Opioid Analgesics


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Opioid Analgesics:

Opioid Analgesics Prepared by: Chandni Dave Roll no:39 M.Pharm Sem II Department of Pharmacology K.B.I.P.E.R .

Overview of presentation:

Overview of presentation Terminology History of Opioids Endogenous Opioid Peptides Opioid Receptors Structure of Opioids Binding of Opioids The Beckett- Casy Hypothesis Molecular Basis for Opioid Receptor Selectivity and Affinity Opioid Receptor Signaling and Consequent Intracellular Events Effects of Clinically Used Opioids Drugs 2


Terminology “opium” is a Greek word derived from opos , meaning “juice,” or the exudates from the poppy “opiate” is a drug extracted from the exudates of the juice of the Papaver somniferum . “ opioid ” is a natural or synthetic drug that binds to opioid receptors producing agonist effects . 3

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they include the natural products morphine, codeine, and thebaine , and many semisynthetic derivatives. “Endogenous opioid ” peptides are the naturally occurring ligands for opioid receptors. The term “ endorphin” is used synonymously with endogenous opioid peptides but also refers to a specific endogenous opioid , -endorphin. The term “ narcotic” was derived from the Greek word for "stupor." At one time, the term referred to any drug that induced sleep, but then it became associated with opioids . It often is used in a legal context 4

History Of Opioids:

History Of Opioids The first undisputed reference to opium is found in the writings of Theophrastus in the third century B.C. Arab physicians were well versed in the uses of opium; it was employed mainly for the control of dysenteries. In 1680, Paracelsus and Thomas Sydenham, father of clinical medicine wrote, "AMONG THE REMEDIES WHICH IT HAS PLEASED ALMIGHTY GOD TO GIVE TO MAN TO RELIEVE HIS SUFFERINGS, NONE IS SO UNIVERSAL AND SO EFFICACIOUS AS OPIUM." 5

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In Persia, Avicenna ( ibn-Sina , 980-1037) recommended opium for eye disease and diarrhea. In 1644, the Chinese emperor banned tobacco smoking; Chinese switched to smoking opium. Greeks dedicated the Opium poppy to the Gods of Death ( Thanatos ), Sleep (Hypnos), and Dreams (Morpheus ) Sixteenth Century is the first reported use of Opium for its Analgesic qualities 6

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Preparations of opium in the form of elixirs became increasingly popular in the 17 th , 18 th , and 19 th centuries Invention of the hypodermic needle in 1856 produced drug abusers who self administered opioids by injection Controlling the widespread use of opioids has been unsuccessful because of the euphoria, tolerance and physiological dependence that opioids produce 7

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Opium contains more than 20 distinct alkaloids . In 1806, Sertürner reported the isolation of a pure substance in opium that he named morphine, after Morpheus, the Greek god of dreams. The discovery of other alkaloids in opium quickly followed— codeine by Robiquet in 1832 and papaverine by Merck in 1848. By the middle of the nineteenth century, the use of pure alkaloids in place of crude opium preparations began to spread. 8

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Until the early 1970s, the endogenous opioid system was totally unknown. The actions of morphine, heroin, and other opioids as antinociceptive (reducing sensitivity to painful stimuli)and addictive agents, well described, typically were studied in the context of interactions with other neurotransmitter systems, such as monoaminergic and cholinergic. In 1973, investigators in three laboratories demonstrated opiate-binding sites in the brain. This was the first use of radioligand -binding assays to demonstrate the presence of membrane-associated neurotransmitter receptors in the brain. 9

Endogenous Opioid Peptides:

Endogenous Opioid Peptides It was not until the 1970’s that research allowed us to understand how the opioid drugs work by studying the endogenous opioid system. In 1973 researchers determined the existence of opiate binding sites in the brain through the use of radioligand -binding assays. Endogenous opioid peptides are the naturally occurring ligands for opioid receptors. The term endorphin is used synonymously with endogenous opioid peptides but also refers to a specific endogenous opioid , the Beta-endorphin” These peptides are produced by the pituitary gland and by the hypothalamus. 10

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Opioid peptides are found in the central nervous system mainly in limbic and brainstem areas associated with pain reception, and the certain areas of the spinal cord. Their distribution corresponds to “areas of the human brain where electrical stimulation can relieve pain”. These natural peptides work as ligands that interact with their specific receptors causing structural changes that result in other changes in the effected neuron such as the opening or closing of ion gated channels or the activation or deactivation of certain enzymes. Opioid peptides work by modulating the release and uptake of specific neurotrasmitters in the neurons they are found. This alteration of neurochemical balance creates a vast amount of possible physiological effects, one of which is analgesia. 11

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In 1975, an endogenous opiate-like factor called enkephalin was found and shortly after this two more classes of endogenous opiate peptides were isolated, the dynophorins and the endorphins . Thus, Three distinct families of classical opioid peptides have been identified: the enkephalins , endorphins, and dynorphins . All of the endogenous opioid peptides are derived from a corresponding precursor proteins and all share a common amino-terminal sequence which is called the “ opioid motif.” 12

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Each family derives from a distinct precursor protein and has a characteristic anatomical distribution. These precursors, prepro-opiomelanocortin (POMC), preproenkephalin , and preprodynorphin , respectively, are encoded by three corresponding genes. Each precursor is subject to complex cleavages and post-translational modifications resulting in the synthesis of multiple active peptides. The opioid peptides share the common amino-terminal sequence of Tyr- Gly - Gly - Phe -(Met or Leu ), which has been called the opioid motif . This motif is followed by various C-terminal extensions yielding peptides ranging from 5 to 31 residues 13

Selected Endogenous Opioid Peptides :

Selected Endogenous Opioid Peptides [Leu 5 ] enkephalin [Met 5 ] enkephalin Dynorphin A Dynorphin B α- Neoendorphin ẞ- Neoendorphin ẞ-Endorphin Novel Endogenous Opioid-Related Peptides Orphanin FQ/ Nociceptin 14

Opioid Receptors:

Opioid Receptors Three classical opioid receptor types:- μ-receptor , δ-receptor , and κ-receptor have been studied extensively. The more recently discovered N/OFQ receptor, initially called the opioid -receptor-like 1 (ORL-1) receptor or "orphan" opioid receptor, has added a dimension to the study of opioids . 15

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The original classification of opioid receptors was based on response patterns to three different opioid compounds in the chronic spinal dog model 38 and resulted in the description of three receptor types, named after the drugs used in the studies: m (morphine), k ( ketocyclazocine ), and s (SKF 10,047 or N - allylnormetazocine ). 17

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The sigma receptors were once thought to be opioid receptors ,however, pharmacological testing indicated that the sigma receptors were activated by drugs completely unrelated to the opioids Also sigma receptor but rather a highaffinity binding site for phencyclidine and related compounds. In addition, sigma-receptor–mediated effects are enantio -selective for dextrorotatory, instead of levorotatory, compounds. Finally, sigma-receptor–mediated effects are not naloxone -reversible. 18

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The receptors are found on cell membranes of cells in the nervous system (neurons) and are found in unique distributions and have different effects. Each major opioid receptor has a unique anatomical distribution in brain, spinal cord, and the periphery. These distinctive localization patterns suggested possible functions that subsequently have been investigated in pharmacological and behavioral studies. 19

The μ-receptor :

The μ -receptor Morphine and its analogues bind most strongly to this receptor and in fact most used opioid analgesic drugs are selective for this specific receptor type. When and opioid binds to the μ -receptor it produces the effects of analgesia. The mu-receptor is also associated with other effects such as “sedation, reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils) and decreased bowel motility often leading to constipation” When an opioid binds to the mu-receptor it induces a change in shape which in turn induces a change in the ion channels of the associated cell membrane Mu receptors respond to morphine and fentanyl (China White). 20

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The μ -receptor opens up the ion channel allowing potassium ions to flow out of the cell causing hyperpolarization of the membrane potential. This hyperpolarization causes it to become extremely difficult for an action potential to be reached and therefore the firing of the neuron become far less frequent and the neurons excitability decreases. The release of potassium ions also causes less calcium ions to enter the terminal end of the neuron. This is where neurotransmitters are stored and as a result this significantly reduces neurotransmitter release. 21

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These effects of a ligand binding to a μ -receptor essentially turn off the neuron and in doing so block the relaying of pain signals from pain receptors. They are seen in significant amounts in all areas of the central nervous system associated with pain control There are two subtypes of the μ -receptor. The μ 1-receptors seem to be associated with its analgesic activities and the μ 2-receptors seem to be associated with the effects of respiratory depression and constipation. Respiratory depression is considered the deadly side effect of opioid analgesic drugs. It is the cause of death in all overdose cases. 22

μ-Receptor: Two Types:

μ -Receptor: Two Types μ-1 Located outside spinal cord Responsible for central interpretation of pain 23 μ-2 Located throughout CNS Responsible for respiratory depression, spinal analgesia, physical dependence, and euphoria

The κ-receptor :

The κ -receptor The kappa receptor is very different from the mu-receptor in the fact that there are not many significant agonist of the κ receptor known The κ- receptor is associated directly with analgesia and sedation but with none of the undesired side effects associated with the mu receptor. Κ - receptors respond to mixed agonist-antagonists, like pentazocine ( Talwin ). Because of this, it is an area of focus in current research and shows promise in the development of a safer analgesic. 24

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When and agonist or ligand binds to the κ- receptor it induces a conformational change that results directly in the closing of the calcium ion channels in the terminal of the neuron and the neuron can not relay pain messages. Another difference between the kappa and mu receptors is that the kappa receptors only effect nerves that relay “pain produced by non-thermal stimuli ,” and mu receptors inhibit all pain signals. There are three subtypes of the κ- receptor. κ 1 , κ 2 , and κ 3 have been characterized. 25

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However only one cDNA clone has been identified, hence these receptor subtypes likely arise from interaction of one κ- opioid receptor protein with other membrane associated proteins. The involvement of the κ- opioid receptor in stress response has been elucidated. Activation of the κ- opioid receptor appears to antagonize many of the effects of the μ- opioid receptor. κ-Opioid receptor ligands are also known for their characteristic diuretic effects, due to their negative regulation of antidiuretic hormone (ADH). κ-Opioid agonism is neuroprotective against hypoxia/ischemia; as such, κ- opioid receptors may represent a novel therapeutic target. 26

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κ-Opioid receptor Agonists Antagonists Asimadoline, Bremazocine, Butorphanol BRL-52537, Cyclazocine Dextromethorphan Dynorphin (endogenous peptide ligand) Enadoline,FE 200665 GR-89696 - selective for κ 2 subtype HZ-2,ICI-204,448 - peripherally selective ICI-199,441 Ketazocine,Levallorphan LPK-26 - highly selective Menthol, Nalbuphine Nalfurafine, Norbuprenorphine Oxycodone (disputed) 5'-Guanidinonaltrindole Buprenorphine Norbinaltorphimine JDTic 27

The δ-receptor:

The δ -receptor This G-protein “inhibits the membrane bound enzyme adenylate cyclase and prevents the synthesis of cAMP . The transmission of the pain signal requires cAMP to act as a secondary messenger, and so inhibition of this enzyme blocks the signal ( 3).” The delta receptor is found in larger cells than the other receptors and seems to be important in spinal analgesia 28

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Subtypes: - δ 1 , δ 2 Location:- Brain Pontine nuclie amygdala olfactory bulbs deep cortex peripheral sensory neurons Functions:- Analgesia Antidepressent Effects Physical dependence 29

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The ORL-1 receptor :

The ORL-1 receptor the ORL-1 receptor or the “orphan” receptor was very recently discovered. The natural opioid peptide that is a ligand for this receptor is nociceptin which is also called orphanin . The ORL-1 receptor is associated with many different biological effects such as memory processes, cardiovascular function, and renal function. It is thought to have effects on dopamine levels and is associated with neurotransmitter release during anxiety. 31

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Selective high affinity ligands with which to attempt pharmacological definitions of the ORL 1 receptor are few in number . Besides the natural heptadecapeptide agonist nociceptin / orphanin FQ and some closely related peptides, the only other ligands offering high affinity and selectivity belong to a class of peptides obtained by a positional scanning approach to combinatorial libraries of hexapeptides . Being basic peptides highly susceptible to degradation, all of those agents are chancy tools in the hands of the unwary. So the paucity of safe and sure pharmacological tools may partly explain some of the confusion in the literature regarding the effect of nociceptin in tests of response latency to noxious stimulation; antinociception , pro- nociception / hyperalgesia , allodynia , or no overt effect, have all been reported. 32

Structure of Opioids:

Structure of Opioids In order to examine important structural features of Opioid analgesics, which are all derived from the opiate structure, we will refer to the structure of morphine, the first identified alkaloid. 33

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The structure of morphine consists of five rings forming a T-shaped molecule. The important binding groups on morphine are the phenol, the aromatic ring, and the ionized amine. These groups are found in all Opioid analgesics. . “A free phenol group is crucial for analgesic activity (3).” The aromatic ring of the opiate also seems to be integral to its function as compounds that lack the aromatic ring show no analgesic activity. The ionized amine also plays an important role in its activity and is common in opioid structure. In experiments where the Nitrogen was replaced by a Carbon no analgesic activity was found. It interacts with certain analgesic receptors in its ionized form. 34

Binding of Opioids:

Binding of Opioids Before specific opioid receptors were discovered in 1973 by the means of new autoradiographic techniques, it was unknown exactly how the opiate alkaloids interacted to produce the physiological effects associated with the drugs. It was assumed that Opioids binding to a single, rigid, analgesic receptor. The Beckett- Casy Hypothesis proposed a method of binding of Opioid drugs to this receptor 35

The Beckett-Casy Hypothesis:

The Beckett- Casy Hypothesis Positively charged nitrogen group of opioid will form an ionic bond with anionic group of receptor In order to accomplish this “there must be a basic nitrogen group which is then ionized at physiological pH for form a positively charged group (3),’ because the positively charged group could not cross the blood brain barrier. This would result in the opioids having a pKa of around 7.8 to 8.9, which is consistent with all opioid analgesics 36

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The hypothesis also proposes van der Waals interaction between the aromatic ring and a hydrophobic region of the binding site This suggests a close spatial relationship between the aromatic ring of the opioid and the surface of the binding sit 37

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The hypothesis also suggests hydrogen bonding with the phenol group of the opioid and the receptor binding site It also proposes that the receptor possesses a unique structural feature that allows the ethylene bridge of the opioid to snugly fit into the binding site and in doing so properly aligning the rest of the molecule with the associated binding regions. 38

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Although the discovery of multiple unique opioid receptors in 1973 violated the assumption of the hypothesis that there was a single, rigid binding site. The binding mechanisms proposed remain valid possible interactions It is evident that the phenol group, the ionized amine, and the aromatic ring are very important structural features of the opioids . 39

Blocking of the Opioid G Receptor (Opioid Agonists):

Blocking of the Opioid G Receptor (Opioid Agonists) 40

Molecular Basis for Opioid Receptor Selectivity and Affinity :

Molecular Basis for Opioid Receptor Selectivity and Affinity charged amino acid residues in the transmembrane domains were important in receptor binding and activation. studies with peptidergic receptors have demonstrated a critical role for extracellular loops in ligand recognition. All three classical opioid receptors appear to combine both properties: Charged residues in transmembrane domains have been implicated in the high-affinity binding of most opioid ligands , whether alkaloid or peptide ( Mansour et al., 1997). However, critical interactions of opioid peptides with the extracellular domains also have been shown. 41

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The opioid peptide Tyr- Gly - Gly - Phe core, sometimes called the message peptide selectivity resides in the carboxy -terminal extension beyond the tetrapeptide core, providing the address dynorphin A selectivity depends on the second extracellular loop of the kappa receptor whereas Mu - and delta-selective ligands have more complex mechanisms of selectivity that depend on multiple extracellular loops 42

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These findings have led to the proposal that high selectivity is achieved by attraction to the most favored receptor and repulsion by the less favored receptor. Results of the research discussed above imply that the alkaloids are small enough to fit completely inside or near the mouth of the receptor core, whereas peptides bind to the extracellular loops and simultaneously extend to the receptor core to activate the common binding site. That one can truly separate the binding of peptides and alkaloids is demonstrated most clearly by a genetically engineered receptor that does not recognize endogenous peptide ligands yet retains full affinity and efficacy for small synthetic kappa -receptor ligands , such as spiradoline . 43

Opioid Receptor Signaling and Consequent Intracellular Events :

Opioid Receptor Signaling and Consequent Intracellular Events Coupling of Opioid Receptors to Second Messengers Receptor Desensitization, Internalization, and Sequestration after Chronic Exposure to Opioids An "Apparent Paradox" 44

1.Coupling of Opioid Receptors to Second Messengers :

1.Coupling of Opioid Receptors to Second Messengers 45

2. Receptor Desensitization, Internalization, and Sequestration after Chronic Exposure to Opioids :

2. Receptor Desensitization, Internalization, and Sequestration after Chronic Exposure to Opioids 46

3. An "Apparent Paradox" :

3. An "Apparent Paradox" A paradox in evaluating the function of endogenous opioid systems is that a large number of endogenous ligands activate a small number of opioid receptors. This pattern is different from that of many other neurotransmitter systems, where a single ligand interacts with a large number of receptors having different structures and second messengers. 47

multiple mechanisms for achieving distinctive responses in the context of the biology described earlier may exist. Some issues to consider are::

multiple mechanisms for achieving distinctive responses in the context of the biology described earlier may exist. Some issues to consider are: The duration of action of endogenous ligands may be a crucial variable that has been overlooked and that may have clinical relevance. The pattern or profile of activation of multiple receptors by a ligand, rather than activation of a single receptor, may be a crucial determinant of effect. Opioid genes may give rise to multiple active peptides with unique profiles of activity. This patterning may be very complex and regulated by various stimuli. Differences inpatterns and/or efficacy of intracellular signaling produced by endogenous ligands at opioid receptors are under investigation. This issue may be particularly relevant for understanding physiological alterations after chronic administration of exogenous opioids . Intracellular trafficking of the receptors may vary as a function of the receptor and of the ligand. This could have interesting implications for long-term adaptations during sustained treatment with opioids and after their withdrawal. 48

Effects of Clinically Used Opioids :

Effects of Clinically Used Opioids Morphine and most other clinically used opioid agonists exert their effects through mu- opioid receptors. These drugs affect a wide range of physiological systems. They produce analgesia affect mood and rewarding behavior alter respiratory, cardiovascular, gastrointestinal, and neuroendocrine function. 49


Analgesia Analgesia simply means the absence of pain without loosing consciousness. “The analgesia system is mediated by 3 major components : the periaquaductal grey matter (in the midbrain), the nucleus raphe magnus (in the medulla), and the pain inhibitory neurons within the dorsal horns of the spinal cord, which act to inhibit pain-transmitting neurons also located in the spinal dorsal horn. ” These areas are the areas in which the chemical mechanisms of opioid analgesics will take place 50

Locations involved in Pain Signaling and Analgesia:

Locations involved in Pain Signaling and Analgesia 51

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A significant feature of the analgesia is that it occurs without loss of consciousness. When therapeutic doses of morphine are given to patients with pain, they report that the pain is less intense, less discomforting, or entirely gone; drowsiness commonly occurs. In addition to relief of distress, some patients experience euphoria. 52

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When morphine in the same dose is given to a normal, pain-free individual, the experience may be unpleasant. Nausea is common, and vomiting may occur. There may be feelings of drowsiness, difficulty in mentation , apathy, and lessened physical activity. As the dose is increased, the subjective, analgesic, and toxic effects, including respiratory depression, become more pronounced. Morphine does not have anticonvulsant activity and usually does not cause slurred speech, emotional lability , or significant motor incoordination . 55

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Continuous dull pain is relieved more effectively than sharp intermittent pain, but with sufficient amounts of opioid it is possible to relieve even the severe pain associated with renal or biliary colic. pain cannot be terminated at will, and the meaning of the sensation and the distress it engenders are markedly affected by the individual's previous experiences and current expectations measurements of the effects of morphine on pain threshold have not always been consistent. 56

Mechanisms and Sites of Opioid-Induced Analgesia:

Mechanisms and Sites of Opioid-Induced Analgesia 57

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There is significant concordance between specific receptor mRNA expression in the central nervous system (CNS) and binding of specific receptor ligands . Many of these areas are in major ascending and descending pain pathways . The transport of opioid receptors is thought frequently to underlie differences that exist in receptor mRNA and ligand binding distributions. Research on opioid receptors has entered a new era in which receptors can be examined with dual labeling techniques utilizing both specific ligands and gene structure and mRNA expression. Resultant anatomic studies will help to characterize the phenotype and function of CNS centers, nuclei, and even individual cells. 52 58

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The periaqueductal gray area is one of the regions in the brain stem where microinjections of morphine or direct electrical stimulation produce analgesia that can be blocked with naloxone . Stimulation of periaqueductal gray receptors with morphine, electricity, or endogenous opiate-like peptides results in impulses that alter the degrees of inhibition of different neuronal pools and contribute to reducing the transmission of nociceptive information from peripheral nerves into the spinal cord and up the neuraxis . Opioid actions at the periaqueductal gray area influence, through direct neural connections, the rostral ventromedial region of the medulla. This region of the medulla, in turn, modulates nociceptive transmission neurons in the dorsal horn of the spinal cord. 59

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The integrity of such neurotransmitter systems connecting the pain-inhibiting system in the brain to the spinal cord is necessary for morphine to exert its full analgesic action. Thus, opioids do not only produce analgesia by direct actions. Whereas opioid application at the spinal cord, for example, produces analgesia at the level of administration, neurally mediated actions at distant CNS sites also enhance analgesia. The systemic administration of opioids activates the analgesic “system” in the CNS. 60

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Local spinal mechanisms, in addition to descending inhibition, underlie the analgesic action of opioids . Opioids act at nerve synapses either presynaptically (as neuromodulators ) or postsynaptically (as neurotransmitters) . The substantia gelatinosa of the spinal cord possesses a dense collection of opiate receptors. Direct application of opioids to these receptors creates intense analgesia. Spinal cord presynaptic substance P release in primary sensory neurons is inhibited by m-, k-, and d- agonists and is one neuraxial mechanism of opioid analgesia. 61

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Opiate receptors are also localized in the substantia gelatinosa of the caudal spinal trigeminal nucleus, the nucleus receiving pain fibers from the face and hands via branches of the fifth, seventh, ninth, and tenth cranial nerves. Opioids inhibit neuronal excitation of the dorsal horn in response to painful sharp stimulation, and sensations via A delta fibers are reduced. Excitatory postsynaptic potential summation is also blocked by opioids in the dorsal horn blocking the development of dull persistent pain transmitted via C fibers. This summation is much easier to block than to treat and underlies the concept of preemptive analgesia as well as the clinical observation that patient responses to surgery are easier to control with opioids before rather than after stimulation. Opioids also affect second-order neurons by preventing excitatory threshold reductions and receptive field expansions at the spinal cord level. Opioids may also inhibit the early expression of DNA that is integral to transforming cellular characteristics necessary for the development of chronic or persistent pain 62

A schematic diagram illustrating the release of the excitatory transmitters from C fibers and the subsequent effects on a dorsal horn nociceptive neuron. The predominant presynaptic action of opioids (reducing the release of these transmitters) and the postsynaptic action (reducing neuronal activity) are shown. :

A schematic diagram illustrating the release of the excitatory transmitters from C fibers and the subsequent effects on a dorsal horn nociceptive neuron. The predominant presynaptic action of opioids (reducing the release of these transmitters) and the postsynaptic action (reducing neuronal activity) are shown. 63

Opioids may also produce some analgesia via peripheral mechanisms outside the CNS :

Opioids may also produce some analgesia via peripheral mechanisms outside the CNS Schematic representation of possible peripheral opioidergic mechanisms. The neuronal cell body is located in the dorsal root ganglion. Opioid receptors are transported toward its central (right) and peripheral (left) terminals. After stimulation with cytokine (interleukin-1) or corticotropinreleasing hormone, opioid peptides are released from monocytes or macrophages (M) or lymphocytes (L). Occupation of neuronal opioid receptors by these ligands decreases the release of excitatory ( proinflammatory ) neuropeptides (e.g., substance P or calcitonin -gene–related peptide) and the excitability of the primary afferent neuron. 64

The Role of N/Ofq and Its Receptor in Pain Modulation:

The Role of N/ Ofq and Its Receptor in Pain Modulation N/OFQ mRNA and peptides are present throughout descending pain control circuits. For instance, N/OFQ-containing neurons are present in the PAG, the median raphe , throughout the RVM, and in the superficial dorsal horn. This distribution overlaps with that of opioid peptides, but the extent of colocalization is unclear. N/OFQ-receptor ligand binding and mRNA are seen in the PAG, median raphe , and RVM. Spinally, there is stronger N/OFQ-receptor mRNA expression in the ventral horn than in the dorsal horn but higher levels of ligand binding in the dorsal horn. There also are high N/OFQ-receptor mRNA levels in the DRG. 65

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Despite clear anatomical evidence for a role of the N/OFQ system in pain modulation, its function is unclear. supraspinal administration has produced either hyperalgesia , antiopioid effects, or a biphasic hyperalgesic /analgesic response. N/OFQ inhibits pain-facilitating and analgesia-facilitating neurons in the RVM. the effects of N/OFQ on pain responses appear to depend on the preexisting state of pain in the animal and the specific neural circuitry inhibited by N/OFQ 66

Mood Alterations and Rewarding Properties :

Mood Alterations and Rewarding Properties The mechanisms by which opioids produce euphoria, tranquility, and other alterations of mood (including rewarding properties) are not entirely clear. the neural systems that mediate opioid reinforcement are distinct from those involved in physical dependence and analgesia Behavioral and pharmacological data point to the role of dopaminergic pathways, particularly involving the nucleus accumbens ( NAcc ), in drug-induced reward. There is ample evidence for interactions between opioids and dopamine in mediating opioid -induced reward 67

Other CNS Effects:

Other CNS Effects Neuroendocrine Effects Miosis Convulsions depress respiration Cough Nauseant and Emetic Effects peripheral vasodilation Tolerance and Physical Dependence 68

Pharmacological effects:

Pharmacological effects CNS : Analgesia : most powerful drug available for relief of pain Euphoria : addict experiences a pleasant floating sensation and freedom from anxiety and distress. Sedation Respiratory depression : Main cause of death from opioid overdose due to reduced responsiveness of respiratory centre in brainstem to blood levels of CO2.

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Increase arterial CO2 retention causes cerebral vasodilation resulting in increase intracranial pressure Cough suppression : suppression of cough centre in nucleus of tractus solitarius Miosis : results from stimulation of Edinger- Westphal nucleus causing pin-point pupils except meperidine. Emesis : due to stimulation of brainstem chemoreceptor trigger zone results in nause and vomiting

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CVS : No significant direct effect on CVS Hypotension may occur if CVS is already stressed. Due to the peripheral arterial and venous dilation resulting from histamine release. GIT: Decrease intestinal propulsive peristalsis and stomach motility leads to constipation Biliary tract: Constriction of biliary smooth muscles leads to biliary colic except meperidine Constriction of sphincter of oddi leads to increase biliary pressure,reflux of biliary and pancreatic secretions and elevated plasma and lipase levels

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Renal functions : depressed due to decrease renal plasma flow. Also has antidiuretic effect.Mechanism involve both CNS and peripheral site Ureteral and bladder tone is increased Increased sphincter tone….urinary retention Occasionally, ureteral colic caused by renal calculus is made worse by opioid induced increase in ureteral tone

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Uterus : decrease uterine tone lead to prolong labor Skin : flushing and warming , sweating,itching due to histamine release Summary Biliary , bladder,ureter tone inc. except meperidine (which block M receptors) GIT,uterine tone dec .

Clinical uses:

Clinical uses Analgesia for MI, terminal illness, surgery, obstetrical procedures, cancer. Cough Diarrhea

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Acute pulmonary edema : decrease dyspnea Proposed mechanism : Reduced anxiety(perception of shortness of breath) Reduced cardiac preload(reduced venous tone) Reduced afterload(decreased peripheral resistance) If respiratory depression is there then use furosemide

Adverse effects:

Adverse effects



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Tolerance occur due to receptor uncoupling. Physical dependence: It results in withdrawal(Abstinence) syndrome if there is failure to continue administer drug. Sudden withdrawal(abstinence syndrome)has following signs/symptoms: lacrimation,yawning,chills,hyperventilation,hyperthermia,diarrhea,vomiting,anxiety

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Psychological dependence: euphoria, Indifference to stimuli and Sedation Morphine poisoning….antidote is naloxone


Morphine 80

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Morphine is administered in subcutaneous, intravenous or epidural injections or orally in the form of a solution (however this form is far less potent). Morphine acts extremely fast and crosses the blood brain barrier quickly but is not as fast acting lipid-soluble opioids such as codeine or heroin. 81


PHARMACOKINETICS Routes of administration (preferred) *Oral latency to onset –(15 – 60 minutes ) * it is also sniffed, swallowed and injected. * duration of action – ( 3 – 6 hours) * First-pass metabolism results in poor availability from oral dosing. * 30% is plasma protein bound 82

Mechanism of action:

Mechanism of action 83

Morphine Metabolism:

Morphine Metabolism Once morphine is administered about one third of it become bound to proteins in the plasma The major pathway for the metabolism of morphine is conjugation with glucoronic acid .” Two metabolites are formed from this conjugation which cross the blood brain barrier. Morphine-6-glucuronide seems to be the metabolite responsible for the associated interactions of morphine with the opioid receptors. 84

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EFFECTS AND MEDICAL USES *symptomatic relief of moderate to severe pain *relief of certain types of labored breathing *suppression of severe cough (rarely) *suppression of severe diarrhea *AGONIST for mu, kappa, and delta receptors. 85

Morphine side effects:

Morphine side effects Nervous system Central nervous system side effects may be either depressant or excitatory. Excitatory symptoms are sometimes ignored as possible side effects of morphine. Severe adverse effects such as respiratory depression can be treated with the opiate antagonist, naloxone . Patients receiving continuous infusion of morphine sulfate via indwelling intrathecal catheter should be monitored for new neurologic signs or symptoms. Further assessment or intervention should be based on the clinical condition of the individual patient. 86

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Myoclonic spasms may occur in patients receiving high dose morphine, particularly in the setting of renal dysfunction. Hyperalgesia has also been reported with high doses. Nervous system side effects have been frequently reported and include drowsiness and sedation. Inflammatory masses including granulomas (some of which have resulted in serous neurologic impairment including paralysis) have been reported to occur in patients receiving continuous infusion of opioid analgesics including morphine sulfate via indwelling intrathecal catheter. Delirium, seizures, tremors, dizziness, muscle twitches, malaise, and confusion have also been reported. 87

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Respiratory Respiratory side effects including respiratory depression have been reported frequently. Bronchospasm has been reported in patients with underlying pulmonary disease. Gastrointestinal Gastrointestinal side effects including nausea, vomiting, dyspepsia, constipation, dry mouth, increased gastroesophageal reflux, intestinal obstruction, and increased biliary pressure have been reported. Morphine may cause constriction of the common bile duct and spasm of the sphincter of Oddi , thereby increasing intrabiliary pressure and worsening, rather than relieving, biliary colic. In addition, morphine may cause intense but uncoordinated duodenal contraction and decreased gastric emptying. 88

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Other Withdrawal symptoms have been reported to have included agitation, restlessness, anxiety, piloerection , insomnia, convulsions, tremor, abdominal cramps, blurred vision, vomiting, and sweating. Other side effects include a withdrawal symptoms after either abrupt cessation or fast tapering of morphine. Cardiovascular Cardiovascular side effects including hypotension related to a transient decrease in systemic arterial resistance has been reported, particularly in the setting of myocardial infarction. Psychiatric Psychiatric side effects have included fearfulness, agitation, thinking disturbances, paranoia, psychosis, hypervigilance , and hallucinations. 89

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Genitourinary Genitourinary side effects including acute urinary retention have been reported. The risk of acute urinary retention is very high when morphine is administered by epidural or intrathecal injection. Clinicians should be attentive to the increased risk of urosepsis in this setting, particularly if instrumentation of the urinary tract is necessary. Hematologic Hematologic side effects including immune thrombocytopenia has been rarely reported. Endocrine Endocrine side effects such as menstrual irregularities including amenorrhea have been reported. Reduced male potency and decreased libido in both men and women have also been reported. 90

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Musculoskeletal Musculoskeletal side effects including opioid -induced involuntary muscle hyperactivity has been reported with chronic, high doses. Dermatologic Dermatologic side effects including sweating, flushing, pruritus have been reported frequently. A case of acute generalized exanthematous pustulosis has also been reported. Ocular Ocular side effects include keratoconjunctivitis and allergic conjunctivitis associated with lid urticaria . Visual disturbances and miosis have also been reported. A study has reported a temporary 26% decrease in pupil diameter following the administration of IV morphine. 91

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Hypersensitivity Hypersensitivity reactions including anaphylactoid reactions have been reported to occur very rarely. General Droperidol (2.5 mg intravenously) has been used successfully to reverse the pruritus associated with epidural morphine 2 or 4 mg dosages. A larger dose of droperidol (5 mg) unexplainably does not appear to reverse the pruritus . General side effects including a sense of warmth has been frequently reported. Hepatic Hepatic side effects including increases in hepatic enzymes have been reported infrequently. 92

Morphine overdose:

Morphine overdose Overdose symptoms may include extreme drowsiness, pinpoint pupils, confusion, cold and clammy skin, weak pulse, shallow breathing, fainting, or breathing that stops. 93

morphine can not be taken with any other following narcotic pain medications, sedatives, tranquilizers, sleeping pills, muscle relaxers, or other medicines that can make you sleepy or slow your breathing. Dangerous side effects may result.:

morphine can not be taken with any other following narcotic pain medications, sedatives, tranquilizers, sleeping pills, muscle relaxers, or other medicines that can make you sleepy or slow your breathing. Dangerous side effects may result. cimetidine ( Tagamet ); buprenorphine ( Buprenex , Subutex ); butorphanol ( Stadol ); nalbuphine ( Nubain ); pentazocine ( Talwin ); or a diuretic (water pill). 94

Morphine use in Pregnancy and Breastfeeding:

Morphine use in Pregnancy and Breastfeeding Morphine has been assigned to pregnancy category C by the FDA. No increased risk of congenital malformations in humans has been associated with use of morphine in pregnancy. There are no controlled data in human pregnancy. Morphine should only be given during pregnancy when benefit outweighs risk. Morphine is excreted into human milk in trace amounts. Adverse effects in the nursing infant are unlikely. Morphine is considered compatible with breast-feeding by the American Academy of Pediatrics. 95

Brand Names:

Brand Names Astramorph TM PF; Duramorph TM ; Infumorph TM ; Kadian TM ; MS Contin TM ; MSIR TM ; Oramorph SR TM ; RMS TM ; Roxanol TM ; Roxanol Rescudose TM ; Roxanol TM Epimorph TM (Canada); Morphine-HP TM (Canada); MST- Continus TM (Mexico); MS-IR TM (Canada); Statex TM (Canada) 96


Hydromorphone PHARMACOKINETICS *Routes of administration (Preferred) *Oral *latency to onset (15 – 30 minutes) *Intravenous *Duration of Action (3-4 hours) *Peak effect (30-60 minutes) PROPERTIES AND EFFECTS * potent analgesic like morphine but is 7-10 times as potent in this capacity. *used fequently in surgical settings for moderate to severe pain. (cancer, bone trauma 97


Codeine Codeine is also an alkaloid that is found in opium but to a far lesser extent than morphine. It differs structurally from morphine in that its phenol group is methylated . It is often referred to as methyl-morphine. 98

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Oxycodone and methadone are analogs of codeine Codeine itself has low binding affinity to all of the opioid receptors. Its analgesia producing effects come from its conversion to morphine. When codeine is administered about ten percent is converted to morphine by O- demethylation that occurs in the liver by an enzyme called cytochrome p450. Because of this Codeine is far less potent than morphine 99

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Codeine is usually administered orally and it is much more effective orally than morphine (about 60%) Because of the side effect of respiratory depression and depressed cough, codeine is often found in cough medicines 100

Abuse of Codeine :

Abuse of Codeine The use of Codeine as a recreational drug for its euphoric effects is spreading greatly. This abuse is mostly isolated to Texas Recreational users refer to codeine as “lean” and will mix the drug with alcohol or other drugs. 101

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Codeine contraindications:

Codeine contraindications asthma, COPD, sleep apnea, or other breathing disorders; liver or kidney disease; underactive thyroid; curvature of the spine; a history of head injury or brain tumor; epilepsy or other seizure disorder; low blood pressure; gallbladder disease; a pancreas disorder; an intestinal disorder; Addison's disease or other adrenal gland disorders; enlarged prostate, urination problems; mental illness; or a history of drug or alcohol addiction. 103

Codeine overdose:

Codeine overdose Overdose symptoms may include extreme drowsiness, pinpoint pupils, confusion, cold and clammy skin, weak pulse, shallow breathing, fainting, or breathing that stops. 104

Codeine side effects:

Codeine side effects serious side effect such as: slow heart rate, weak pulse, fainting, shallow breathing; feeling like you might pass out; confusion, agitation, hallucinations, unusual thoughts or behavior; feelings of extreme happiness or sadness; seizure (convulsions); or problems with urination. 105

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Less serious codeine side effects include: feeling dizzy or drowsy; nausea, vomiting, stomach pain,; constipation; sweating; or mild itching or rash. 106

Codeine Dosing Information:

Codeine Dosing Information Usual Codeine Adult Dose for Cough: Initial dose: 15 mg orally every 6 hours as necessary. May titrate up to 20 mg every 4 hours. Maximum 120 mg/day. Usual Adult Dose for Pain: Initial dose: 30 mg orally, IM, subcutaneously, or IV every 6 hours as necessary. May titrate dose to achieve desired analgesic effect. Doses up to 60 mg orally, IM, subcutaneously, or IV every 4 hours have been used. Usual Geriatric Codeine Dose for Cough: Initial dose: 10 mg orally every 6 hours as necessary. May titrate cautiously up to 20 mg every 4 hours. Maximum 120 mg/day. Usual Geriatric Dose for Pain: Initial dose: 15 mg orally, IM, subcutaneously, or IV every 6 hours as necessary. May titrate dose to achieve desired analgesic effect. Doses up to 60 mg orally, IM, subcutaneously, or IV every 4 hours have been used. Usual Pediatric Dose for Cough: 2-6 years: 2.5 to 5 mg orally every 4 to 6 hours. Maximum 30 mg/day. 6-12 years: 5 to 10 mg orally every 4 to 6 hours. Maximum 60 mg/day. Usual Pediatric Codeine Dose for Pain: >=1 years: 0.5 mg/kg or 15 mg/m2 orally, IM, or subcutaneously every 4 to 6 hours as needed. 107

Tramadol :

Tramadol Tramadol (ULTRAM) is a synthetic codeine analog that is a weak - opioid receptor agonist. Part of its analgesic effect is produced by inhibition of uptake of norepinephrine and serotonin. In the treatment of mild-to-moderate pain, tramadol is as effective as morphine or meperidine . However, for the treatment of severe or chronic pain, tramadol is less effective. Tramadol is as effective as meperidine in the treatment of labor pain and may cause less neonatal respiratory depression. 108

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Tramadol is 68% bioavailable after a single oral dose and 100% available when administered intramuscularly. Its affinity for the mu - opioid receptor is only 1/6000 that of morphine. However, the primary O - demethylated metabolite of tramadol is two to four times as potent as the parent drug and may account for part of the analgesic effect half-life of 6 hours for tramadol and 7.5 hours for its active metabolite. Analgesia begins within an hour of oral dosing and peaks within 2 to 3 hours. The duration of analgesia is about 6 hours. The maximum recommended daily dose is 400 mg. 109

Side effects-tramadol:

Side effects- tramadol serious side effects: agitation, hallucinations, fever, fast heart rate, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, fainting; seizure (convulsions); a red, blistering, peeling skin rash; or shallow breathing, weak pulse. Less serious tramadol side effects may include: dizziness, spinning sensation; constipation, upset stomach; headache; drowsiness; or feeling nervous or anxious. 110


Heroin Heroin is mostly found in a white crystalline form diacetylmorphine hydrochloride. It is administered through intravenous injections but can also be administered orally or vaporized. It binds most strongly to the mu receptor and is also active in the form of morphine as its acetyl groups are removed. It produces euphoric effects similar to morphine, however, it is thought that these effects are greater and more addicting because of its extremely rapid effect. Its fast action is a result of being extremely lipid-soluble because of its acetyl groups and therefore it immediately crosses the blood brain barrier. 111

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The use of Heroin causes the body to produce far less of its natural opioid peptides, the endorphins. This creates a dependence on heroin. When a heroin user stops using the drug the withdrawal symptoms are severe. Withdrawal symptoms include anxiety, depression, cramps, vomiting, diarrhea, restless leg syndrome (hence kicking the habit), and a severe sense of pain caused by nothing. Many addicts in withdrawal experience “itchy blood” which can drive the addict to scratch cuts and bruises into his body 112

Effects of Heroin Use:

Effects of Heroin Use The short-term effects of heroin abuse appear soon after a single dose and disappear in a few hours. After an injection of heroin, the user reports feeling a surge of euphoria ("rush") accompanied by a warm flushing of the skin, a dry mouth, and heavy extremities . Following this initial euphoria, the user experiences an alternately wakeful and drowsy state. Mental functioning becomes clouded due to the depression of the central nervous system. Other effects that heroin may have on users include respiratory depression, constricted pupils and nausea. Effects of heroin overdose include slow and shallow breathing, clammy skin, convulsions, coma, and possible death. 113

Treatment of Heroin addiction:

Treatment of Heroin addiction There is a broad range of treatment options for heroin addiction, including medications as well as behavioral therapies. Methadone, a synthetic opiate medication that blocks the effects of heroin for about 24 hours, has a proven record of success when prescribed at a high enough dosage level for people addicted to heroin. LAAM, also a synthetic opiate medication for treating heroin addiction, can block the effects of heroin for up to 72 hours. Other approved medications are naloxone , which is used to treat cases of overdose, and naltrexone , both of which block the effects of morphine, heroin, and other opiates. Several other medications for use in heroin treatment programs are also under study. 114

Methadone :

Methadone Methadone is often used to treat heroin addiction because it is a longer lasting opioid. It has a half life of 24 to 48 hours compared to 2 to 4 hours found with morphine and codeine. It is an analog of codeine and it was first synthesized in 1937.


Fentanyl Fentanyl is a narcotic ( opioid ) pain medicine. Fentanyl buccal is used to treat "breakthrough" cancer pain that is not controlled by other medicines. Fentanyl buccal is taken together with other non- fentanyl narcotic pain medicine that is used around the clock. This medication is not for treating pain that is not cancer-related, such as general headaches or back pain. Fentanyl may also be used for purposes not listed in this medication guide. 116

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Fentanyl is about 1000 times stronger than morphine. 117

Fentanyl contraindicated to…:

Fentanyl contraindicated to… a breathing disorder such as chronic obstructive pulmonary disease (COPD); a history of head injury or brain tumor; a heart rhythm disorder; seizures or epilepsy; mental illness such as depression, hallucinations; low blood pressure; liver or kidney disease; or a history of drug or alcohol addiction. 118

Fentanyl side effects:

Fentanyl side effects a serious side effect such as: weak or shallow breathing; pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating; or feeling very thirsty or hot, being unable to urinate, heavy sweating, or hot and dry skin. 119

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Less serious fentanyl side effects may include: nausea, vomiting, constipation; dizziness, drowsiness; headache; feeling weak or tired; swelling in your hands or feet; or pain or mouth sores where the medicine was placed. 120


Sufentanil 10 fold more potent than fentanyl Slightly slower onset More rapid recovery Very clean pharmacologically


Alfentanil Less potent than fentanyl Much more rapid onset (including more rapid onset of rigidity and respiratory depression) Much more evenascent effect with a single bolus With brief infusions will be almost indistinguishable from fentanyl, except for potency


Remifentanil Similar potency to fentanyl Pharmacokinetics are in a class by themselves (ester metabolism) Reduce the dose by about 2/3s in the elderly No pharmacokinetic interactions Onset is similar to alfentanil


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


Meperidine Meperidine is a narcotic pain reliever. It is similar to morphine. Meperidine is used to treat moderate-to-severe pain. Meperidine may also be used for purposes not listed in this medication guide. 125

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serious side effects : weak or shallow breathing, slow heartbeat; severe drowsiness, feeling like you might pass out; seizure (convulsions); cold, clammy skin; muscle movements you cannot control; confusion, mood changes; severe weakness or dizziness; or agitation, hallucinations, fever, fast heart rate, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, fainting; Less serious side effects may include: constipation; loss of appetite; headache, dizziness, mild weakness; dry mouth; sweating; itching; urinating less than usual; or loss of interest in sex. 126

Future of Opioid Analgesics:

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

Future of Opioid Analgesics:

Future of Opioid Analgesics Another area of research important to the future of opioid analgesics is the study of the endogenous opioid peptides. Because these peptides are endogenous, on metabolic degradation (unlike opiates) they break down to amino acids. Hence, the metabolites are nontoxic and to not cause kidney and liver damage (6).” Also, because they are made from amino acid residues, “a large number of analogs can be synthesized from a few basic building blocks and simple modifications may be attempted to develop analogs with a desired biological effect (6).” The further study of the endogenous opioid peptides seems to be integral to development of new safer drugs.

Tolerance and Dependence:

Tolerance and Dependence

Tolerance :

Tolerance Tolerance is a diminished responsiveness to the drug’s action that is seen with many compounds Tolerance can be demonstrated by a decreased effect from a constant dose of drug or by an increase in the minimum drug dose required to produce a given level of effect Physiological tolerance involves changes in the binding of a drug to receptors or changes in receptor transductional processes related to the drug of action This type of tolerance occurs in opioids

Tolerance continued:

Tolerance continued Molecular basis of tolerance involves glutaminergic mechanisms (glutamate-excitatory amino acid neurotransmitter) 1997, Gies and colleagues stated that activation of glutamate NMDA receptors correlates with resistance to opioids and the development of tolerance Mu-receptor mRNA levels are regulated by activation of these receptors NMDA receptor blocker ketamine prevented the development of this late-onset and long-lasting enhancement in pain sensitivity after the initial analgesia effect dissipated

Tolerance continued:

Tolerance continued Thus, glutaminergic NMDA receptors MAY regulate mu-receptor mRNA, accounting for the development of tolerance to the continuous presence of opioid Cross-tolerance is the condition where tolerance for one drug produces tolerance for another drug – person who is tolerant to morphine will also be tolerant to the analgesic effect of fentanyl, heroin, and other opioids * note that a subject may be physically dependent on heroin can also be administered another opioid such as methadone to prevent withdrawl reactions Methadone has advantages of being more orally effective and of lasting longer than morphine or heroin

Tolerance continued :

Tolerance continued Methadone maintenance programs allow heroin users the opportunity to maintain a certain level of functioning without the withdrawl reactions Although most opioid effects show tolerance, locomotor stimulation shows sensitization with repeated opioid administration Toxic effects of opioids are primarily from their respiratory depressant action and this effect shows tolerance with repeated opioid use Opioids might be considered “safer” in that a heroin addicts drug dose would be fatal in a first-time heroin user


Dependence Physiological dependence occurs when the drug is necessary for normal physiological functioning – this is demonstrated by the withdrawl reactions Withdrawl reactions are usually the opposite of the physiological effects produced by the drug

Withdrawl Reactions:

Withdrawl Reactions Acute Action Analgesia Respiratory Depression Euphoria Relaxation and sleep Tranquilization Decreased blood pressure Constipation Pupillary constriction Hypothermia Drying of secretions Reduced sex drive Flushed and warm skin Withdrawl Sign Pain and irritability Hyperventilation Dysphoria and depression Restlessness and insomnia Fearfulness and hostility Increased blood pressure Diarrhea Pupillary dilation Hyperthermia Lacrimation, runny nose Spontaneous ejaculation Chilliness and “gooseflesh”

Dependence cont…:

Dependence cont… Acute withdrawl can be easily precipitated in drug dependent individuals by injecting an opioid antagonist such as naloxone or naltrexone – rapid opioid detoxification or rapid anesthesia aided detoxification The objective is to enable the patient to tolerate high doses of an opioid antagonist and undergo complete detox in a matter of hours while unconscious After awakening, the person is maintained on orally administered naltrexone to reduce opioid craving

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