids . Before specific opioid receptors were . Before specific opioid receptors were

discovered in 1973 by the means of new discovered in 1973 by the means of new autoradiographic techniques, it was unknown autoradiographic techniques, it was unknown exactly how the opiate alkaloids interacted to exactly how the opiate alkaloids interacted to produce the physiological effects associated produce the physiological effects associated with the drugs. with the drugs.

It was assumed that Opioids binding to a It was assumed that Opioids binding to a single, rigid, analgesic receptor. single, rigid, analgesic receptor.

The Beckett-Casy Hypothesis proposed a The Beckett-Casy Hypothesis proposed a method of binding of Opioid drugs to this method of binding of Opioid drugs to this receptorreceptor

The Beckett-Casy HypothesisThe Beckett-Casy Hypothesis

Positively charged nitrogen group of Positively charged nitrogen group of opioid will form an ionic bond with opioid will form an ionic bond with anionic group of receptoranionic group of receptor

In order to accomplish this “there must In order to accomplish this “there must be a basic nitrogen group which is then be a basic nitrogen group which is then ionized at physiological pH for form a ionized at physiological pH for form a positively charged group (3),’ because positively charged group (3),’ because the positively charged group could not the positively charged group could not cross the blood brain barrier. cross the blood brain barrier.

This would result in the opioids having This would result in the opioids having a pKa of around 7.8 to 8.9, which is a pKa of around 7.8 to 8.9, which is consistent with all opioid analgesicsconsistent with all opioid analgesics

The Beckett-Casy HypothesisThe Beckett-Casy Hypothesis

The hypothesis also proposes The hypothesis also proposes van der Waals interaction van der Waals interaction between the aromatic ring and a between the aromatic ring and a hydrophobic region of the hydrophobic region of the binding site binding site

This suggests a close spatial This suggests a close spatial relationship between the relationship between the aromatic ring of the opioid and aromatic ring of the opioid and the surface of the binding sitethe surface of the binding site

The Beckett-Casy HypothesisThe Beckett-Casy Hypothesis

The hypothesis also suggests The hypothesis also suggests hydrogen bonding with the phenol hydrogen bonding with the phenol group of the opioid and the receptor group of the opioid and the receptor binding sitebinding site

It also proposes that the receptor It also proposes that the receptor possesses a unique structural feature possesses a unique structural feature that allows the ethylene bridge of the that allows the ethylene bridge of the opioid to snugly fit into the binding site opioid to snugly fit into the binding site and in doing so properly aligning the and in doing so properly aligning the rest of the molecule with the rest of the molecule with the associated binding regions. associated binding regions.

The Beckett-Casy HypothesisThe Beckett-Casy Hypothesis

Although the discovery of multiple unique Although the discovery of multiple unique opioid receptors in 1973 violated the opioid receptors in 1973 violated the assumption of the hypothesis that there assumption of the hypothesis that there was a single, rigid binding site. The was a single, rigid binding site. The binding mechanisms proposed remain binding mechanisms proposed remain valid possible interactionsvalid possible interactions

It is evident that the phenol group, the It is evident that the phenol group, the ionized amine, and the aromatic ring are ionized amine, and the aromatic ring are very important structural features of the very important structural features of the opioids. opioids.

MORPHINEMORPHINE Morphine is the golden standard Morphine is the golden standard

among opioid analgesics to which among opioid analgesics to which the structure and strengths of all the structure and strengths of all other drugs are comparedother drugs are compared

It is the primary ingredient in opium It is the primary ingredient in opium and was isolated in 1806and was isolated in 1806

Morphine has strong binding affinity Morphine has strong binding affinity for the mu and delta opioid for the mu and delta opioid receptors and some weak affinity for receptors and some weak affinity for the kappa receptor the kappa receptor

MORPHINEMORPHINE Morphine is administered in Morphine is administered in

subcutaneous, intravenous or subcutaneous, intravenous or epidural injections or orally in epidural injections or orally in the form of a solution the form of a solution (however this form is far less (however this form is far less potent). potent).

Morphine acts extremely fast Morphine acts extremely fast and crosses the blood brain and crosses the blood brain barrier quickly but is not as barrier quickly but is not as fast acting lipid-soluble fast acting lipid-soluble opioids such as codeine or opioids such as codeine or heroin. heroin.

Morphine MetabolismMorphine Metabolism

Once morphine is administered about one third Once morphine is administered about one third of it become bound to proteins in the plasma of it become bound to proteins in the plasma

The major pathway for the metabolism of The major pathway for the metabolism of morphine is conjugation with glucoronic acid morphine is conjugation with glucoronic acid (5).” (5).”

Two metabolites are formed from this Two metabolites are formed from this conjugation which cross the blood brain barrier. conjugation which cross the blood brain barrier. Morphine-6-glucuronide seems to be the Morphine-6-glucuronide seems to be the metabolite responsible for the associated metabolite responsible for the associated interactions of morphine with the opioid interactions of morphine with the opioid receptors. receptors.

Side Effects of MorphineSide Effects of Morphine Side effects of morphine include a Side effects of morphine include a

depression of cough due to respiratory depression of cough due to respiratory depression, nausea caused by increased depression, nausea caused by increased vestibular sensitivity, and decreased vestibular sensitivity, and decreased gastric motility and some constipation.gastric motility and some constipation.

Morphine use is also thought to be Morphine use is also thought to be associated with some cases of renal associated with some cases of renal failure as well as acute pancreatitis. failure as well as acute pancreatitis.

CodeineCodeine

Codeine is also an Codeine is also an alkaloid that is found in alkaloid that is found in opium but to a far lesser opium but to a far lesser extent than morphine. extent than morphine.

It differs structurally from It differs structurally from morphine in that its morphine in that its phenol group is phenol group is methylated. It is often methylated. It is often referred to as methyl-referred to as methyl-morphine. morphine.

CodeineCodeine

Oxycodone and methadone are analogs of Oxycodone and methadone are analogs of codeinecodeine

Codeine itself has low binding affinity to all of Codeine itself has low binding affinity to all of the opioid receptors. Its analgesia producing the opioid receptors. Its analgesia producing effects come from its conversion to morphine. effects come from its conversion to morphine.

When codeine is administered about ten When codeine is administered about ten percent is converted to morphine by O-percent is converted to morphine by O-demethylation that occurs in the liver by an demethylation that occurs in the liver by an enzyme called cytochrome p450.enzyme called cytochrome p450.

Because of this Codeine is far less potent than Because of this Codeine is far less potent than morphine morphine

CodeineCodeine

Codeine is usually Codeine is usually administered orally and it is administered orally and it is much more effective orally much more effective orally than morphine (about 60%)than morphine (about 60%)

Because of the side effect of Because of the side effect of respiratory depression and respiratory depression and depressed cough, codeine depressed cough, codeine is often found in cough is often found in cough medicinesmedicines

Abuse of Codeine Abuse of Codeine The use of Codeine as a recreational The use of Codeine as a recreational

drug for its euphoric effects is spreading drug for its euphoric effects is spreading greatly.greatly.

This abuse is mostly isolated to TexasThis abuse is mostly isolated to Texas Recreational users refer to codeine as Recreational users refer to codeine as

“lean” and will mix the drug with alcohol “lean” and will mix the drug with alcohol or other drugs.or other drugs.

HeroinHeroin

Heroin is diacetylmorphine Heroin is diacetylmorphine produced from the acetylation produced from the acetylation of morphine.of morphine.

Heroin was first synthesized in Heroin was first synthesized in 1874.1874.

Although Heroin is illegal, it is Although Heroin is illegal, it is still legally prescribed, mostly still legally prescribed, mostly in terminal patients, as in terminal patients, as diamorphine.diamorphine.

HeroinHeroin Heroin is mostly found in a white crystalline form Heroin is mostly found in a white crystalline form

diacetylmorphine hydrochloride. diacetylmorphine hydrochloride. It is administered through intravenous injections but It is administered through intravenous injections but

can also be administered orally or vaporized.can also be administered orally or vaporized. It binds most strongly to the mu receptor and is also It binds most strongly to the mu receptor and is also

active in the form of morphine as its acetyl groups are active in the form of morphine as its acetyl groups are removed.removed.

It produces euphoric effects similar to morphine, It produces euphoric effects similar to morphine, however, it is thought that these effects are greater and however, it is thought that these effects are greater and more addicting because of its extremely rapid effect.more addicting because of its extremely rapid effect.

Its fast action is a result of being extremely lipid-soluble Its fast action is a result of being extremely lipid-soluble because of its acetyl groups and therefore it because of its acetyl groups and therefore it immediately crosses the blood brain barrier.immediately crosses the blood brain barrier.

HeroinHeroin The use of Heroin causes the The use of Heroin causes the

body to produce far less of its body to produce far less of its natural opioid peptides, the natural opioid peptides, the endorphins. This creates a endorphins. This creates a dependence on heroin.dependence on heroin.

When a heroin user stops using When a heroin user stops using the drug the withdrawal the drug the withdrawal symptoms are severe.symptoms are severe.

Withdrawal symptoms include Withdrawal symptoms include anxiety, depression, cramps, anxiety, depression, cramps, vomiting, diarrhea, restless leg vomiting, diarrhea, restless leg syndrome (hence kicking the syndrome (hence kicking the habit), and a severe sense of pain habit), and a severe sense of pain caused by nothing.caused by nothing.

Many addicts in withdrawal Many addicts in withdrawal experience “itchy blood” which experience “itchy blood” which can drive the addict to scratch can drive the addict to scratch cuts and bruises into his body.cuts and bruises into his body.

Methadone Methadone Methadone is often used to Methadone is often used to

treat heroin addiction treat heroin addiction because it is a longer lasting because it is a longer lasting opioid. opioid.

It has a half life of 24 to 48 It has a half life of 24 to 48 hours compared to 2 to 4 hours compared to 2 to 4 hours found with morphine hours found with morphine and codeine. and codeine.

It is an analog of codeine and It is an analog of codeine and it was first synthesized in it was first synthesized in 1937.1937.

Other Opioid AnalgesicsOther Opioid Analgesics

Many other opioid Many other opioid analgesics exists and are analgesics exists and are currently being developed currently being developed that our based from the that our based from the common opiate structurecommon opiate structure

These drugs have These drugs have differences in their differences in their substituents that changes substituents that changes their effects and methods of their effects and methods of action at their receptorsaction at their receptors

Other Opioid AnalgesicsOther Opioid Analgesics

Fentanyl is about Fentanyl is about 1000 times stronger 1000 times stronger than morphine.than morphine.

Carfentanil is about Carfentanil is about 10,000 more times 10,000 more times more potent than more potent than morphine (It is used morphine (It is used as a tranquilizer for as a tranquilizer for large animals)large animals)

Opioid AntagonistsOpioid Antagonists

Opioid Antagonists are used to treat opioid Opioid Antagonists are used to treat opioid overdose cases.overdose cases.

Most are derived from Thebaine (an alkaloid of Most are derived from Thebaine (an alkaloid of Opium)Opium)

The have strong binding affinity for the mu The have strong binding affinity for the mu receptorsreceptors

They work by competitive inhibition at the They work by competitive inhibition at the binding site (It binds but does not change the binding site (It binds but does not change the receptor while at the same time blocking the receptor while at the same time blocking the agonist).agonist).

Opioid AntagonistsOpioid Antagonists Naloxone is an example of a Naloxone is an example of a

opioid antagonist.opioid antagonist. It is administered It is administered

intravenously.intravenously. It can rapidly produce the It can rapidly produce the

withdrawal symptoms withdrawal symptoms associated with opioid associated with opioid addiction.addiction.

Naltrexone is another Naltrexone is another example of an opioid example of an opioid antagonist. It is more potent antagonist. It is more potent than Naloxone and is used in than Naloxone and is used in the treatment of alcohol the treatment of alcohol addiction but its mechanism addiction but its mechanism in this treatment is unknown.in this treatment is unknown.

Future of Opioid Future of Opioid AnalgesicsAnalgesics

The future of Opioid Analgesics seems to The future of Opioid Analgesics seems to be linked to the study of the Kappa be linked to the study of the Kappa Receptor. The kappa receptor induces Receptor. The kappa receptor induces analgesia without the dangerous and analgesia without the dangerous and unwanted side effects that the mu and unwanted side effects that the mu and delta receptors are associated with. delta receptors are associated with. However there are not any selectively However there are not any selectively strong agonists to this receptor as of strong agonists to this receptor as of now. now.

Future of Opioid Future of Opioid AnalgesicsAnalgesics

Another area of research important to the future of Another area of research important to the future of opioid analgesics is the study of the endogenous opioid opioid analgesics is the study of the endogenous opioid peptides.peptides.

Because these peptides are endogenous, on metabolic Because these peptides are endogenous, on metabolic degradation (unlike opiates) they break down to amino degradation (unlike opiates) they break down to amino acids. Hence, the metabolites are nontoxic and to not acids. Hence, the metabolites are nontoxic and to not cause kidney and liver damage (6).” cause kidney and liver damage (6).”

Also, because they are made from amino acid Also, because they are made from amino acid residues, “a large number of analogs can be residues, “a large number of analogs can be synthesized from a few basic building blocks and synthesized from a few basic building blocks and simple modifications may be attempted to develop simple modifications may be attempted to develop analogs with a desired biological effect (6).” analogs with a desired biological effect (6).”

The further study of the endogenous opioid peptides The further study of the endogenous opioid peptides seems to be integral to development of new safer seems to be integral to development of new safer drugs.drugs.