Pain occurs in up to 80% of patients in the intensive care unit (ICU) and is a significant source of fear and stress for the critically ill, varying among many subgroups, such as surgical patients and even those at rest.1

If not adequately managed, pain can have many psychological and physiologic consequences, along with increased cost and morbidity.2,3 Opioids, such as fentanyl, hydromorphone, methadone, and morphine, have long been the mainstay treatment for managing pain in patients in the ICU and are equally effective when titrated to similar pain intensity end points.1 However, patients in the ICU often experience many adverse effects (AEs) of opioids, such as constipation, nausea, and vomiting.

Increasing concerns about the opioid crisis is also driving the search for other methods of pain relief. The number of overdose deaths involving opioids was 6 times higher in 2017 than in 1999, according to the CDC.4

Taken together, these concerns suggest a greater role for a multimodal approach to acute pain management in the critically ill.

Multimodal analgesia is defined as the use of multiple analgesic medications of different classes to target different areas of the central and/or peripheral nervous system affecting pain. Although there are not much data regarding use in the ICU, studies have shown that a combination of pharmacologic agents may offer additive or synergistic effects and more effective pain relief than single-modality interventions.5 Nonopioid analgesics have been considered for this multi-modal approach because of their ability to help reduce opioid use and AEs.1,5 Adjuncts, such as acetaminophen, α receptor agonists, gabapentin, 2 ketamine, lidocaine, and nonsteroidal anti-inflammatory drugs (NSAIDs), may play a role in acute pain management.

Adjunctive Therapies for Opioid Use
Acetaminophen is an antipyretic, nonopioid analgesic that is considered a weak inhibitor of prostaglandin synthesis. Studies have shown that intravenous (IV) acetaminophen added to opioid therapy produces superior pain control, with a decrease in opioid-related AEs, such as postoperative nausea or vomiting.6,7 The benefits of IV administration include its greater central nervous system penetration and shorter onset of action—about 5 to 10 minutes versus 30 to 60 minutes for IV and oral administration, respectively. However, the cost of IV acetaminophen is 400-fold greater than that of oral acetaminophen, posing a significantly larger cost burden.8 The AE profile for both routes of administration is similar, as total daily doses are recommended to not exceed 3 to 4 g per day because of the risk of liver toxicity.6 Recent case reports note other AEs, such as IV acetaminophen–induced hypotension, that may be particularly concerning in the critically ill population. Patients in the ICU are often admitted for sepsis/septic shock requiring fluid and vasopressor support, and any change in mean arterial pressure and potential increase in vasopressor requirements following IV acetaminophen administration warrants close monitoring.9 To date, limited evidence supports the use of IV acetaminophen in the ICU, but ongoing trials are further assessing the efficacy and safety of IV acetaminophen.

α2-Receptor agonists include drugs such as clonidine and dexmedetomidine. Their analgesic properties come from inhibition of nociceptive neurotransmission and of norepinephrine release, which causes hyperpolarization and impedespain signals to the brain.10

Dexmedetomidine has an onset of 5 to 10 minutes, whereas oral clonidine can take up to 60 minutes. Common AEs of this class are bradycardia and hypotension, whereas rebound hypertension is a more common AE with clonidine.10,11 Use of α2-receptor agonists has been associated with decreased postoperative opioid consumption, nausea, and pain intensity, which are significant end points for patients in the ICU.12

Gabapentinoids include anticonvulsants used for neuropathic pain, such as gabapentin and pregabalin. Their analgesic properties are exhibited through mechanisms of binding to voltage-gated calcium channels and inhibiting release of excitatory neurotransmitters.13 Recent trials illustrated that coadministering gabapentin and opioids reduced opioid consumption and demonstrated a modest effect in promoting postoperative opioid cessation.14 Likewise, pregabalin was found to have clinically relevant opioid-sparing effects when given with opioids.15 However, both agents are available only for administration via the enteral route and possess similar AEs of dizziness and sedation.13,15 Although gabapentinoids appear promising, several questions remain regarding adjunctive use, such as the length of therapy, optimal dosage, and timing of therapy.

Ketamine is an N-methyl-D-aspartate receptor antagonist that blocks glutamate and can cause down regulation of central sensitization, which is thought to be involved in inducing pain.16 Ketamine is noted to have an opioid-sparing effect, decreasing patient opioid consumption when used as a continuous IV infusion in the ICU, and has been shown in trial findings to decrease postoperative nausea and vomiting.17,18 IV ketamine has an onset of 30 seconds, and potential AEs include increased blood pressure or psychomimetic effects with higher doses. Although ketamine is excreted primarily in the urine, there is a risk of accumulation of active metabolites in severe disease. Ketamine has a potential role as an adjunct to analgesic therapy and as use for acute pain in opioid-tolerant patients.16

Lidocaine is a local anesthetic with analgesic properties thought to occur by reducing sodium ions’ ability to permeate the neuronal membrane, suppressing nerve impulses. It can be given intravenously or topically, with an onset of 45 to 90 seconds and 4 hours, respectively. Because of the 90% hepatic metabolism of the drug, liver function tests should be frequently monitored to prevent accumulation. When used with opioids, continuous IV lidocaine infusion therapy exhibits opioid-sparing effects without a significant increase in serious AEs, though extra caution is still necessary for patients with diseases potentially exacerbated by an antiarrhythmic.19

NSAIDs work by inhibiting cyclooxygenase (COX) iso-enzymes, which lead to their anti-inflammatory and anti- platelet mechanisms, because synthesis of prostaglandins and thromboxanes is likewise affected. Agents in this class have varying selectivity of COX enzymes with AEs, such as bleeding and gastrointestinal effects. Examples include celecoxib, diclofenac, ibuprofen, and ketorolac. In the acute setting, NSAID use may be limited for patients with kidney injury. However, NSAIDs have a proven prominent role in providing analgesia and opioid-sparing effects associated with a decrease in opioid-related AEs, such as postoperative nausea and vomiting. 20

Conclusion
Although opioids are the mainstay of pain management in the ICU, these agents pose many risks in regard to their AEs and high potential for abuse. The use of nonopioid adjunctive therapies is associated with reducing opioid consumption and the ability to reduce opioid-related AEs. It is important to consider a patient’s comorbidities and provide appropriate monitoring to address AEs, especially when using a multimodal approach. Pharmacists should be aware of the many analgesic options available and the value of nonopioid adjunctive therapies for pain management.

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