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level: opioids

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level questions: opioids

Question	Answer
Most drugs in this class are well absorbed when taken orally, but morphine, hydromorphone, and oxymorphone undergo extensive first-pass metabolism. In most cases, opioids can be given parenterally, and sustained-release forms of some drugs are now available, including morphine and oxycodone. Fentanyl is available as a transdermal patch.They cross the placental barrier and exert effects on the fetus that can result in both respiratory depression and, with continuous exposure, physical dependence in neonates.	A. Absorption and Distribution
These are designated by the Greek letters µ (mu), κ (kappa), and δ (delta) All 3 receptor subtypes appear to be involved in antinociceptive and analgesic mechanisms at both spinal and supraspinal levels. The μ-receptor activation plays a major role in the respiratory depressant actions of opioids and together with κ-receptor activation slows gastrointestinal transit; κ-receptor activation also appears to be involved in sedative actions; δ-receptor activation may play a role in the development of tolerance.	RECEPTOR
The analgesic properties of the opioids are primarily mediated by the µ receptors. However, the κ receptors in the dorsal horn also contribute (eg, butorphanol and nalbuphine) primarily owe their analgesic effect to κ-receptor activation. The enkephalins interact more selectively with the 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 . opioid receptors are located on primary afferents and spinal cord pain transmission neurons (ascending pathways) and on neurons in the midbrain and medulla (descending pathways) that function in pain modulation. Other opioid receptors that may be involved in altering reactivity to pain are located on neurons in the basal ganglia, the hypothalamus, the limbic structures, and the cerebral cortex.	receptor mechanism
Morphine is the major analgesic drug contained in crude opium and is the prototype strong agonist. Codeine is present in crude opium in lower concentrations and is inherently less potent, making codeine the prototype of the weak opioid agonists. Morphine and several other opioids have high affinity for µ receptors, whereas other agents have varying affinities for δ and κ receptors.	III. STRONG AGONISTS
the opioids are metabolized by hepatic enzymes, usually to inactive glucuronide conjugates, before their elimination by the kidney. However, morphine-6-glucuronide has analgesic activity equivalent to that of morphine, and morphine-3-glucuronide (the primary metabolite) is neuroexcitatory. Codeine, oxycodone, and hydrocodone are metabolized by cytochrome CYP2D6, an isozyme exhibiting genotypic variability. In the case of codeine, this may be responsible for variability in analgesic response because the drug is demethylated by CYP2D6 to form the active metabolite, morphine. The ingestion of alcohol causes major increases in the peak serum levels of several opioids including hydromorphone and oxymorphone. Meperidine is metabolized to normeperidine, which may cause seizures at high plasma levels. Depending on the specific drug, the duration of their analgesic effects ranges from 1–2 h (eg, fentanyl) to 6–8 h (eg, buprenorphine). However, long-acting formulations of some drugs may provide analgesia for 24 h or more. The elimination half-life of opioids increases in patients with liver disease. Remifentanil, a congener of fentanyl, is metabolized by plasma and tissue esterases and has a very short half-life.	B. Metabolism
Opioid receptors are thought to be activated by endogenous peptides under physiologic conditions. These peptides, which include endorphins such as a-endorphin, enkephalins, and dynorphins, are synthesized in the cell body and are transported to the nerve endings where they accumulate in synaptic vesicles. On release from nerve endings, they bind to opioid receptors and can be displaced from binding by opioid antagonists. Endorphins have highest affinity for μ receptors, enkephalins for δ receptors, and dynorphins for κ receptors. Although it remains unclear whether these peptides function as classic neurotransmitters, they appear to modulate transmission at many sites in the brain and spinal cord and in primary afferents. Opioid peptides are also found in the adrenal medulla and neural plexus of the gut.	B. Opioid Peptides
Opioid analgesics inhibit synaptic activity partly through direct activation of opioid receptors and partly through release of the endogenous opioid peptides, which are themselves inhibitory to neurons. All 3 major opioid receptors are coupled to their effectors by G proteins and activate phospholipase C or inhibit adenylyl cyclase. At the postsynaptic level, activation of these receptors can open potassium ion channels to cause membrane hyperpolarization (inhibitory postsynaptic potentials). At the presynaptic level, opioid receptor activation can close voltage-gated calcium ion channels to inhibit neurotransmitter release.Presynaptic actions result in the inhibition of release of multiple neurotransmitters, including acetylcholine (ACh), norepinephrine, serotonin, glutamate, and substance P.	C. Ionic Mechanisms
They attenuate both emotional and sensory aspects of the pain experience. Strong agonists (ie, those with the highest analgesic efficacy, full agonists) include morphine, methadone, meperidine, fentanyl, levorphanol, and heroin. Drugs with mixed agonistantagonist actions (eg, buprenorphine) may antagonize the analgesic actions of full agonists and should not be used concomitantly. Codeine, hydrocodone, and oxycodone are partial agonists with mild to moderate analgesic efficacy. They are commonly available in combinations with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). Propoxyphene, a very weak agonist drug, is also available combined with acetaminophen.	A. Analgesia
These effects may occur at doses lower than those required for maximum analgesia. The sedation is additive with other CNS depressants, but there is little amnesia. Some patients experience dysphoric effects from opioid drugs. At higher doses, the drugs may cause mental clouding and result in a stuporous, or even a comatose, state.	B. Sedation and Euphoria
Opioid actions in the medulla lead to inhibition of the respiratory center, with decreased response to carbon dioxide challenge. With full agonists, respiratory depression may be seen at conventional analgesic doses. Increased Pco2 may cause cerebrovascular dilation, resulting in increased blood flow and increased intracranial pressure. Opioid analgesics are relatively contraindicated in patients with head injuries.	C. Respiratory Depression
Suppression of the cough reflex by unknown mechanisms is the basis for the clinical use of opioids as antitussives. This action can be obtained with the use of doses lower than those needed for analgesia.	D. Antitussive Actions
Nausea and vomiting are caused by opioid activation of the chemoreceptor trigger zone and are increased by ambulation.	E. Nausea and Vomiting
Constipation occurs through decreased intestinal peristalsis, which is probably mediated by effects on opioid receptors in the enteric nervous system. This powerful action is the basis for the clinical use of these drugs as antidiarrheal agents.	F. Gastrointestinal Effects
Opioids (with the exception of meperidine) cause contraction of biliary tract smooth muscle, which can result in biliary colic or spasm, increased ureteral and bladder sphincter tone, and a reduction in uterine tone, which may contribute to prolongation of labor.	G. Smooth Muscle
Pupillary constriction is a characteristic effect of all opioids except meperidine, which has a muscarinic blocking action. Little or no tolerance occurs. Miosis is blocked by the opioid antagonist naloxone and by atropine.	H. Miosis
Opioid analgesics, especially morphine, can cause flushing and pruritus through histamine release. They cause release of antidiuretic hormone (ADH) and prolactin but may inhibit the release of luteinizing hormone (LH). Exaggerated responses to opioid analgesics may occur in patients with adrenal insufficiency or hypothyroidism.	endocrine
Marked tolerance can develop to the acute pharmacologic effects, with the exception of miosis and constipation. The mechanism of opioid tolerance development may involve receptor uncoupling. Antagonists of glutamate N-methyl-daspartate (NMDA) receptors (eg, ketamine), as well as δ-receptor antagonists, are reported to block opioid tolerance. Although there is cross-tolerance between different opioid agonists, it is not complete. This provides the basis for “opioid rotation,” whereby analgesia is maintained (eg, in cancer patients) by changing from one drug to another.	A. Tolerance
Physical dependence is an anticipated physiologic response to chronic therapy with drugs in this group, particularly the strong agonists. Physical dependence is revealed on abrupt discontinuance as an abstinence syndrome, which includes rhinorrhea, lacrimation, chills, gooseflesh, muscle aches, diarrhea, yawning, anxiety, and hostility. A more intense state of precipitated withdrawal results when an opioid antagonist is administered to a physically dependent individual.	B. Dependence
Treatment of relatively constant moderate to severe pain is the major indication. Although oral formulations are most commonly used, buccal and suppository forms of some drugs are available. In the acute setting, strong agonists are usually given parenterally. Prolonged analgesia, with some reduction in adverse effects, can be achieved with epidural administration of certain strong agonist drugs (eg, fentanyl and morphine). Fentanyl has also been used by the transdermal route providing analgesia for up to 72 h. For less severe pain and in the chronic setting, moderate agonists are given by the oral route, sometimes in combinations with acetaminophen or NSAIDs.	A. Analgesia
Useful oral antitussive drugs include codeine and dextromethorphan. The latter, an over-the-counter drug, has recently been the subject of FDA warnings regarding its abuse potential. Large doses of dextromethorphan may cause hallucinations, confusion, excitation, increased or decreased pupil size, nystagmus, seizures,coma, and decreased breathing.	B. Cough Suppression
Selective antidiarrheal opioids include diphenoxylate and loperamide. They are given orally.	C. Treatment of Diarrhea
Morphine (parenteral) may be useful in acute pulmonary edema because of its hemodynamic actions; its calming effects probably also contribute to relief of the pulmonary symptoms.	D. Management of Acute Pulmonary Edema
Opioids are used as preoperative medications and as intraoperative adjunctive agents in balanced anesthesia protocols. High-dose intravenous opioids (eg, morphine, fentanyl) are often the major component of anesthesia for cardiac surgery.	E. Anesthesia
Methadone, one of the longer acting opioids, is used in the management of opioid withdrawal states and in maintenance programs for addicts. In withdrawal states, methadone permits a slow tapering of opioid effect that diminishes the intensity of abstinence symptoms. Buprenorphine has an even longer duration of action and is sometimes used in withdrawal states. In maintenance programs, the prolonged action of methadone blocks the euphoria-inducing effects of doses of shorter acting opioids (eg, heroin, morphine).	F. Opioid Dependence
Most of the adverse effects of the opioid analgesics (eg, nausea, constipation, respiratory depression) are predictable extensions of their pharmacologic effects. In addition, overdose and drug interaction toxicities are very important.	TOXICITY
A triad of pupillary constriction, comatose state, and respiratory depression is characteristic; the latter is responsible for most fatalities. Diagnosis of overdosage is confirmed if intravenous injection of naloxone, an antagonist drug, results in prompt signs of recovery. Treatment of overdose involves the use of antagonists such as naloxone and other therapeutic measures, especially ventilatory support.	A. Overdose
The most important drug interactions involving opioid analgesics are additive CNS depression with ethanol, sedative-hypnotics, anesthetics, antipsychotic drugs, tricyclic antidepressants, and antihistamines. Concomitant use of certain opioids (eg, meperidine) with monoamine oxidase inhibitors increases the incidence of hyperpyrexic coma. Meperidine has also been implicated in the serotonin syndrome when used with selective serotonin reuptake inhibitors.	B. Drug Interactions
The analgesic activity of mixed agonist-antagonists varies with the individual drug but is somewhat less than that of strong full agonists like morphine. Buprenorphine, butorphanol, and nalbuphine afford greater analgesia than pentazocine, which is similar to codeine in analgesic efficacy.	A. Analgesic Activity agonist antagonist
Butorphanol, nalbuphine, and pentazocine are κ agonists, with weak μ-receptor antagonist activity. Butorphanol may act as a partial agonist or antagonist at the μ receptor. Buprenorphine is a μ-receptor partial agonist with weak antagonist effects at κ and δ receptors. These characteristics can lead to decreased analgesia, or even precipitate withdrawal symptoms, when such drugs are used in patients taking conventional full μ-receptor agonists. Buprenorphine has a long duration of effect, binding strongly to μ receptors. Although prolonged activity of buprenorphine may be clinically useful (eg, to suppress withdrawal signs in dependency states), this property renders its effects resistant to naloxone reversal, since the antagonist drug has a short half-life. In overdose, respiratory depression caused by nalbuphine may also be resistant to naloxone reversal. Naloxone is included in some formulations of these agonist-antagonist drugs to discourage abuse.	B. Receptors
The mixed agonist-antagonist drugs often cause sedation at analgesic doses. Dizziness, sweating, and nausea may also occur, and anxiety, hallucinations, and nightmares are possible adverse effects. Respiratory depression may be less intense than with pure agonists but is not predictably reversed by naloxone. Tolerance develops with chronic use but is less than the tolerance that develops to the full agonists, and there is minimal cross-tolerance. Physical dependence occurs, but the abuse liability of mixed agonist-antagonist drugs is less than that of the full agonists.	C. Effects
Tramadol is a weak μ-receptor agonist only partially antagonized by naloxone. Its analgesic activity is mainly based on blockade of the reuptake of serotonin; it is a weak norepinephrine reuptake blocker. Tramadol is effective in treatment of moderate pain and has been used as an adjunct to opioid analgesics in chronic pain syndromes. The drug is relatively contraindicated in patients with a history of seizure disorders, and there is risk of the serotonin syndrome if it is co-administered with SSRIs. No significant effects on cardiovascular functions or respiration have been reported.	Tramadol
Tapentadol has strong norepinephrine reuptake-inhibiting activity (blocked by α antagonists) and only modest μ-opioid receptor affinity. It is less effective than oxycodone in the treatment of moderate to severe pain but causes less gastrointestinal distress and nausea. Tapentadol has been implicated in the serotonin syndrome and should be used with caution in seizure disorders.	Tapentadol
Naloxone, nalmefene, and naltrexone are pure opioid receptor antagonists that have few other effects at doses that produce marked antagonism of agonist effects. These drugs have greater affinity for μ receptors than for other opioid receptors.	OPIOID ANTAGONISTS
A major clinical use is in the management of acute opioid overdose. Naloxone and nalmefene are given intravenously. Because naloxone has a short duration of action (1–2 h), multiple doses may be required in opioid analgesic overdose. Nalmefene has a duration of action of 8–12 h. Naltrexone has a long elimination half-life, blocking the actions of strong agonists (eg, heroin) for up to 48 h after oral use.	OPIOID ANTAGONISTS metabolism
Naltrexone decreases the craving for ethanol and is approved for adjunctive use in alcohol dependency programs. Unlike the older drugs, two new antagonists, methylnaltrexone and alvimopan, do not cross the blood-brain barrier. These agents block adverse effects of strong opioids on peripheral μ receptors, including those in the gastrointestinal tract responsible for constipation, with minimal effects on analgesic actions and without precipitating an abstinence syndrome.	OPIOID ANTAGONISTS uses
1. Mechanism of action: Opioids cause hyperpolarization of nerve cells, inhibition of nerve firing, and presynaptic inhibition of transmitter release. Morphine acts at κ receptors in laminae I and II of the dorsal horn of the spinal cord, and it decreases the release of substance P, which modulates pain perception in the spinal cord. Morphine also appears to inhibit the release of many excitatory transmitters from nerve terminals carrying nociceptive (painful) stimuli.	A. Morphine 1. Mechanism of action:
is conjugated with glucuronic acid in the liver. Morphine-6-glucuronide is a very potent analgesic, whereas the conjugate at position 3 (morphine-3-glucuronide) has been found not to have opioid activity, but is believed to cause the neuro-excitatory 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 6 hours when administered systemically to morphine-naïve individuals but considerably longer when injected epidurally, because its low lipophilicity prevents redistribution from the epidural space. [Note: A patient’s age can influence the response to morphine. Elderly patients are more sensitive to the analgesic effects of the drug, possibly due to decreased metabolism or other factors, such as decreased lean body mass, renal function, etc. They should be treated with lower doses. Neonates should not receive morphine because of their low conjugating capacity.]	c. Fate: Morphine
5. Adverse effects: Severe respiratory depression can occur and result in death from acute opioid poisoning. A serious effect of the drug is stoppage of respiratory exchange in patients with emphysema or cor pulmonale. [If used in such individuals, respiration must be carefully monitored.] Other effects include vomiting, dysphoria, and histamine-enhanced hypotensive effects. The elevation of intracranial pressure, particularly in head injury, can be serious. Morphine enhances cerebral and spinal ischemia. In benign prostatic hyperplasia, impaired renal function.morphine may cause acute urinary retention. Patients with adrenal insufficiency or myxedema may experience extended and increased effects from the opioids. Morphine should be used cautiously in patients with bronchial asthma, liver failure, or	5. Adverse effects:
6. Tolerance and physical dependence: Repeated use produces tolerance to the respiratory depressant, analgesic, euphoric, and sedative effects of morphine. However, tolerance usually does not develop to the pupil-constricting and constipating effects of the drug. Physical and psychological dependence readily occur with morphine and with some of the other agonists. Withdrawal produces a series of autonomic, motor, and psychological responses that incapacitate the individual and cause serious (almost unbearable) symptoms. However, it is very rare that the effects are so profound as to cause death. [Note: Detoxification of morphine-dependent individuals is usually accomplished through the oral administration of methadone buprenorphine, or clonidine.]	morphine tolerance and physical dependence:
7. Drug interactions: Drug interactions with morphine appear to be rare, although the depresB. Meperidine	morphine Drug interactions:
Meperidine is a synthetic opioid structurally unrelated to morphine. It is used for acute pain.	meperidine
Meperidine binds to opioid receptors, particularly µ receptors. It also binds well to κ receptors.depressant actions of morphine are enhanced by phenothiazines, (MAOIs), and tca.	meperidine mechanism of action
Meperidine causes a depression of respiration similar to that of morphine, but it has no significant cardiovascular action when given orally. On IV administration, meperidine produces a decrease in peripheral resistance and an increase in peripheral blood flow, and it may cause an increase in cardiac rate. As with morphine, meperidine dilates cerebral vessels, increases CSF pressure, and contracts smooth muscle (the latter to a lesser extent than does morphine).Meperidine causes the pupils to dilate because of an anticholinergic action.	2. Actions meperidine
it provides analgesia but is not recommended for long-term use due to its active metabolite, normeperidine, which has significant neurotoxic properties.	3. Therapeutic uses: Meperidine
is well absorbed from the GI tract, and is available for oral administration. However, meperidine is most often administered parenterally. The drug has a duration of action of 2 to 4 hours, which is shorter than that of morphine. Meperidine is N-demethylated to normeperidine in the liver and is excreted in urine.	Pharmacokinetics: Meperidine
Large or repetitive doses of meperidine can cause anxiety, tremors, muscle twitches, and, rarely, convulsions, due to the accumulation of normeperidine. The drug differs from opioids in that, when given in large doses, it dilates the pupil and causes hyperactive reflexes. Severe hypotension can occur when the drug is administered postoperatively. Due to its antimuscarinic (anticholinergic) action, patients may experience dry mouth and blurred vision. When used with major antipsychotic drugs, depression is greatly enhanced. Administration to patients taking MAOIs or dextromethorphan can provoke severe reactions, such as convulsions and hyperthermia. Meperidine is considered to be inappropriate for use in geriatric patients and patients with impaired renal function, due to the accumulation of normeperidine. It should be avoided in elderly patients. Adverse effects associated with normeperidine are not reversible by administration of naloxone.	meperidine 5. Adverse effects:
Methadone is a synthetic, orally effective opioid which has variable equianalgesic potency compared to that of morphine and the conversion between the two products is not linear. Methadone induces less euphoria and has a somewhat longer duration of action.	C. Methadone
The actions of methadone are mediated by µ receptors. In addition, methadone is an antagonist of the N-methylD-aspartate (NMDA) receptor, which is useful in the treatment of neurogenic pain.	1. Mechanism of action: methadone
it is well absorbed when administered orally, unlike morphine, which is only partially absorbed from the GI tract. Like morphine, methadone increases biliary pressure and is also constipating (but less so than morphine).	2. Actions: Methadone
it is used as an analgesic in nociceptive and neurogenic pain as well as in the controlled withdrawal of dependent abusers from heroin and morphine. Orally administered, methadone is substituted for the injected opioid. The patient is then slowly weaned from methadone. Methadone causes a withdrawal syndrome that is milder but more protracted (days to weeks) than that of other opioids.	3. Therapeutic uses: Methadone
it is readily absorbed following oral administration. The drug is biotransformed in the liver and is excreted almost exclusively in feces. It is important to understand the pharmacokinetics of methadone when using this medication, due to multiple variables associated with it. Methadone is very lipophilic, leading to accumulation in the fat tissues. The slow release from these fat tissues causes the half-life to range from 12 to 40 hours and has been reported to extend up to 150 hours. The actual duration of analgesia ranges from 4 to 8 hours. Upon repetitive dosing, methadone levels can accumulate due to this long terminal half-life, thereby leading to toxicity. The metabolism is variable because it relies on multiple cytochrome P450 (CYP450) enzymes, some of which are affected by known genetic polymorphisms and are susceptible to many drug interactions.	Pharmacokinetics: Methadone
it can produce physical dependence like that of morphine but has less neurotoxicity than what is seen with morphine due to the lack of active metabolites. Methadone can cause torsades de pointes in certain situations. Overdosing is possible when prescribers are not aware of the incomplete cross-tolerance between methadone and other opioids, the long half-life associated with methadone and the proper titration guidelines to avoid its accumulation, and the multiple drug-drug interactions that can occur with this agent.	Adverse effects: Methadone
Fentanyl , which is chemically related to meperidine, has 100-fold the analgesic potency of morphine and is used in anesthesia. The drug is highly lipophilic and has a rapid onset and short duration of action (15–30 minutes). It is usually administered IV, epidurally, or intrathecally. Epidural fentanyl is used to induce anesthesia and for analgesia postoperatively and during labor. An oral transmucosal preparation and a transdermal patch are also available. The transmucosal preparation is used in the treatment of cancer patients with breakthrough pain who are tolerant to opioids. The transdermal patch must be used with caution, because death resulting from hypoventilation has been known to occur. [Note: The transdermal patch creates a reservoir of the drug in the skin. Hence, the onset is delayed 12 hours, and the offset is prolonged.] Fentanyl is metabolized to inactive metabolites by the CYP450 3A4 system, and drugs that inhibit this isozyme can potentiate the effect of fentanyl. Most of the drug and metabolites are eliminated through the urine.	D. Fentanyl metabolism
Fentanyl is often used during cardiac surgery because of its negligible effects on myocardial contractility. Muscular rigidity, primarily of the abdomen and chest wall, is often observed with fentanyl use in anesthesia.	fentanyl use
Adverse effects of fentanyl are similar to those of other µ-receptor agonists. Because of life-threatening hypoventilation, the fentanyl patch is contraindicated in the management of acute and postoperative pain and in pain that can be ameliorated with other analgesics. Unlike meperidine, it causes pupillary constriction.	fentanyl adverse effects
Three drugs related to fentanyl, sufentanil, alfentanil, and remifentanil, differ in their potency and metabolic disposition. Sufentanil is even more potent than fentanyl, whereas the other two are less potent and shorter acting.	E. Sufentanil, alfentanil, and remifentanil
Heroin does not occur naturally. It is produced by diacetylation of morphine, which leads to a threefold increase in its potency. Its greater lipid solubility allows it to cross the blood-brain barrier more rapidly than morphine, causing a more exaggerated euphoria when the drug is injected. Heroin is converted to morphine in the body, but its effects last about half as long. It is used therapeutically in other countries for the severe pain of cancer.	F. Heroin
Oxycodone is a semisynthetic derivative of morphine. It is orally active and is sometimes formulated with aspirin or acetaminophen. It is used to treat moderate to severe pain and has many properties in common with morphine. Its oral analgesic effect is approximately twice that of morphine. Oxycodone is metabolized via CYP450 2D6 and 3A4 enzyme systems. Excretion is via the kidney. Abuse of the sustained-release preparation (ingestion of crushed tablets) has been implicated in many deaths. It is important that the higher-dosage forms of the latter preparation be used only by patients who are tolerant to opioids.	G. Oxycodone
Oxymorphone is a narcotic analgesic with a potency similar to that of hydromorphone. It is available in both immediate-acting and extended-release formulations. There are not any clinically relevant drug-drug interactions associated with the CYP450 enzyme system compared to oxycodone.	Oxymorphone
Hydromorphone and hydrocodone are orally active, semisynthetic analogues of morphine and codeine, respectively. Oral hydromorphone is approximately eight to ten times more potent than oral morphine as an analgesic and is used most often to treat severe pain. Hydromorphone is preferred over morphine in patients with renal dysfunction due to less accumulation of active metabolites compared to morphine.	H. Hydromorphone
Hydrocodone is the methyl ether of hydromorphone, but is much weaker an analgesic than hydromorphone. The analgesic potency of oral hydrocodone is approximately that of morphine. Hydrocodone is often combined with acetaminophen or ibuprofen to treat moderate-to-severe pain. It is also used as an antitussive. Hydrocodone is metabolized in the liver to several metabolites, one of which is hydromorphone via the actions of CYP450 2D6, which can be affected by drug-drug interactions.	hydrocodone
The analgesic actions of codeine derive from its conversion to morphine by the CYP450 2D6 enzyme system, whereas the drug’s antitussive effects are due to codeine itself. Thus, codeine is a much less potent analgesic than morphine. Codeine’s analgesic potency is approximately 30 percent that of morphine. Codeine shows good antitussive activity at doses that do not cause analgesia. At commonly used doses, the drug has a lower potential for abuse than morphine. Codeine is often used in combination with aspirin or acetaminophen. In most nonprescription cough preparations, codeine has been replaced by drugs such as dextromethorphan, a synthetic cough depressant that has relatively no analgesic action and a relatively low potential for abuse in usual antitussive doses.	A. Codeine
Drugs that stimulate one receptor but block another are termed mixed agonist-antagonists. The effects of these drugs depend on previous exposure to opioids. In individuals who have not recently received opioids (naïve patients), mixed agonist-antagonists show agonist activity and are used to relieve pain. In the patient with opioid dependence, the agonist-antagonist drugs may show primarily blocking effects (that is, produce withdrawal symptoms).	V. MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS
Pentazocine acts as an agonist on κ receptors and is a weak antagonist at µ and δ receptors. Pentazocine promotes analgesia by activating receptors in the spinal cord, and it is used to relieve moderate pain. It may be administered either orally or parenterally. Pentazocine produces less euphoria compared to morphine	A. Pentazocine
In higher doses, the drug causes respiratory depression and decreases the activity of the GI tract. High doses increase blood pressure and can cause hallucinations, nightmares, dysphoria, tachycardia, and dizziness. The latter properties have led to its decreased use. In angina, pentazocine increases the mean aortic pressure and pulmonary arterial pressure and, thus, increases the work of the heart. The drug decreases renal plasma flow. Despite its antagonist action, pentazocine does not antagonize the respiratory depression of morphine, but it can precipitate a withdrawal syndrome in a morphine abuser. Tolerance and dependence develop on repeated use.	A. Pentazocine adverse effects
Buprenorphine is classified as a partial agonist, acting at the µ receptor. It acts like morphine in naïve patients, but it can also precipitate withdrawal in morphine users. A major use is in opiate detoxification, because it has a less severe and shorter duration of withdrawal symptoms compared to methadone. It causes little sedation, respiratory depression, and hypotension, even at high doses. In contrast to methadone, which is available only at specialized clinics, buprenorphine is approved for office-based detoxification or maintenance. Buprenorphine is administered sublingually, parenterally, or transdermally and has a long duration of action because of its tight binding to the μ receptor. The tablets are indicated for the treatment of opioid dependence and are available in buprenorphine alone (Subutex) and also in a combination product containing buprenorphine and naloxone (Suboxone). Naloxone was added to buprenorphine to prevent the abuse of buprenorphine via IV administration.	B. Buprenorphine
There is no clinical effect seen with oral naloxone, but, upon IV administration, opioid antagonism will occur, and the patient will experience withdrawal. The injectable form and the once weekly transdermal patch are indicated for the relief of moderate to severe pain. It is metabolized by the liver and excreted in bile and urine. Adverse effects include respiratory depression that cannot easily be reversed by naloxone and decreased (or, rarely, increased) blood pressure, nausea, and dizziness.	B. Buprenorphine adverse effects
Nalbuphine and butorphanol, like pentazocine, play a limited role in the treatment of chronic pain. Neither is available for oral use. Their propensity to cause psychotomimetic (actions mimicking the symptoms of psychosis) effects is less than that of pentazocine. Nalbuphine does not affect the heart or increase blood pressure, in contrast to pentazocine and butorphanol. A benefit of all three medications is that they exhibit a ceiling effect for respiratory depression	C. Nalbuphine and butorphanol
Naloxone 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. [Note: Because of its relatively short duration of action, a depressed patient who has been treated and recovered may lapse back into respiratory depression.] Naloxone is a competitive antagonist at µ, κ, and δ, receptors, with a tenfold higher affinity for µ than for κ receptors. This may explain why naloxone readily reverses respiratory depression with only minimal reversal of the analgesia that results from agonist stimulation of κ receptors in the spinal cord. Naloxone produces no pharmacologic effects in normal	naloxane use
Tramadol is a centrally acting analgesic that binds to the µ-opioid receptor. The drug undergoes extensive metabolism via CYP450 2D6, leading to an active metabolite that has a much higher affinity for the µ receptor than the parent compound. In addition, it weakly inhibits reuptake of norepinephrine and serotonin. It is used to manage moderate to moderately severe pain. Its respiratory-depressant activity is less than that of morphine.	A. Tramadol
Naloxone can only partially reverse the analgesia produced by tramadol or its active metabolite. Anaphylactoid reactions have been reported. Toxicity through drug-drug interactions with medications, such as selective serotonin reuptake inhibitors and tricyclic antidepressants, or in overdose, leads to CNS excitation and seizures. Tramadol should also be avoided in patients taking MAOIs.	nolaxone adverse
The opioid antagonists bind with high affinity to opioid receptors but fail to activate the receptor-mediated response. Administration of opioid antagonists produces no profound effects in normal individuals. However, in patients dependent on opioids, antagonists rapidly reverse the effect of agonists, such as morphine or any full µ-agonist, and precipitate the symptoms of opiate withdrawal.	antagonists
Tapentadol is a centrally acting analgesic that binds the µ-opioid receptor and is also a norepinephrine reuptake inhibitor that is believed to create an additive effect to the opioid actions. It has been used to manage moderate to severe pain, both chronic and acute.	B. Tapentadol
Limited drug-drug interactions have been seen with tapentadol due to the pharmacokinetic profile. Tapentadol does not appear to inhibit or induce the CYP450 enzyme system because it is mainly metabolized by glucuronidation. Because tapentadol does not produce active metabolites, dosing adjustment is not necessary in mild to moderate renal impairment. Tapentadol should be avoided in patients currently taking MAOIs and those who have taken MAOIs within the last 14 days. Tapentadol is currently available in an immediate-release formulation.	B. Tapentadol metabolism and adverse effect