Nonopioid Analgesics for the Perioperative Geriatric Patient

A Narrative Review

Sylvia H. Wilson, MD; P. Ryan Wilson, MD; Kathryn H. Bridges, MD; L. Hannah Bell, MD; Carlee A. Clark, MD

Disclosures

Anesth Analg. 2022;135(2):290-306.

Abstract and Introduction

Abstract

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Management of acute perioperative pain in the geriatric patient can be challenging as the physiologic and pharmacokinetic changes associated with aging may predispose older patients to opioid-related side effects. Furthermore, elderly adults are more susceptible to postoperative delirium and postoperative cognitive dysfunction, which may be exacerbated by both poorly controlled postoperative pain and commonly used pain medications. This narrative review summarizes the literature published in the past 10 years for several nonopioid analgesics commonly prescribed to the geriatric patient in the perioperative period. Nonopioid analgesics are broken down as follows: medications prescribed throughout the perioperative period (acetaminophen and nonsteroidal anti-inflammatory drugs), medications limited to the acute perioperative setting (N-methyl-D-aspartate receptor antagonists, dexmedetomidine, dexamethasone, and local anesthetics), and medications to be used with caution in the geriatric patient population (gabapentinoids and muscle relaxants). Our search identified 1757 citations, but only 33 specifically focused on geriatric analgesia. Of these, only 21 were randomized clinical trials, and 1 was a systematic review. While guidance in tailoring pain regimens that focus on the use of nonopioid medications in the geriatric patient is lacking, we summarize the current literature and highlight that some nonopioid medications may extend benefits to the geriatric patient beyond analgesia.

Introduction

The geriatric population, comprising adults ≥65 years, is projected to increase by almost 50% between 2015 and 2030.^[1] This expanding population comprises roughly one-third of surgical procedures.^[2,3] As surgery is often synonymous with pain, geriatric analgesic regimens are needed.

While acute and chronic pain are prevalent and complex in geriatric patients,^[4] analgesic management is not simplistic. Physiological changes in the elderly patient impact pharmacokinetics including age-associated increases in body fat with decreased muscle mass and total body water (Table 1).^[5]

The reduced volume of distribution (V_d) for hydrophilic drugs and increased V_d for lipophilic medications alter the onset and effective dose of medications. Age-associated changes in protein quantity and binding can alter drug bioavailability, while decreased hepatic and renal function can impact drug metabolism and elimination. As neural fiber density and transmission along pain fibers are altered,^[6] overall analgesic requirements are decreased with aging.^[7] Concurrently, geriatric patients are at increased risk of postoperative delirium (acute changes in cognition and attention) and postoperative cognitive dysfunction (POCD; more subtle cognitive decline after surgery persisting for several months to a year or more involving disorientation, language difficulties, and learning or memory impairment).^[8,9] Opioids, the traditional mainstays of pain regimens, are associated with increased rates of delirium,^[10] POCD,^[11] and respiratory depression in geriatric patients.^[5] Thus, pain management strategies incorporating nonopioid therapies should be strongly considered in aged patients.

Specific guidance regarding analgesic medication management in elderly patients remains inadequate as this population is frequently excluded from trials.^[7,12] Limited geriatric-specific education for health care providers and concerns for medication-related harm may foster inadequate analgesic therapy for aged patients. This review aims to summarize the literature for nonopioid analgesics in the perioperative geriatric population, develop recommendations, and identify areas for future research.

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Table 1. Physiologic Changes of Aging and Associated Pharmacologic Consequences
Organ system	Physiologic changes	Physiologic consequence	Drug consequence
Body composition	↑ Body fat (20%–40%)	↑ V_d (lipophilic drugs)	↓ Drug onset
	↓ Muscle mass	↑ V_d (lipophilic drugs)	↓ Drug onset
	↓ Total body water (10%–15%)	↑ Plasma concentration (hydrophilic drugs)	↓ Elimination
	↓ Total body water (10%–15%)	↑ Plasma concentration (hydrophilic drugs)	↑ SE or toxicity risk
Neurologic	Neuronal loss/atrophy	Decreased inhibitory pain control Altered pain pathways	Altered response to pain
	↓ Neurotransmitter synthesis		↑ Drug sensitivity
	↓ CBF
	↓ Opioid receptor density
Cardiac	↓ Cardiac output	Rapid, higher drug peak plasma concentration	↑ Toxicity risk
GI	↓ Blood flow	↓ Transit time	Altered bioavailability
	↓ Motility	Altered drug absorption
	↓ Motility	Constipation
	↓ Digestive enzyme activity
	↑ pH
	Mucosal atrophy	GI distress
Hepatic	↓ Liver mass	↓ Serum albumin	↑ Drug half-lives
	↓ Hepatic blood flow	↓ Drug metabolism	↑ Plasma concentration
	↓ CYP450 enzymes	↓ First pass effect	Altered protein binding
Renal	Atrophy	↓ Renal elimination	↑ Plasma concentration
Renal	↓ RBF/GFR	↓ Renal elimination	Accumulation of active metabolites
Integumentary	Thinned epidermis	Augmented transdermal absorption	↑ Peak plasma concentrations
Integumentary	Weakened dermis	Augmented transdermal absorption	↑ Peak plasma concentrations

Adapted from Andres et al.⁵
Abbreviations: CBF, cerebral blood flow; GFR, glomerular filtration rate; GI, gastrointestinal; RBF, renal blood flow; SE, side effect; V_d, volume of distribution.

Table 2. Summary of Nonopioid Analgesics Commonly Prescribed Throughout the Perioperative Period: Acetaminophen and NSAIDs
Medication and dosing	Analgesic mechanism	Pharmacokinetics	Specific properties or concerns
Acetaminophen (paracetamol)IV/oral: 1000 mg q 6–8 h MAX: 4 g/d	Under investigation	Hepatic, renal, and GI metabolism	NAPQI (reactive metabolite) binds glutathione excreted in urine. NAPQI responsible for acetaminophen-induced toxicity. Doses >4g/d ↑ NAPQI and may overwhelm glutathione stores
	Activate cannabinoid	Hepatic, renal, and GI metabolism
	CB1 receptorsInhibits NO pathways	T_1/2 1.5–2.5 h
	CB1 receptorsInhibits NO pathways	Onset: 15 min IV and 30 min oral
	Peripherally ↓ PGE2	Peak: 30 min IV, 1 h oral	Liver dysfunction or alcohol abuse may ↑ hepatotoxicity risk
	Peripherally ↓ PGE2	Duration: 4–6 h IV/oral
NSAIDs	↓ Prostaglandins by COX-1 and 2 inhibition	Hepatic metabolism	Concern for ↑ GI ulcer formation, ↑ bleeding, ↑ MI/CVA risk, and ↓ RBF
NSAIDs	↓ Prostaglandins by COX-1 and 2 inhibition	Renal excretion
Ibuprofen	COX-1 and 2 inhibition	Onset: 1 h oral	Anti-inflammatory properties may require days to 2 wk
Oral: 400–800 mg q 6–8 h		Peak: 2–4 h oral
MAX: 3200 mg/d		Peak: 2–4 h oral
Diclofenac	COX-1 and 2 inhibition	Onset: 15 min oral	IV: contraindicated with moderate to severe renal impairment Volume status correction for prevention of hypovolemia before IV initiation Topical: comparable or slightly ↓ efficacy versus oral NSAIDs. Safety profile may be slightly superior to oral NSAIDs⁵¹
IV: 37.5 mg q 6 h		Duration: 8 h oral
Oral: 18–50 mg three times daily
MAX: 150 mg/d
Ketorolac	COX-1 and 2 inhibition	Onset: 30 min IV	Limit geriatric patients to 15 mg q 6 h (max 60 mg/d) Restrict IV to 5 d
IV: 15–30 q 6 h		Peak: 1–2 h IVDuration: 4–6 h IV
IM: 60 mg q 6 h
MAX IV/IM: 120 mg/d
Oral: 10 mg q 4–6 h
MAX oral: 40 mg/d			Oral typically reserved for continuation after IV dose
Celecoxib	COX-2 inhibition	Onset: 12–24 h	May ↑ MI and CVA risk
Chronic: 200 mg/d or 100 mg twice daily			Max geriatric dose 400 mg/d
Chronic: 200 mg/d or 100 mg twice daily			Limit poor CYP2C9 metabolizers to half the lowest recommended dose
Postop: 200 mg twice daily
Meloxicam	Preferential COX-2 inhibition	Bioavailability 89% Hepatic metabolism Biliary and renal excretion T_1/2 20–24 h Peak: 4–11 h (oral and PR)	Strongly bound to plasma proteins Improved GI tolerability versus traditional NSAIDs No studies examining CV impact Pharmacokinetics: ↑ C_max in geriatric (>65 y) females versus younger females (<55 y). No difference in geriatric males
7.5–15 mg oral daily	Preferential COX-2 inhibition
7.5–15 mg oral daily	Mild (25%–35%) COX-1 inhibition at doses over 7.5 mg oral

Adapted from Liukas et al,⁴⁶ Ottani et al,⁴⁷ Bacchi et al,₄₉ Patrono,₅₀ and Rainsford.⁵²
Abbreviations: C_max, maximum plasma concentration; COX, cyclooxygenase; CV, cerebrovascular; CVA, cerebrovascular accident; GI, gastrointestinal; IM, intramuscular; IV, intravenous; MI, myocardial ischemia; NAPQI, N-acetyl-p-benzoquinone imine; NO, nitric oxide; NSAID, nonsteroidal anti-inflammatory drug; PGE2, prostaglandin E2; PR, rectal; RBF, renal blood flow; T_1/2, half-life.

Table 3. Summary of Nonopioid Analgesics Primarily Limited to the Acute Perioperative Period: NMDA Antagonists, ^{71,72,80,87–89} Dexmedetomidine, ^73,75,76 Dexamethasone, ^74,77,78 and Lidocaine ⁷⁹
Medication and dosing	Analgesic mechanism	Pharmacokinetics	Specific properties or concerns
NMDA antagonists	NMDA receptor inhibition at dorsal horn and hippocampus		May prevent or decrease central sensitization
Ketamine	Noncompetitive antagonist	Hepatic metabolism	↓ POCD and ↓ CRP after cardiac surgery (0.5 mg/kg)
IV 0.25–1 mg/kg bolus, infusion 0.05–0.25 mg/kg/h	↓ Nuclear factor kB and ↓ IL-6 and TNF-α in animal models (0.5 mg/kg)	Renal elimination
		Onset: 30-s IV, 3–4 min IM, and 30 min oral
		Onset: 30-s IV, 3–4 min IM, and 30 min oral	May ↑ hallucinations and nightmares at higher doses (>1 mg/kg). Consider ↓ doses (0.5 mg/kg) to minimize
IM 2–6 mg/kg		T_1/2: 10–15 min
Oral 4–8 mg/kg		T_1/2: 10–15 min
Magnesium	Competitive and noncompetitive antagonism of hippocampal presynaptic Ca²⁺ channels ↓ Ca²⁺ influx (amplifies morphine-induced analgesia)	Renal excretion	↓ Catecholamine release
IV bolus 30–50 mg/kg and infusion 8–15 mg/kg/h		Onset: 1–2-min IV and 1-h IM	↑ Coronary and systemic vasodilation
		Onset: 1–2-min IV and 1-h IM	↓ SAH and vasospasm
		Duration: 30-min IV and 3–4-h IM	↓ Arrhythmias. ↑ bronchodilation
			↓ SA and ↓ AV node conduction
			↓ Dose: ↓ GFR or ↓ cardiac conduction
			Potentiates neuromuscular blockade
Dexmedetomidine	Alpha-2 agonist	Onset: 2–5-min IV	Sedation, anxiolysis, and analgesia
IV bolus: 0.25–0.6 μg/kg	↓ Hyperalgesia	Peak: 15-min IV	↓ Doses needed to sedate elderly
IV infusion: 0.1–0.5 μg/kg/h	↓ Microglia activationHypothesized to have no impact on GABA	T_1/2: 2–3 h	May ↓ postoperative delirium
			↓ Catecholamines
			Potential hypotension and bradycardia
			↓ Minimal respiratory depression
Dexamethasone	Inhibits bradykinin and neuropeptide release	Hepatic metabolism	25–30 times potency of hydrocortisone or cortisol
IV: 0.1 mg/kg (× 1)	Inhibits bradykinin and neuropeptide release	Renal excretion	25–30 times potency of hydrocortisone or cortisol
PONV: 4 mg IV	↓ Prostaglandin	Moderate albumin binding	Nearly no mineralocorticoid effect
	↓ Signaling from nociceptive C-fibers	Onset: 1–2 h
	↓ Chemokines, cytokines, and phospholipase A	T_1/2: 35–54 h
Lidocaine	Na⁺ channel inhibition	Hepatic metabolism and plasma protein binding (largely unchanged in elderly unless liver disease)	Consider lower doses in elderly (eg, 1.5 mg/kg bolus; 2 mg/kg/h infusion)
IV bolus: 2 mg/kg	Theorized central mechanism for systemic analgesia
IV infusion: 1–5 mg/kg/h
			Low threshold to check systemic levels
			Bradycardia
			Local anesthetic systemic toxicity
			Topical: apply 12 h then remove for 12 h

Abbreviations: AV, atrioventricular; CRP, C-reactive protein; GABA, gamma-aminobutyric acid; GFR, glomerular filtration rate; IL, interleukin; IM, intramuscular; IV, intervenous; Na⁺, sodium; NMDA, N-methyl-D-aspartate; POCD, postoperative cognitive dysfunction; PONV, postoperative nausea and vomiting; SA, sinoatrial; SAH, subarachnoid hemorrhage; T_1/2, half-life; TNF-α, tumor necrosis factor-α.

Table 4. Summary of Nonopioid Analgesics That Should Be Considered With Caution in the Geriatric Patient: Gabapentinoids ^131,132 and Muscle Relaxants ^133,134
Medication and dosing	Analgesic mechanism	Pharmacokinetics	Specific concerns or side effects
Gabapentinoids	Inhibit voltage dependent Ca²⁺ channels (α₂δ subunit)	Renal elimination (unchanged)	↓ Dose based on GFR
		Renal elimination (unchanged)	Perioperative use currently questioned
		Not bound by plasma proteins	May be associated with respiratory complications in patients with risk factors for respiratory compromise¹⁰⁰
Gabapentin		T_1/2 5–9 h	Caution in elderly
IR: 100–1200 mg q 8 h		Peak: 3–4 h
ER: 300–3600 mg/d		Peak: 3–4 h
Pregabalin		T_1/2 5–7 h	Caution in elderly
IR: 75–600 mg/d (divided twice daily or three times daily)		T_1/2 5–7 h
IR: 75–600 mg/d (divided twice daily or three times daily)		Peak: 1 h
ER: 165–330 mg/d		Peak: 1 h
Muscle relaxants	AChE inhibition (CNS and ANS)	Hepatic metabolism	Not recommended in elderly
↑ Age or liver disease will ↑ T_1/2 and ↓ protein binding	AChE inhibition (CNS and ANS)	Renal elimination	↑ Respiratory depression if combined with opioids or benzodiazepines
↑ Age or liver disease will ↑ T_1/2 and ↓ protein binding	↓ Somatic muscle activity	(↓ GFR = ↓ dose)	May ↑ fracture risk from sedation¹²⁹
Methocarbamol		T_1/2 1–2 h	Inhibits AChEI
IV/IM: 1 g q 8 h		Plasma protein binding 46%–50%	Side effects: dizziness, headache, and sedation
(MAX IV/IM: 3 g/d × 3 d)
Oral: 1000–1500 mg q 6–8 h
(MAX oral: 4–6 g/d)
Cyclobenzaprine IR: 5–10 mg three times daily ER: 15–30 mg/d		T_1/2 18 h	Anticholinergic effects
		T_1/2 18 h	ER not recommended in elderly
		Highly plasma protein bound(↑ Concentrations with liver disease and ↑ age)	Avoid in patients on MAOIs (↑ risk of hyperpyretic crisis and/or seizures)
			Avoid with CHF or recent MI
		Elimination relatively slow	Side effects: drowsiness, dry mouth, fatigue, headache, and dizziness

Abbreviations: AChE, acetylcholinesterase; AChEI, acetylcholinesterase inhibitor; ANS, autonomic nervous system; Ca²⁺, calcium; CHF, congestive heart failure; CNS, central nervous system; ER, extended release; GFR, glomerular filtration rate; IM, intramuscular; IR, immediate release; IV, intravenous; MAOIs, monoamine oxidase inhibitors; MI, myocardial ischemia; T_1/2, half-life.