Medical Pharmacology Chapter 13 Opioids: Advanced Topics

 

 

¹Intravenous Opioid Anesthetics:  Cerebral Blood Flow

• ¹Administration of other drugs/anesthetics influence the effect of opioids on cerebral blood flow. 

  • However, opioids themselves slightly decrease cerebral metabolic rate by about 17% and decrease intracranial pressure (ICP). 

    • In the context of vasodilation produced by inhalational agents, opioids they will produce cerebral vasoconstriction. 

    • In the presence of nitrous oxide, opioids will diminish cerebral blood flow (CBF). 

    • Cerebral blood flow is not affected substantially by opioids alone.

• ^1,1tPositron emission tomography analysis following fentanyl administration (1.5g/kg, IV) to human volunteers indicated that fentanyl effects on blood flow were heterogeneous. 

  • For example, pain increased regional cerebral blood flow in the anterior cingulate, ipsilateral thalamus, prefrontal cortex, in contralateral supplementary motor area. 

    • Fentanyl increased regional blood flow in the anterior cingulate in contralateral motor cortices but decreased the regional blood flow in the thalamus (bilateral effect) and posterior cingulate during both stimuli. 

    • With pain stimulation as well as fentanyl administration, fentanyl appeared to augment pain-related regional blood flow increases in the supplementary motor area and prefrontal cortex.

    • This PET-based  activation pattern accompanied decreased pain perception using the visual analogue scale. 

      • This analysis indicated that fentanyl analgesia appeared to augment pain-evoked cerebral responses in some areas but activated and inhibited other brain regions that were not responding to pain stimulation by itself.  

• ¹For patients undergoing carotid artery surgery, CBF during fentanyl-nitrous oxide or isoflurane (0.75%)-nitrous oxide anesthesia was reduced relative to halothane (0.5%)-nitrous  oxide anesthesia.

  • Furthermore, balanced anesthesia with fentanyl-nitrous oxide appeared to better maintain the cerebrovascular response to CO₂ in those patients with an edematous brain relative to isoflurane-nitrous oxide anesthesia protocols.

• ¹Sufentanil and fentanyl have been noted to increase middle cerebral artery blood flow velocity by about 25%; other clinical research indicated that in healthy human volunteers, sufentanil (0.5 g/kg IV) did not result in effect on CBF. 

  • In a patient group consisting of those undergoing carotid endarterectomy, sufentanil 1.5-2.0-μg/kg bolus + 0.2-0.3-μg/kg/h infusion of-nitrous oxide anesthesia caused CBF effects comparable to that observed with isoflurane (0.75%)-nitrous oxide anesthesia with maintenance of CO₂ cerebrovascular reactivity.

• Alfentanil (25 or 50 μg/kg IV) given to patients who were receiving isoflurane (0.4-0.6%)-nitrous oxide anesthesia resulted in very small reductions in middle cerebral artery flow velocity. 

  • CBF values during remifentanil-nitrous oxide anesthesia were reported similar to CBF values measured during fentanyl-nitrous oxide and isoflurane-nitrous oxide anesthesia,  at the same time cerebrovascular reactivity to CO₂ remained.

¹Intravenous Opioid Anesthetics:  Intracranial Pressure

• Generally, opioids do not have significant effects on intracranial pressure (ICP). 

  • For patients undergoing craniotomyfor supratentorial space-occupying tumors, opioids do not cause significant increases in ICP or CSF pressure (anesthesia was provided utilizing isoflurane-nitrous oxide). 

    • ICP does not appear to be altered in head-injury patients who are receiving opioids sedation.

      • However, other research indicates that harmful opioid-induced ICP effects could be produced-- even in the context of patients undergoing craniotomy for supratentorial tumors with mass effect, opioids could increase ICP, perhaps particularly if intracranial compliance has been compromised by tumor dimensions. 

      • Accordingly, the precise effect of opioid administration on intracranial pressure may vary depending on the precise clinical circumstance as well as on potentially the nature of the background anesthetic.

  • For certain brain tumor patients anesthetized with thiopental-nitrous oxide-vecuronium, following sufentanil (1 μg/kg) CSF pressure increased nearly twofold and increased by about 1.2X following alfentanil (50 μg/kg). 

    • Comparable patients exhibit a reduction in CSF (5%) following fentanyl (5 μg/kg). 

      • This last result has been verified by an additional worker with respect to fentanyl and alfentanil. 

      • Again, on the other hand, other studies reported no effect of alfentanil (70g/kg infused over 6 minutes) on ICP in hydrocephalic patients (age range:  1.3-20 years) who were operated on for shunt revision under isoflurane (0.5%)-nitrous oxide anesthesia. 

        • Yet, in a different study results indicated that sufentanil (0.6 μg/kg) and fentanyl (3 μg/kg) administration caused significant increases in ICP in fully resuscitated individuals who had severe head trauma. 

    • In reviewing all these studies, it appears difficult to predict the exact effect on opioids in any specific circumstance. 

      • It is possible that inconsistent results could be due to differences in ICP or CSF pressure assessment methodologies, due to influences of other drugs present, or for reasons undetermined.

        • Consult the details in reference 1, if desired, for references to the primary literature, the results from some of which have been noted above). 

          • The possible effects of opioids on ICP-focusing on increases in ICP may be due to direct cerebrovascular influences and/or more indirect effects secondary to changes in mean blood pressure or cerebral perfusion pressure with compensatory cerebral vasodilatation. 

          • Which one of these possibilities is more likely true remains for future research to decide. 

            • If ICP effects to the opioids were principally secondary to opioid-induced cardiovascular effects, then rapid management of such cardiovascular effects could reduce or prevent adverse ICP effects.

    • ICP increases could also be secondary to opioid-induced rigidity.  

    • At least for fentanyl, CSF production rates and CSF reabsorption rates do not appear to be affected.

¹Intravenous Opioid Anesthetics:  Muscle Rigidity

• ¹Increases in muscle tone and muscle rigidity may be associated with opioid administration.

  • Patients receiving dehydrobenzperiol (0.44 mg/kg)  along with fentanyl (8.8 μg/kg) have a four out of five chance of exhibiting some rigidity. 

    • A single IV fentanyl dose of 0.5-0.8 mg will reliably induce chest wall rigidity within about 60-90 seconds.

    • Variations in dosage and administration speed are probably responsible for differing incidence of rigidity. 

      • Other factors that contribute to variability include whether or not nitrous oxide is used, the presence or absence of muscle relaxants in patients age.

  • ²Relatively large doses of IV morphine ( 2 mg/kg infused at a rate of 10 mg/minute) induces abdominal muscle rigidity with reduced thoracic compliance. 

    • The maximal effect under these circumstances is reached at about 10 minutes following administration. 

      • Individuals receiving smaller morphine doses in the rate of 10-15 mg have recounted feelings of muscle tension usually in the neck or legs with occasional presentations around the chest. 

      • Elaborating on the nitrous oxide effect noted above, muscle rigidity is significantly increased by 70% nitrous oxide. 

        • Following high-dose opioids, myoclonus in the absence of the EEG evidence of seizure activity has also been noted.

  • ²Muscle rigidity secondary to opioid administration appears to be a μ-receptor mediated activity at supraspinal sites such as the nucleus raphe pontis in addition to lateral proximal sites.

  • ²Opioid-induced rigidity can be managed or eliminated by drugs such as naloxone as well as those agents which increased GABA agonist action including thiopental and diazepam and other muscle relaxants.

  • ¹Rigidity secondary to opioids may be described by increasing muscle tone which can progress to severe stiffness. 

    • The clinically significant opioid-induced rigidity is usually first detectable just as or immediately after the patient loses consciousness. 

      • In conscious patients relatively mild presentations of rigidity manifest as hoarseness. 

        • The most frequent initial identifier of opioid rigidity is wrist flexion.

      • Time course of rigidity: occasionally rigidity can occur upon anesthesia emergence and less commonly hours following the last opioid dose administration. 

      • These delayed or postoperative events are most likely explained by pharmacokinetic manifestations -- i.e. second peaks in plasma opioid concentrations.

• ¹Pulmonary consequences:

  • Rigidity can cause a reduction in pulmonary compliance as well as reduced functional residual capacity. 

    • Sometimes more importantly, opioid-induced rigidity may diminish or even prevent adequate ventilation resulting in hypercarbia, hypoxia with elevations in ICP.

• ¹Cardiovascular consequences:

  • Opioid-induced rigidity changes in number of hemodynamic parameters-including causing an increase in pulmonary artery and central venous pressures as well as an increase in pulmonary vascular resistance. 

    • Arterial blood pressure and cardiac output remained relatively constant.

• ¹Abdominal and/or thoracic muscle rigidity (wooden chest syndrome) was thought to be the reason for opioid-induced impairment of spontaneous or controlled ventilation in the nonparalyzed individual.

  •  Apparently, the difficulty in bag ventilation and masking following opioid administration is mostly due to vocal cord closure.

• ¹More about the opioid induced rigidity mechanisms:

  • Opioid-induced rigidity is not to due to a direct action on muscle fibers; however the precise mechanism remains to be elucidated.

    • This conclusion follows from the observation that opioid-induced fiber rigidity can be prevented by pretreatment with muscle relaxants. 

      • Furthermore, opioid-induced muscle rigidity is not accompanied by increases in creatinine kinase -- a result indicating that limited or no muscle damage occurs with rigidity. 

      • From the electrophysiological point of view, opioids have limited effects on neuromuscular conduction depressing only minimally monosynaptic reflexes associated with muscle stretch receptors.

  • -receptor agonists as opposed to -or - agonists are effective in inducing rigidity (in the rat model). 

    • Stimulation of GABA interneurons can result in a rigidity which can be blocked by stray lesions. 

      • Striatonigral  GABA pathways thought to be rigidity-related are influenced by GABA agonists and antagonists.

  • There has been some suggestion of relationships between basic neurochemical mechanisms that are involved in Parkinson's disease and opioid-induced catetonia and rigidity.

    • This consideration follows from the increase opioid-induced rigidity with age as well as muscle movement abnormalities similar to extrapyramidal side effects.

• ¹More about management of opioid-induced rigidity:

  • Rapid termination of opioid-induced rigidity follows from succinylcholine administration. 

    • Succinylcholine also obviates associated cardiovascular changes and typically allows controlled ventilation. 

      • Preventative measures are however considered more definitive in dealing with this problem.

    • Administration of nondepolarizing muscle relaxants reduces severity and incidence of rigidity. 

      • Beyond this observation some inconsistency exists in the literature concerning other approaches. 

        • For example thiopental induction doses with reduced relative to anesthetic doses of diazepam and midazolam may prevent, reduced, or effectively manage rigidity. 

          • On the other hand, the reliability of benzodiazepines in this application has been questioned.

          • Opioid-induced rigidity may also be attenuated by administration of ketanserin, amantadine, and ₂-agonists.

    • The best method to avoid rigidity in clinical practice  appears to involve concomitant administration of a "priming" size dose of a nondepolarizing agent along with avoiding rapid large dose administration of any opioid.

      • The use of an "priming"  dose of nondepolarizing agent is to avoid the possibility of muscle relaxation prior to unconsciousness. 

        • Opioid-induced rigidity in the presence of apnea has been taken to indicate unconsciousness.

    • Anesthetists  may choose to demonstrate the ability to mask ventilate the patient following anesthesia induction but prior to the administration of a muscle relaxant. 

      • This approach will be of only questionable value should opioid-induced rigidity occur during induction, resulting in increased difficulty or even impossibility of patient ventilation. 

        • In view of this observation, should a patient presents with a difficult airway, or the possibility of a difficult airway, or other circumstances exist requiring assurance of the patient must be/can be manually ventilated prior to neuromuscular blockade, as a consequence that only small opioid doses should be given during induction.

    • Efforts to mask ventilate a patient with opioid-induced muscle rigidity can result in gastric insufflation with inadequate ventilation and oxygenation pending administration and activity of muscle relaxant. 

      • With large doses of opioids used, anticipation of the need for rapid neuromuscular blockade should be part of preoperative planning.

²Intravenous Opioid Anesthetics:  Nausea and Vomiting

• Nausea and vomiting are significant side effects of morphine and related compounds. 

  • Interoperative opioids as well as morphine premedication may be associated with increased incidence of postoperative vomiting. 

    • This issue is particularly important in view of increasing prominence of same day surgical procedures and the observation that nausea and vomiting may predispose to an overnight stay.

      • Independent of the route of administration (oral, intravenous, intramuscular, transmucosal, subcutaneous, transdermal,  intrathecal, epidural, or intramuscular)  the likelihood of opioid-induced nausea turns out to be similar. 

      • At least concerning morphine, meperidine, fentanyl, sufentanil, and alfentanil, the severity and incidence of nausea and vomiting appear similar through the series.

  • Neuropharmacology of opioid-induced nausea and vomiting is complex and is represented in the figure below:

²"The chemotactic trigger zone (CTZ) located in the area postrema the brainstem, contains dopamine, serotonin, histamine, and muscarinic acetylcholine is well as opioid receptors.  The vomiting center receives input from the CTZ as well as peripheral sites via the vagus nerve.  As illustrated, the role of opioids as complex, and they appear to have both emetic and antiemetic effects."

• The vomiting center receives neuronal input from the chemotactic triggers on (CTZ) in the area postrema of the medulla, as well as from the pharynx, GI tract, mediastinum, and visual center.

  • The CTZ is associated with a number of receptor systems including opioid, dopamine (D₂), serotonin (5-HT₃), histamine, and acetylcholine (muscarinic). 

    • The CTZ receives input from the vestibular portion of these cranial nerve.  Increased vestibular sensitivity is associated with morphine administration and morphine as well as related opioids can cause nausea by direct CTZ stimulation. 

    • Morphine's nausea and emetic effects are increased by vestibular stimulation which can accompany walking, for example. 

      • At the vomiting center, higher morphine (and other opioid) doses  exhibits an antiemetic effect which is naloxone-reversible. 

        • The antiemetic effect does not appear to last as long as emetic action of morphine. 

          • The results of an experiment which demonstrated this relationship indicated that morphine-induced nausea and vomiting tended to increase when a morphine infusion was discontinued.  (Another possibility was noted -- accumulation of the active morphine metabolite, morphine-6-glucuronide continue to accumulate throughout this period which resulted in a worsening of nausea.)

  • Treatment of opioid induced nausea and vomiting (and prophylaxis) has involved administration of other medications which are antagonists at a number of the receptor sites in the CTZ. 

    • Some antiemetic agents have not had their mechanisms elucidated; some of these agents include benzodiazepines and propofol.

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• ⁵Substantia Gelatinosa Image:  Courtesy of The Digital Slice of Life, a cooperative project with the Slice of Life office, KUED Media Solutions, and the Knowledge Weavers Project.
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