Opioids vs. Nonopioids: A Chinese Menu Dilemma vs...Opioids vs. Nonopioids: A Chinese Menu Dilemma...
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Opioids vs. Nonopioids: A Chinese Menu Dilemma Kindly Select 1 from column A or 2 from column B
Opioids vs. Nonopioids: A Chinese Menu Dilemma vs...Opioids vs. Nonopioids: A Chinese Menu Dilemma Kindly Select 1 from column A or 2 from column B. You will find a fortune cookie
Opioids vs. Nonopioids: A Chinese Menu DilemmaKindly Select 1 from column A or 2 from column B
Presenter
Presentation Notes
You will find a fortune cookie on your seat. Sometime during the hour feel free to open your cookie to see if you are the winner of a free APEX CRNA CE subscription for 60 class A credits. A $599 value. Probably more appropo to state “and” not “or” because we will want to do a multimodal approach to pain management.
Disclosure StatementI have no financial relationships with any commercial interest related to the content of this activity.
I will discuss the following medications off-label use for post-operative pain relief during my presentation:
First, Lets make sure we understand the process of pain
Learner Outcomes• The Learner will name at least 2 alternative non-opioid
medications used for post-operative pain.• The learner will be able to state the MOA of 2 alternative non-
opioid medications used in the peri-operative arena.• The learner will be able to list the benefits of non-opioid
treatment over opioid treatment in the surgical setting.
Presenter
Presentation Notes
First, Lets make sure we understand the process of pain
APEX
Anes
thes
ia Re
view
1 From Column A…Daniel Frasca CRNA, DNAP
Buddy Hackett
Presenter
Presentation Notes
Buddy Hackett had a skit about a cranky waiter at a Chinese restaurant who made the already confusing Chinese menu more confusing. Probably not politically correct now but was funny at the time. The point is Menus at restaurants are not the only confusing choices out there. You will find a fortune cookie on your seat. Sometime during the hour feel free to open your cookie to see if you are the winner of a free APEX CRNA CE subscription for 60 class A credits. A $599 value.
Pain Definitions• Nociception - From the Latin word nocere 'to harm or hurt’
• The sensory nervous system's response to harmful stimuli, the ability to feel pain.
• Nociceptors – A sensory receptor for painful stimuli• Nociceptive compounds – Chemicals released from damaged
cells and immune cells• Non-nociceptive pain – Neuropathy, damage to the nerves
themselves.
Presenter
Presentation Notes
The vast majority of nociceptors are free nerve endings with large receptive fields but can also be produced by nonneuronal cells such as macrophages, mast cells and platelets.
Four Steps to Pain (Nociception)• Transduction• Transmission• Modulation• Perception
Presenter
Presentation Notes
First, Lets make sure we understand the process of pain. Nociception is made up of 4 processes.
Four Steps to Pain• Transduction• Transmission• Modulation• Perception
• Damaged tissue releases chemicals
• Immune cells release proinflammatory compounds
• A-Delta and C-fibers are stimulated (fast, slow)
Presenter
Presentation Notes
Most distal step. Damaged tissue releases certain chemicals and immune cells release proinflammatory compounds both of which stimulate peripheral nerves. These are nociceptive compounds that activate nociceptor pathways A-delta & C-fibers. Fast- remove hand from stove quickly, slow lasting burning pain, throbbing, aching, dull
Four Steps to Pain• Transduction• Transmission• Modulation• Perception
• Myelinated A-delta fibers and unmyelinated C fibers
Pain is transmitted from the periphery towards the central nervous system by way of myelinated A-delta fibers and unmyelinated C fibers. Action potentials produced by the specialized nociceptors are conducted by A-delta fibers. These neurons transmit “fast pain” that is sharp and well localized. Action potentials produced by free nerve endings are conducted by C fibers. These neurons transmit “slow pain” that is dull and not well localized. Transmission of the pain signal occurs along a three-neuron pathway. The first-order neuron transmits the action potential from the site of tissue injury to the dorsal horn of the spinal cord. It may synapse with the second-order neuron at the level where it enters the spinal cord or it can travel along the track of Lissauer before synapsing at a higher or lower level. Glutamate and substance P are two important excitatory neurotransmitters in the dorsal horn. After synapsing, the vast majority of second order neurons cross to the contralateral side of the spinal cord and ascend towards the brain via the spinothalamic tract. The second- and third-order neurons synapse in the thalamus, and the third-order neuron projects to other brain regions including the cerebral cortex and limbic system.
Four Steps to Pain• Transduction• Transmission• Modulation• Perception
• Enhances or inhibits the pain signal
• Takes place in the substantia gelatinosa of the dorsal horn
• Also brain and peripheral nerve endings
Presenter
Presentation Notes
Modulation either enhances or inhibits the pain signal, and this process primarily takes place in the substantia gelatinosa of the dorsal horn. How does it work? When the pain signal reaches the dorsal horn, the body must decide whether it wants to enhance the pain signal or suppress it. The signal can be enhanced by neuroplastic changes that characterize the process of central sensitization, where wind-up of wide dynamic range neurons is a key example. While a number of highly complex processes are involved, the net result is that the brain perceives a higher degree of pain for a given stimulus. Additionally, these processes may contribute to the development of chronic pain. Alternatively, the pain signal can be inhibited by the endogenous pain suppression system, where the descending pain pathway plays a star role. Key cerebral structures in this pathway include the periaqueductal gray and nucleus raphe magnus. From here, motor fibers project to the dorsal horn and influence neurotransmission between the first- and second-order neurons. The pain signal is suppressed when the descending pain pathway releases norepinephrine, serotonin, and endorphins. A complex network of interneurons in the spinal cord also plays a key role in pain modulation, where release of GABA and glycine can inhibit the pain signal.
How Does Modulation Work?
• Controls release of substance P and glutamate• Stimulates NMDA receptors• Stimulates neurokinin receptors• Antidromic loops• Responsible for chronic pain• Inhibitory pathways to be discussed later
• Involve norepinephrine, serotonin, and endorphins
Presenter
Presentation Notes
How does it work? When the pain signal reaches the dorsal horn, the body must decide whether it wants to enhance the pain signal or suppress it. The signal can be enhanced by neuroplastic changes that characterize the process of central sensitization, where wind-up of wide dynamic range neurons is a key example. While a number of highly complex processes are involved, the net result is that the brain perceives a higher degree of pain for a given stimulus. Additionally, these processes may contribute to the development of chronic pain. Alternatively, the pain signal can be inhibited by the endogenous pain suppression system, where the descending pain pathway plays a star role. Key cerebral structures in this pathway include the periaqueductal gray and nucleus raphe magnus. From here, motor fibers project to the dorsal horn and influence neurotransmission between the first- and second-order neurons. The pain signal is suppressed when the descending pain pathway releases norepinephrine, serotonin, and endorphins. A complex network of interneurons in the spinal cord also plays a key role in pain modulation, where release of GABA and glycine can inhibit the pain signal.
Four Steps to Pain• Transduction• Transmission• Modulation• Perception
• Perception describes the higher-order processing of pain signals by the cerebral cortex and limbic system.
Presenter
Presentation Notes
We will return to these 4 steps at the end of the lecture.
Column A: Opioids• Opioid Receptors
• Mu• Delta• Kappa• ORL1 (NOP)
Mu ReceptorsMultiple subsets… Or are there??
• Mu 1• Mu 2
Presenter
Presentation Notes
The classic thought is that there are multiple subsets of Mu receptors ie Mu1, Mu2 Mu3 etc. This teaching is now being questioned. New research is challenging the existence of these subset and that in reality they are variants of complex RNA transcription. What does that mean? Not sure but that isn’t why we are here. For sake of argument let’s define 2 of the subsets Mu1 – Responsible for supraspinal analgesia and bradycardia Mu2 – Spinal analgesia
Presenter
Presentation Notes
MOA –The opioid or ligand couples with the opioid receptor which is linked to a G-protein. (The same sort of g protein complex associated or as seen with muscarinic, adrenergic and GABA) Ultimately, the stimulation of these receptors reduce the intraneural concentration of cAMP (2nd messenger). This suppresses the pain response ( Stoelting Pharm and Phys 5th edition (219)) Opioids work pre-and post-synaptically. In the pre-synaptic neuron, stimulation of the opioid receptor reduces calcium conductance which reduces neurotransmitter release. In the post-synaptic neuron, stimulation of the opioid receptor increases K+ conductance which in turn hyperpolarizes the neuron. This reduces the threshold potential and makes it more resistance to stimulation. The end result is the excitatory neurotransmitters are inhibited from sending nocioceptic signals to the brain.
Locations of Opioid Receptors• Brain• Spinal cord• Peripherally
Rostral ventralMedulla
Brain
Presenter
Presentation Notes
Periaquaductal gray – is the primary control center for descending pain. Has enkephalin producing cells the suppress pain. Also used for target for brain stimulating implants with chronic pain. Rostral ventral medulla sends descending inhibitory and excitatory fibers to the dorsal horn. Locus Ceruleus found in the pons and responsible for physiologic responses to stress and panic. This is responsible for symptoms of opioid withdrawl Brain – periaqueductal gray, locus coeruleus, rostral ventral medulla Found in the descending inhibitory pathways. Act on higher cortical centers where they can alter perception and response to pain.
Spinal Cord
Presenter
Presentation Notes
Found in the descending inhibitory pathway where they acitate Spinal cord – Primary afferent neurons in the dorsa horn and the interneurons Releas endorphins, serotonin, and norepinephrine in the substantia gelatinosa of the dorsal horn.
Peripheral
Presenter
Presentation Notes
Peripherally – Sensory neurons and immune cells such as leukocytes that influence inflammation and the immune response
Why NOT choose from Column A??• Metabolism• Common know side effects• Side Effects that make you go hmmm• Public Perception
Why NOT choose from Column A??Active Metabolites• Meperidine - Normeperidine• Morphine – Morphine-6-glucuronide & Morphine-3-
M6G and m3g M6g – respiratory depression drowsiness, n/v, coma M3g – hyperalagesia, agitation, delirium Normeperidine – increasies seizure activity. Serotonin syndrome Codeine metabolizes to morphine FDA warns not to use in children under 12. Genetic alterations in metabolism (hypermetboizes). Hydromorphone - neuro excitation.
Why not choose from Column A??
Presenter
Presentation Notes
Good points of narcotics: Pain relief. Bad points…Myriad effects we all know and love but the big ones are: Respiratory depression Pruritus N/V Constipation Physical dependence Tolerance
Why not choose from Column A??Side Effects that make you go hmmm• Opioid-induced hyperalgesia
• Paradox• Mu and ORL1 receptors
• Opioids and Cancer progression• Complex clinical picture• Linked to immunosuppression, angiogenesis, apoptosis
Presenter
Presentation Notes
Link to cancer progression secondary to immunosuppression and potentiation of angiogenesis Complex clinical picture causing conflicting data Need more research
Presenter
Presentation Notes
Publics understanding of
Multimodal Approach• Consideration to use some form of regional anesthesia• A regimen of nonopioids, including NSAIDs, COX-specific
analgesics, and/or acetaminophen• Preoperative administration of gabapentin or pregabalin• Dexamethasone to decrease postop pain and PONV
Presenter
Presentation Notes
So what does a multimodal approach look like? Here are the recommendations from a 2012 task force on acute pain management (4).
Multimodal Approach• Pain management using more than 1 mechanism of action• Decreases chronic pain• Enhances patient satisfaction• Promotes faster GI function• Decreases cardiopulmonary morbidity
NMDA – N-Methyl-aspartic acid The resurgence of ketamine (from its heydays of the 1980s) is in part due to its value as an adjunct to a volatile anesthetic and opioid-based approach to care, advantaging both its analgesic and anti-inflammatory properties. In larger doses (those above 1 mg/kg IV) ketamine creates a dissociative anesthetic state, while lower sub-anesthetic doses produce a centrally mediated analgesia with a minimal effect on consciousness or cognition. In recent years, many clinical studies have supported the use of sub-anesthetic doses of ketamine for managing pain in the perioperative setting.
KetamineLocation:
• Dorsal horn of the spinal cord*• Also present throughout the CNS
Presenter
Presentation Notes
The resurgence of ketamine (from its heydays of the 1980s) is in part due to its value as an adjunct to a volatile anesthetic and opioid-based approach to care, advantaging both its analgesic and anti-inflammatory properties. In larger doses (those above 1 mg/kg IV) ketamine creates a dissociative anesthetic state, while lower sub-anesthetic doses produce a centrally mediated analgesia with a minimal effect on consciousness or cognition. In recent years, many clinical studies have supported the use of sub-anesthetic doses of ketamine for managing pain in the perioperative setting.
The resurgence of ketamine (from its heydays of the 1980s) is in part due to its value as an adjunct to a volatile anesthetic and opioid-based approach to care, advantaging both its analgesic and anti-inflammatory properties. Ketamine’s analgesic effect is believed to result from NMDA receptor antagonism in the dorsal horn of the spinal cord, however it should be underscored that NMDA receptors are present throughout the central nervous system, so it is not unreasonable to propose a more widespread mechanism of action. Furthermore, ketamine selects for a variety of other receptor targets including opioid, norepinephrine, serotonin, muscarinic, and nicotinic receptors. What is clear is that ketamine’s effects in the central nervous system are exceedingly complex with much still to be unraveled.
Ketamine• Dosing:
• High dose• 1 mg/kg
• Low dose• 0.1-0.3 mg/kg• 0.1-0.3 mg/kg/hr
• Epidural
Presenter
Presentation Notes
In larger doses (those above 1 mg/kg IV) ketamine creates a dissociative anesthetic state. Much of the literature to date related to sub-anesthetic ketamine dosing is designed to improve pain scores and reduce perioperative opioid consumption. Although there is no consensus guideline on the dosing regimens, the current literature suggests a loading dose of 0.1 – 0.3 mg/kg IV followed by a continuous infusion of 0.1 – 0.3 mg/kg/hr. There are some reports that detail epidural use as well. Emerging investigations will better clarify the ideal indications for sub-anesthetic dosing of ketamine as well as its long-term implications. Furthermore, clinical data continues to emerge that ketamine may be useful in patients with opioid tolerance and even in preventing chronic postsurgical pain (6).
Ketamine• Much of the literature to date
related to sub-anesthetic ketamine dosing
• May be useful in:• Patients with opioid tolerance• Preventing chronic postsurgical
pain• Post-traumatic stress disorder
and depression
Presenter
Presentation Notes
What does the literature say?... Much of the literature to date related to sub-anesthetic ketamine dosing is designed to improve pain scores and reduce perioperative opioid consumption. Although there is no consensus guideline on the dosing regimens, the current literature suggests a loading dose of 0.1 – 0.3 mg/kg IV followed by a continuous infusion of 0.1 – 0.3 mg/kg/hr. There are some reports that detail epidural use as well. Emerging investigations will better clarify the ideal indications for sub-anesthetic dosing of ketamine as well as its long-term implications. Furthermore, clinical data continues to emerge that ketamine may be useful in patients with opioid tolerance and even in preventing chronic postsurgical pain (6).The most current literature is beginning to illuminate how ketamine can create and/or impede neurobiological processes that result in analgesia as well as influence psychiatric conditions such as post-traumatic stress disorder and depression. Further demonstrating this complexity is the observation that once administered, ketamine is quickly metabolized by liver microsomal enzymes, most notably to norketamine and hydroxynorketamine. While norketamine is about one-third the potency of its parent compound, hydroxynorketamine is absent of anesthetic effect. Interestingly, it is this metabolite, possibly working at the AMPA receptor, that may contribute to the antidepressant effect of ketamine (3, 4).
Dextromethorphan• Antitussive• Antagonizes the effect of glutamate at the NMDA receptor• Potential side effects of dextromethorphan include PONV,
dizziness, and excessive sedation.
Presenter
Presentation Notes
Commonly used as an antitussive agent in over-the-counter cold medicine, the use of dextromethorphan has been explored as part of a multimodal approach to analgesia. Dextromethorphan is proposed to produce analgesia by noncompetitively antagonizing the effect of glutamate at the NMDA receptor. This modulates the pain response in the central nervous system by reducing calcium currents and preventing wind-up.
Dextromethorphan• 2016 meta-analysis of 21 randomized
trials• Revealed reduced postoperative pain
scores at 1, 4, 6, and 24 hours• 15 of the studies found either no
statistically significant side effects or a clinically meaningful reduction in side effects when compared to control or opiate-only groups
Presenter
Presentation Notes
What does the literature say?... Although a 2005 systematic review found inconsistent outcomes with dextromethorphan, a 2016 meta-analysis of 21 randomized trials revealed reduced postoperative pain scores at 1, 4, 6, and 24 hours, and a decreased need for opioid medication 24 to 48 hours after surgery. Potential side effects of dextromethorphan include PONV, dizziness, and excessive sedation. Fifteen of the studies found either no statistically significant side effects or a clinically meaningful reduction in side effects when compared to control or opiate-only groups (1).
Additional uses include anxiolysis, treatment of postoperative shivering, and as an additive to neuraxial and peripheral nerve blocks. MAC is decreased, and there’s an additive effect with other sedatives. Because it doesn’t depress the respiratory drive, it’s particularly useful during awake intubation.
DexmedetomidineDoes NOT cause:• Respiratory depression• Change in ICP• Change in oxygenation
Presenter
Presentation Notes
Additional uses include anxiolysis, treatment of postoperative shivering, and as an additive to neuraxial and peripheral nerve blocks. MAC is decreased, and there’s an additive effect with other sedatives. Because it doesn’t depress the respiratory drive, it’s particularly useful during awake intubation.
DexmedetomidineMost common side effects are:• Bradycardia• Hypotension• *Hypertension with rapid administration
Presenter
Presentation Notes
CV effects seen with rapid administration. Alpha 2 stimulation in the vasculature causes vasoconstriction prior to the central mediated reduction in SNS tone. Usually short lived
Alpha-2 agonists• Both clonidine and
dexmedetomidine reduced morphine consumption after surgery
• The use of both α-2 agonists resulted in a lower incidence of PONV.
• There was no evidence that either drug prolonged recovery.
Presenter
Presentation Notes
What does the literature say?... Both clonidine and dexmedetomidine reduced morphine consumption after surgery. The degree of morphine sparing effect was stronger than that seen with acetaminophen but weaker than that reported from ketamine or NSAIDs. With both α-2 agonists, pain intensity at 24 hours was decreased by about 0.7 cm on a 10 cm pain scale. The use of both α-2 agonists resulted in a lower incidence of PONV. There was no evidence that either drug prolonged recovery at any time in the patients’ care. Both drugs were associated with hemodynamic consequences. Clonidine was more likely to produce hypotension, and dexmedetomidine was more likely to produce bradycardia. Despite these observations, no major adverse outcomes occurred. The POISE-2 trial conflicts with this finding, as it found that low-dose clonidine was associated with an increased risk of hypotension and non-fatal cardiac arrest (2).
Alpha-2 agonists• Both drugs were associated
with hemodynamic consequences.
• Clonidine was more likely to produce hypotension
• Dexmedetomidine was more likely to produce bradycardia.
• No major adverse outcomes occurred.
• The POISE-2 trial conflicts with this finding
Presenter
Presentation Notes
Both clonidine and dexmedetomidine reduced morphine consumption after surgery. The degree of morphine sparing effect was stronger than that seen with acetaminophen but weaker than that reported from ketamine or NSAIDs.With both α-2 agonists, pain intensity at 24 hours was decreased by about 0.7 cm on a 10 cm pain scaleThe use of both α-2 agonists resulted in a lower incidence of PONV.There was no evidence that either drug prolonged recovery at any time in the patients’ care.Both drugs were associated with hemodynamic consequences. Clonidine was more likely to produce hypotension, and dexmedetomidine was more likely to produce bradycardia. Despite these observations, no major adverse outcomes occurred. The POISE-2 trial conflicts with this finding, as it found that low-dose clonidine was associated with an increased risk of hypotension and non-fatal cardiac arrest (2).
LidocaineThe new golden child of multimodal analgesia and ERAS (Enhanced Recovery After Surgery)• When used intravenously it:
• Decreases post-op pain• Decreases N/V• Decreases hospital stay• Increases return of bowel function
Presenter
Presentation Notes
Commonly used for regional anesthesia or for the treatment of ventricular dysrhythmias, lidocaine has established itself as a useful component of multi-modal analgesia and advanced recovery protocols. Administered as an intravenous bolus followed by a continuous intravenous infusion, lidocaine’s benefits include an opioid-sparing effect with a reduction of post-operative pain, decreased incidence of PONV by 10 – 20%, a faster return of bowel function by up to 8 hours, and a shorter hospital stay. What’s particularly interesting about intraoperative lidocaine infusion, is that it’s benefits appear to persist for many hours beyond the life of the drug inside the body
LidocaineDosing:• Loading dose 1.5-2 mg/kg• Infusion of 1.5-2 mg/kg/hr• Avoid infusions in patients with Hx of:
• Dysrhythmias• Heart block• CAD• Heart failure
Presenter
Presentation Notes
Dosing algorithms vary among advanced recovery protocols, but a good reference point is a loading dose of 1.5 - 2 mg/kg followed by an infusion of 1.5 – 2 mg/kg/hr. These doses result in a therapeutic plasma concentration of 1 – 5 mcg/μl. Cardiac and neurotoxicity is a risk when Cp exceeds 5 mcg/μl. Early signs of toxicity include perioral numbness and tinnitus. Lidocaine infusion should be avoided in the patient who is susceptible to the conduction altering effects of lidocaine including those with a history of dysrhythmias, heart block, coronary artery disease, and heart failure. Some clinicians will discontinue the infusion an hour before the end of the surgical procedure, while others will continue it well into the postoperative period. Patients may appear more drowsy during emergence, however there is no data that says PACU discharge times are prolonged (1).
LidocaineMOA?• Peripherally primes polymorphonuclear granulocytes to
produce an anti-inflammatory response.• Centrally reduces pain transmission, possibly in the wide
dynamic range neurons in the spinal cord.• Efficacy of lidocaine infusion appears to be dependent on
the surgical procedure.
Presenter
Presentation Notes
While it’s precise mechanism remains to be elucidated, lidocaine possibly works through a combination of several mechanisms. It may act peripherally where it primes polymorphonuclear granulocytes to produce an anti-inflammatory response. It may act centrally, where it reduces pain transmission, possibly in the wide dynamic range neurons in the spinal cord. It’s important to note that the efficacy of lidocaine infusion appears to be dependent on the surgical procedure. Therefore, we must be selective in its application. The bulk of promising outcomes are found in patients presenting for open and laparoscopic abdominal surgery. Patients undergoing radical retropubic prostatectomy benefit as well. When used in patients undergoing spine surgery, lidocaine infusion is associated with a reduction in both acute post-surgical pain as well as an improved quality of life at 1 and 3 months following surgery. While lidocaine infusion doesn’t appear to reduce acute post-surgical pain in mastectomy patients, research has revealed a lower incidence of chronic post-surgical pain. Lidocaine infusion does not appear to help those undergoing cardiac surgery, hip surgery, or open abdominal hysterectomy. Use of an intravenous lidocaine infusion may be particularly useful in the patient who is unable (or unwilling) to receive neuraxial anesthesia
LidocaineGood outcome:
• Open abdominal• Laparoscopic abdominal• Radical prostatectomy• Spine surgery
No change in outcome:• Mastectomies• Cardiac surgery• Hip surgery• Open abdominal hysterectomies
Presenter
Presentation Notes
What does the literature say?... It’s important to note that the efficacy of lidocaine infusion appears to be dependent on the surgical procedure. Therefore, we must be selective in its application.The bulk of promising outcomes are found in patients presenting for open and laparoscopic abdominal surgery. Patients undergoing radical retropubic prostatectomy benefit as well. When used in patients undergoing spine surgery, lidocaine infusion is associated with a reduction in both acute post-surgical pain as well as an improved quality of life at 1 and 3 months following surgery. While lidocaine infusion doesn’t appear to reduce acute post-surgical pain in mastectomy patients, research has revealed a lower incidence of chronic post-surgical pain. Lidocaine infusion does not appear to help those undergoing cardiac surgery, hip surgery, or open abdominal hysterectomy. Use of an intravenous lidocaine infusion may be particularly useful in the patient who is unable (or unwilling) to receive neuraxial anesthesia
NSAIDs
Presenter
Presentation Notes
NSAIDs inhibit the cyclooxygenase enzymes (COX) that catalyze the conversion of arachidonic acid to prostaglandins, thus reducing pain, inflammation, and even fever. Recall that COX-1 is always present. It plays an essential role in maintaining the GI mucosa, platelet function, and renal blood flow. COX-2 is inducible, which is to say that it’s only synthesized during certain situations including tissue injury, inflammation, and fever. Aspirin irreversibly inhibits COX-1 and -2, while the effect of ibuprofen and ketorolac is reversible. Intravenous options include ketorolac as well as ibuprofen (under the trade name Caldolor). Renal prostaglandins are essential for ensuring renal blood flow, so caution is advised in the patient with renal insufficiency. Patients who are hypovolemic or those with congestive heart failure may also be at risk for renal related morbidity. NSAIDs should be avoided in the patient with Samter’s triad (asthma, nasal polyps, and aspirin sensitivity), as this patient population has an increased risk of bronchospasm. The effect of NSAIDs on bone healing continues to be debated, and as of this writing there are no clear guidelines available on this matter. COX-2 inhibitors remove the risk of gastric, platelet, and renal effects, however in 2005 the FDA issued a black box warning on their use due to an association with myocardial infarction and stroke. Celecoxib is indicated in the perioperative treatment of pain, however it should be avoided in the patient with coronary artery disease, cerebrovascular disease, or an allergy to sulfonamides.
NSAIDs
Presenter
Presentation Notes
30 Toradol is = ~ 10 mg morphine Use to give loading dose of 60 mg anyone do that still? Max 5 days
Blocks COX 3?• Acts centrally• IV vs ORAL• Acetaminophen toxicity
Can J Hosp Pharm. 2015 May-Jun; 68(3): 238–247.
Presenter
Presentation Notes
What does the literature say?... Acetaminophen’s action is not fully understood, but it appears to work in the CNS rather than in the peripheral nervous system. It may do this by centrally blocking COX-3, but this is debatable. Key benefits of acetaminophen are that it doesn’t affect platelet function, renal perfusion, or the integrity of the gastric mucosa. Proposed benefits of the IV formulation include a more predictable pharmacokinetic and pharmacodynamic profile, a higher peak plasma concentration, and a smaller first pass metabolism (possibly beneficial in patients with liver disease). A 2015 systematic review compared the intravenous and oral formulations of acetaminophen. The authors concluded that, in patients who were able to take the oral formulation, there was no clear benefit offered by the intravenous formulation of acetaminophen (1). Of note, acetaminophen toxicity is the most common cause of liver failure in the United States.
AcetaminophenDosing:• Adults and adolescents weighing 50 kg and over: the
recommended dosage of OFIRMEV is 1000 mg every 6 hours or 650 mg every 4 hours, with a maximum single dose of OFIRMEV of 1000 mg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 4000 mg per day.
Presenter
Presentation Notes
What does the literature say?... Acetaminophen’s action is not fully understood, but it appears to work in the CNS rather than in the peripheral nervous system. It may do this by centrally blocking COX-3, but this is debatable. Key benefits of acetaminophen are that it doesn’t affect platelet function, renal perfusion, or the integrity of the gastric mucosa. Proposed benefits of the IV formulation include a more predictable pharmacokinetic and pharmacodynamic profile, a higher peak plasma concentration, and a smaller first pass metabolism (possibly beneficial in patients with liver disease). A 2015 systematic review compared the intravenous and oral formulations of acetaminophen. The authors concluded that, in patients who were able to take the oral formulation, there was no clear benefit offered by the intravenous formulation of acetaminophen (1). Of note, acetaminophen toxicity is the most common cause of liver failure in the United States.
Gabapentinoids
• Gabapentin & Pregabalin• MOA:
• Reduce glutamate release in the dorsal horn • Modulate norepinephrine activity in the descending inhibitory pain
pathway• May stop progression of acute to chronic pain• Combined with opioids may see an increase in respiratory
depression• Administer preoperatively
Presenter
Presentation Notes
What does the literature say?... Gabapentin & Pregabalin Traditionally used in fibramyalgia, postherpetic neuralgia, and partial onset seizures. MOA – reduce glutamate release in the dorsal horn as well as modulate norepinephrine activity in the descending inhibitory pain pathway. May stop progression of acute to chronic pain by reducing central sensitization Combined with opioids may see an increase in respiratory depression Administer preoperatively need 4-8 hours to achieve peak CSF concentrations.
Dexamethasone• Inhibits prostaglandin and
leukotrienes• Given during the pre-op
period• Facilitates regional blocks
Presenter
Presentation Notes
What does the literature say?... Dexamethasone produces analgesic effects by inhibiting prostaglandin and leukotriene production as a function of decreased phospholipase A2 activity. The recommended dose range is 0.11 to 0.2 mg/kg. It should be given during the preoperative period, but caution is advised against bolus administration as the incidence of perineal irritation can be as high as 50 – 70%. Dexamethasone is a useful addition to the local anesthetic cocktail used for peripheral nerve blockade. The dose should not exceed 1 mg per plexus. There is also evidence that 4 – 10 mg of IV dexamethasone prolongs the duration of interscalene blockade (2).
NSAIDs
Presenter
Presentation Notes
NSAIDs inhibit the cyclooxygenase enzymes (COX) that catalyze the conversion of arachidonic acid to prostaglandins, thus reducing pain, inflammation, and even fever. Recall that COX-1 is always present. It plays an essential role in maintaining the GI mucosa, platelet function, and renal blood flow. COX-2 is inducible, which is to say that it’s only synthesized during certain situations including tissue injury, inflammation, and fever. Aspirin irreversibly inhibits COX-1 and -2, while the effect of ibuprofen and ketorolac is reversible. Intravenous options include ketorolac as well as ibuprofen (under the trade name Caldolor). Renal prostaglandins are essential for ensuring renal blood flow, so caution is advised in the patient with renal insufficiency. Patients who are hypovolemic or those with congestive heart failure may also be at risk for renal related morbidity. NSAIDs should be avoided in the patient with Samter’s triad (asthma, nasal polyps, and aspirin sensitivity), as this patient population has an increased risk of bronchospasm. The effect of NSAIDs on bone healing continues to be debated, and as of this writing there are no clear guidelines available on this matter. COX-2 inhibitors remove the risk of gastric, platelet, and renal effects, however in 2005 the FDA issued a black box warning on their use due to an association with myocardial infarction and stroke. Celecoxib is indicated in the perioperative treatment of pain, however it should be avoided in the patient with coronary artery disease, cerebrovascular disease, or an allergy to sulfonamides.
Magnesium• Antagonizes glutamate in the
NMDA receptor• Smaller dose used than for
preeclampsia• Potentiates effects of muscle
relaxantsKorean J Anesthesiol 2013 July 65(1): 4-8 http://dx.doi.org/10.4097/kjae.2013.65.1.4
Presenter
Presentation Notes
What does the literature say?... Magnesium produces an analgesic effect by antagonizing glutamate at the NMDA receptor Dosing begins with a loading dose of 30-50 mg/kg followed by an infusion of 8-10 mg/kg/hr until the end of surgery. Watch for loss of deep tendon reflexes which is the first sign of toxicity (obviously can’t do this in GA) IV Calcium treatment of choice Be careful in that mg can antagonize the presynaptic nicotinc receptor at the NMJ therefore potentiating the effects of NMBs
Nonopioid Analgesics Summary
Esmolol
• MOA• Opioid clearance• Fentanyl at the BBB• Inhibitory transmission
at the dorsal horn• Dose
• Loading – 0.5-1 mg/kg• Gtt – 5-30 mcq/kg/min
• May reduce anesthetic requirements
Presenter
Presentation Notes
What does the literature say?... Numerous studies suggest esmolol produces opioid sparing effect. It reduces blood flow to the liver through a reduction in cardiac output which decreases opioid delivery to the liver and decreases clearance. It may increase fentanyl’s permeability across the BBB Last it may facilitate inhibitory neurotransmission in the substantial gelatinosa in the dorsal horn of the spinal cord. Whatever the cause, it is reported that esmolol reduces the requirement of opioids in the intra an post operative setting. Also enhances fast tracking in outpatient surgery Dose maxes at 250 mcg/kg/min. Assessing anesthetic depth may be more difficult with esmolol in the mix. Does it mask light anesthesia?. Therefore other methods of measuring anesthetic depth may be needed.. But there have been no reports of a higher incidence of awareness when esmolol is used.
Putting It All Together• Transduction – NSAIDs, Local anesthetic cream, antihistamines,
opioids, drugs that antagonize the effects of bradykinin and serotonin
• Transmission – Local anesthetics in peripheral and neuraxial blockade
• Modulation – NMDA antagonists, alpha-2-agonists, cholinesterase inhibitors, drugs that inhibit reuptake of serotonin and norepinephrine, massage, TENS unit
Transduction is blocked by NSAIDs, local anesthetic cream, membrane stabilizing agents, antihistamines, opioids, and drugs that antagonize the effects of bradykinin and serotonin. Transmission is blocked by local anesthetics used for either peripheral or neuraxial nerve blockade. Modulation is affected by neuraxial opioids, NMDA antagonists (such as ketamine), alpha-2 agonists (such as dexmedetomidine), cholinesterase inhibitors, and drugs that inhibit the reuptake of serotonin and/or norepinephrine. Massage and transcutaneous electrical nerve stimulation affect modulation by taking advantage of the gate theory of pain. Perception is reduced or inhibited by general anesthetics, opioids, and alpha-2 antagonists as well , , such as music therapy or guided imagery.
Further Reading
Presenter
Presentation Notes
What does the literature say?... Dexamethasone produces analgesic effects by inhibiting prostaglandin and leukotriene production as a function of decreased phospholipase A2 activity. The recommended dose range is 0.11 to 0.2 mg/kg. It should be given during the preoperative period, but caution is advised against bolus administration as the incidence of perineal irritation can be as high as 50 – 70%. Dexamethasone is a useful addition to the local anesthetic cocktail used for peripheral nerve blockade. The dose should not exceed 1 mg per plexus. There is also evidence that 4 – 10 mg of IV dexamethasone prolongs the duration of interscalene blockade (2).
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