16.1 Introduction

Pain, an unpleasant sensory and emotional experience, presents unique challenges to care providers in the neuro-intensive care unit (neuro-ICU). Over the last decade, convincing data has driven a paradigm shift in the general ICU toward maintaining patient arousal while treating pain. ¹ The ICU liberation collaborative focuses on treating pain first and utilizing numerous tools for continued assessment in distinguishing pain from agitation and delirium (PAD). The endpoint is earlier liberation from ICU and mechanical ventilation by reducing sedative medications and supporting early mobility. ^{1 , 2} The Critical Care Medicine (CCM) collaborative created the ABCDEF bundle to accomplish this purpose which stands for:

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  Assess, Prevent, and Manage Pain

  
  
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  Both spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs)

  
  
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  Choice of Sedation

  
  
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  Delirium: Assess, Prevent, and Manage

  
  
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  Early Mobility and Exercise

  
  
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  Family Engagement and Empowerment ^{1 , 2 , 3}

Several risks limit these strategies of caring for neurologically injured patients, and there is a paucity of data to validate the current trend in the neuro-ICU population. ^{4 , 5} Nonetheless, guidelines recommend whenever it is safe, treat pain judiciously and preserve the neurologic examination, the gold standard monitor for the central nervous system (CNS). ^{1 , 4}

This chapter aims to highlight the challenges of managing pain in the neuro-ICU while practicing within the framework of the current ICU liberation movement. Individualized therapy will be discussed for postoperative patients, patients with neurodegenerative diseases at risk for pain, and special cases that make management of pain in the neuro-ICU particularly difficult. Although opioid therapy is the mainstay for pain management historically, these medications often over-sedate frail neurologically susceptible patients. ⁴ Thus, opioid-sparing therapies such regional anesthesia, adjunct pain medications, and various relaxation techniques are discussed in detail. This chapter intends to provide a quick guide for the A component (assess, prevent, and manage pain) of the ABCDEF bundle in the neuro-ICU.

16.2 Modern Strategy of Pain Management in ICU Liberation

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  Joint Commission on Accreditation of Healthcare Organization (JCAHO) mandated in 2002 “implementation of standards” in pain assessment, prevention, and treatment which was termed the “5^th vital sign” in the ICU. ^{1 , 4}

  
  
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  Studies supported reducing sedation and mobilizing patients improved ICU outcomes. ^{1 , 2 , 3 , 6}

  
  
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  ABCDEF bundle implemented liberation strategy to address CCM Guideline 2012. ^{1 , 2}

  
  
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  CCM guidelines excluded neurologically injured patients for safety reasons. ¹

  
  
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  Addressing the A component (assess, prevent, and treat pain) of the ABCDEF bundle first was recommended since pain confounds delirium and agitation. ^{1 , 2}

  
  
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  The use of different pain scales for continuous ongoing assessment was recommended. ^{1 , 6 , 7}

  
  
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  Prevent/anticipate pain prior to surgery and painful procedures in ICU. ¹

  
  
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  Opioid adjuncts reduce dose and ultimately neuro-confounding and neurotoxic effects. ^{3 , 5 , 6}

16.3 Challenges of Pain Management in Neuro-ICU

^{1 , 4 , 5 , 7}

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  Balance maintaining neurologic examination versus providing comfort.

  
  
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  Balance neurologic examination versus offering enough sedation for “neuro-specific” issues such as reducing cerebral blood volume (CBV), intracranial pressure (ICP), and cerebral metabolic rate for oxygen (CMRO2) and seizure control. ^{4 , 5 , 8}

  
  
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  Severity of brain injury dictates, and ICP and other multimodality monitoring may be helpful. ⁴

  
  
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  Balance neurologic examination versus offering enough sedation to provide endotracheal tolerance, ventilator synchrony, and shivering control. ⁷

  
  
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  Early mobilization recommended only if neuro-specific issues are well controlled.

16.4 Individualizing Therapy in NICU

16.4.1 Pharmacologic Interventions of Pain

(Table 16‑1)

Table 16.1 Properties of commonly used analgesics in critical care

Drug/Class	Mechanism of action	Dose	Advantages	Disadvantages	Metabolism	Notes
Acetaminophen	Exact mechanism unknown; antipyretic effect on hypothalamus; prostaglandin synthesis inhibition	IV: 1,000 mg every 6 hours PO: 650–1,000 mg every 4–6 hours (≤4,000 mg/day)	Has analgesic and antipyretic properties IV formulation rapid acting	No anti-inflammatory property	Hepatic	Available in IV formulation, may mask an infectious process IV formulation is costly and may be restricted Caution use with liver failure
Nonsteroidal anti-inflammatory drug*
Ketorolac	COX-1 and 2 inhibitor	IV: 15–30 mg every 6 hours up to 5 days	Potent analgesia, no respiratory depression Good anti-inflammatory property	Risk of bleeding and renal dysfunction	Hepatic (with renal clearance)	Available in IV formulation, use is limited to 5 days, avoid in renal failure Infrequently used in neuro-ICU due to bleeding risk
Ibuprofen	COX-1 and 2 inhibitor	IV: 400–800 mg every 4–6 hours (<3,200 mg/day)	No respiratory depression	Risk of bleeding and renal dysfunction	Renal	Avoid in renal failure, available in IV formulation
Naproxen Sodium	COX-1 and 2 inhibitor	PO: 500 mg every 12 hours (Max 1,250 mg.day)	No respiratory depression Used for arthritic pain, migraines, gout	Risk of bleeding and renal dysfunction	Hepatic	Not recommended with CrCl <30 mL/minute Delayed-release not recommended for acute pain
Celecoxib	COX-2 inhibitor	200 mg twice a day	No respiratory depression, reduce risk gastric bleeding	Some risk of bleeding	Hepatic	Not commonly used in ICU setting
Opioids
Tramadol	Partially binding opioid µ receptor Inhibits reuptake of norepinephrine and serotonin	Immediate release: 50–100 every 4–6 hours (max 400 mg/day)	Good for moderate to moderate-severe pain	CNS and respiratory depression Increased risk of seizures Serotonin syndrome in patients on SSRI, SNRIs, TCAs, and neuroleptics	Hepatic	Titrating may improve tolerability Active metabolite has 200-fold greater affinity for opioid receptor Max dose for renal failure is 200 mg/day Max dose for patients with cirrhosis 50 mg/12 hours Toxicity may be due to mono-amine effect rather than opioid effect 28
Morphine	Opioid receptor agonist	IV: 2–5 mg every 2–4 hours Initial continuous infusion: 1–2 mg/hour PO: 10–30 mg every 3–4 hours	Easy titration	Risk of respiratory depression, active metabolites in renal failure	Hepatic (renal clearance)	Avoid in renal failure, pruritus related to histamine release
Fentanyl	Opioid receptor agonist	IV: 25–50 mcg every 5–15 minutes Initial continuous infusion: 10–20 mcg/hour	Easy titration, available in several formulations; rapid onset	Risk of respiratory depression, chest wall rigidity at high doses	Hepatic	Short half-life, significant increase in context-sensitive half-life with prolonged infusion
Hydromorphone	Opioid receptor agonist	PO: 1–2 mg every 3–4 hours IV: 0.5–1 mg every 3–4 hour Initial continuous infusion: 0.2–0.3 mg/hour	Easy titration	Risk of respiratory depression	Hepatic	Shorter duration of action compared to morphine, may require frequent dosing in opioid tolerant, less pruritic than morphine
Remifentanil	Opioid receptor agonist	Loading dose: 1.5 mcg/kg Continuous infusion: 0.5–15 mcg/kg/hour	Easy titration, ultra-rapid onset and elimination	Risk of respiratory depression, rebound hyperalgesia	Plasma esterases	Consider longer acting opioid before discontinuation
Oxycodone	Opioid receptor agonist	Initial PO: 5–10 mg every 3–4 hour	Intermediate duration of action	Respiratory depression	Hepatic	Available in combination with acetaminophen, caution with patients with simultaneous use of acetaminophen
Membrane channel stabilizers
Gabapentin	Analgesic mechanism is unknown: GABA analogue (no effect on GABA receptor)	100 mg three times a day can titrate up to 1,800 mg/day	Effective in neuropathic pain and partial seizures Reduction in opioid requirement when used as part of multi-modal therapy	Sedation	Negligible (renal excretion)	Rapid discontinuation may precipitate seizure, gradual titration Adjust dose for renal impairment based on CrCl
Pregabalin	Exact mechanism unknown: GABA analogue that binds to voltage gated calcium channel	50 mg three times a day, may increase to 100 mg three times a day	Effective in neuropathic pain, fibromyalgia and epilepsy Reduction in opioid requirement when used as part of multi-modal therapy	Dose-dependent symptoms of dizziness and sedation Requires titration	Negligible (renal excretion)	Gradual titration Adjust dose for renal failure based on CrCl No effect on opiate receptor
Anesthetics
Ketamine	NMDA antagonist	Loading dose: 0.1–0.5 mg/kg Infusion dose: 0.05–0.4 mg/kg/hour	Minimal respiratory depression, prevention in pain chronicization	Psychomimetic reactions	Hepatic	Minimal effect on ICP at subanesthetic dose, useful with opioid tolerant patients
Dexmedetomidine	Central α2-receptor agonist	Loading dose: 1 mcg/kg over 10 minutes Infusion dose: 0.2–0.7 mcg/kg/hour	Easy titration, no respiratory depression, mild analgesic property, minimal effect on ICP	Hypotension, bradycardia at high doses	Hepatic	Useful with mechanical ventilation weaning process, cooperative sedation Loading dose not commonly used due to rapid decrease in BP Extended use up to 5–7 days feasible in appropriate patient selection
Lidocaine 30	Sodium channel blocker	Loading dose: 1–2 mg/kg Infusion dose: 1–2 mg/kg/hour optimal dose	Effective in treatment of acute pain Anti-inflammatory properties Reduction in opioid requirement when used as part of multi-modal therapy	Cardiac toxicity at high dose Seizures Prolonged time to reach steady state without bolus	Hepatic	Avoid in chronic liver failure Therapeutic plasma level 2.5–3. 5µg/mL CNS toxicity can occur at levels of >5 µg/mL. CNS toxicity signs: numbness of tongue, metallic taste, light headedness, tinnitus, drowsiness, muscle twitching, unconsciousness, coma, and death
Note: *NSAIDs are contraindicated for perioperative pain in the setting of coronary artery bypass graft surgery. Abbreviations: BP, blood pressure; CNS, central nervous system; GABA, gamma aminobutyric acid; ICP, intracranial pressure; ICU, intensive care unit; IV, intravenous; NMDA, N-methyl-D-aspartate; NSAIDs, nonsteroidal anti-inflammatory drugs; SNRIs, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCAs, tricyclic antidepressants.

Specific comorbidities that require special considerations for pain management (Table 16‑2)

Table 16.2 Pain management in specific patient populations

Pathophysiology	Notes
Elderly	Decreased GFR, drug doses adjusted based on creatinine clearance Decreased respiratory center sensitivity, opioids started at lower dose Decreased receptors in CNS (5HT, AcH, and Dop); therefore, side effects of buprenorphine, tramadol, and tapentadol are potentiated
End-stage renal disease	Decreased GFR and increased volume of distribution, renal dosing
Chronic liver disease	Decreased hepatic blood flow and drug metabolism, doses should be decreased
Cardiac disease	Caution drugs that may cause bradycardia or hypotension (e.g., high doses of opioids, dexmedetomidine) or hypertension or arrhythmias (e.g., ketamine)
Pulmonary disease	Obese patients have obstructive sleep apnea and decreased FRC Supplemental oxygenation or CPAP use may be helpful Minimize opioid use and maximize adjuncts
Dementia	Avoid drugs that potentiate cognitive impairment (e.g., opioids, membrane channel stabilizers) Avoid polypharmacy PCA less suitable
Opioid tolerant	Exhibit opioid-induced hyperalgesia; therefore, higher doses of opioids required Respiratory depression less common Variable opioid cross-tolerance Ketamine helpful in opioid tolerance Maximize use of adjuvants
Substance use disorder	Methadone maintenance therapy should continue with addition of opioids to manage acute pain Should discontinue the use of buprenorphine; intravenous opioids which exhibit high μ-receptor affinity should be used to manage pain Maximize use of adjunct agents PCA to maintain a more stable plasma concentration compared to intermittent intravenous boluses
Alcoholism	Acute ingestion has depressive effect on CNS and increases sensitivity to sedatives Alcohol increases endogenous opioid levels Chronic alcohol ingestion causes chronic liver disease which decreases drug metabolism
Postoperative spine	NSAIDs may inhibit bone healing Membrane channel stabilizers help with neuropathic pain Treat muscle spasms with muscle relaxants (e.g., diazepam, cyclobenzaprine, tizanidine, baclofen)
Craniotomy	Frequent neurologic assessments; thus, easily titratable drugs preferred Avoid drugs that sedate and decrease respiratory function Opioids decrease ICP in adequately ventilated patients Dexmedetomidine and subanesthetic ketamine have minimal effect on ICP Scalp blocks reduce opioid requirements
Abbreviations: CNS, central nervous system; CPAP, continuous positive airway pressure; FRC, functional residual capacity; GFR, glomerular filtration rate; ICP, intracranial pressure; NSAIDs, nonsteroidal anti-inflammatory drugs; PCA, patient-controlled analgesia.

Nonopioid Analgesics (Primarily for Mild Pain)

⁵

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  Acetaminophen ^{10 , 11}

  
  
  
  
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    Useful in patients unable to receive oral medications

    
    
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    Intravenous (IV) dose may reduce opioid requirements ¹¹

  
  
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  Nonsteroidal anti-inflammatory drugs (NSAIDs) ¹²

  
  
  
  
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    Avoid in neurosurgical population for platelet inhibition

    
    
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    May lead to kidney injury with chronic use and risk aseptic meningitis

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