Multimodal analgesia
Gabapentinoids
Gabapentinoids are another class of analgesic agents that work by a different MOA than opioids or anti-inflammatory agents. Pregabalin and gabapentin are synthetic analogues of the neurotransmitter gamma aminobutyric acid (GABA) and bind to the α2δ subunit of voltage-gated Ca channels in the spinal cord/brain to produce anti-hyperalgesic effects. Anti-nociceptive action is produced by inhibiting release of excitatory neurotransmitters (neuromodulation in the spinal cord/brain). Gabapentenoids have been shown to significantly reduce postop pain and opioid consumption. Commonly RXed periop gabapentin doses are 300-1200mg PO TID. A 1st dose of 600mg is usually given preop. Pregabalin is better absorbed. Its been studied more for fibromyalgia and neuropathic pain than for periop analgesia. A common side effect of gabapentinoids is sedation which may limit its use in some pt categories (ex outpatient, elderly).
acetaminophen
IV acetaminophen is widely used and helpful for postop pain control; however, controversy exists as to whether IV is better than PO and does IV acetaminophen really reduce opioid requirements. Large doses of IV acetaminophen (1000 mg q6hrs up to 3,000mg) has been associated w/ liver failure.
benefits of multimodal analgesia
Improved analgesia is helpful for pts beyond feeling better. Effective pain control decreases complications such as pneumonia and cognitive dysfxn. Using many drugs from different classes can reduce side effects, tolerance, and lessen the likelihood of diversion.
more on ketamine
Ketamine has hypnotic, analgesic, and amnestic effects. Its also been shown to have anti-tolerance, anti-hyperalgesia, and anti-allodynia effects which are the main components of opioid resistance. Both single doses and infusions at sub-anesthetic doses have been shown to provide periop analgesia; however, optimal dose/timing havent been conclusively determined. Side effects include increasing sympathetic activity, nystagmus, hallucinations, elevated ICP, increased salivation (may need antisialogogue). Hallucinations are uncommon at sub-anesthetic doses.
Magnesium
Magnesium is the 4th MC cation in the human body. The MOA for effects on pain arent well understood. Proposed mechanism include anti-inflammatory effects, NMDA receptor agonism, and anti adrenergic properties. Evidence for efficacy in postop pain control is weak to moderate. Its been shown to reduce periop pain in a variety of surgeries. The MC dose range is a 30-50mg/kg bolus. In some cases this is followed by an infusion (1gm/hr). Evidence is lacking to support any particular dose or dosing strategy. Major side effects can arise for overdose (MC in renal failure or w/ IV infusions) and include somnolence, muscle weakness, and cardiac conduction abnormalities. Mg is known to decrease time to onset and increase DOA of neuromuscular blockade. These effects may begin to manifest w/ doses as low as 30mg/kg.
pathophysiology of pain
A basic understanding of the pathophysiology is necessary to appreciate how multimodal analgesia modulates pain via multiple different mechanisms. Nociceptive nerve endings detect mechanical, thermal, and chemical changes. The painful stimulus is then transduced into action potentials and transmitted to dorsal root ganglion by unmyelinated C fibers and myelinated A fibers. These afferent nerve fibers propagate the action potential to the dorsal horn of the spinal cord, releasing glutamate. The dorsal horn is the primary integration site of afferent pain signals and is subject to inhibitory modulation. The pain stimulus is then relayed to thalamus and limbic system via ascending spinothalamic tracts.
multimodal analgesia interventions
All of the things on this list are important to consider when developing a multimodal analgesia regimen for your pt. We will go through them one at a time, starting w/ pt education. It's at the top of the list, bc its very important to make sure the pt understands that they will likely have pain after surgery, that you will be treating the pain, but that taking away all the pain is an unrealistic expectation.
analgesic efficacy
Alpha 2 agonists have both central and peripheral effects. Theyve been used intrathecally in different surgical settings w/ results consistent w/ a decrease in postop opioid consumption and opioid related side effects. Dexmedetomidine 10mcg added to intrathecal bupivacaine has been shown to prolong duration of analgesia. Intrathecal clonidine increased risk of bradycardia, hypotension and sedation d/t systemic reabsorption. Systemic admin of both agents has been shown to also cause analgesia but is also associated w/ side effects (hypotension, bradycardia, and sedation). Bc of ease of periop admin and a higher affinity for the alpha 2 receptor, dexmedetomidine periop use has been increasing.
Risk of Perioperative NSAIDs
Although it makes physiologic sense to use NSAIDs during the periop period to decreased the risk of peripheral sensitization and for analgesia, periop use is controversial d/t potential adverse effects of NSAIDs. The most significant risks are increased periop bleeding and increased risk for MI. Investigators found that periop use of a NSAID was associated w/ a increased risk of AMI for all traditional NSAIDS including Naprosyn. The onset of AMI occurred in the 1st week and appeared greatest in the 1st month of tx w/ higher doses. However, Liu et al performed a large retrospective review of the risk of MI after total joint replacement. The use of NSAIDs in the periop period did not increase risk. Although many believe that periop use of NSAIDs increases bleeding risk, systematic reviews have failed to find a significant increase in bleeding that requires a surgical intervention. Periop NSAIDs can increase the risk of GI mucosal ulcerations. GI mucosal ulcerations are d/t NSAID's action on the (COX) inhibition and the subsequent prostaglandin deficiency. NSAID's block the action of cyclo-oxygenase -1 that forms thromboxane. Without thromboxane platelets can't stick together.
central sensitization
Another important component of pain is central sensitization. Central sensitization is a process that leads to the development/maintenance of chronic pain. It can take place immediately after or up to several wks after surgery. Its influenced by preop pain, intraop tissue injury, and postop inflammatory processes. Several theories suggest that blocking prostaglandin and NMDA pathways in the dorsal root ganglion, spinal cord and brain may help prevent this process. Despite recent advances in our understanding of the physiology of acute pain and the development of new opioid and nonopioid analgesics, pain control after surgical interventions remains a challenge.
NSAIDS
As discussed earlier tissue damage releases inflammatory mediators which can decrease the firing threshold of peripheral nociceptors. One of the inflammatory mediators implicated in this process is arachidonic acid. Tissue damage causes release of arachidonic acid from membrane phospholipids. The arachidonic acid is metabolized to prostaglandins which the decrease threshold of peripheral nociceptors. Inhibition of COX-1 and COX-2 stops conversion of arachidonic acid to prostaglandins and thromboxane and highlights the role of NSAIDs in multimodal analgesia.
Corticosteroids
Corticosteroids have been shown to inhibit prostaglandin synthesis. Theyve also been shown to reduce capillary permeability. A single preop dose of 0.1mg/kg has been shown to reduce periop pain, opioid consumption and N/V. Dexamethasone has also been used as an adjunct to peripheral nerve blockade w/ widely heterogenous results. Systematic reviews of RCTs have concluded dexamethasone btwn 4-8mg prolongs block duration by about 3 hrs. Many trials have been criticized for not comparing dexamethasone in the block to an IV dexamethasone control which has also been shown to improve analgesia.
ERAS and Pain Mgmt
Memtsoudis et al observed 1.5 million pts who had TKA and THA and reported proportional reduction in postop cxns, opioid usage, and LOS. Analgesic techniques considered were opioids, peripheral nerve blocks, acetaminophen, steroids, gabapentin, NSAIDs, COX-2 inhibitors, or ketamine. Conclusions were that the optimal protocol is still not known however the author's findings encourage the use of multiple modalities in periop protocols.
ketamine
NMDA receptor blocker. Glutamate is the primary excitatory neurotransmitter in the CNS. These agents block the N-methyl-D-aspartate (NMDA) glutamate receptors located on peripheral afferent nociceptive neurons in the dorsal horn of the spinal cord. Blockade here inhibits afferent nociceptive signaling. NMDA receptors are also present in the arousal system and cerebral cortex. Blockade of these NMDA glutamate receptors contribute to decreased arousal.
Adverse Effects of Dexamethasone
Of note, even a single dose of 4-8mg of dexamethasone has been shown to increase serum glucose by ~50gm/dL. Blood sugar should be followed if pts are diabetic, otherwise normalization of blood sugar is expected after 24hrs.
opioids
Opioids remain an important class of drugs for the anesthesiologist and periop physician. However, they have severe side effects and shouldn't be the sole source of pain modulation after surgery. Side effects include pruritus, N/V, respiratory depression, constipation, ileus, and urinary retention. Not only are they associated w/ numerous side effects, periop admin has been identified as a contributor to the opioid crisis, which kills ~116 people each day.
patient education
Preop information gives the pt realistic expectations of the care that can be provided. Its an opportunity to set the pt's expectations correctly in terms of how much pain to expect and the course of postop pain. Providing this type of education can influence how the pt experiences postop pain and has been shown to significantly reduce postop opioid consumption. However, one must be aware of the nocebo effect which occurs when negative expectations of the pt regarding tx causes the tx to have a more negative effect than it otherwise would have.
Negative Expectations
Pt education can also be used to influence pt's expectations or desire to be RXed opioids by the potential AEs of opioids. Shindo et al reported on 1702 pts scheduled for parathyroidectomy and thyroidectomy. Pts were educated preop regarding pain and multimodal pain mgmt. Pts also were told what to expect after surgery and the potential AEs of opioid administration. They were able to show a significant reduction in opioid consumption in pts given preop education.
LA infiltration
Similar to other regional anesthesia techniques, local infiltration of LA has been shown to significantly reduce periop opioid consumption and can be an integral part of a multimodal analgesic approach. Advantages include ease of admin (can be given by the surgeon) and lack of motor impairment. Recently depo forms of LA (e.g. liposomal bupivacaine) have shown promise to prolong analgesic effects w/o increasing the risk of LAST. Of note, recent systematic reviews cite the lack of high quality trials and have not conclusively demonstrated that liposomal bupivacaine is superior to plain bupivacaine. More research is needed in this area to evaluate efficacy and duration of novel sustained release forms of LA.
IV lidocaine
Surgery-induced stimulation of the inflammatory response plays a major role in the development of several postop disorders. LAs possess anti-inflammatory activity and have been shown to positively affect outcomes after surgery, esp colorectal or abdominal surgery. In these procedures IV lidocaine is associated w/ reduced pain scores and opioid usage as well as earlier return of bowel fxn. The MOA by which the clinical effects of systemic lidocaine are achieved is unknown. Systemic admin doesnt result in high enough local conc to block peripheral nociception. Its been proposed that the low conc achieved may preferentially affect damage or sensitized nerves or thru prevention of neoproliferation of Na channels. Other MOA include systemic anti-inflammatory effects or prevention of central sensitization. The clinical evidence supporting IV lido use as a periop analgesic is low to moderate. A meta-analysis was only able to demonstrate a weak effect in the immediate postop period that was not evident at 48hrs. There appears to be dose effect, w/ intraop infusion doses >2mg/kg/hr or infusions that are continued for 24hrs are more effective. Although lidocaine toxicity is a concern, doses of 1-2 mg/kg/hr even w/ a loading dose of 1 mg/kg result in plasma conc well below levels associated w/ signs of systemic toxicity. However, when lidocaine infusions are combined w/ other routes of LA admin (e.g. local infiltration, TAP block) toxicity is possible and has been reported.
Multimodal definition
The combination of different analgesics that act by different mechanisms, resulting in additive or synergistic analgesia with lowered adverse effects Note the emphasis on the combination of agents that act by different mechanisms. This should result in synergistic analgesia w/ lowered AEs compared to sole administration of an individual pharmacological agent.
glutaminergic pathways
The lower portion of this figure from Brown et al shows the inhibitory effect of ketamine (and Mg) by blocking transmission in the dorsal horn of the spinal cord from the peripheral afferent neuron (PAF) and dorsal root ganglion (DRG) to the projecting neuron (PN) - the ascending pathway. The upper portion of the figure shows multiple projections from the arousal centers in the brainstem that are mediated by glutamatergic receptors. These projections are targets of the inhibitory effects of ketamine.
why do we need multimodal analgesia
The main reasons we need multimodal analgesia is to improve analgesia and reduce AEs. Several recent surveys have found that up to 80% of pts report moderate-severe pain after surgery—even when analgesics are given. Admin of a sole analgesic medication to achieve pain control may produce unwanted side effects like respiratory depression w/ opioids or sedation w/ gabapentin
Regional Anesthesia
The use of regional anesthesia as a part of multimodal analgesic regimen may decrease periop opioid consumption for many surgical procedures. Significant advantages have been demonstrated for hip and knee surgery w/ both neuraxial and peripheral nerve blocks. Subcostal TAP blocks and thoracic epidurals are being used for abdominal surgery. Paravertebral and pectoralis nerve blocks are being used w/ breast surgery. Infusions of LA via perineural catheters can prolong effects and provide superior analgesia compared to opioids.
alpha 2 agonists
These agents work by binding to alpha 2 receptors in the brain and spinal cord that results in inhibition of norepinephrine release. They exert their effect by inhibiting cyclic AMP which reduces K efflux and Ca influx resulting in a hyperpolarized state. This hyperpolarization reduces norepinephrine release. Theres a high density of alpha-2 adrenergic receptors in the substantia gelatinosa in the dorsal horn of the spinal cord, the peripheral afferent nerves synapse. Inhibition of norepinephrine transmission here results in analgesia. Classic alpha 2 agonists include dexmedetomidine, tizanidine and clonidine.
peripheral sensitization
Tissue injury results in release of inflammatory mediators which alter the response of peripheral nociceptors causing them to fire at a much lower threshold. This results in peripheral sensitization whereby a nonpainful stimulus produces pain (allodynia) and a painful stimulus produces an exaggerated response (hyperalgesia).
opioid crisis
We all are aware of the opioid crisis but we cannot ignore the contribution of periop pain mgmt to the crisis. Up to 10% of opioid naïve post surgical pts become chronic users. Data suggests that pts who have a high requirement for opioids as an inpatient require large doses at home contributing to the risk of becoming a chronic user.
