1. 19
Opioid Analgesics

2. Pain The sensation of pain consists of at least two elements:
The local irritation (stimulation of peripheral nerves)
The recognition of pain (within the CNS)
Learning Outcomes
19 .1 Explain the pathway for pain recognition and how opioids produce analgesia
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
The sensation of pain is comprised of at least two elements: the local irritation (stimulation of peripheral nerves) and the recognition of pain (within the CNS). Free nerve endings called nociceptors are located in the skin, muscle, joints, bones, and viscera. Nociceptors respond to tissue injury and painful stimuli. When there is no injury, there is no pain stimulus, so the nociceptors are quiet.
Usually, prostaglandins, histamine, bradykinins, serotonin, and Substance P are among the peripheral neurotransmitters released that trigger nociceptors. Nociceptors alert the brain to theintensity of the pain by increasing the frequency of signals sent to the spinal cord and then to specialized areas within the CNS.
Pain signals arrive in the spinal cord through A-delta nociceptor and C-nociceptor fibers. If the originating (point-of-injury) signal is transmitted through the A-delta fibers (myelinated), the pain is consciously experienced as sharp. If the signal is passed through C fibers (unmyelinated), dull, aching pain is felt.

3. Learning Outcomes
19 .1 Explain the pathway for pain recognition and how opioids produce analgesia
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
The sensation of pain is comprised of at least two elements: the local irritation (stimulation of peripheral nerves) and the recognition of pain (within the CNS). Free nerve endings called nociceptors are located in the skin, muscle, joints, bones, and viscera. Nociceptors respond to tissue injury and painful stimuli. When there is no injury, there is no pain stimulus, so the nociceptors are quiet.
Usually, prostaglandins, histamine, bradykinins, serotonin, and Substance P are among the peripheral neurotransmitters released that trigger nociceptors. Nociceptors alert the brain to theintensity of the pain by increasing the frequency of signals sent to the spinal cord and then to specialized areas within the CNS.
Pain signals arrive in the spinal cord through A-delta nociceptor and C-nociceptor fibers. If the originating (point-of-injury) signal is transmitted through the A-delta fibers (myelinated), the pain is consciously experienced as sharp. If the signal is passed through C fibers (unmyelinated), dull, aching pain is felt.

4. Pain There are two different types of pain:
Nociceptive
Neuropathic
Pain duration is classified as:
Acute
Chronic
Learning Outcomes
19 .1 Explain the pathway for pain recognition and how opioids produce analgesia
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
Nociceptive pain can only occur when all neural equipment is working properly. When pain results from abnormal signals or nerves damaged by entrapment, infection, amputation, or diabetes, it is called neuropathic pain.
Pain duration is either acute or chronic. Acute pain usually appears in association with an observable injury and disappears when the injury heals. Chronic pain persists for weeks, months, or years even with analgesic therapy. Nociceptive pain can be either acute or chronic. Neuropathic pain is chronic, even though it may be intermittent.
In neuropathic conditions sensitization also can occur within the spinal neurons observed as over responsiveness (hyperalgesia), prolonged pain, or the spread of pain to an uninjured area (referred pain).

6. Pain
No matter what type of pain is present, relief from pain is the therapeutic goal.
Selection of the most appropriate analgesic depends upon the type and duration of pain.
Learning Outcomes
19 .1 Explain the pathway for pain recognition and how opioids produce analgesia
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
No matter what type of pain is present, relief from pain (analgesia) is the therapeutic goal. Pain management and selection of the most appropriate analgesic depend on the type and duration of pain present. Although the terminology used to describe the mechanism of analgesia is relatively new, opioid analgesics, in their natural plant form, have been medicinally used for 5000 years.

7. Opioid Analgesics Opioids are considered first-line therapy for:
Pain associated with procedures
Pain due to trauma or cancer
Visceral pain (appendicitis)
Used to relieve acute or chronic pain
Also used to suppress cough and treat diarrhea
Learning Outcomes
19 .1 Explain the pathway for pain recognition and how opioids produce analgesia
19 .3 Discuss the pharmacological effects of these drugs
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
Opioid analgesics are first-line therapy for pain associated with procedures (bone marrow biopsy), pain due to trauma (burns, vehicular accident), cancer, or visceral pain (pancreatitis, appendicitis). It is held that opioid analgesics can relieve virtually any type of pain.
The majority of the opioid analgesics are used for the relief of acute and chronic pain. A few, such as fentanyl (Sublimaze, Duragesic), alfentanil (Alfenta), and sufentanil (Sufenta), are primarily indicated for preoperative sedation to reduce patient apprehension.
Other opioids, such as codeine, hydrocodone, and dextromethorphan, are widely used to suppress coughing, while difenoxen (Motofen) and loperimide (Immodium) are the active agents in antidiarrheal medications.

8. Opioid Analgesics
Opioid analgesics were previously called narcotic analgesics.
The term opioid is used today for any molecule, natural or synthetic, that acts on the opioid receptors.
The naturally occurring opiates include morphine and codeine.
Learning Outcomes
19 .1 Explain the pathway for pain recognition and how opioids produce analgesia
19 .2 Describe the sources of opioid analgesics
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
Until recently, drugs that were extracted from opium (opiates) or synthetic chemicals that produced the same pharmacological effects as opium were called narcotic analgesics. While this name still applies to the laws that govern the use of this class of drugs, current medical and research terminology refer to these drugs as opioid analgesics.
The naturally occurring opiates (derivatives of opium) include morphine and codeine. Morphine is the largest component of the chemicals (alkaloids) extracted from the poppy plant. The term opioids is used today for any molecule, whether natural or synthetic, that acts on opioid receptors.
Three opioid receptors are the most clinically important— mu, kappa, and delta. There are two types of mu receptors. Mu 1, located outside the spinal cord (CNS), “interprets pain.” Mu 2, found throughout the CNS, is responsible for respiratory depression, analgesia, euphoria, and physical dependence.

9. Opioid Analgesics Tolerance and dependency influence opioid use.
Opioids are called central analgesics because they work in the CNS.
Morphine is the standard for showing the potency of all other opioid analgesics.
Learning Outcomes
19 .1 Explain the pathway for pain recognition and how opioids produce analgesia
19 .3 Discuss the pharmacological effects of these drugs
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
Tolerance and physical dependence are factors that influence opioid use. Tolerance (decreasing effects) develops to all opioids. Physical dependence develops with long-term daily use of all strong opioids. Because of the potential for abuse, opioid analgesics are federally restricted (controlled) substances.
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 patients respond as though they can tolerate the pain.
Morphine is the standard by which the potency of all the other opioid analgesics is measured. The opioids vary in their potency, onset of action, and incidence of opioid side effects.

10. Learning Outcomes
19 .1 Explain the pathway for pain recognition and how opioids produce analgesia
19 .3 Discuss the pharmacological effects of these drugs
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
Tolerance and physical dependence are factors that influence opioid use. Tolerance (decreasing effects) develops to all opioids. Physical dependence develops with long-term daily use of all strong opioids. Because of the potential for abuse, opioid analgesics are federally restricted (controlled) substances.
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 patients respond as though they can tolerate the pain.
Morphine is the standard by which the potency of all the other opioid analgesics is measured. The opioids vary in their potency, onset of action, and incidence of opioid side effects.

11. Opioid Analgesics
Opioid analgesics act by binding to opioid receptors and mimicking the effects of the analgesic peptides.
Opioids influence CNS activity:
Decrease mental alertness
Euphoria
Dysphoria
Respiratory depression
Learning Outcomes
19 .1 Explain the pathway for pain recognition and how opioids produce analgesia
19 .3 Discuss the pharmacological effects of these drugs
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
Reduction in the awareness and reaction to pain is controlled through a combination of mu, kappa, and delta receptors within the brain. Morphine and the other opioid analgesics act by binding to opioid receptors and mimicking (agonist) the effects of the analgesic peptides. Opioids interact with their receptors at different CNS levels.
Opioid analgesics may influence CNS function by increasing or decreasing certain CNS activity. In particular, opioid analgesics produce changes in mood and decrease mental alertness. Some individuals experience a feeling of well-being—a warm glow—known as euphoria. Other individuals may experience dysphoria, an unpleasant reaction, which enhances anxiety and fear. In low doses, most opioid analgesics produce nausea and vomiting. Emesis (vomiting) is a direct result of activation of delta or kappa receptors. One of the most important CNS effects produced by these analgesics is respiratory depression.

12. Opioid Analgesics
Opioids have direct action on smooth muscle in the GI tract, which can lead to constipation.
They can also cause:
Bronchoconstriction
Decreased urination
Learning Outcomes
19 .1 Explain the pathway for pain recognition and how opioids produce analgesia
19 .3 Discuss the pharmacological effects of these drugs
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
Opioids have spasmogenic activity through a direct action on smooth muscle and mu 2 receptors in the GI tract. Opioid analgesics increase smooth muscle tone, causing intermittant muscle contractions or spasms. When spasms occur within the intestinal smooth muscle, peristalsis is inhibited which can lead to constipation.
Many opioid analgesics, especially morphine, produce spasm of the common bile duct, which causes pressure to increase in the gallbladder. Opioid analgesics affect bronchial smooth muscle by two actions. In addition to their spasmogenic action, these analgesics cause the release of histamine, which directly constricts the bronchioles. Urine formation and urination are both decreased by opioid analgesics, since these drugs stimulate the secretion of antidiuretic hormone (ADH), which allows the kidneys to reabsorb water.

13. Opioid Analgesics Opioids do not depress cardiac function.
Most opioids cause miosis.
Meperidine causes mydriasis.
Learning Outcomes
19 .1 Explain the pathway for pain recognition and how opioids produce analgesia
19 .3 Discuss the pharmacological effects of these drugs
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
Opioid analgesics do not depress cardiac function in therapeutic doses. This lack of effect is important because it allows these drugs to relieve the pain accompanying myocardial infarction without worsening the condition.
Most opioid analgesics produce miosis. This effect is caused by stimulation of the mu receptors in the brain. Most opioid analgesics produce pinpoint pupils in toxic doses. However, meperidine produces mydriasis (dilation). Therefore, the pupil size cannot be used to determine what drug was used by unconscious (overdose) patients.

14. Drug Administration
Opioids are available in oral and parenteral dosage forms.
Opioids are given on a repeated schedule to avoid intense pain.
Specialists are now using aggressive treatment schedules in which dosing is often under patient control.
Learning Outcomes
19 .4 Discuss administration, absorption, and metabolism of these drugs
Opioid analgesics are frequently administered on a repeated schedule (every 4 to 8 hours) to relieve moderate to severe pain. To be effective, these analgesics must be given before intense pain is present.
The opioids are available for oral and parenteral administration. Parenteral formulations are used more in surgery and postsurgical recovery. Oral preparations are used to treat acute and chronic pain. All of the oral formulations should be swallowed, never chewed.
Recently there has been a significant change in the attitude and methods regarding the treatment of chronic severe pain. Specialists in pain and symptom management use aggressive drug treatment schedules where dosing is often under the control of the patient.

15. Drug Administration
Because opioid analgesics are CNS depressants at any dose, patients should be closely monitored for overdose.
Opioid analgesics are metabolized by the liver and then excreted by the kidneys.
Anything that causes alkaline urine increases the concentration of opioids in the blood.
Learning Outcomes
19 .4 Discuss administration, absorption, and metabolism of these drugs
Opioid analgesics are CNS depressants at any dose. It is therefore important to monitor vital signs when patients, especially the elderly, are receiving these drugs. Indications of decreased blood pressure or respiration may be a clue that patients have been overmedicated and are experiencing cardiovascular or respiratory depression.
Since these 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.
Eventually, the kidneys excrete the metabolic products. Anything that causes the urine to become alkaline, such as alkalosis and diuretics increases tubular reabsorption of the opioids. This action elevates the concentration of drug in the blood and increases the risk of developing drug toxicity.

16. You can alkalinize your urine by decreasing the amount of acid you take in. You can lower the amount of acid you eat (and therefore the amount of acid your kidneys have to get rid of) by eating less animal protein. Protein is what muscle is made of, and includes fish, beef, chicken and pork. These products also contain some cystine, so limiting your intake of these has 2 benefits.
You can also take in more base to alkalinize your urine. If you eat more fruits and vegetables when you reduce your protein intake, you will take in more base. Base comes in the form of molecules called “organic anions”, such as citrate and malate. They are converted to bicarbonate by the liver. Bicarbonate is the blood’s form of base. One citrate is converted to 3 bicarbonates. So taking citrate and bicarbonate are equivalent.

17. Adverse Effects Adverse effects of opioid analgesics: Mental confusion
Nausea
Vomiting
Dry mouth
Constipation
Urinary retention
Respiratory depression
Learning Outcomes
19 .5 List the adverse effects of these drugs
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
The most common effects produced by these analgesics include mental confusion, nausea, vomiting, dry mouth, constipation, and urinary retention.
Several, but not all, opioids have black box warnings in their instructions for use. Fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and propoxyphene have special cautionary warnings that emphasize the level of abuse liability is highest among these opioids. Deaths from respiratory depression have occurred.

18. Adverse Effects
Opioid analgesics are contraindicated in patients with:
Bronchial asthma or heavy pulmonary secretion
Convulsive disorders
Biliary obstruction
Head injuries
Pregnancy—risk to benefit must be assessed
Opioids should not be given if a nonopioid analgesic will work.
Learning Outcomes
19 .5 List the adverse effects of these drugs
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
Opioid analgesics should not be used in patients with bronchial asthma, heavy pulmonary secretions, convulsive disorders, biliary obstruction, or head injuries. In these cases, opioids may worsen the existing condition. Since opioid analgesics will cross the placental barrier and affect fetuses, use of these drugs during pregnancy should be minimized. Short-term exposure of the fetus at term presents relatively little potential danger to the newborn.
Opioid analgesics should never be used when a nonopioid analgesic is indicated to relieve the pain.

19. Tolerance and Physical Dependence
Tolerance may develop due to changes in the opioid receptors.
Physical dependence can develop with chronic use of opioids.
Addiction is a complex interaction of several factors that lead to a lack of control over drug use.
Learning Outcomes
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
The effects associated with the chronic use of opioid analgesics are the development of tolerance and physical dependence. Tolerance may result from several changes in the opioid receptors. Although the opioid is present in increasingly larger amounts, it has fewer competent receptors to produce the responses. Tolerance develops to the euphoria, analgesia, sedation, and respiratory depression produced by the opioid analgesics. Tolerance does not develop equally to all opioid effects.
Physical dependence upon any opioid can develop with chronic use of the analgesic. This means that with sustained use the body reacts (withdrawal syndrome) to sudden removal or rapid dose reduction of the drug. Many people, including medical professionals and patients who have access to opioid drugs especially meperidine, develop physical dependence.
Physical dependence is not the same as addiction. Addiction is a complex interaction of genetic, psychological, and socioenvironmental factors that describe behaviors in the individual and lack of control over drug use. The mechanism by which addiction occurs is not fully understood; however, it is now considered a primary disease rather than a side effect of drug usage.

20. Tolerance and Physical Dependence
Methadone is used in the treatment of opioid addiction:
Satisfies opioid hunger
Does not produce severe withdrawal symptoms
Buprenorphine:
Pushes opioids out of receptors
Blocks attachment of opioids to receptors
Learning Outcomes
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
Methadone is particularly useful in the treatment of addiction because it satisfies the opioid hunger so that the individual actually becomes acclimated to methadone. Methadone does not produce severe withdrawal symptoms. The newest drug to treat addiction is buprenorphine. Buprenorphine is a partial agonist/antagonist that is used for the management and treatment of addiction. It has a high affinity (binding) for mu receptors so it pushes other opioids out of the way, blocking their attachment to receptors.

21. Opioid Antagonists
Opioid poisoning presents with coma, depressed respiration, cyanosis, and hypotension.
Antagonists are drugs that attach to opioid receptors and displace the analgesic, rapidly reversing poisoning.
Pure
Partial
Learning Outcomes
19 .6 Explain acute opioid poisoning
19 .7 Discuss the actions of opioid antagonists
Opioid antagonists are drugs that attach to the opioid receptors and displace the analgesic. Displacement rapidly reverses life-threatening respiratory depression. There are two types of antagonists—pure antagonists and partial antagonists
Pure antagonists, such as naloxone and nalmefene, are competitive blocking drugs. Naloxone inhibits the analgesic from attaching to the receptors but does not produce any pharmacological action of its own.
Partial antagonists such as butorphanol, nalbuphine, and pentazocine have two actions on the respiratory system. These drugs produce weak morphine-like effects in normal individuals, resulting in respiratory depression. In cases of acute opioid poisoning, however, partial antagonists reverse the respiratory depression.
The symptoms of poisoning include coma, decreased respiration, cyanosis, hypotension, and a fall in body temperature. Once patients are adequately ventilated with a respirator, the poisoning can be treated with specific opioid antagonists such as naloxone.

22. Opioid Antagonists Learning Outcomes
19 .6 Explain acute opioid poisoning
19 .7 Discuss the actions of opioid antagonists
Opioid antagonists are drugs that attach to the opioid receptors and displace the analgesic. Displacement rapidly reverses life-threatening respiratory depression. There are two types of antagonists—pure antagonists and partial antagonists
Pure antagonists, such as naloxone and nalmefene, are competitive blocking drugs. Naloxone inhibits the analgesic from attaching to the receptors but does not produce any pharmacological action of its own.
Partial antagonists such as butorphanol, nalbuphine, and pentazocine have two actions on the respiratory system. These drugs produce weak morphine-like effects in normal individuals, resulting in respiratory depression. In cases of acute opioid poisoning, however, partial antagonists reverse the respiratory depression.
The symptoms of poisoning include coma, decreased respiration, cyanosis, hypotension, and a fall in body temperature. Once patients are adequately ventilated with a respirator, the poisoning can be treated with specific opioid antagonists such as naloxone.

23. Opioid Antitussives
Antitussives are drugs that suppress the cough reflex:
Codeine
Hydrocodone
Dextromethorphan
Expectorants are commonly combined with antitussives to aid in the removal of mucus.
Learning Outcomes
19 .3 Discuss the pharmacological effects of these drugs
19 .4 Discuss administration, absorption, and metabolism of these drugs
19 .9 Discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors
Codeine, hydrocodone, and dextromethorphan are antitussive, which means they effectively suppress the cough reflex at therapeutic doses. Dextromethorphan and codeine are the most commonly used antitussives.
These drugs do not cure the underlying cause of the irritation; they merely decrease the intensity and frequency of the cough.
Dextromethorphan is an active ingredient in more than 100 OTC products. Nonprescription products containing these drugs have been used to achieve a “cheap high” among some people under 18. Concern has prompted attempts to change current regulations in order to restrict the sale of such products to minors.
Expectorants (ammonium chloride, guaifenesin, and terpin hydrate) are often combined with antitussive drugs to alter the volume and viscosity of mucus retained in the respiratory tract. Expectorants promote the discharge of mucus from the respiratory tract, thus reducing chest irritation and congestion.

24. Drug Interactions
Opioid analgesics potentiate the effects of CNS depressants.
Meperidine and dextromethorphan should not be given with MAO inhibitors.
Rifampin and phenytoin have caused withdrawal symptoms when administered with methadone.
Learning Outcomes
19 .8 List drug interactions
A few specific drug interactions occur with these analgesics. Opioid analgesics potentiate the depression of any CNS depressant drug (sedative-hypnotics, alcohol, and general anesthetics).
Meperidine undergoes an unusual, potentially fatal, reaction when used in the presence of monoamine oxidase (MAO) inhibitors. Sweating, hypotension, or hypertension may occur in patients taking meperidine with pargyline, phenelzine, or tranylcypromine concomitantly.
Dextromethorphan should not be given to patients who are receiving MAO inhibitors. Rifampin and phenytoin have been associated with reduction in the plasma concentrations of methadone sufficient to induce withdrawal symptoms.
Certain opioid analgesics may be administered as parenteral solutions; therefore, it is important to be aware of incompatibilities that may result in drug inactivation.