Narcotic Agonists and Antagonists

Chapter 184 Narcotic Agonists and Antagonists



Ralph C. Harvey, DVM, MS, DACVA



KEY POINTS



• Opioids are an important class of drugs for critically ill veterinary patients because of their efficacy and relative cardiovascular safety.

• Opioids are most commonly used for analgesia, but may also be prescribed for antitussive or sedative therapy.

• The most commonly used analgesics include morphine, fentanyl, hydromorphone or oxymorphone, buprenorphine, and butorphanol.

• It is important that the veterinarian understand the various opioids’ clinical efficacies, potencies, and potential side effects before using them.

• Opioid antagonists include naloxone, nalmefene, and naltrexone. Butorphanol and nalbuphine commonly are used for partial reversal of pure μ-agonist drugs.


INTRODUCTION


Opioids serve a variety of roles in veterinary critical care. The foremost of these is as the foundation of analgesic therapy, but they are also used for their sedative and antitussive effects. Less frequent applications may include supporting right heart function and control of compulsive behaviors. In the past, opioids were also used to decrease gastrointestinal (GI) motility.


As analgesics, the opioids are the first line of defense in managing pain due to injury and disease. The remarkable cardiovascular sparing effects and inherent safety of opioid therapy in critically ill patients are prominent advantages of this class of drugs. Opioids anchor contemporary balanced or multimodal strategies for pain management. Although this chapter deals specifically with the opioids, other publications extend the topic of analgesia in critical care to encompass complementary classes of analgesic drugs and other approaches to pain management.1,2



TERMINOLOGY AND HISTORY



Opium


At least 20 distinct alkaloids are derived from juice of the poppy. Among these, the phenanthrenes are represented by morphine and the benzylisoquinoline derivatives by papaverine.



Opiate


The term opiate specifically refers to drugs derived from opium. The first of these was morphine, isolated and recognized in 1803 as the active ingredient in laudanum by Friedrich Wilhelm Adam Ferdinand Serturner, an assistant apothecary. This contribution has been recognized as the beginning of the modern era of pharmacology.



Opioid


The term opioid is a more precise, yet broadly inclusive, term for synthetic as well as opium-derived compounds that bind specifically to several opioid receptors and thereby have some morphine-like effects.



Narcotic


The word narcotic was derived from a Greek term for sleep or stupor. Because this group of compounds does not readily and reliably produce sleep in all veterinary patients, it is a less than appropriate descriptor in veterinary medicine. Law enforcement organizations may refer to many substances with a potential for diversion and abuse as narcotics. This inclusion of opioid and nonopioid controlled substances can lead to confusion. Controlled substances, including the opioids, must be kept secure under lock and key. Accurate and appropriate inventory is required, with the level of control for each drug related generally to the relative potential for abuse.



STRUCTURE ACTIVITY RELATIONSHIP


The phenanthrene opioid compounds have a three-ring nucleus and a piperidine ring structure with a tertiary amine nitrogen. The levorotatory forms are much more active agonists than the dextrorotary forms.



MECHANISM OF ACTION


Opioids bind to stereospecific Opioid Receptors located most notably in the central nervous system (CNS), but also in many other sites throughout the body. The receptor affinity correlates well with analgesic potency for the opioids classified as pure agonists only. Receptor binding of endogenous or exogenous legends activates G proteins as second messengers, modulates adenylate cyclase activity, and thereby alters transmembrane transport of effectors. Opioids also interfere presynaptically with the release of neurotransmitters. These changes result in interruption of the pain message to the brain and a decreased sensation of pain within the brain. Opioids do not alter the responsiveness of afferent nerve endings to noxious stimuli, nor do they impair conduction of nerve impulses along peripheral nerves.



OPIOID RECEPTORS


There are a variety of opioid receptors and subtypes of receptors within many locations in various tissues. Differential binding and activation at specific receptors (μ-receptors, κ-receptors, and δ-receptors) and locations serve to mediate the spectrum of opioid effects.



PHYSIOLOGIC EFFECTS OF OPIOIDS


Occupation of CNS receptor sites by opioids produces analgesia, sedation, muscle relaxation, and behavior modification. The CNS depressant action of the opioids results from their effects on the cerebral cortex. In contrast to the more typical sedation and narcosis produced in human patients, disorientation and excitement may also occur in veterinary patients receiving opioid therapy. The excitatory behavioral activity results from effects of the drug on the hypothalamus. The ability of the opioids to cause depression or excitement is highly drug and species dependent. Excitatory responses may be linked to an indirect activation of dopaminergic receptors. The major tranquilizers, the benzodiazepines and phenothiazines, can block this activation.


Combinations of some opioids and tricyclic antidepressants can produce hypotension. Meperidine, and occasionally other opioids, when administered to patients receiving monoamine oxidase inhibitors (e.g., selegiline, L-deprenyl [Anipryl]) can result in rare but severe and immediate reactions that include excitation, rigidity, hypertension, and severe respiratory depression.


Opioids can be potent respiratory depressants, depressing both respiratory rate and tidal volume. Although this is rarely a clinically significant problem in healthy patients, special attention is warranted in critically ill patients. Animals with increased susceptibility to respiratory effects include those with underlying airway obstruction (e.g., brachycephalic animals) and those with pulmonary disease. The opioids directly depress the pontine and medullary respiratory centers. They also produce a delayed response (altered threshold) and decreased response (altered sensitivity) to arterial carbon dioxide, leading to retention of carbon dioxide. Tachypnea is sometimes observed after narcotic administration and may be due to excitation and/or alteration of the thermoregulation center. Panting in dogs is most notable with oxymorphone and hydromorphone administration.


Bronchoconstriction may also occur. A rare and incompletely understood complication of opioid therapy is a phenomenon known as “wooden chest.” With this syndrome, the patient’s chest wall muscles become spastic, making ventilation difficult. Treatment involves reversal of the opioid drug and, if necessary, muscle relaxant therapy.


At therapeutic dosages, the opioids have minimal effects on the cardiovascular system. There is little or no change in blood pressure and myocardial contractility. The opioids can produce a bradycardia that is responsive to atropine or other anticholinergic agents. Decreased heart rate is vagally mediated and a manifestation of relieved pain. The opioids affect the ability of the vascular system to compensate for positional and blood volume changes, although orthostatic hypotension is presumably more problematic in bipedal than quadrupedal patients. Among the opioids, both morphine and meperidine can cause histamine release, leading to marked hypotension. To minimize histamine-related complications following intravenous administration of morphine, the drug should be diluted with saline and the injection given slowly over 10 to 20 minutes.1,3 Morphine and meperidine are contraindicated in patients with mast cell tumors or other histamine-based diseases. Other opioids are much less likely to cause significant histamine release.


A variety of other physiologic effects may be of interest in the critical care setting. The opioids produce an initial stimulation of the GI tract (vomiting, defecation, or both) followed by a decrease in motility. Most opioids cause release of antidiuretic hormone. Urine retention due to bladder atony is an infrequent, but clinically significant, problem in some animals receiving opioid therapy. Bladder emptying should be verified in all patients.


Some animals receiving opioids may unexpectedly over-respond to noises or sensory stimuli. When this occurs, it can contribute to dysphoria and increase stress in the critically ill patient. The importance of a quiet and calming environment is recognized, but this is challenging to achieve in many critical care settings. Placing cotton balls in the ears may help to alleviate the noise sensitivity.


Decreased body temperature may be observed with opioids because the thermoregulatory center in the hypothalamus is reset to a lower setting. Panting in dogs is one manifestation of altered body temperature regulation. Alternatively, significant increases in body temperature occasionally occur after opioid administration. This appears to be most common in cats and somewhat drug and dosage dependent. Cats receiving higher-than-usual clinical dosages of morphine, meperidine, and hydromorphone frequently developed increased body temperature (40° to 41.7° C or 104° to 107° F) in one study. Buprenorphine did not result in hyperthermia in feline clinical or research models.4



METABOLISM AND EXCRETION


Metabolic elimination of opioids is accomplished by hepatic conjugation and metabolite excretion in the urine. The principal metabolites can be highly active, as in the case of morphine in humans. In the case of meperidine, the metabolite normeperidine is a convulsant. Extended therapy with meperidine can lead to neurotoxicity and seizures. Opioid overdoses can effectively change the kinetics of elimination from “first order” to “zero order” by saturating the processes responsible for elimination, thereby greatly prolonging the duration of action. This is perhaps most notable with large overdoses of butorphanol, which lead to prolonged sedation but cause little increase in the magnitude of sedation or analgesia as a result of the “ceiling effect” seen with this agonist-antagonist opioid. Independent of any conditions altering elimination, the duration of action of the clinically useful opioids ranges widely, from 0.5 to 8 hours.

Related posts:

  1. Deteriorating Mental Status
  2. Hyperthermia and Fever
  3. Ventilator-Associated Lung Injury
  4. Allergic Airway Disease in Dogs and Cats and Feline Bronchopulmonary Disease

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Narcotic Agonists and Antagonists

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