Pain Pharmacology: Part-1 Opioid PDF

DSPM I Pain Pharmacology: Part-1 Opioid Farzana Alam, PhD OF Learning Objectives Opioids and physical function of Opioid Name of the drugs Mechanism of action, adverse-effects, Drug-drug interactions Antagonists Dental implication...

DSPM I Pain Pharmacology: Part-1 Opioid Farzana Alam, PhD OF Learning Objectives Opioids and physical function of Opioid Name of the drugs Mechanism of action, adverse-effects, Drug-drug interactions Antagonists Dental implication Withdrawal symptoms opioidreceptor Reduce pain Opioid receptor and endogenous synthesize  The major effects of the opioids are mediated by three receptor families, which are commonly designated as μ (mu), κ (kappa), and δ (delta). Each receptor family exhibits a different specificity for the drug(s) it binds. Opioid receptors The analgesic properties of the opioids are primarily mediated by the μ receptors that modulate responses to thermal, mechanical, and chemical nociception. majoropioiddrugs we use ind to ulmus The κ receptors in the dorsal horn also contribute to analgesia by modulating the response to chemical and thermal nociception.  highlyefficient potent ootency smallamountofdrughas highefficacy theseare even in small doses Name opioid receptor agonists and most common antagonists  ec I 9 I to GTPcomp bind activatesubtypes of G proteinreceptor phosphorylation formation of dimer conformationalchangeof receptor opiods block Calciums ability to be released preventing AP Mechanism inhibits excitory signal of action sedation opiodsbind µ mu refceptor inhibits calcium influx inhibits neurotransmission of glutamate  g try Morphine: Pharmacology Central Nervous System Pharmacology Analgesia painkiller Respiratory depression slowed breathing Cough suppression Pupillary acJon Nausea vomiJng Peripheral pharmacology GastrointesJnal tract Cardiovascular system Al NO Q from this slide Morphine pharmacology  Pharmacokinetics of morphine Absorption Distribution Fate rename enzyme Morphine 6 Glucuronidehas a high wout Affinityfor the y mu receptor Codeine undergoes metabolism and activation (demethylation) to a potentdeficient analgesicmorphine accounting for most of its analgesic effect. Advantage of usingmorphine After 24hrs 90 ofdrugisgone Adverse effects worst one  I Tolerance and physical dependance Repeated use produces tolerance to the respiratory depressant, analgesic, euphoric, and sedative effects of morphine. Tolerance usually does not develop to the pupil- constricting and constipating effects of the drug. Tylenol3 Acetaminophen hydrocodone Drug-drug interac>on  Other drugs More agonists: Mixed agonists-antagonists: Codeine Buprenorphine Oxycodone and Pentazocine oxymorphone Nalbuphine and butorphanol Hydromorphone and hydrocodone Fentanyl Other analgesics: Sufentanil, alfentanil, and Tapentadol remifentanil Tramadol Methadone Severity of opioid withdrawal symptoms after abrupt withdrawal Meperidine of equivalent doses of heroin, buprenorphine, and methadone.  mostcommonlyused Antagonists: Naloxone Naloxone [nal-OX-own] is used to reverse the coma and respiratory depression of opioid overdose. It rapidly displaces all receptor-bound opioid molecules and, therefore, is able to reverse the effect of a morphine overdose. Within 30 seconds of IV injection of naloxone, the respiratory depression and coma characteristic of high doses of morphine are reversed, causing the patient to be revived and alert. Naloxone has a half-life of 30 to 81 minutes; therefore, a patient who has been treated and recovered may lapse back into respiratory depression. Whatistheantagonist of opioidreceptor Naloxone Antagonists: Naltrexone highpotency Naltrexone [nal-TREX-own] has actions similar to those of naloxone. It has a longer duration of action than naloxone, and a single oral dose of naltrexone blocks the effect of injected heroin for up to 24 hours. Naltrexone in combination with clonidine (and, sometimes, with buprenorphine) is used for rapid opioid detoxification. Although it may also be beneficial in treating chronic alcoholism by an unknown mechanism, benzodiazepines and clonidine are preferred. Naltrexone can lead to hepatotoxicity.  sp Dental implica>ons Use Caution Genetic variation in response to codeine **Mentioned in the supplement slides in detail Withdrawal symptoms References Pharmacology and therapeutics in dentistry; 10 ed Lippincott’s illustrated pharmacology; 7 ed Supplemental slides Opioid receptor physiology The enkephalins interact more selectively with δ receptors in the periphery. All three opioid receptors are members of the G protein– coupled receptor family and inhibit adenylyl cyclase. They are also associated with ion channels, increasing postsynaptic K+ efflux (hyperpolarization) or reducing presynaptic Ca2+ influx, thus impeding neuronal firing and transmitter release Morphine’s effect Analgesia Morphine and other opioids cause analgesia (relief of pain without the loss of consciousness) and relieve pain both by raising the pain threshold at the spinal cord level and, more importantly, by altering the brain’s perception of pain. Patients treated with opioids are still aware of the presence of pain, but the sensation is not unpleasant. Euphoria: Morphine produces a powerful sense of content- ment and well-being. Euphoria may be caused by disinhibition of the dopamine-containing neurons of the ventral tegmental area. Respiratory Respiration: Morphine causes respiratory depression by reduction of the sensitivity of respiratory center neurons to car- bon dioxide. This can occur with ordinary doses of morphine in patients who are opioid-naïve and can be accentuated as the dose is increased until ultimately respiration ceases. Respiratory depression is the most common cause of death in acute opioid overdoses. Tolerance to this effect does develop quickly with repeated dosing, which allows the safe use of morphine for the treatment of pain when the dose is correctly titrated. Cough suppression: Both morphine and codeine have antitussive properties. In general, cough suppression does not correlate closely with the analgesic and respiratory depressant properties of opioid drugs. The receptors involved in the antitussive action appear to be different from those involved in analgesia.  Miosis: The pinpoint pupil (Figure 14.8) characteristic of morphine use results from stimulation of μ and κ receptors. There is little tolerance to the effect, and all morphine abusers demonstrate pinpoint pupils. [Note: This is important diagnos- tically, because many other causes of coma and respiratory depression produce dilation of the pupil.] Emesis: Morphine directly stimulates the chemoreceptor trig- ger zone in the area postrema that causes vomiting. 1. GI tract: Morphine relieves diarrhea by decreasing the motility and increasing the tone of the intestinal circular smooth muscle. Morphine also increases the tone of the anal sphincter. Overall, morphine and other opioids produce constipation, with little tol- erance developing. [Note: A nonprescription laxative combina- tion of the stool softener docusate with the stimulant laxative senna is useful to treat opioid-induced constipation.] Morphine can also increase biliary tract pressure due to contraction of the gallbladder and constriction of the biliary sphincter. 2. Cardiovascular: Morphine has no major effects on the blood pressure or heart rate at lower dosages. With large doses, hypotension and bradycardia may occur. Because of respira- tory depression and carbon dioxide retention, cerebral vessels dilate and increase cerebrospinal fluid pressure. Therefore, morphine is usually contraindicated in individuals with head trauma or severe brain injury.  Histamine release: Morphine releases histamine from mast cells causing urticaria, sweating, and vasodilation. Because it can cause bronchoconstriction, morphine should be used with caution in patients with asthma. Hormonal actions: Morphine increases growth hormone release and enhances prolactin secretion. It increases antidi- uretic hormone and leads to urinary retention. Labor: Morphine may prolong the second stage of labor by transiently decreasing the strength, duration, and frequency of uterine contractions. Pharmacokinetics Administration: Because significant first-pass metabolism of morphine occurs in the liver, intramuscular, subcutaneous, and IV injections produce the most reliable responses. Absorption of morphine from the GI tract after oral absorption is slow and erratic. When used orally, morphine is commonly administered in an extended-release form to provide more consistent plasma levels. It is important to note that morphine has a linear pharmacokinetic profile that allows dosing to be more predictable and more flexible. Distribution: Morphine rapidly enters all body tissues, including the fetuses of pregnant women. It should not be used for analgesia during labor. Infants born to addicted mothers show physical dependence on opioids and exhibit withdrawal symptoms if opioids are not administered. Only a small per- centage of morphine crosses the blood–brain barrier, because morphine is the least lipophilic of the common opioids. In contrast, the more lipid-soluble opioids, such as fentanyl and methadone, readily penetrate into the CNS. Fate: Morphine is conjugated with glucuronic acid in the liver to two main metabolites. Morphine-6- glucuronide is a very potent analgesic, whereas morphine-3-glucuronide does not have analgesic activity, but is believed to cause the neuroexcitatory effects seen with high doses of morphine. The conjugates are excreted primarily in urine, with small quantities appearing in bile. The duration of action of morphine is 4 to 5 hours when administered systemically to morphine-naïve individuals, but considerably longer when injected epidurally because the low lipophilicity prevents redistribution from the epidural space. [Note: Age can influence the response to morphine. Elderly patients are more sensitive to the analgesic effects of the drug, possibly due to decreases in metabolism, lean body mass, or renal function. Lower starting doses should be considered for elderly patients. Neonates should not receive morphine because of their low conjugating capacity.] Physical and psychological dependance and Physical dependence results from adaptations at cellular, synaptic, and systemic levels that in some ways are analogous to adaptive processes better understood as nervous system plasticity in the context of learning and memory (i.e., long-term potentiation). The underlying cellular and synaptic mechanisms that contribute to the develop- ment of opioid physical dependence are unknown. Psychological dependence is more difficult to define and measure. Psychological dependence may contribute more to drug-seeking behavior than does physical dependence and contributes more significantly to addiction. As defined by the American Society of Addiction Medicine, addiction is the extreme of compulsive drug use and is characterized by continued use, and most importantly, loss of control over drug use and craving despite harm. Physical dependence can exist in the absence of psychological dependence, and it is inappropriate to identify as “addicted” an individual who becomes physically depen- dent after repeated opioid administration. All three phenomena— tolerance, physical dependence, and psychological dependence—are reversible, although psychological dependence provides a strong drive to continue the use of opioids.  It is now well documented that opioids ac2vate endogenous reward pathways in the brain and that this mechanism contributes to their abuse. Opioids release or prolong the ac2ons of the mono- amine neurotransmions Use Pain of dental origin frequently arises from, or is accompanied by, inflammaOon. Because opioids are not anOinflammatory, nonopioid analgesic drugs with anOinflammatory efficacy (e.g., aspirin, ibuprofen) are oRen the first choice for relief of pain. Opioids are parOcularly useful when addiOonal pain control is required. The opioids used in denOstry are primarily those available for oral administraOon, including codeine, hydrocodone, and oxycodone. Morphine, meper- idine, and fentanyl are used parenterally. CombinaOons of opioids with acetaminophen, aspirin, or ibuprofen are commonly used and are ra;onal because different, complementary central and peripheral mechanisms of pain relief are invoked. Although aspirin and ibu- profen have anOinflammatory efficacy, acetaminophen is not anOin- flammatory and is not a good choice, used singly, when it is desired to reduce inflammaOon. Acetaminophen does, however, have anal- gesic acOvity. Caution The opioid analgesics are subject to misuse and abuse. Additional implications for dentistry relate to the possible inter- actions of opioids with other medications that may be prescribed or substances (prescription and nonprescription drugs, herbals, nutri- tional supplements, etc.) that patients may take for other reasons. Drug interactions with orally administered opioids are uncommon or not usually of great clinical importance when they do occur. There are recognized interactions, however, between opioids and CNS depressants, neuroleptics, tricyclic antidepressants, mono- amine oxidase inhibitors, local anesthetics, and oral anticoagulants that can be clinically significant, particularly if opioids are given parenterally. Generally, the coadministration of CNS depressants produces summation of effects and occasionally a greater than anticipated depression (i.e., supra-additive effect). Opioids and phenothiazines (e.g., chlorpromazine) are known to produce at least additive CNS depression, including respiratory depression. This combination may also produce a greater incidence of orthostatic hypotension than either drug administered alone. Increased hypotension has also been reported with combinations of opioids and tricyclic antidepressants. The clinical significance of these interactions, particularly at the doses of opioids used orally in dentistry, is uncertain. When combinations of opioids with other CNS depressants are given by intravenous infusion, the effects can be titrated to the desired level. When opioids are used orally, doses should have a sufficient margin of safety to avoid dose- dependent toxicity.  The coadministraOon of local anestheOcs and parenteral opioid analgesics is a common and generally safe pracOce. Large doses of these classes of drugs display supra-addiOve toxicity, however. It is likely that respiratory acidosis caused by an opioid can increase the entry of a local anestheOc into the CNS. nteracOon of opioids with oral anOcoagulants has been reported to result in an enhanced response to the la\er, but the clinical signifi- cance has not been established, and it is unlikely that short-term opioid administraOon has an appreciable effect on the paOent’s response to oral anOcoagulants. A well-documented interacOon between meperidine and mono- amine oxidase inhibitors results in severe and immediate reacOons that include excitaOon, rigidity, hypertension, and someOmes death. Chemically unrelated opioids are unlikely to cause a similarly violent reacOon. DenOsts are oRen confronted with the report by paOents that they are allergic to codeine. The nature of these adverse effects needs to be explored with the paOents. Nausea and vomiOng, without hives and itching, is most like due to sOmulaOon of the chemoreceptor trigger zone (CTZ) during the iniOal period of therapy. This is not a hyper- sensiOvity reacOon. If on the other hand, the previous adverse reacOon had the appearance of a hypersensiOvity reacOon with hives, itching, and perhaps difficulty in breathing, codeine and other phenanthrenes such as morphine, hydrocodone, dihydrocodeine, and oxycodone should be avoided. The CTZ mechanism is more likely to occur than the hypersensiOvity reacOon. Gene>c varia>on of codeine response The pathway of codeine metabolism by which it is acOvated to morphine. VariaOons in the acOvity of cytochrome P450 2D6 range from poor metabolizers, to intermediate metabolizers, to extensive metabolizers (the most common geneOc type), to ultra-rapid metabolizers. Therefore, depending on the paOent’s geneOc profile, the rate and degree of conversion of codeine to morphine can range from low to high. Codeine, at typical doses, would be ineffecOve in the paOent who is a poor metabolizer but potenOally toxic in the paOent who is an ultra-rapid metabolizer. Codeine is more affected than other opioids by variaOons in enzyme makeup, although tramadol and hydrocodone are also somewhat affected by variaOons in acOvity of cytochrome P450 2D6. (See case study for chapter 4.) Future medicine and denOstry will take into account these variaOons using the benefits of geneOc tesOng. DenOsts should be aware that a higher percentage of some Asian groups have slower metabolism involving cytochrome P450 2D6 (intermediate metabolizers) and therefore are likely to have a lower analgesic response to codeine than most Caucasians.