Tripoli University Faculty of Pharmacy Drug Treatment of Pain 2011-2012 BYPROF. ABDALLA SALEM ELHWUEGI (Ph.D.)
Receptor Effector MechanismsReceptors coupled to GTP-binding proteins1. Postsynaptic agonist effects produce increased K+ efflux leading to hyperpolarization and reduction in the firing rate blocking pain transmission2. Presynaptic agonist actions decrease voltage-gated Ca++ influx and reducing excitatory neurotransmitter release.3. Inhibition of adenylyl cyclase activity decreases intracellular calcium thus reducing neurotransmitters release.
Properties of Opioid Agonists1. Bind with high affinity to opioid receptors.2. Binding reversed by narcotic antagonists.3. Cross-tolerance exhibited to narcotic agonist administration.4. Dependence is produced with chronic administration.5. Withdrawal reaction induced by the administration of narcotic antagonist in dependent animals.
Pharmacokinetics A) absorption1. Depending on the agent, oral absorption is usually poor and variable due to first pass metabolism and glucuronidation (the bioavailability of morphine is only 25%)2. Absorption following IM administration is usually complete with maximum blood levels is 15-30 min
Pharmacokinetics B) Distribution1. Distribution to tissues is based largely on blood flow.2. CNS levels based on:• Blood-brain barrier.• Lipid solubility.• Protein binding.• Rapid conjugation with glucuronic acid.
Pharmacokinetics C) Metabolism1. Rapid conjugation with glucuronic acid2. Esters such as meperidine are hydrolyzed by esterases3. Morphine-6-glucuronide is an active metabolite4. Accumulation of the n-demethylation product of meperidine (normeperidine) can produce seizures D) Elimination1. Water soluble metabolites eliminated by renal mechanisms2. Glucuronide conjugates are eliminated in bile.
Pharmacological ActionsI) Central nervous system effects1. AnalgesiaA. Inhibit nociception primarily by interacting with mu1 receptors•Raise the threshold for pain perception.•Diminish the reaction to the pain (even though pain is perceived)B. Continuous dull pain is relieved more effectively than sharp,intermittent pain.C. Pain relieving is usually accompanied by euphoria.
Pharmacological Actions2. Respiratory depressionAll narcotic analgesics produce dose-dependent respiratory depression• Decreased sensitivity of the respiratory center chemoreceptors to CO2• Direct effects to decrease respiratory rhythmicity,• Decrease in rate, minute volume and tidal exchange.
Pharmacological Actions3. SedationA. Drowsiness and sedation produced by the narcotic analgesics is quite variable based on age, debilitation, other drugs.B. Decreased anxiety may also be a component.4. Mood changesA. Patient response varies, first dose may produce unpleasant experience (dysphoria) if the agent is given in the absence of pain.B. Euphoria or a feeling of being “detached” (pleasant floating sensation with a relaxed, dreamy state) after repeated administration (reason for abuse).
Pharmacological Actions5. Separate central effectsA. Miosis occurs as a result of increased activity in the parasympathetic nerve innervating the pupilB. Nausea/vomiting occurs as a result of direct stimulation of the chemoreceptor trigger zone for emesis, in the area postrema of the medulla. All clinically useful mu agonists produce some degree of nausea and vomiting.C. Cough suppression is a useful effect (antitussive) and results from direct depression of the cough center in the medulla.D. Truncal rigidity occurs as a result of increased tone in large trunk muscles probably due to increased impulse activity from supraspinal sites.
Pharmacological ActionsII) Peripheral effects1. Minimal effects on the cardiovascular system (blood pressure, cardiac rate and rhythm) in the supine patient. Morphine does produce arteriolar and venous dilation and may produce orthostatic hypotension (see histamine release effects).2. Histamine release (especially with morphine) can produce cutaneous flushing and loss of body heat (hypothermia). Although the effects vary according to different opiates, bronchoconstriction and hypotension may occur.
Pharmacological Actions3. Constipation due to decreased propulsive contractility (peristalsis) in the small and large intestine.4. Biliary colic due to constriction of biliary smooth muscle and the sphincter of Oddi in the biliary tract.5. Urinary retention due to increase tone in the ureter, detrusor muscle of the urinary bladder and vesicle sphincter.
Tolerance and Physical Dependence Tolerance1) toleranceA. With repeated administration, fast & strong tolerance to the effects of morphine and other opiates can develop over a period of 1-3 weeks. Tolerance can be as great as 35 fold the initial dose.B. Tolerance is gained to all agonist effects except miotic and constipating effects.C. Cross tolerance to all agonists occurs and includes tolerance to analgesic, euphoric, sedative and respiratory depressant effects.D. Less tolerance is gained to the agonist/antagonist drugs and also tolerance to methadone develops more slowly and to a lesser degree. Tolerance is gained.
Tolerance and Physical Dependence Tolerance2) DependenceA. Physical dependence parallels the development of tolerance.B. Without the continued presence of agonist at the receptor site, the cellular processes linked to the receptor become hyperexcitable, leading to characteristic withdrawal or abstinence syndromeC. Withdrawal can be precipitated in a dependent individual by administering a narcotic antagonist.
3) Withdrawal Syndroms A. Are not fetal but are not pleasant. B. The followings are the signs & symptoms.SYMPTOMS SIGNSRegular WithdrawalCraving for opioids Pupillary dilationRestlessness, irritability SweatingIncreased sensitivity to pain Piloerection ("gooseflesh")Nausea, cramps TachycardiaMuscle aches Vomiting, diarrheaDysphoric mood Increased blood pressureInsomnia, anxiety Yawning and FeverProtracted WithdrawalAnxiety Cyclic changes in weight, pupil size, respiratoryInsomnia center sensitivityDrug craving
Treatment of opioid withdrawal & physical dependenceOpioid withdrawal & physical dependence signs and symptoms can be treated by three different approaches:1. Change the patient from a short-acting opioid such as heroin to a long-acting one such as methadone. A 20% per day dose reductions during the course of detoxification is applied.2. A second approach to detoxification involves the use of clonidine or lofexidine which blocks autonomic hyperactivity. Clonidine, acting via distinct receptors but by cellular mechanisms that mimic opioid effects, can alleviate many of the symptoms of opioid withdrawal. However, clonidine does not alleviate generalized aches and opioid craving characteristic of opioid withdrawal.
Treatment of opioid withdrawal & physical dependence 3. Naltrexone (opioid antagonist) treatment can be utilized after detoxification for patients with high motivation to remain opioid free. It will also acts to restore normal opioid receptors sensitivity. 4. New treatment options. Buprenorphine is a mu opioid partial agonist, it has minimal withdrawal symptoms, low potential for overdose, long duration of action, and ability to block heroin effects comparable to that of naltrexone.
Interactions with OpioidsI) Disease states/injuryA. Presence of pulmonary disease or hepatic dysfunction are major considerations.B. Contraindication for narcotic analgesics in head injury without assisted ventilation.C. Patients with pancreatitis may experience a further increase in biliary tract pressure with narcotic analgesics
Interactions with OpioidsII) Drugs1. Combined administration of narcotic analgesics and CNS depressants (barbiturates, antianxiety agents, antipsychotics) result in potentiation of the sedative effects.2. Meperidine (and possibly other narcotic analgesics) administered to patients taking MAO inhibitors can produce excitation, convulsions, hyperpyrexia, respiratory depression and hypotension.
Opioids overdose toxicityA. “Triad”1. Depressed respiration2. Pinpoint pupils (except with meperidine)3. Coma.B. Treatment1. First step in treatment is to establish an airway for ventilatory support2. Judicious administration of a narcotic antagonist.
Narcotic Antagonists1) Full antagonistbinds to the mu, kappa and delta opiate receptors (affinity), but has no action or effect on the receptor (efficacy=zero).A. Naloxone antagonizes the actions of narcotic analgesic agonists. Half-life of 1-2 hrs following IV administration.B. Nalmefene has a longer half-life (8 hrs) and thus provides better matching of kinetics of longer half-life agonists.C. Naltrexone is also a pure antagonist which is much longer acting than naloxone and can be given orally.
Narcotic Antagonists2) Agonist - antagonistbinds to mu, kappa or delta receptors, but also has partial agonist effects at kappa or delta receptorsA. Nalorphine has antagonist actions at mu receptorsB. Pentazocine has weak antagonist actions at mu receptors and moderate agonist actions at kappa receptorsC. Butorphanol is similar to pentazocine but more potent as an agonist at kappa receptorsD. Buprenorphine functions as an agonist-antagonist in the presence of morphine (greater affinity for mu receptor), but as a selective “partial” agonist since does not interact with kappa and delta receptors.
Narcotic AntagonistsUses of full antagonists1. Intravenously to reverse excessive respiratory and CNS depression due to narcotic analgesic administration (naloxone, nalmefene)2. Orally to decrease craving and maintain opiate-free state in opiate-abusing patients (naltrexone)Precautions1. Reversal of the beneficial effects of the agonist when attempting to reverse the deleterious effects (respiratory depression).2. Antagonist may have a shorter half-life compared to morphine and respiratory depression will reoccur.3. Precipitation of withdrawal in physically dependent individuals
Clinical Uses of OpioidsOpioid analgesics provide symptomatic relief of pain, cough, or diarrhea, but generally the underlying disease remains.I) Pain.For many types of pain, aspirin should be tried first. If relief of pain is insufficient, these drugs then can be combined with orally effective morphine-like agents, such as codeine, or with agonist/antagonist opioids. Combinations of these two classes of drugs usually can achieve an analgesic effect with fewer side effects.
Clinical Uses of OpioidsMorphine (10 mg/70 kg) given either subcutaneously or intramuscularly is sufficient to relieve moderate-to-severe pain in 70% of patients. Intravenous administration may be indicated for severe pain, using either continuous infusion or intermittent dosing. Morphine is available orally in standard tablets and controlled-release preparations. Codeine is widely used orally due to its high oral/parenteral potency ratio. Orally, codeine at 30 mg is approximately equianalgesic to 325 to 600 mg of aspirin. Combinations of codeine with aspirin or paracetamol usually provide additive actions, and at these doses analgesic efficacy can exceed that of 60 mg of codeine.
Clinical Uses of OpioidsPain of terminal illness and cancer pain.The management of chronic pain associated with malignant disease or terminal illness recommend that opioids be administered at sufficiently short, fixed intervals so that pain is continually under control.Postoperative pain.Oral codeine or oxycodone combined with nonsteroidal antiinflammatory agents often provides adequate analgesia for mild pain. When pain is more severe, opioid analgesics are used in the immediate postoperative period.
Clinical Uses of OpioidsObstetrical analgesiaThe use of morphine-like drugs in obstetrical analgesia is a highly specialized field requiring experience and sound judgment to ensure effective analgesia, safety for the fetus, and minimal interference with the progress of labor.
Clinical Uses of Opioids2) Cough.Cough suppression (antitussive) often occurs with lower doses than those needed for analgesia.A 10- or 20-mg oral dose of codeine, although ineffective for analgesia, produces a demonstrable antitussive effect, and higher doses of codeine produce even more suppression of chronic cough.Noscapine is a naturally occurring opium alkaloid of the benzylisoquinoline group; except for its antitussive effect, it has no significant actions on the CNS in doses within the therapeutic range. The drug is a potent releaser of histamine, and large doses cause bronchoconstriction and transient hypotension.
Clinical Uses of OpioidsDextromethorphan is the d isomer of the codeine analog levorphanol; however, unlike the l isomer, it has no analgesic or addictive properties and does not act through opioid receptors. In therapeutic dosages, the drug does not inhibit ciliary activity, and its antitussive effects persist for 5 to 6 hours. Its toxicity is low, but extremely high doses may produce CNS depression. Levopropoxyphene napsylate, the l-isomer of dextropropoxyphene, in doses of 50 to 100 mg orally, appears to suppress cough to about the same degree as does 30 mg of dextromethorphan. Unlike dextropropoxyphene, levopropoxyphene has little or no analgesic activity.
Clinical Uses of Opioids3) Dyspnea.Intravenous morphine is used to alleviate the dyspnea of acute left ventricular failure and pulmonary edema. The mechanism underlying this relief may involve an alteration of the patients reaction to impaired respiratory function and improvement of cardiac output through a decreased of peripheral resistance and an increased capacity of the peripheral and splanchnic vascular compartments .
Clinical Uses of Opioids4) Antidiarrheal effectThe morphine-like opioids are effective in treating diarrhea after ileostomy or colostomy, and in treating exhausting diarrhea and dysenteries due to a number of causes. Synthetic opioids such as diphenoxylate, loperamide, and difenoxin, are used exclusively for this purpose as they have no CNS effects.
Clinical Uses of Opioids5) Special AnesthesiaHigh doses of morphine or other opioids have been used as the primary anesthetic agents in certain surgical procedures. Although respiration is so depressed that physical assistance is required, patients can retain consciousness.