OPIOIDS (NARCOTICS) ANALGESIC

PHARMACHODYNAMICS OF OPIOIDS: A. SITE AND MECHANISM of ACTION OF OPIATE: Recognition of pain involves a component that intensifies the response to pain because the CNS anticipates how painful the injury will be. This recognition leads to anxiety and apprehension (CNS stimulation) which heightens the reaction to pain. Opioid analgesics are called central analgesics because they selectively act within the CNS to reduce the reaction to pain. Opioid analgesics do not impair the function of peripheral nerves. The pain is still present but patient either can tolerate the pain. Several different types of opioid receptors have identified with in the spinal cord and brain. Morphine was thought to interact with membrane-bound receptors as long as 40 years ago. However, it was not until the 1970s that evidence for an opioid receptor in the body was confirmed by the discovery of the endogenous peptides. These peptides include endorphin, enkephlin, dynorphin, and the newest ones, noceciptin and nocistatin. The word endorphin is derived from the words endogenous and morphine. These peptides are believed to be important for survival because, when released, they provide pain relief that allows the injured person to move away from the harmful stimulus. Endorphin has been shown to be more than four times more potent than intravenous morphine. Eventually, the peptides are metabolized, level decrease, and the pain signal returns to causing the person to seek help to reduce the continuing pain. Three opioid receptors are most clinically important-mu, kappa, and delta. Each of the peptides has a preference for one of the opioid receptors. Endorphins are produced within the pituitary and hypothalamus and are selective for mu receptors. Encephalin, produced throughout the CNS and peripheral nerve ending, prefer delta receptors, while dynorphins found in pain nerve ending, interact with kappa receptors. Reduction in the awareness and reaction to pain is controlled through a combination of mu, kappa and delta receptors.

Morphine and other analgesics act by binding to the opioid receptors and mimicking (agonist) the effect of the analgesic peptides. The therapeutically important opioid analgesics interact with mu and kappa receptors, inhibit neurotransmitters release such as substance P, inhibit nociceptor signals from reaching the spinal cord, reduce nerve excitability, and alter pain perception. All of these agonists action contribute to the pain relief. Most of the traditional opioids (morphine, oxymorphone, oxycodone, methadone, fentanyl are pure agonists referred to mu agonists. This means they bind to the receptor and produce a response. Agonists for different opioid receptors are believed to relieve different types of pain. Other opioids (nalbuphine, butorphanol) are partial agonists because they initiate kappa receptors but block mu receptors. Finally drug like naloxone, are pure antagonists. These drugs do not produce effects but bind to the receptor so that other agonists cannot and in this way reverse the mu effect of opioids B. OPIOID RECEPTOR-MEDIATED CELLULAR CHANGES ARE INHIBITORY: Each of the three receptors types are linked to G proteins. Multiple forms of G proteins have two principal actions. Some G proteins directly stimulate or inhibit the opening of ion channels and other stimulates or inhibits the enzymes to alter second messenger production. Opioid work by both of two mechanisms to open K channels, close Ca channels, and inhibit adenyl cyclase activity. The overall effects of opiates on nerve functioning include the reduction of membrane excitability and slowing of cell firing and inhibition of neurotransmitter release. There are three principal ways that endorphins reduce synaptic transmission:(1)post synaptic

inhibition;(2)axoaxonic inhibition;(3)via presyanaptic auto receptors. First, opioid receptor-G protein activation opens K channels, which increase K conductance. Potassium exist the cell, forced by its concentration gradient, causing hyperpolarization. When the receptors are in the soma, the hyperpolarization decreases the cell firing rate. Second, opioid also produce an inhibitory effect by closing Ca channels. In this case opioid receptors in the presynaptic terminal activate G protein, which in turns close Ca channels. For example, opioid induced inhibition of norepinephrine and dopamine release has been found in many brain areas. As expected this effect is prevented by naloxone.

Third, opioid auto receptors also produce inhibitory effects. Somatodendritic auto receptors hyperpolarize cells in the locus coeruleus by enhancing K conductance and reducing cell firing. In summary, opioid effects on both K and Ca channels produce inhibitory effects and reduce neurotransmitters release. These actions in the appropriate circuitry and ultimately responsible for the analgesic effects.

PHARMACHOKINETICS OF OPIOIDS: Since the analgesics are weak bases, these drugs are not well absorbed in the acid environment of the stomach. They are absorbed in the intestines, where the pH is more alkaline. Regardless of the route of administration, metabolic inactivation of the opioid eventually occurs in the hepatic drug microsomal metabolizing system. Heroin is a particularly unusual drug because it is not metabolize to an inactive product. Heroin is rapidly changed into morphine. Several of the opioids are metabolized to products that produce analgesia. Therefore the circulating active metabolites increase the duration of analgesic activity. Eventually, the kidneys excrete the metabolic products. Anything that causes the urine to become alkaline, such as alkalosis and diuretics, increase tubular reabsorption of the opioids. This action elevates the concentration of drug in the blood and increases the risk of developing drug toxicity. 1. Morphine pharmacokinetics: Elimination halftime for morphine following bolus administration is about 1.7-4.5 hours. Following bolus administration onset time is relatively slow (15-30 minutes) because: morphine exhibits relatively low lipid solubility about 2.5% of fentanyl (Sublimaze) at physiological pH, morphine, a weak base with the pKa of about 8.0, is primarily ionized. The ionized form does not favor passage through the lipid membrane; accordingly, only about 10%20% of molecules are un-ionized. Relatively high plasma clearance (15-40 ml/kg/minute) has implicated extra hepatic clearance mechanisms, most likely renal.

2. Fentanyl (Sublimaze) pharmacokinetics: Fentanyl (Sublimaze) is significantly more lipid-soluble, compared morphine and, relative to morphine, has a more rapid onset of action (fentanyl (Sublimaze) is also a weak base and at physiological pH only about 10% of molecules are un-ionized). Clearance of about 10-20 ml/kg/minute is consistent with a primary hepatic mechanism. Fentanyl (Sublimaze)'s short duration of action following bolus administration is explained by rapid redistribution from brain to other compartments such as skeletal muscle and fat. If, however, fentanyl (Sublimaze) is administered by continuous IV infusion or multiple IV dosing, other non-CNS compartments will saturated and remaining CNS fentanyl will contribute to postoperative ventilatory depression. 3. Remifentanil (Ultiva): pharmacokinetics Remifentanil (Ultiva) is unique among the various opioids used in IV anesthesia mainly because of its susceptibility to the ester hydrolysis. There are two ester-linkages in the molecule one of which is rapidly cleaved by nonspecific plasma and tissue enzymes {different from pseudocholinesterase which hydrolyzes for instance succinylcholine (Anectine) and mivacurium (Mivacron). This agent is somewhat less soluble than other opioids, contributing factor to its rapid onset of action, onset that occurs within a time frame similar to that seen with alfentanil (Alfenta), i.e. very rapid. Furthermore, rapid ester hydrolysis limits its duration of action so significantly that, following its redistribution from the brain, its plasma half-life is extremely short. In fact, the plasma half-life is so short that there is very little redistribution to other compartments. The special degradative pathway is responsible for elimination halftimes on the order of 10-25 minutes -- much less than in other IV agents. The "context sensitive" halftime for remifentanil (Ultiva) is about four minutes and is independent of infusion duration. Remifentanil (Ultiva)'s

pharmacokinetic characteristics results in important clinical consequences: The very brief pharmacological activity allows careful titration of dose to effect. The drug does not accumulate. Accumulation is a typical concern following repeated administrations of other drugs. Following continuous intravenous infusion, recovery is rapid limiting the likelihood of postoperative respiratory depression or other complications

SIDE EFFECTS OF OPIOIDS: Common side effects of opioids administration include sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance and respiratory depression. Physical dependence and addiction are clinical concerns that may prevent proper prescribing and in turn inadequate pain management. Less common side effects may include delayed gastric emptying, hyperalgesia, immunologic and hormonal dysfunction, muscle rigidity, and myoclonus. The most common side effects of opioids usage are constipation (which has a very high incidence) and nausea. These 2 side effects can be difficult to manage and frequently tolerance to them does not develop; this is especially true for constipation. They may be severe enough to require opioid discontinuation, and contribute to over-dosing and inadequate analgesia. Several clinical trials are underway to identify adjunct therapies that may mitigate these side effects. Switching opioids and/or routes of administration may also provide benefits for patients. Proper patient screening, education, and preemptive treatment of potential side effects may aid in maximizing effectiveness while reducing the severity of side effects and adverse events. Opioids can be considered broad spectrum analgesic agents, affecting a wide number of organ systems and influencing a large number of body functions. Opioids also effects sexual function. Reduced libido is a well-known phenomenon for those using heroin or those in a methadone maintenance program; however, clinicians prescribing opioids for pain poorly understand this effect. Early case studies of persons using heroin or methadone described diminished libido, sexual dysfunction, reduced testosterone levels in men, and amenorrhea in women. These effects resolve after the opioid has been discontinued.

OPIOID TOLERANCE, SENSITIZATION AND DEPENDENCE:

Although the opiates are the best pain reducing drugs presently available, their use continues to be problematic because of potential for abuse. The drugs in this class are highly reinforcing, and despite strict legal controls they sometimes wind up in the hands of individuals who abuse these substances. Furthermore chronic use leads to neuroadaptive changes in the nervous system, which are responsible for tolerance, sensitization and dependence. TOLERANCE: Tolerance refers to diminishing effect of a drug with repeated use and it occurs for all the opioids, including the indorphins. Although tolerance to the opiates develops quite rapidly, tolerance does not occur for all of the pharmacological effects to the same extent or at the same rate. For example, tolerance to the analgesic effect occurs relatively rapidly, but the constipation effects and the pinpoint pupils persist even after prolonged opiate use. CROSS -TOLERANCE: Cross tolerance among the opiates also exist. For this reason, when tolerance develops to one opiate drug, other chemically relater drug also show a reduced effectiveness. For instance, following chronic heroin use, treatment with codeine will elicit a smaller than normal response even if the individual has never used codeine before. Opiate receptors subtypes play a role in cross-tolerance. Indeed it seems the selective agonists for the ureceptor reduce the effectiveness of other u-receptor agonists, but only minimally reduce kagonist activity. Likewise repeated exposure to k agonists diminishes the effect of the other kagonists but not u-agonists. Several mechanisms are responsible for the development of tolerance to the opioids. An increased rate of metabolism with repeated use drug dispositional tolerance is responsible for some small portion of opioid tolerance. Classical conditioning process also contributes to this phenomenon. However most tolerance is based on changes in nerve cells that compensate for the presence of chronic opiates (pharmacodynamics tolerance). SENSITIZATION: Under some circumstances, repeated exposure to opiates produces sensitization. Sensitization refers to the increase in drug effects that occurs with repeated administration. Robinson and

Berridge(2001) propose that in case of substance abuse the motivation(incentive) to approach, better called craving or desire for the drug, undergoes sensitization. Meanwhile the neural mechanism responsible for the high, or liking for the drug, remain unchanged or decreases as tolerance develops over repeated administration. Both the decrease in liking or increase in craving leads to further drug taking and may explain the intense compulsion to use a drug that no longer produces pleasurable effects. DEPENDENCE: The third consequences of chronic opioid use in the occurrence of physical dependence which is a neuroadaptive state that occurs in response to the long term occupation of opioid receptors. When the drug is no longer present, cell functions no only returns to normal, but over shoot basal level. The effects of drug withdrawal are a rebound in nature and are demonstrated by occurrence of a pattern of physical disturbance called the withdrawal or abstinence syndrome. Since opiates in general depress CNS function, opiate effects are due to drug action at various receptors in a variety of location in CNS and elsewhere in the body, so it should not be surprise to learn that the abstinence signs reflect a loss of inhibitory opioid action at all of those same receptors as blood level of the drug gradually declines. With drawl can also be produced by administering an opioid antagonist that compete with the drug molecule for the receptor and thus functionally mimics the termination of the drug use. However, that the withdrawal following antagonist administration is far more severe than that following drug cessation because the opiate receptors are more rapidly derived of opiate. Opiate withdrawal is not considered life-threatening, but the symptoms are extremely un pleasant and include pain and dysphoria, restlessness and fearfulness as well as several symptoms that are flu-like in nature. How severe the symptoms are added how long they last depends on a number of factors: the particular drug use as well as the dose, frequency, and duration of drug use and the health and personality of addict. For example, morphine withdrawal symptoms generally peak 36 to48 hours after the last administration and disappear within 7 to 10 days. In contrast methadone, which has a gradual onset of action and is longer lasting, has a withdrawal syndrome that does not abruptly peak but increase to a gradual maximum after several days and decrease gradually after several weeks. Abstinence for the very long acting opiate L acetylmethadol(LAAM) is even more prolonged but as is true for all of the longer lasting opiates, the withdrawal signs are

milder. Longer the duration of action of the opiates, the more prolonged is the abstinence syndrome but lower the intensity of syndrome, At the point when abstinence signs end the user is considered to be detoxified. Re-administering the opiate any time during the withdrawal will dramatically eliminate all the symptoms. In addition, administering any other drug will stop or reduce the withdrawal symptoms because all these agents show cross-tolerance. This characteristic plays an important role in drug abuse treatment. ROLE OF ENVIRONMENT IN TOLERANCE AND DRUG ABUSE: Environmental factors can be classically conditioned to part of the drug experience. Conditioning theory has also been applied to development of tolerance to opiates. Siegel(1989)and Tiffany(1992) propose that narcotic tolerance is in part is the result of learning of association between the effects of drug and the environmental cues that reliably precedes the drug effects. Several experiments have shown that after repeated drug administration in a particular environment, the animals begins to show anticipatory physiological responses when it is in that same situation. Thus it is argued that the tolerance to the analgesic effects of morphine results because the environmental cues regularly paired with drug administration begin to elicit te compensatory responses of hyperalgesia, which diminishes the analgesic effect of the drug. Some have suggested this mechanism as the basis for some of the drug overdose fatalities among addicts. It is assumed that an addict who has developed significant tolerance to his drug of choice in his standard environment might find that his tolerance is much less if he uses the drug in a novel situation. Abstinence symptoms can likewise be classically conditioned. When detoxified rat showed an increase in withdrawal wet-dog when returned to a physically distinctive cage where they had undergone morphine withdrawal several month earlier.

FORMS & ROUTES OF ADMINITRATION: Unlike non-opioid analgesics, which are primarily given orally, opioid analgesics are administered using a variety of routes. The availability of more concentrated dosage forms, controlled release oral opioid preparations, and

transdermal opioid preparations are among the most important recent innovations in opioid analgesia treatment. Due to their long duration of action, these preparations lessen the severity of pain that may be experienced at the end of dose effectiveness and often allows the patient to sleep through the night. For example, MS Contin, Oramorph-SR, and OxyContin provide 8 to 12 hours of analgesia with a single dose. Kadian and Avinza are controlled release morphine preparations that may provide pain relief for 12 to 24 hours, respectively, with a single dose.

Oral administration: Giving an opioid analgesic orally is the most common route of administration, and is the preferred route of administration whenever possible. Enteric-coated tablets and controlled release or sustained release forms of opioids delay the drug from dissolving quickly in the stomach and are slower to be absorbed. Liquid preparations of opioids are absorbed more rapidly than solid tablets. Oral opioids, such as morphine, hydromorphone, hydrocodone and oxycodone, can be used for acute or chronic pain. There is no ceiling dose limit on single opioid drugs unless the adverse effects of excessive sedation or respiratory depression occur. The onset of pain relief is not as rapid as opioids that are given intravenously. Sublingual and buccal administration: When a drug is given sublingually, it is placed under the tongue. Buccal administration refers to placing a tablet between the teeth and the mucous membranes of the cheek. Opioids given via these routes are absorbed rapidly. Rectal administration: This route may be used for patients who cannot swallow or when intravenous sites are not available. There are many suppository combinations available. Subcutaneous administration: When a drug is given subcutaneously, it is absorbed beneath the skin into the connective tissue or into fat under the dermis. Drug solubility and vasoconstriction of blood vessels may cause delays in drug absorption when an opioid is given subcutaneously. However, the subcutaneous route can provide rapid pain relief without requiring intravenous access. Intramuscular administration: When this route is used, the drug is injected into a muscle, most often the deltoid or vastus lateralis muscles. Giving analgesics by the intramuscular route is not recommended for pain management, because intramuscular injections are often painful and drug absorption is variable and unpredictable. Intravenous administration: When this route is used, the drug is given directly into a vein

where it immediately enters the systemic circulation. Almost all opioids can be given by the intravenous route. An intravenous bolus provides the most rapid onset of pain relief. For a patient with severe acute pain or exacerbated cancer pain, repeated intravenous boluses may be used to titrate the analgesic to concentrations that provide effective pain relief, followed by a maintenance infusion if necessary. Intravenous drug administration should always be done slowly to minimize adverse effects. Extreme caution is needed in administering a continuous infusion of opioids to opioid "naive" patients, either as a sole infusion or in combination with patient controlled analgesia (PCA) bolus doses. Intravenous opioid administration requires skilled nursing and pharmacy support and requires an infusion pump for continuous or patient controlled administration. Transdermal administration: When the transdermal route is used, the opioid is absorbed through the surface of the skin. Fentanyl is available in a transdermal drug delivery system that provides continuous opioid administration without pumps or needles. Transdermal fentanyl may be given to patients with chronic pain who can benefit from continuous opioid administration. Transdermal fentanyl has a long duration of action and can be used in patients who cannot take medications orally. Transdermal opioids are contraindicated for use in acute post-operative pain or in opioid naive patients, due to the risk of respiratory depression. Transdermal fentanyl has a slow onset of action and the side effects of respiratory depression and sedation may not be quickly reversible. It is difficult to titrate an optimum dose, requiring additional short acting oral opioids to manage breakthrough pain. Adherence of the patch to the skin may be problematic for some patients. Intraspinal (epidural and intrathecal) administration: Intraspinal administration refers to the administration of medications into the spaces or potential spaces surrounding the spinal cord. Intrathecal catheters to manage acute pain are most often used for anesthesia or for giving a single bolus dose of an analgesic. A long term epidural catheter can also be inserted and tunneled subcutaneously for intermittent bolus dosing or for continuous infusion via an external pump. This form of opioid administration is used to control pain following a variety of surgical procedures, for other painful procedures, and for cancer pain. The two opioids most commonly used via this route are morphine and fentanyl. The patient who is having any intraspinal opioid

treatment must be managed by a skilled healthcare team that is familiar with the benefits and risks of this type of therapy. Other administration routes: Opioids may also be given via the intra-arterial route (injected directly into an artery), intraperitoneal route, (injected into the large surface lining of the abdominal cavity), pulmonary (using the large surface area of the pulmonary epithelium and mucous membranes), and cutaneous (applying drugs topically to the mucous membranes of the conjunctiva of the eyes, the nasopharynx, oropharynx, vagina, colon, urethra, and urinary bladder) routes for local effects. Patient controlled analgesia: Patient controlled analgesia (PCA) is a technique in which the patient controls the amount of analgesia he or she receives. PCA provides the important advantage of relieving pain as it begins, and minimizes the delays that can lead to pain exacerbation. When a patient feels pain, he or she pushes a button that releases a pre-set dose of opioid to be delivered into his or her intravenous line. The medication is delivered as long as the lockout interval (a predetermined time between doses) has not been exceeded. PCA is most often used for the intravenous administration of opioid analgesics for severe acute pain, such as following a major surgical procedure. Short and long-term management of cancer pain by PCA has also been shown to be safe and effective.