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
Table 1. -
Physiologic Changes of Aging and Associated Pharmacologic Consequences
||↑ Body fat (20%–40%)
||↑ Vd (lipophilic drugs)
||↓ Drug onset
|↓ Muscle mass
|↓ Total body water (10%–15%)
||↑ Plasma concentration (hydrophilic drugs)
|↑ SE or toxicity risk
||Decreased inhibitory pain control
||Altered response to pain
|↓ Neurotransmitter synthesis
||↑ Drug sensitivity
|Altered pain pathways
|↓ Opioid receptor density
||↓ Cardiac output
||Rapid, higher drug peak plasma concentration
||↑ Toxicity risk
||↓ Blood flow
||↓ Transit time
||Altered drug absorption
|↓ Digestive enzyme activity
||↓ Liver mass
||↓ Serum albumin
||↑ Drug half-lives
|↓ Hepatic blood flow
||↓ Drug metabolism
||↑ Plasma concentration
|↓ CYP450 enzymes
||↓ First pass effect
||Altered protein binding
||↓ Renal elimination
||↑ Plasma concentration
||Accumulation of active metabolites
||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; Vd, volume of distribution.
The reduced volume of distribution (Vd) for hydrophilic drugs and increased Vd 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.
Table 2. -
Summary of Nonopioid Analgesics Commonly Prescribed Throughout the Perioperative Period: Acetaminophen and NSAIDs
|Medication and dosing
||Specific properties or concerns
IV/oral: 1000 mg q 6–8 h MAX: 4 g/d
||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
|CB1 receptorsInhibits NO pathways
||T1/2 1.5–2.5 h
|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
|Duration: 4–6 h IV/oral
||↓ Prostaglandins by COX-1 and 2 inhibition
||Concern for ↑ GI ulcer formation, ↑ bleeding, ↑ MI/CVA risk, and ↓ RBF
||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
||COX-1 and 2 inhibition
||Onset: 15 min oral
||IV: contraindicated with moderate to severe renal impairmentVolume status correction for prevention of hypovolemia before IV initiationTopical: 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
||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 IV
Duration: 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
||Onset: 12–24 h
||May ↑ MI and CVA risk
| Chronic: 200 mg/d or 100 mg twice daily
||Max geriatric dose 400 mg/d
|Limit poor CYP2C9 metabolizers to half the lowest recommended dose
| Postop: 200 mg twice daily
||Preferential COX-2 inhibition
||Bioavailability 89%Hepatic metabolismBiliary and renal excretionT1/2 20–24 hPeak: 4–11 h (oral and PR)
||Strongly bound to plasma proteins
Improved GI tolerability versus traditional NSAIDs
No studies examining CV impact
Pharmacokinetics: ↑ Cmax in geriatric (>65 y) females versus younger females (<55 y). No difference in geriatric males
| 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
Abbreviations: Cmax, 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; T1/2, half-life.
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.
We conducted a systematic literature search to identify articles using Medical Subject Heading (MeSH) terms and medication names in the PubMed, Scopus, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. Articles were limited to the English language and published in or after 2010. The search was created by a research librarian, and exact terms are detailed in Supplemental Digital Content 1, Appendix 1, https://links.lww.com/AA/D847. The literature search identified 1757 citations (Figure 1). After removal of duplicates, all 5 authors reviewed titles, abstracts, and publications to determine relevance. Given the paucity of literature on this topic, publications with a mean study population age ≥65 years in all arms were included, even if all subjects were not 65 years or older. The search identified 33 studies examining the impact of nonopioid analgesics on pain scores or opioid consumption in geriatric patients. Of these, 21 were randomized controlled trials (RCTs),13–31 and 1 was a systematic review32 (Supplemental Digital Content 2, Appendix 2, https://links.lww.com/AA/D848). The rest were RCTs describing nonpharmacologic interventions,33,34 prospective nonrandomized designs,35,36 or cohort studies.37–45 Notably, 2 trials described uncommon perioperative medications.31,44 While all included studies had a mean age over 65 years, 29 studies included subjects <65 years old,13–22,24–27,29–36,38–40,42–45 3 studies included only geriatric patients,28,37,41 and 1 publication did not clearly describe the age range for subjects.23 As there is a paucity of data regarding analgesic management in elderly patients, we will summarize the identified literature by medication type, supplement findings when able with nongeriatric publications, and present both concerns and benefits these medications may offer.
NONOPIOID ANALGESICS COMMONLY PRESCRIBED THROUGHOUT THE PERIOPERATIVE PERIOD
Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) provide effective analgesia throughout the perioperative period. Dosing, analgesic mechanisms, and pharmacokinetics are summarized in Table 2.46–50
Scheduled acetaminophen is associated with improved analgesia over per-request dosing. A retrospective review of geriatric patients with hip fractures found that scheduled acetaminophen (1000 mg intravenous [IV] every 8 hours) was associated with decreased length of stay (LOS), opioid consumption, pain scores, and missed therapy sessions versus those receiving per request acetaminophen (1000 mg orally).37 Likewise, a retrospective evaluation of 123 patients over 60 years old with hip fractures found scheduled postoperative acetaminophen (1000 mg IV every 8 hours for 24 hours) to be associated with less opioid consumption on postoperative day (POD) 1 (P = .008), decreased incidence of delirium (15.4% vs 32.8%; P = .024), and shorter hospital LOS (6.37 days vs 8.47 days, P = .037) compared with not receiving scheduled acetaminophen.53 Similarly, while single-dose preoperative acetaminophen improves pain after minor surgery,18,19 single-dose acetaminophen not continued in a scheduled manner may not provide the same analgesic benefit for more invasive surgical procedures.15,17 Finally, multiple RCTs have failed to persistently demonstrate any analgesic advantage of using IV acetaminophen compared to oral formulations with similar dosing strategies.13,16,54,55
Concerns Beyond Analgesia
Not exceeding the maximum recommended dose (4 g/d) of acetaminophen minimizes the risk of hepatotoxicity.7 As acetaminophen is often found in combination with other medications, current therapies must be reviewed when adding acetaminophen, and patients are advised to avoid toxicity. Although the US Food and Drug Administration (FDA) did not reduce the maximum recommended dose (despite a committee suggestion), certain pharmaceuticals have recommended a daily dose of 3 g on their instructions.
It is unknown whether decreased dosing is warranted in geriatric patients. An observational cohort study examined alanine aminotransferase (ALT) levels in young (18–55 years), older (≥70 years) fit, and older frail adult inpatients after 3–4 g/d of paracetamol for 5 days versus none.56 They found higher paracetamol concentrations in the older frail group after 5 days but no abnormalities in ALT levels. A recent review of 27 studies examined pharmacokinetics and safety of acetaminophen in patients over age 60 years and did not find any difference in absorption associated with aging.57 They did find acetaminophen clearance decreased with age (29%–45.7%) and frailty (37.5%) compared to younger patients, but safety concerns with standard dosing were not noted in elderly patients.57 While more studies are needed to clarify dosing in elderly patients, acetaminophen is recommended for acute or chronic pain in this population.7 However, in a systematic review evaluating the hemodynamic effects of IV acetaminophen, a majority of studies documented significant hypotension and increased vasopressor requirements in critically ill patients following administration of IV acetaminophen (500–1000 mg).58 These findings have not been reported with oral or rectal formulations.
In summary, acetaminophen is considered safe and effective in elderly patients and should be given preoperatively or intraoperatively and scheduled postoperatively. While IV formulations are available, caution may be needed in critically ill patients,58 and oral medications have noninferior efficacy and may be more cost effective.13,16,54,55
Perioperative NSAIDs are commonly utilized for orthopedic surgery in geriatric patients. In a cohort study of >190,000 geriatric adults admitted with traumatic hip fracture, day-of-surgery NSAID administration was associated with decreased opioid consumption, pulmonary complications, intensive care unit (ICU) admission, and hospital LOS with no increased incidence of acute renal insufficiency or postoperative transfusion requirement.41 Parecoxib (40 mg IV, cyclooxygenase-2 [COX-2] selective NSAID not approved in the United States) administered 30 minutes before surgery reduced pain scores in the recovery room compared with saline in an RCT of patients (mean age 66 years) undergoing total knee arthroplasty (TKA).21 Finally, an RCT of geriatric adults undergoing TKA found preoperative meloxicam therapy (preferential COX-2 inhibitor) to decrease postoperative pain scores at rest (6, 12, and 24 hours) and with flexion (6, 12, 24, and 48 hours) compared to patients starting meloxicam after surgery.22
NSAIDs are frequently administered in combination with acetaminophen for synergistic effects and improved analgesia.59 In a placebo-controlled RCT of 556 geriatric patients undergoing hip arthroplasty, acetaminophen, ibuprofen, a combination, or placebo was given before surgery and every 6 hours postoperatively for 24 hours.20 A combination of oral acetaminophen (1000 mg) and ibuprofen (400 mg) decreased 24-hour morphine consumption by 44% compared to acetaminophen alone (P < .001). However, median morphine consumption was not lower in the combination group compared to ibuprofen alone (28% reduction) due to adjustments for multiple comparisons. However, NSAIDs alone may not be adequate as sole therapy for geriatric patients. Loxoprofen (180 mg, not approved for use in the United States or Europe) provided inferior analgesia compared to tramadol-acetaminophen following TKA.23
Concerns Beyond Analgesia
As COX-1 mediates cytoprotective prostaglandins (gastrointestinal tract) and thromboxane A2 production (platelet aggregation and hemostasis), NSAIDs should be used with caution in patients with pre-existing gastropathy, elevated creatinine, or heart failure.52,60 Notably, a retrospective cohort of 316 trauma patients over 60 years old and receiving ketorolac reported a 2.5% incidence of acute kidney injury.61 Multivariate analysis revealed loop diuretics and the total number of comorbidities as predictors of AKI, but not age. Since adverse side effects are more likely at higher dosages and longer durations of use,52,62 guidelines recommend avoiding chronic use of NSAIDs in geriatric patients except for those meeting certain criteria: failure of other therapies, favorable risk/benefit profile, ongoing monitoring of therapy, and concurrent proton pump inhibitor administration.7 Notably, chronic NSAID use was a time-dependent predictor of a second hip fracture after primary hip fracture surgery.63 Coadministration of low-dose aspirin has been used for cardioprotection during NSAID therapy; however, this inherently worsens gastrointestinal risks and often necessitates concomitant ulcer prophylaxis.7
Impact Beyond Analgesia
As inflammation may play a role in the development of POCD,64 perioperative NSAIDs may reduce the incidence of delirium and POCD, benefiting the geriatric patient.65 In lower extremity arthroplasty patients randomized to parecoxib or placebo, delirium was reduced from 11% to 6.2% in the parecoxib group.65 Two meta-analyses (MAs) of patients receiving parecoxib for orthopedic surgery found reduced incidences of POCD and delirium compared to placebo, without an increase in adverse events.66,67 Similarly, in geriatric TKA patients, perioperative celecoxib reduced POCD rates (34% vs 12%) and lowered proinflammatory cytokines compared with placebo.68 While large RCTs are needed to determine if this effect can be generalized to all NSAIDs, it has been hypothesized that decreased POCD or delirium by NSAIDs is mediated through improved analgesia, opioid-sparing, or inhibition of neuroinflammatory cytokines.65,69,70
Table 3. -
Summary of Nonopioid Analgesics Primarily Limited to the Acute Perioperative Period: NMDA Antagonists,71,72,80,87–89
|Medication and dosing
||Specific properties or concerns
||NMDA receptor inhibition at dorsal horn and hippocampus
||May prevent or decrease central sensitization
||↓ 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)
|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
||T1/2: 10–15 min
| Oral 4–8 mg/kg
||Competitive and noncompetitive antagonism of hippocampal presynaptic Ca2+ channels
||↓ 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
|↓ SAH and vasospasm
|Duration: 30-min IV and 3–4-h IM
||↓ Arrhythmias. ↑ bronchodilation
|↓ Ca2+ influx (amplifies morphine-induced analgesia)
||↓ SA and ↓ AV node conduction
|↓ Dose: ↓ GFR or ↓ cardiac conduction
|Potentiates neuromuscular blockade
||Onset: 2–5-min IV
||Sedation, anxiolysis, and analgesia
| IV bolus: 0.25–0.6 μg/kg
||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
||T1/2: 2–3 h
||May ↓ postoperative delirium
|Potential hypotension and bradycardia
|↓ Minimal respiratory depression
||Inhibits bradykinin and neuropeptide release
||25–30 times potency of hydrocortisone or cortisol
| IV: 0.1 mg/kg (× 1)
| PONV: 4 mg IV
||Moderate albumin binding
||Nearly no mineralocorticoid effect
|↓ Signaling from nociceptive C-fibers
||Onset: 1–2 h
|↓ Chemokines, cytokines, and phospholipase A
||T1/2: 35–54 h
||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
|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; T1/2, half-life; TNF-α, tumor necrosis factor-α.
In summary, short-term perioperative use of NSAIDs is likely appropriate for many geriatric patients. The potential protective role of NSAIDs in reducing delirium and POCD is promising; however, clinical decision-making must consider patient comorbidities for therapy choice, dosing, and duration.
NONOPIOID ANALGESICS PRIMARILY LIMITED TO THE ACUTE PERIOPERATIVE PERIOD
Certain analgesics are limited to the acute perioperative period. These medications include N-methyl-d-aspartate (NMDA) receptor antagonists,71,72 dexmedetomidine,73 dexamethasone,74 and local anesthetics (Table 3).
N-Methyl-d-Aspartate Receptor Antagonists
NMDA receptor antagonists provide stable anesthesia while augmenting analgesia.72,80
A noncompetitive, high-affinity NMDA antagonist, perioperative ketamine has been studied in numerous surgeries and dosing strategies.71,80 A 2021 review concluded that patients undergoing procedures associated with high levels of expected pain, inflammation, and tissue damage (eg, arthroplasty, abdominal, and thoracic surgeries) benefit most from perioperative ketamine.81 While dosing varies, a 2018 review noted common ketamine ranges to include boluses of 0.25 to 1 mg/kg and 2 to 5-mcg/kg/min infusions.82 Continuous infusions may have advantages over single bolus dose administration.81 A 2016 RCT found that 48-hour minimal dose infusion (0.25 μg/kg/min) of S(+)-ketamine had similar analgesic efficacy to low-dose bolus (0.25 mg/kg) with 48-hour low-dose infusion (2 μg/kg/min) as part of a multimodal regimen for abdominal surgery.83 Pertinent to geriatric patients, the minimal dose group boasted lower rates of delirium. Notably, S(+) ketamine has twice the receptor affinity and potency as racemic ketamine and is not currently available in the United States.81 While analgesic benefits from ketamine may be most pronounced 6 to 24 hours after surgery,81 morphine-sparing effects may extend to 48 hours postoperative.82
Concerns Beyond Analgesia
Although an MA of perioperative ketamine RCTs found no difference in the incidence of central nervous system (CNS) side effects between the ketamine and control groups,82 this may differ in geriatric patients. In an RCT of surgical patients over age 60 years who received IV ketamine (bolus 0.5 mg/kg or 1.0 mg/kg) or placebo, increased ketamine dose was associated with postoperative hallucinations and nightmares.84 While ketamine does not appear to increase rates of POCD or delirium,84,85 elderly patients remain at risk for dose-dependent psychomimetic effects and lower ketamine doses (0.25–0.5 mg/kg bolus dose or 0.5–2 μg/kg/min infusions for up to 48 hours postoperative) may be preferable. Notably, most ketamine side effects, including increased intracranial pressure and myocardial depression, appear to be insignificant with subanesthetic dosing, but diplopia and nystagmus may still occur.86
Magnesium has well-documented antinociceptive effects.87–91 A 2013 MA of 25 trials found that perioperative magnesium use decreased cumulative opioid consumption by 24.4% and lowered numeric pain scores at rest and during movement compared with placebo at 24 hours postoperative.87 Similarly, a 2017 MA of 13 studies reported that intraoperative magnesium decreased intraoperative fentanyl consumption without compromising hemodynamic stability over a range of magnesium doses (bolus 30–50 mg/kg; infusion 6–25 mg/kg/h).88 Most recently, a 2020 MA of 51 trials found that intraoperative magnesium decreased opioid consumption at 24 hours postoperative and prolonged the time to first analgesic request without increased bradycardia.89
Impact Beyond Analgesia
Compared to their analgesic properties, the anti-inflammatory effects of NMDA antagonists and their impact on delirium, cerebral perfusion, and hemodynamic stability are less well elucidated. Ketamine and magnesium are hypothesized to decrease POCD and delirium via opioid-sparing through analgesia by NMDA antagonism, antidepressant properties,92 and anti-inflammatory effects.93,94 Suppression of the systemic and CNS inflammatory response to surgery by NMDA antagonism reduces both excitotoxicity (a key neuroinflammatory mechanism involved in neuronal cell injury) in vitro93 and postoperative inflammation in vivo,94 which may provide neuroprotection and improve neurological outcomes. In an RCT of adults undergoing endoscopic sinus surgery, magnesium infusion reduced postoperative agitation at all time points compared to placebo.90 Similarly, POCD rates 1 week after cardiac surgery were reduced in patients randomized to ketamine (0.5 mg/kg) on anesthetic induction compared to placebo.85 This effect was attributed to anti-inflammatory properties given concomitant reductions in postoperative serum C-reactive protein levels. In an RCT of mechanically ventilated ICU patients randomized to placebo or ketamine (3.3 μg/kg/min), both the incidence and duration of delirium were lower in the ketamine group.95 Similarly, an MA of 6 RCTs found that rates of POCD were decreased in patients who received ketamine, although the incidence of delirium did not differ from placebo.96 Conversely, in 672 adults over age 60 years undergoing major surgery and randomized to placebo, low-dose ketamine (0.5 mg/kg) bolus or high-dose ketamine (1.0 mg/kg) bolus, delirium rates, opioid consumption, and pain scores did not differ.84 Thus, more RCTs are needed to further examine the impact of NMDA antagonists on postoperative neurocognitive outcomes.
In addition to reducing inflammation, ketamine and magnesium may also stabilize hemodynamics and mediate bronchodilation. An MA of 5 RCTs for noncardiac surgery found that both medications reduced hemodynamic lability.72 Specifically, ketamine reduced blood pressure variability without impacting heart rate compared with placebo, while magnesium decreased heart rate variability without impacting blood pressure.72 As magnesium has antiarrhythmic properties, promotes arterial vasodilation, and prevents catecholamine secretion, these effects seem logical. However, given magnesium’s ability to prolong the absolute and relative cardiac refractory periods, cautious use is warranted in the presence of bradycardia.97 In contrast, ketamine likely maintains hemodynamics through sympathetic stimulation.
Although ketamine is often noted for bronchodilation, magnesium is also a bronchodilator. In a review of 7 RCTs, magnesium improved forced and peak expiratory volumes in patients with acute severe asthma exacerbations and reduced admission rates (adult dosing 1.2–2-g IV bolus).98 Bronchodilation may be mediated by anti-inflammatory activity or antagonism of calcium-induced muscle contractions.99 These pulmonary benefits sharply contrast with the potential respiratory complications associated with gabapentinoids in patients with risk factors for respiratory compromise.100
In summary, NMDA antagonists have many potential benefits to the perioperative geriatric patient. However, comorbidities should be considered when choosing medication and dosage. In patients with severe bradycardia, hypotension, or muscle weakness, ketamine may be preferable as magnesium may amplify these conditions. Likewise, magnesium may be preferable to ketamine in patients already experiencing hallucinations or nightmares.
A selective α–2 agonist, dexmedetomidine provides sedation, anxiolysis, and analgesia with minimal respiratory depression.73,75,76 Animal studies also suggest that dexmedetomidine may have neuroprotective effects and reduce apoptosis.101,102 A systematic review of geriatric patients undergoing cataract surgery found intraoperative dexmedetomidine to improve analgesia and increase patient satisfaction compared to other sedatives.32
MAs have consistently found perioperative dexmedetomidine to reduce postoperative opioid consumption and pain intensity compared to placebo.75,76 In the postoperative period, dexmedetomidine combined with opioids for IV patient-controlled analgesia decreased pain intensity, opioid consumption, nausea, vomiting, and pruritus with improved patient satisfaction compared to opioids alone.103 Although age does not impact dexmedetomidine’s pharmacokinetic profile, hemodynamic and sedative effects may manifest earlier in the geriatric patient.104 In an RCT of male patients receiving dexmedetomidine for light sedation, the ED50 (medication dose to produce a desired pharmacologic effect in 50% of subjects) was 0.25 μg/kg in 65 to 78 years old compared to 0.35 μg/kg for 45 to 64 years old.104 The ED95 was 33% lower in the geriatric group (0.38 μg/kg vs 0.57 μg/kg, respectively). As the most common side effect is bradycardia, monitoring and slow titration are warranted.75,76
Impact Beyond Analgesia
The neuroprotective effects101,102 of dexmedetomidine may decrease delirium.105 Although not all studies have found dexmedetomidine to prevent delirium,106 many RCTs for elderly surgical patients have shown promising results. In 700 ICU patients, dexmedetomidine (0.1 μg/kg/h) administered from the end of surgery until 0800 the next morning decreased the incidence of delirium.107 In 346 participants over 65 years old undergoing lung cancer surgery, dexmedetomidine resulted in a lower incidence, reduced severity, and shorter duration of delirium compared to placebo with lower pain and better sleep quality.108 In 619 patients randomized to dexmedetomidine or saline, dexmedetomidine patients had reduced rates of delirium (5.5% vs 10.3%) and lower complication rates at 30 days.109 In an MA of 11 trials (2890 elderly patients), dexmedetomidine reduced the incidence of delirium, time to extubation, and hospital LOS, although bradycardia and hypotension were also increased.110 Thus, while future studies are needed to determine the optimal dose for neuroprotection with minimization of side effects, dexmedetomidine administration should be considered for elderly patients to minimize delirium.
Glucocorticoids can decrease postoperative inflammation, incidence and severity of PONV, and postoperative pain.77 Evaluation of the analgesic impact of glucocorticoids is challenging, with high study variability regarding dose and agent used, and few studies evaluating pain as a primary outcome or glucocorticoids as the primary analgesic.77,78 Although few dose-finding studies are available, 1 MA noted 8 mg as the most frequent dose, with higher doses found in orthopedic, otolaryngologic, and cardiac procedures.78 A 2011 MA of 29 RCTs comparing dexamethasone to placebo noted a lack of opioid-sparing with doses under 0.1 mg/kg and a ceiling effect with doses exceeding 0.2 mg/kg.77 Notably, an RCT in geriatric patients undergoing lower extremity arthroplasty found that dexamethasone (10 mg IV preoperative and POD 1) improved postoperative pain scores, joint range of motion, and LOS compared to patients who received either preoperative ondansetron or preoperative ondansetron and dexamethasone.26 Less studied than dexamethasone, methylprednisolone was noted to decrease postoperative pain at rest and movement in a prospective cohort study.35 Although many studies have found glucocorticoids to reduce postoperative pain independent of multimodal regimens,111,112 no studies have evaluated the need for dose adjustments in elderly adults.
Concerns Beyond Analgesia
Adverse effects of steroids are related to dose and duration, and single-dose perioperative use is generally considered safe; however, common concerns for perioperative use include impaired wound healing, infection, and hyperglycemia.78,113 Single-dose dexamethasone is associated with a transient (typically <24 hours) increase in glucose levels that is dose-dependent, more pronounced in diabetic patients, and of unknown significance.78 Notably, several large reviews and MAs have failed to show an association between perioperative dexamethasone and increased rates of wound infection; however, infection was not always a primary outcome.77,78,113
Impact Beyond Analgesia
Perioperative dexamethasone may reduce POCD and delirium. Elderly patients undergoing elective noncardiac, nonneurosurgical procedures were randomized to single-dose dexamethasone (8 mg IV) or placebo and assessed for POCD.114 Patients who received preoperative dexamethasone and had bispectral index levels maintained at 46 to 55, as opposed to 35 to 45, had the lowest rates of POCD. However, an MA of 5 studies did not find dexamethasone to decrease the incidence of delirium or POCD; although clinical heterogeneity and limited evidence were limitations.115
In summary, perioperative steroids reduce postoperative pain,111,112 but studies focused on elderly adults are lacking and caution may be warranted in patients with poorly controlled diabetes.113
Local anesthetics may be delivered by systemic or regional methods.
Systemic lidocaine RCTs in geriatric patients are lacking. Published systemic lidocaine therapy varies widely by dose (1–5 mg/kg/h) and infusion duration (end of procedure to several days postoperative) but may improve acute perioperative analgesia.79 A review of 23 trials concluded that systemic lidocaine mildly reduced pain scores in the immediate postoperative period (1–4 hours) versus placebo; however, this effect was lost at 24 hours postoperative.79
In geriatric patients, local anesthetic hepatic metabolism remains unaltered despite a 20%–40% reduction in hepatic blood flow associated with age-related decreases in cardiac output.5 Combined with comorbidities and decreased muscle mass, the risk of local anesthetic toxicity is disproportionately increased in the geriatric patient.116 When considering systemic lidocaine use for older patients, the preference should be for lower loading and infusion rates (eg, 1.5 mg/kg bolus and 2 mg/kg/h) with a low threshold to check systemic lidocaine levels (therapeutic 2.5–3.5 µg/mL; toxicity >5 µg/mL).
While regional anesthesia improves analgesia and reduces acute perioperative opioid consumption in all patients, this may be of even greater importance in geriatric patients with hip fractures. Renal dysfunction has been noted in over one-third of patients with hip fractures,117 increasing the risk of morphine accumulation and consequent respiratory depression, hypoxia, and delirium.118 Conversely, regional anesthesia improves analgesia, pain with movement, time to mobilization, and pneumonia risk following hip fracture surgery.119,120 In an RCT of 53 patients with proximal hip fractures requiring surgical intervention, fascia iliaca blocks (40 mL; 0.25% levobupivacaine) improved postoperative pain scores greater than scheduled postoperative acetaminophen (1000 mg IV every 6 hours for 2 doses).14 In a separate RCT of 82 elderly patients undergoing hemiarthroplasty for hip fracture, intraoperative articular injection combined with pre-emptive oral multimodal analgesics reduced postoperative pain and opioid consumption compared with placebo.121 In addition to improving analgesia,122 reducing opioid consumption, and minimizing side effects,123 including delirium,122,124 intraoperative regional anesthesia may reduce morbidity and mortality.125,126 However, spinal anesthesia for hip fracture surgery was not superior to general anesthesia with respect to survival and recovery of ambulation at 60 days in a 2021 RCT of 1600 patients over age 50 years.127 While some benefits of regional anesthesia may be debated due to study heterogeneity, guidelines from the American College of Surgeons and the American Geriatrics Society (AGS) promote regional techniques as important adjuncts in the pain management of older adults to improve analgesia with decreased sedation and opioid usage.128
Topical medications, including lidocaine, diclofenac, and capsaicin, provide pain relief to targeted areas with less systemic absorption.24,25,51 These therapies are often forgotten in the perioperative period but should be considered for localized analgesia to minimize opioid consumption and adverse systemic side effects.
Table 4. -
Summary of Nonopioid Analgesics That Should Be Considered With Caution in the Geriatric Patient: Gabapentinoids131,132
and Muscle Relaxants133,134
|Medication and dosing
||Specific concerns or side effects
||Inhibit voltage dependent Ca2+ channels (α2δ subunit)
||Renal elimination (unchanged)
||↓ Dose based on GFR
|Perioperative use currently questioned
|Not bound by plasma proteins
||May be associated with respiratory complications in patients with risk factors for respiratory compromise100
||T1/2 5–9 h
||Caution in elderly
| IR: 100–1200 mg q 8 h
||Peak: 3–4 h
| ER: 300–3600 mg/d
||T1/2 5–7 h
||Caution in elderly
| IR: 75–600 mg/d (divided twice daily or three times daily)
|Peak: 1 h
| ER: 165–330 mg/d
||AChE inhibition (CNS and ANS)
||Not recommended in elderly
|↑ Age or liver disease will ↑ T1/2 and ↓ protein binding
||↑ Respiratory depression if combined with opioids or benzodiazepines
|↓ Somatic muscle activity
||(↓ GFR = ↓ dose)
||May ↑ fracture risk from sedation129
||T1/2 1–2 h
| 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
||T1/2 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; T1/2, half-life.
In summary, regional and topical analgesia should be considered for the geriatric patient to improve analgesia,122 reduce opioid consumption, and minimize some side effects,123 including delirium.122,124 The role of systemic lidocaine is less clear as it may only mildly reduce pain in the immediate postoperative period.79 Elderly patients are at an increased risk of local anesthetic toxicity, and the minimal dose, whether delivered systemically or via regional technique, should be used.116
NONOPIOID ANALGESICS THAT SHOULD BE USED WITH CAUTION IN THE GERIATRIC PATIENT
Gabapentinoids and muscle relaxants are increasingly prescribed as part of multimodal pain regimens. However, these medications may have sedating side effects and should be considered with caution in elderly adults (Table 4).100,129,130
Developed as anticonvulsant medications, gabapentinoids (ie, gabapentin and pregabalin) are utilized for a variety of conditions including as perioperative analgesic adjuncts.131,132 Early studies found gabapentinoids to decrease postoperative opioid requirements when part of a multimodal pain strategy,135–138 leading to the recommendation for perioperative use by professional societies.139 However, a recent large MA of over 24,000 surgical patients concluded that gabapentinoids offered no clinically important difference in acute pain, although they noted a small decrease in pain scores and a 20% reduction in postoperative opioid consumption with gabapentinoid use.132 This assessment is supported by recent RCTs in geriatric surgical patients showing no clinically important analgesic effects in those receiving pregabalin for postoperative pain for TKA27,29 or eyelid surgery.30 One RCT in geriatric patients did find pregabalin (75 mg orally twice daily for 5 days) to reduce opioid consumption following cardiac surgery; however, they also noted increased sedation and prolonged time to extubation.28 As using >1 type of nonopioid analgesic strategy can have a greater impact on opioid consumption than using 1 nonopioid strategy alone,140,141 this raises the question of whether gabapentinoids alone with opioids are beneficial for analgesia or whether their use should be limited to multimodal analgesic regimens that incorporate several strategies.
Concerns Beyond Analgesia
In addition to efficacy concerns for acute perioperative pain, gabapentinoids have additional specific concerns in the elderly. The 2019 AGS Beers Criteria noted gabapentinoids, when administered in combination with opioids, as potentially inappropriate medications in older patients due to the risk of sedation-related adverse events, including respiratory depression and death.130 Gabapentinoids are renally cleared, and dose reductions are recommended for CrCl <60 mL/h.130 Age-associated decreases in renal function put geriatric patients at increased risk for drug accumulation. Older patients and those receiving higher amounts of intraoperative opioids have been specifically identified as having increased risk of postoperative respiratory depression associated with perioperative gabapentinoid use.100 Given these concerns, gabapentinoids should likely be restricted to patients receiving minimal, if any, opioid therapy and those undergoing procedures in which proven benefit has been established. If perioperative gabapentinoids are administered, care should be taken to minimize opioid consumption to avoid compounding sedative effects.
While several muscle relaxants are approved for the treatment of acute musculoskeletal pain, methocarbamol and cyclobenzaprine are commonly prescribed for perioperative analgesia. They are thought to provide analgesia through inhibition of acetylcholinesterase at synapses in the CNS and ANS, leading to CNS depression and a reduction in somatic muscle activity without direct action at the neuromuscular junction.133,134 Methocarbamol has been examined for pain with mixed results. A retrospective, matched cohort study of trauma patients who did (n = 100) and did not (n = 100) receive methocarbamol found no difference in mean verbal pain scores for the first 3 days of hospitalization.142 However, in another retrospective cohort study of 592 adult trauma patients with rib fractures, methocarbamol administration was associated with reduced hospital LOS.143 Given that an increased number of rib fractures in patients over age 65 years is associated with overall increased morbidity and mortality independent of patient comorbidities,144 methocarbamol could add benefit to the geriatric analgesic literature. However, other studies have shown no benefit to adding methocarbamol or cyclobenzaprine to standard NSAID therapy.145,146 In an RCT of patients with acute low back pain, cyclobenzaprine (5 mg) with naproxen (500 mg) did not improve functional outcomes compared to naproxen alone after 1 week of treatment.146 Likewise, in a study of similar design, methocarbamol (750 mg orally) combined with naproxen (500 mg) did not improve functional outcomes compared to naproxen alone after 1 week.145 RCTs evaluating efficacy of muscle relaxants in the perioperative period are lacking in general and for geriatric patients.
Concerns Beyond Analgesia
Given the paucity of RCTs, routine administration of these medications is difficult to justify, especially for elderly patients with increased risk for CNS depression. In a retrospective cohort of veterans over age 65 years, muscle relaxants were associated with increased risk for emergency department visits and hospitalizations.147 Due to sedation and anticholinergic effects, methocarbamol and cyclobenzaprine are considered high-risk medications in older adults130 and may increase fracture risk.129,130 Due to the higher plasma concentration and frequent incidence of drowsiness, the lowest dose of cyclobenzaprine (5 mg) should be started if muscle relaxants are clinically indicated in elderly patients.
Although elderly adults represent a growing segment of perioperative patients, investigations focused on geriatric analgesia remain sparse. Nonopioid analgesics, key ingredients for multimodal analgesia, should be utilized routinely for perioperative geriatric patients, after consideration of comorbidities and age-related physiological and pharmacological changes. Regional anesthesia and topical medications should also be considered, while opioids should be reserved to supplement analgesia (Figure 2). Nonpharmacologic analgesic therapies should be used. Moist heat, ice therapy, electroacupuncture, relaxation, behavioral instruction, and psychological support strategies may have utility for analgesia,34,148–150 while inferential current muscle stimulation may not reduce acute pain.33 Exercise can reduce both pain and fall risk,151 while patient education can decrease opioid consumption.36,152 Furthermore, while sleep disturbances can be associated with delirium, poor or inadequate sleep can also exacerbate pain.153
Finally, certain analgesics have additional benefits. Medications with anti-inflammatory properties (ie, NSAIDs,65,68 dexamethasone, NMDA antagonists,93,94 and dexmedetomidine)101,102 may all positively impact POCD and/or delirium,64 although additional studies are needed for confirmation and dosing. NMDA antagonists improve hemodynamic stability and bronchodilation. Conversely, there is less evidence to support the administration of gabapentinoids and muscle relaxants as primary analgesic therapies in the geriatric population, and there is increasing concern that their risks and side effects may exceed the potential analgesic benefits.100,130,132
This review has limitations. Our literature search excluded studies before 2010 to highlight recent evidence regarding perioperative analgesic medications, as evidence for several of these medications has recently shifted. While the authors feel that this time restriction provides a current practice focus, this remains a limitation. Another limitation to our recommendations remains the paucity of geriatric-specific data. Therefore, some recommendations are based on extrapolation of benefit to geriatric populations, although studied in the general adult population. Evidence regarding NSAIDs also includes parecoxib, a drug not currently available in the United States; however, the concepts presented may be extrapolated when evaluating celecoxib or general NSAID use.
Although investigations focused on geriatric analgesia remain sparse, most nonopioid analgesics appear to be safe and should be utilized in a multimodal, opioid-sparing regimen. However, the changes in geriatric physiology and pharmacology and comorbidities must be considered. While acetaminophen, NSAIDs, NMDA antagonists, α-2 agonists, and topical analgesics can be efficacious, dosing and risk assessment must be individualized to each patient and pain severity (Figure 2), and evidence suggests gabapentinoids, and muscle relaxants have increased risks in aged patients. Furthermore, improved geriatric care is multifactorial and likely necessitates the incorporation and empowerment of caregivers.154 While studies have highlighted the safety and overall benefit of enhanced recovery after surgery bundles for aged patients, including nonopioid analgesics and regional anesthesia, they lack details of multimodal regimens.155–157 Future research should focus on analgesic dosing and acute perioperative management of nonopioid analgesics in geriatric patients.
We thank and acknowledge the efforts of Ms Teri Lynn Herbert, Associate Professor in the College of Academic Affairs at the Medical University of South Carolina, who assisted with our database search to identify all relevant articles of interest.
Name: Sylvia H. Wilson, MD.
Contribution: This author helped with literature review, drafting of the manuscript, reference formatting, and final review of the manuscript.
Name: P. Ryan Wilson, MD.
Contribution: This author helped with literature search, drafting of the manuscript, and editing of the manuscript.
Name: Kathryn H. Bridges, MD.
Contribution: This author helped with literature search, drafting of the manuscript, and final review of the manuscript.
Name: L. Hannah Bell, MD.
Contribution: This author helped with literature search, drafting of the manuscript, and final review of the manuscript.
Name: Carlee A. Clark, MD.
Contribution: This author helped with literature search, drafting of the manuscript, and final review of the manuscript.
This manuscript was handled by: Honorio T. Benzon, MD.
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