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Authors

Andreopoulos K.
Giannaki Ch.
Koraki E.
Trikoupi A.

DOI

The Greek E-Journal of Perioperative Medicine 2014; 12(a): 2-27

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DOI: The Greek E-Journal of Perioperative Medicine 2014; 12(a): 2-27

ABSTRACT

Effective postoperative analgesia in geriatric patients is both challenging and rewarding. Inadequate pain control after surgery is associated with adverse outcomes in the older patient. This review will attempt to describe the difficulty with assessment of pain and variations in pain experience of elder-ly patients. Physiological changes related to aging need to be also carefully considered, because a-ging is individualized and progressive. Pharmacokinetic and pharmacodynamic changes in geriatric patients, the higher incidence of co-morbidities and concurrent use of other drugs, must be carefully adjusted to suit each geriatric patient, concerning postoperative pain management. Medication for postoperative pain will be discussed. Unfortunately, many medications have not been studied well in the older population.Non-pharmacological approaches to postoperative pain management will not be discussed, although this would be an interesting topic for further discussion.

INTRODUCTION

Advanced diagnostic and therapeutic facilities have enhanced the life expectancy of humans, as a result of which geriatric population is ex-pected to increase 25% by 2020 worldwide1. In Greece, according to the last population census conducted at 2011, in a total of 10.787.690 population, the residents above the age of 65 were 1.873.2452.Life expectancy in Greece increased from 77,79 years in 1996 to 79,05 in 2004 and 80,2 years in 20092 .Given that the elderly undergo surgery four times more often than other age groups, anesthesio-logists can look to the future and see a time when the majority of surgical patients will be older than 65 years and many older than 80 ye-ars3. In 2007, approximately 35% of surgical procedures, in USA, were performed in pati-ents 65 years and older4. Although the criteri-on of 65 years of age and greater is followed worldwide for classifying this subset of popu-lation into geriatric category, the biological a-ge, which results from cellular aging, is more important than the chronological age in defi-ning the capacity of the elderly to cope with the massive surgical and anesthetic stress5,6,7. Age is considered as one of the strongest pre-dictors in population undergoing anesthetic stress. As a result, mortality increases twofold in this subset of population as compared to young healthy adults, especially in patients un-dergoing major surgery5,8. Therefore, it is ne-cessary that the national health system adjusts to the new data and also insures the quality of the services, including postoperative pain ma-nagement services, provided to this group of patients.

Elderly surgical patients often have multiple co-morbid conditions that limit their functional capacity and recovery and increase the risk of severe complications. They also take more pre-scription medications; on average two to five medications per person9.Additionally, inap-propriate prescribing of medications places the older patient at risk for adverse reactions and preventable hospitalizations10.Unfortunately, nearly 35% of medication trials exclude older patients based on age alone11.Therefore, the ef-fect of aging on pharmacokinetics and pharma-codynamics of drugs is incompletely chara-cterized. Preoperative assessment in geriatric patients is very important for the detection of all the co-existing diseases in these patients. Co-morbid pain conditions, in elderly patients, such as osteoarthritis have been associated wi-th decreased functional status at one and three months post hospital discharge12. Preventive actions such as positioning during and after surgery can reduce pain from these sources12.

The purpose of this article is to discuss major clinical issues specific to the management of postoperative pain in geriatric patients.

Inadequate postoperative pain relief and consequences in elderly patients

Inadequately postoperative pain management in elderly patients has a great impact on phy-sical, psychological and cognitive symptoms, and consequently, on the overall quality of life.

The endocrine system reacts to pain by rele-asing an excessive amount of hormones, ulti-mately resulting in carbohydrate, protein, and fat catabolism (destruction); poor glucose use; and other harmful effects13. This reaction com-bined with inflammatory processes can produ-ce weight loss, tachycardia, increased respire-tory rate, fever, shock and death. Continuous, unrelieved pain activates the pituitary-adrenal axis, which can suppress the immune system and result in postsurgical infection and poor wound healing13.

Sympathetic activation can have negative ef-fects on the cardiovascular, gastrointestinal, and renal systems, predisposing patients to ad-verse events such as cardiac ischemia and ile-us. The cardiovascular system responds to stress caused by pain by activating the sympa-thetic nervous system, which produces a varie-ty of unwanted effects. In the postoperative pe-riod, these include hypercoagulation and incre-ased heart rate, blood pressure, cardiac work load, and oxygen demand. Aggressive pain control is required to reduce these effects and prevent thromboembolic complications. Cardi-ac morbidity is the primary cause of death after anesthesia and surgery14.

Postoperative pain is the most important factor responsible for regional impairment of ventila-tion, ineffective cough reflexes and gecrease a-bility to sigh and beath deeply, resulting in ate-lectasis, hypoxemia, infection and respiratory failure14.

All above mentioned postsurgical complicati-ons, related to inadequate pain management, negatively affect the patient’s welfare and the hospital performance because of extended lengths of stay and readmissions, both of whi-ch increase the cost of care.

Continuous, unrelieved pain also affects the psychological state of the patient and family members. Common psychological responses to pain include anxiety and depression. Between 8% and 20% of older patients display depressi-ve symptoms and depression has been associa-ted with worsened pain15. Additionally, posto-perative pain in geriatric patient has been asso-ciated with increased sleep disturbances, de-creased socialization and impaired ambulati-on16. Reasons for inadequate pain control in-clude lack of training, inappropriate pain as-sessment, and reluctance to prescribe opio-ids10.

Postoperative cognitive dysfunction can be u-sefully defined as a long term, possibly perma-nent, disabling deterioration in cognitive fun-ction following surgery17. The risk of postope-rative delirium (POD) and postoperative cog-nitive dysfunction (POCD) increases with a-ge18.Although the overall prevalence of posto-perative delirium in elderly adults after major elective surgery has been estimated to be 10%17, for specialprocedures such as hip fra-cture repair, the rate of incident postoperative delirium has been reported to be as high as 40%19. POD and POCD are also associated wi-th preoperative cognitive impairment, vision impairment, depression and other common co-morbidities, such as vascular disease and renal dysfunction11.POCD may be independent of the type of anesthesia received11,18. Although it may be assumed that general anesthesia and complex surgery would result in an increased likelihood of POCD, a recent study challenges this assumption20.In this study, patients who received procedural sedation had the same risk of cognitive decline, as those undergoing ele-ctive total hip joint replacement surgery or co-ronary artery bypass surgery. Cognitive im-pairment may make pain assessment more dif-ficult, and many practitioners express concern regarding evidence that opioid administration may precipitate postoperative delirium17.

Poorly managing of pain may put also clinici-ans at risk for legal action. Having standards of care in place increases the risk of legal action against clinicians and institutions for poor pain managementand there are instances of law su-its, in USA, filed for poor pain management by physicians21.

Assessing and experiencing pain in geriatric population

The majority of older adults describe moderate to severe pain at some point after major surge-ry22. Even though older adults report pain si-milar to middle-aged and younger adults23and have similar opioid needs in the post-anesthe-sia care unit22 older adults continue to be un-dertreated for postoperative pain.

Assessment of pain in the older adult can be complicated by numerous factors, including difficulties with communication, the high pre-valence of disability, dementia and sensory di-sturbances in this population11. Postoperative pain assessment during movement provides a more accurate pain measure than assessment at rest23.

Cognitively impaired patients are known to be at greater risk of undertreatment of acute pain24. Patients with hip fracture, with POCD re-ceived one third the amount of opioid analgesia as compared to cognitively intact patients. The majority of dementia patients were in severe pain postoperatively25.

Assessment of pain in the older adult can be more time consuming and difficult and an assessment should include, if possible, direct pa-tient response, provider observation, as well as input from family and/or caregivers. Various tools for assessing pain have been developed and several have been validated in the older population such as Verbal Rating Scale (VRS), Visual Analogue Scale (VAS), Numerical Rating Scale (NRS) and Faces Pain Scale11. El-derly patients have been reported to experience more difficulties with VAS14.Jensen et al., ob-served that there was a significant correlation between age and incorrect response to VAS scores26. Even if the VAS is the most frequent used method, the NRS and the VRS seem to be the preferred scales14. Gagliese et al., observed that age differences in pain scores depended on the scale used23. Table 1 summarizes several pain assessment tools that have been validated in the elderly11,27. In patients with POCD or POD assessment of pain is more challenging. The Check-list of Nonverbal Pain Indicators

(CNPI), a behavioral observation scale for nonverbal older adults with severe cognitive impairment is one of the more rigorously test-ed pain assessment instruments22.

Several studies have suggested that elderly pa-tients report lower pain intensity than younger patients14. This is thought to be due to the mis-conceptions that pain is a normal part of aging, pain perception decreases with age, older peo-ple who do not complain of pain are not in pa-in, and pain reports may be a way of seeking attention11. Also, pain-transmitting C and Aδ peripheral nerve fiber function declines pro-gressively with age11. Postoperative pain has been reported to be less in older persons and diminish with time28. The point, at which pain is first felt experimentally, is likely slightly higher. However, pain tolerance, the maximum pain level endured, is probably reduced14.

Preoperative pain management education for older adults can significantly reduce their postoperative pain29.Pain management content should provide a general overview of pain that includes defining pain, understanding the causes of surgical pain, how to use pain assessment scales, and the importance of both preventing pain and managing pain that does occur pharmacologically.

Table 1.  Pain assessment tools.

Tool Description Discussion
Visual Analogue Scale A vertical or horizontal 100-mm line anchored by verbal descriptors such as ‘no pain’ and ‘worst pain possible’. Patients make a mark on the line that represents their pain intensity Requires abstract thoughtDifficult to use in cognitively or visually impairedMay be less valid in older adults
Numerical Rating Scale Available in a variety of scale ranges and anchors, such as 0–10, with 0 being ‘no pain’ and 10 being ‘worst pain possible’ Requires abstract thoughtValid in cognitively impairedCommonly recommended scale for pain assessment in older adults
Verbal Descriptor Scale Available in a variety of scale types (e.g., pain thermometer, present pain intensity index and graphic rating scale) Limited amount of choicesRequires some command of languageHighly preferred by older adultsLow failure rate in cognitively impaired
Faces Pain Scale Consists of seven faces ranging from neutral face (no pain) to grimacing face (worst pain possible) Requires abstract thoughtDifficult to use in cognitively impairedMay be less preferred by older adults
Behavioral Pain Scale Observational assessment tool for nonverbal patients compiled by nurse or physician Generally takes longer to completeRequires knowledge of how scale is usedBetter results if observer is very familiar with patient

Physiological changes of aging

Aging is characterised by a failure to maintain homeostasis under conditions of physiological stress. Physiologic changes associated with de-crease in viability and an increase in vulnerabi-lity. This means that older people present pro-gressive decrease in organ function and pro-gressive loss of organism reserves, but the idi-osyncratic factor loss of reserves is important. The co-existence of morbid situations in the el-derly affects the regulating mechanisms and restricts the responsiveness in stress conditi-ons, such as postoperative pain.

Aging is typified by changes in the cardiovas-cular system. The biggest change in the car-diovascular system is the decrease in cardiac output (CO)and vascular resistance.The decre-ase in CO is about 1% every year after the age of 3014.Aging heart is volume dependant and volume tolerant. Small changes in intravascu-lar volume or venous capacitance may induce cardiovascular instability. Also, there is a de-crease in autonomic nervous system responsi-veness, such that following spinal or epidural anesthesia, there is an increased risk of pro-found hypotension. In addition, the decrease in CO induces a decrease in hepatic blood flow. Clearances of opioids would be unafected by the activity of hepatic enzymes but sensitive to hepatic blood flow. Thus a 25% to 40% redu-ction in clearance could be expected secondary to reduce hepatic blood flow in geriatric pati-ents14. The initial high arterial concentration observed in the first few minutes after injecti-on of an i.v bolus dose is a function of this di-lution with CO and the kinetics of the first pass of the drug (e.g morphine) through the lungs. Thus, a 0% to 20% reduction in CO would le-ad to higher peak arterial concentrations after i.v administration. Therefore, the initial dose should be reduced and also slow injection rate should be used in elderly patients30. Degenera-ting alterations are causing a decrease in con-tractility and sensitivity of adrenergic rece-ptors, reduction of co-pliance of the heart mus-cle and increase the incidence of arrhyth-mias14. Also, in these patients co-exists usually arterial hypertension, diastolic dysfunction and valvular heart disease. The changes of vessels that progressively lose their elasticity and small changes of intravascular volume may le-ad to hemodynamic disorders, after regional a-nalgesia or high dose of opioids. Inadequate treatment of postoperative pain leads to an in-crease of arterial blood pressure and heart rate and that can lead to an increase of oxygen con-sumption, which may cause ischemic heart fai-lure and infraction31.

The impairment of respiratory function is cau-sed by structural changes in the lung tissue and chest wall. There is a decrease in sensitivity of the respiratory centres to hypoxia and hyper-

capnia. Furthermore, elderly patients have in-creased periodic breathing or apnea periods during sleep, which makes them more likely to have apnea and airway obstruction in postope-rative period. There is an increase risk of hy-poxemia, in elderly patients that require opio-ids14.

Aging is associated with a decrease of neuro-nal and neurotransmitter density and activity. Also, there is a decrease of the number of neu-rotransmitter receptor sites14. Additionally, age reduces β-endorphins levels, the synthesis of γ–aminobutiric acid (GABA) and serotonergic receptors32. Brain atrophy characterises the el-derly patients and is caused due to a decrease in neuron size. The decrease of the number of neurons of the autonomic nervous system can also cause hemodynamic disorders11.

Renal function declines progressively with a-ge. There is a decrease in the glomerular filtra-tion rate (GFR 1% to 1,5% per year after 2nd de-cade), secondary to decreased renal blood flow (10% per decade in the adult years). The com-bination of reduced kidney mass and reduced glomerular function leads elderly patient to be more prone to dehydration, sodium loss and impaired fluid handling. Co-existing diseases such as diabetes, arterial hypertension and vas-cular disease play a significant role in worsen-ing renal function in elderly patients14. Decre-ased glomerular filtration rate may be balanced by an age-related decrease in muscle mass, and therefore, creatinine may not be a reliable indi-cator of glomerular filtration rate in the elder-ly11.On average, glomerular filtration rate de-creases less than 1 ml/min/year after middle a-ge33.The aging kidney is more sensitive to pain and surgical stress due to the decreased renal blood flow and decreased response to vasocon-striction. Decreased renal function can lead to toxic accumulation of drugs and metabolites, if dosing is not adjusted according to renal cle-arance

Advancing age is associated with a progressive reduction in liver volume and liver blood flow14. Alteration of hepatic structure and en-zymatic functions with ageing is moderate. In healthy elderly person, routine tests of liver function involving the metabolism and elimi-nation of specific dyes, radioisotopes, and pro-tein synthesis do not show significant differen-ces between individuals aged 50–69 and 70–89 years33.

The main changes involve the secretion of hy-drochloric acid and pepsin, which are decree-sed under basal conditions. This may be the di-rect consequence of changes in the enzyme se-creting cells and organs or hormonal and neu-ral regulatory alterations33. By contrast, ga-stric emptying in elderly subjects is similar to that of young subjects33. Disorders of gastric mucosa make elderly patients more sensitive to mucosa injuries from the use of NSAIDs14.

Pharmacodynamic and Pharmacokinetic changes in the elderly patients

With age, the pharmacodynamics and pharma-cokinetics of drugs change. Pharmacodyna-mics is usually related to specific drug rece-ptors, which can change in function and densi-ty with age.The number and the affinity of re-ceptors for neurotransmitters present in a tis-sue decreases with age11. Older adults display pharmacodynamic changes, particularly in the central nervous and cardiac systems.Advan-cing age is also associated with increased sen-sitivity to the central nervous system effects of benzodiazepines and opioids14. Sedation is in-duced by diazepam at lower doses and lower plasma concentrations in elderly subjects33.The sedating effects of benzodiazepines can be increased by up to 50% despite the pharmaco-kinetics being similar between the young and old11. Autonomic nervous system dysfunction, impaired thermoregulation and reduced cogni-tive function may affect drug responses, in el-derly patients14. The loss of homeostasis in ge-riatric population can lead to hemodynamic di-sorders or delirium, after the use of local anes-thetic drugs for regional anaesthesia14.Phar-macodynamicinteraction may occur with sy-nergistic effects when taking more than one se-dative or anticholinergic agent resulting in de-lirium, sedation, urine retention or constipati-on14. Table 2 summarizes the selected pharma-codynamic changes with ageing.

Table 2. Selected pharmacodynamic changes with ageing.

Drug Pharmacodynamic effect Age-related change
Adenosine Heart-rate response
Diazepam Sedation, postural sway
Diltiazem Acute and chronic antihypertensive effect
Acute PR interval prolongation
Diphenhydramine Postural sway
Enalapril ACE inhibition
Furosemide Peak diuretic response
Heparin Anticoagulant effect
Isoproterenol Chronotropic effect
Morphine Analgesic effect
Respiratory depression
Phenylephrine α1-adrenergic responsiveness
Propranolol Antagonism of chronotropic effects of isoproterenol
Scopolamine Cognitive function
Temazepam Postural sway
Verapamil Acute antihypertensive effect
Warfarin Anticoagulant effect

= increase; ↓ = decrease; ↔ = no significant change; ACE = angiotensin-converting enzyme.

Pharmacokinetic studies on the effect of age-ing on drug absorption have provided conflict-ing results. Some studies have not shown si-gnificant age-related differences in absorption

rates for different drugs34. The absorption of vitamin B12, iron and calcium through active transport mechanisms is reduced35 whereas the absorption of levodopa is increased, probably secondary to a reduced amount of dopadecar-boxylase in the gastric mucosa33.

Hepatic metabolism of drugs relies on two im-portant steps, Phase I and Phase II metabolism. The oxidation, reduction and hydrolysis reacti-ons of Phase I metabolic capability probably decrease with age, but this may or may not be clinically significant11. The Phase II reactions of conjugation through methylation, sulfation, acetylation or glucuronidation are likely unal-tered with aging11. As mentioned before, de-creased hepatic blood flow and mass can lead to reduced metabolism and prolonged elimina-tion, especially for drugs with blood flow limi-ted metabolism, such as morphine.

The consequence of renal impairment on the pharmacokinetics of analgesic drugs typically outweighs the potential impact of reduced he-patic function36. For example, renal insuffici-ency can play a significant role in the reduced clearance and accumulation of both drugs and drug metabolites. Morphine and its metabolites (morphine-6-glucuronide and morphine-3-glu-curonide) and meperidine and its metabolite (normeperidine) are probably the most clini-cally relevant11.

Changes in the percentage of body water and fat, with reduction of water and increase of bo-dy fat, causes an increase in the concentration of the drug in the blood. Fat-soluble drugs su-ch as diazepam and fentanyl have an increased volume of distribution, whereas drugs that are water-soluble have a decreased volume of di-stribution14.

Geriatric patients present decreased production and concetration of albumin (which binds aci-dic drugs), that can cause an increase of the free fraction of the drug in the plasma and a re-duction in the degree of plasma protein bind-ing drugs14.Protein binding of lidocaine in el-derly is increased as is the elimination half-ti-me and there is a reduction in clearance of lo-cal anesthetic drugs. The dose of local anesthe-tic required to achieve a given sensory level during epidural anesthesia is often perceived to be less with aging, although some reports describe a linear relationship between dose and age14.

Because of the wide variation of physiological parameters present between geriatric patients, the expression «start low and go slow» should be always remembered when initiating drug therapy in the older patient11.

Postoperative analgesic techniques and agents for geriatric patients

A multimodal approach to analgesia is critical to help older adults achieve maximum pain re-lief and avoid side effects from analgesics. Ad-dition of non-opioid analgesics to the regimen can increase pain relief and reduce the opioid dose. Advances in the knowledge of molecular mechanisms have led to the development of new pharmaceutical products to treat postope-rative pain in elderly patient.

Regional techniques

Over the past 20 years, anesthesiologists have played a more aggressive role in the treatment of postoperative pain. In addition to designing anesthetic techniques, to minimize the impact of pain through the use of tailored pharmacolo-gic interventions, many anesthesiologists in-clude the extended use of anesthetic techni-ques, such as epidural, intrathecal analgesia and nerve blocks.

Epidural postoperative analgesia

Epidural postoperative analgesia can provide great pain relief37and is frequently used with older adults patients22 for postoperative pain management.

Epidural analgesia is an excellent option for pain control following upper abdominal and intrathoracic surgical procedures14. In elderly patients, epidural opioid and local anesthetic combinations are very effective analgesics, consistently demonstrating lower pain scores with significantly lower systemic opioid expo-sure, compared to intravenous opioid admini-stration15. Analgesia via epidural route after e-lective colon surgery, using bupivacaine and morphine, accelerates postoperative recovery of gastrointestinal function, provides quicker mobilization and reduces hospital stay38.

Continuous epidural analgesia (PCEA) impro-ves early rehabilitation, after knee surgery, compared with the patient-controlled analgesia group (PCA)14. Another study compared the efficacy and safety of PCEA and PCA, after major abdominal surgery, in elderly patients37. Pain relief was better at rest and at movement in the PCEA group during the first 5 postope-rative days37. Cardiorespiratory complications and the incidence of delirium were similar be-tween the 2 groups37.

Despite that PCEA reduced significantly syste-mic opioid consumption compared to PCA, e-pidural analgesia does not appear to offer a si-gnificant advantage over intravenous opioids with respect to central nervous system side ef-fects, including respiratory depression, sedate-on, and pruritis39.Local anesthetics are helpful in reducing the amount of opioid needed, but may introduce a greater risk of hypotension, pressure sores, and peripheral nerve compres-sion injuries15. A reduced epidural dose of lo-cal anesthetic and opioid and frequent moni-toring decreases the possibility of toxic ef-fects37.

A major advantage of epidural analgesia is that it can provide continuous pain control without disruption. Although there are occasional te-chnical and anatomic difficulties due to advan-ced age, when epidural analgesia works well, it can provide a near pain free experience.

Intrathecally opiod administration

Intrathecal morphine provides effective anal-gesia after hip or knee arthroplasty, after gy-naecologic surgery or prostate transurethral re-section14. Intrathecal morphine may be asso-ciated with dose-related side effects like nau-sea, vomiting, drowsiness, urinary retention or delayed respiratory depression. According to Murphy et al., 100μgintrathecal morphine se-ems to provide the best balance between anal-gesic efficacy and adverse effects, in elderly patient after hip surgery40.

Peripheral nerve blocks

Peripheral nerve blocks provide excellent po-stoperative analgesia without significant com-plications. Many extremity surgeries are con-ducted with brachial and femoral plexus nerve blocks and those prove to be useful options in reducing pain in the early postoperative peri-od15. While they seldom provide more than 8-10h of anesthesia, they do allow for significant reductions in consumption of opioids during the first postoperative day.

Peripheral nerve blocks effects may be extend-ed through the use of a continuous analgesic infusion via a catheter introduced into the ap-propriate neural plexus. Catheter placement in-creases even more the duration of analgesia and upgrades the mobilization and comfort of the geriatric patients41. Probably that occurs because of the reduced excretion of the local a-nesthetic and the slowest action on the peri-pheral nerves41.Since most of these patients a-re able to transition to oral medications follow-ing the majority of extremity surgeries, this is a useful approach for ambulatory procedures, as the nerve block may allow for fewer opioid si-de effects as well as a reasonably comfortable first night. In-dwelling plexus catheters may be inserted at the time of the initial nerve block, which will allow a continuous infusion or re-peated bolus injections of local anesthetic; ho-wever, these techniques have not yet gained wide-spread acceptance outside of few acade-mic centers. For selected patients, this may be an option if the patient is anticipated to en-counter severe pain, poorly tolerates systemic analgesics, or if dense analgesia is required for repeated manipulation15.

Continuous local anesthetic infusion through catheter

Pain control infusion pumps automatically and continuously deliver local anesthetic through an intraoperatively placed catheter. Continuous local anesthetic models have been examined in the shoulder and knee42. Evidence supports the use of pain control infusion pumps in cardio-vascular, cardiothoracic, obstetric, and ortho-pedic surgery42. Unfortunately, the chondroto-xity associated with local anesthetic delivery, in orthopedic knee surgery, has made intrarti-cular application a dangerous and unpopular choice for postoperative pain control42.

In this analgesic technique, there are specific problems concerning the local anesthetic ca-theter placement. As some of the catheters are invariably accidentally prematurely partially pulled out, patients may not receive the bene-fits of pain control infusion pumps. Intuitively, when placed on suction, effective drainage may work against pain control infusion pump infu-sion. It is also unclear how much of the local anesthetic remains in the surgical site. High concentrations of local anesthetic have been found in the copious drainage at the site of the catheter–skin in-terface42. Lastly, the ideal concentration of local anesthetic catheter has not been identified. The cardiotoxic effects of local anesthetic are real and dangerous, especi-ally for elderly patients. For these reasons in bilateral total knee arthroplasty, patients recei-ve twice the volume but half the local anesthe-tic concentration in each operative knee in comparison to patients undergoing unilateral procedures42. This lower concentration may be inadequate to control pain.

 

Systemic analgesic agents

Opiods

Opioids remain the gold standard for the treat-ment of moderate to severe acute pain. The choice of opioid for most of older adults re-mains morphine sulfate22. In literature the use of oxycodone and hydromorphone for postope-rative analgesia, in elderly, is widely spread22. Certain opioids should be avoided in elderly patients when possible. Propoxyphene is tho-ught to be no more effective than aspirin or a-cetaminophen, but it is associated with ataxia, dizziness, and neuroexcitatory effects due to drug accumulation22. Meperidine hydrochlo-ride should not be used because of the accu-mulation of a nephrotoxic metabolite22.

Morphine is a potent opiate analgesic that can be administered orally, intramuscularly, subcu-taneously and intravenously. Postoperative i.v morphine titration is used to obtain rapid and complete postoperative pain relief30. Because of rapid onset of analgesia, small i.v bolus do-ses permit titration of the dose of morphine ne-eded to provide adequate analgesia14. Aubrun F. et al.30 proved that i.v morphine titration can be safely administrated to elderly patients u-sing the same protocol, as that used in younger patients. According to the study protocol, when VAS scores in the PACU increased more than 30mm, i.v morphine was titrated every 5 minutes by 2-or 3-mg bolus do-es, until pain was relieved (pain defined by a VAS score less than 30mm). Nevertheless, these results apply only to short-term control of pain in the PACU and not to long-term use of morphine. How-ever, these results may not apply to a frail ge-riatric population or to patients with severe POCD14.

The mean elimination half-time for morphine is 4,5 hours in elderly, significantly longer than 2,9 hours that has been observed in youn-ger patients. There is a decrease volume in di-stribution, a 50% reduction in clearance and a reduction of protein binding30. Intravenous morphine can be safely used in cognitively in-tact older patients11and additionally, to the la-sting analgesic effect, morphine is inexpen-sive.

Morphine is broken down in the liver to phar-macologically active metabolites (morphine-6-glucuronide and morphine-3-glucuronide), which are then excreted by the kidneys. In the setting of renal impairment, these metabolites can accumulate, causing respiratory depression and/or neuroexcitation. In the setting of renal impairment, opioids that do not have active metabolites, such as fentanyl, are preferred for continuous use (PCA).

Oral oxycodone is also being administered wi-th increased frequency as part of a multimodal approach to acute postoperative pain11,43. Oral oxycodone undergoes less first-pass metabo-lism and has higher bioavailability than oral morphine43. This results in more consistent plasma levels post-administration. Unlike mor-phine, renal impairment does not appear to af-fect plasma concentrations of oxycodone or it’s active metabolite oxymorphone11.The admini-stration of scheduled controlled-release oxyco-done may avoid the peaks and troughs associa-ted with i.v bolus dosing, resulting in stable plasma levels and improved pain control. Scheduled oral oxycodone (controlled release) improved patients’ pain control, patient satisfa-ction, and decreased postoperative nausea and vomiting compared with i.v morphine PCA in patients after post-lumbar discectomy44.

Increased sensitivity to opioids appears to be the result of both pharmacokinetic and phar-macodynamic changes14. Older persons likely express a lower density of µ-opioid receptors making them more vulnerable to the effects of opioids22. Although, older adults experience more frequently side effects from opioids. Au-brun F. et al.30 showed that acutely, after sur-gery, in PACU, the total dose of morphine, pa-in relief achieved and risk of adverse events was not significantly different in older than in younger patients30. Side effects, such as nau-sea, vomiting, sedation, itching, constipation, and respiratory depression, tend to define the limits of clinical therapy. Pain in most patients can be controlled without encountering excess-ive side effects, but side effects may limit sati-sfactory pain relief. In these patients aggressi-ve management of the side effects becomes an essential component of providing adequate pa-in control30.To adjust for the potential age dif-ferences and to reduce the incidence of side ef-fects, the opioid dose should be started at a do-se 25-50% lower than the recommended dose for adults and increased slowly by 25-50% in-crements until the person reports satisfactory pain relief or a 50% reduction in pain intensity is achieved22. Opioids should be withheld, if the patient is sedated when awake and/or has a respiratory rate of less than 8 breaths per min22. Prophylaxis to prevent constipation sho-uld be initiated postoperatively and bowel fun-ction monitored. If nausea and vomiting occur, metoclopramide use avoids the anticholinergic side effects of many antiemetics22.

Opioids, often, are underutilized, or even with-held, in the elderly postoperative patient, espe-cially among individuals experiencing cogniti-ve impairment. The more severe the communi-cation deficit, the more likely the patient will have opioids limited, out of concern that they are contributing, or will contribute to the deve-lopment of postoperative delirium18. Although sedative medications may contribute to deliri-um, several studies suggest that the opioid use for postoperative pain displays an inverse rela-tionship15. Elder patients, undergoing surgical repair of a hip fracture, who received less than 10mg of morphine per 24h span, were more li-kely to develop postoperative delirium15.

An extensive literature has documented that long-acting benzodiazepines, tricyclic antide-pressants, serotonin selective antidepressants, and anticonvulsants contribute to the likely-ho-od of falling in the over 65 year old populati-on. Although the opioids are sedatives, the exi-sting literature does not strongly implicate the opioids as contributing to falls in elders15.

Opioid tolerance develops rapidly following administration, even in the acute pain setting; however, in most circumstances, rapid resolu-tion of pain over 3 days following surgery helps to prevent drug tolerance from becoming a significant factor in the postoperative pati-ent15. With chronic use of opioids, opioid rece-ptors decrease in population, as well as possi-bly in excitability. This ‘downregulation’ of o-pioid receptors manifests as increasing doses of opioids needed to obtain the same effect, and is usually clinically noted as ‘tolerance’ to a drug. Unfortunately, in up to 30–40% of pa-tients that chronically consume opioids, opi-oid-induced hyperalgesia occurs11.Minor me-dical procedures, such as immunizations, ve-nopunctures or intravenous catheter insertions, are perceived as excruciating. Higher doses of opioids are often prescribed by well-intention-ed clinicians, but are not helpful, and frequen-tly cause a further pain sensitivity11.

Tramadol

Tramadol is a centrally acting opioid, which is effective for moderate-severe pain and is being used for various acute and chronic pain scena-rios45. Tramadol is a synthetic opioid and has local anaesthetic effect on peripheral nerves which was shown in clinic and laboratory stu-dies45,46. Analgesia begins within 1h and starts to peak in 2h . It is rapidly and extensively ab-sorbed after oral doses and is metabolized in the liver. It has been proposed that tramadol has a lidocaine-like mechanism of action, whi-ch involves voltage dependent sodium chan-nels causing axonal blockade46. In patients with moderate postoperative pain, i.v. or i.m. tramadol is roughly equal in efficacy to mepe-ridine or morphine; for severe acute pain, tra-madol is less effective than morphine47.

Tramadol and meperidine are equally effective in postoperative patient-controlled analgesia47. In epidural administration for pain after abdo-minal surgery, tramadol is more effective than bupivacaine but less effective than morphi-ne47. Kapral et al., adding 100 mg tramadol to 40 ml mepivacaine 1% in axillary brachial ple-xus block, shown that tramadol prolongs the duration of sensory and motor block without causing any significant side effects, this can be given as an example to the peripheral action of tramadol which was mentioned above48.

In current literature there is limited description of tramadol use for geriatric postoperative pain relief. Potential advantages of administering tramadol for postoperative pain, in elderly pa-tients, include satisfactory analgesia, long du-ration of action and limited respiratory de-pressant effects49,50.Since seizures have been described with tramadol administration, con-current use of monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibi-tors (SSRIs), and tricyclic antidepressants should be avoided40. Tramadol may cause diz-ziness and reduce the seizure threshold40. Do-sages should be reduced for patients older than 75 years or for patients with renal or hepatic dysfunction47.

Patient controlled analgesia

In a general sense, patient‐controlled analgesia (PCA) refers to a process where patients can determine when and how much medication they receive, regardless of analgesic technique. However, the term is more commonly used to describe a method of pain relief which uses disposable or electronic infusion devices and allows patients to self‐administer analgesic drugs. Patient-controlled analgesia (PCA) with i.v opioid and patient-controlled epidural anal-gesia (PCEA) with a local anaesthetic in com-bination with an opioid are indicated for mode-rate or very painful surgery and are the route of choice after major abdominal or thoracic surgery. However, these techniques have been inadequately evaluated in elderly patients51.

One of the reasons of pain underestimation in elderly patients is that this age group is relu-ctant to request analgesia14. In this situation, PCA provides a continuous i.v titration of a-nalgesic regimens.All common opioids have been used successfully for PCA, with mor-phine the most. Whichever opioid is chosen for PCA, knowledge of its pharmacology is prerequisite for setting the dosing variables of the PCA device. In the setting of renal impair-ment, opioids that do not have active metaboli-tes, such as fentanyl, are preferred for PCA11.

In comparison with young patients, the elderly reported greater pain relief in response to a fi-xed dose of morphine30. Using PCA, they self-administer less opioid than young patients but report comparable pain relief14.It has also be-en demonstrated that cognitively intact older patients are quite capable of using a PCA, ac-hieve similar reductions in pain and self-administer less overall opioid; however, they use the PCA for a longer duration compared with younger adults11.A Cochrane review con-cluded that PCA provided superior analgesia and improved patient satisfaction compared with other conventional methods of delivery52. A study compared PCA and i.m analgesics in elderly patients after major surgery14. The re-sults showed that PCA presented significantly fewer major confusional episodes, fewer major pulmonary complications, improved analgesia and early mobilization without increased seda-tion14.

One potential problem with PCA is the practi-ce of patient-controlled analgesia (PCA) by proxy (the administration of an PCA bolus do-se by someone other than the patient). PCA by proxy is of particular concern in older patients who are not cognitively intact and cannot relia-bly use PCA. The Joint Commission on Accre-ditation of Healthcare Organizations (JCAHO) recommended PCA by nurse proxy be utilized only at those institutions where patient sele-ction criteria and monitoring standards have been established15.Licht Eet al., describe three challenges when attempting to manage pain vi-a PCA devices in hospitalized patients with cognitive impairment. The initial challenge in-volves making a determination the patient will be able to use the device appropriately. Asses-sing whether the PCA is being appropriately u-sed constitutes the second challenge. Evidence that patients are using the device, no way gua-rantees that they are operating it correctly. The third challenge involves the timing of PCA discontinuation. PCA use in this population re-quires continual reassessment and documenta-tion of its effectiveness. Cognitively impaired patients are at particular risk for delirium and any changes in mental status demand prompt attention53.

Non-opiod analgesic agents

Non Steroidal Anti Inflammatory Drugs (NSAIDs)

NSAIDs are among the most commonly used pain medications in the elderly, because they provide effective rapid and sustained relief for mild to moderate pain11. These drugs exert the-ir analgesic and anti-inflammatory effects by diminishing peripheral and/or central prosta-glandin production through the inhibition of the COX enzyme. The COX enzyme exists in two forms: COX-1 and -2. These enzymes are reversibly inactivated by nonselective NSA-IDs. Nonselective NSAIDs enhance pain reli-ef, induce opioid-sparing effects and may re-duce opiate adverse effects such as urinary re-tention, nausea and vomiting11.A meta-analy-sis showed that NSAID reduce morphine re-quirements in patient controlled analgesia fol-lowing major surgery along with a concomi-tant reduction in morphine-related nausea, vo-mitingand sedation54.Additionally, periopera-tive NSAID administration can provide phar-macological action (antipyretic and anti-in-flammatory activity) that when used in combi-nation with regional anesthesia may enhance patient satisfaction and quality of their recove-ry55.

However, NSAIDs are associated with signifi-cant adverse effects, especially gastrointestinal and renal toxicity, which are particularly pre-valent in the elderly. An age-related decrease in gastric bicarbonate secretion, blood flow, and mucosal function, as well as delayed ga-stric emptying time, all contribute to a loss of stomach protection and an increased risk of ga-stritis, ulcer formation, and gastrointestinal bleeding56. An age-related decline in renal blo-od flow, in functional renal mass, in glomeru-lar filtration rate and in creatinine clearance, affect drug elimination by the kidne-ys11.Therefore, the elderly depend more on prostacyclin-mediated renal afferent arteriolar vasodilatation to maintain glomerular blood flow. Because NSAIDs impair this compensa-tory mechanism, a further decrease in renal eli-mination of drugs occurs54.The possible con-sequences are delirium or other impaired cog-nitive function, decreased functional indepen-dence, depression, poorer clinical outcomes, as well as increased hospital length of stay, health care use and overall costs11,54,56. The cycloo-xygenase-2 inhibitors (COX-2 inhibitors) were and are excellent choices for perioperative a-nalgesia11. Their lack of effect on platelet fun-ction make them extremely useful during the pre- and post-operative phase, provided care is taken to avoid patients at risk for renal failure and those with severe ischemic15.

An additional concern associated with NSAIDs is that the very anti-inflammatory ef-fects that make them effective analgesics may adversely affect healing processes that require inflammation11. Such area is bone healing, in-cluding fractures and effectiveness of bone fu-sions in spine surgery. NSAID administration has been shown to inhibit osteogenic activity and fracture healing in animal models11.

To date, NSAIDs as a class of medication have not been deemed inappropriate for use in the elderly population because of inadequate evi-dence, with 2 specific exceptions. Indometha-cin has been labeled as inappropriate because of toxicity to the central nervous system, as well as phenylbutazone because of its risk of bone marrow suppression56. Current guidelines call for judicious use of NSAIDs, especially in elderly patients, with low doses (dose reducti-on at 25% to 50%) and short-term therapy, as well as close monitoring of renal and gastro-intestinal function, blood pressure, and fluid status during and immediately after therapy in all elderly patients56.

Paracetamol

Paracetamol is a safe and effective analgesic in the management of post-operative mild to mo-derate pain and other acutely painful conditi-ons57. Its antinociceptive (pain-relieving) acti-vity is generally thought to be due to central prostaglandin; inhibition however, central COX-2 inhibition and descending serotonergic modulation may also contribute to its analgesic properties11. Paracetamol is rapidly and com-pletely absorbed from the gastrointestinal tract and neither the rate nor the extent of absor-ption appears to be age-dependent57. Elderly patients present a reduction in paracetamol cle-arance57. Unlike NSAIDs, it has minimal peri-pheral COX enzyme inhibition. In patients wi-th severe liver disease elimination half-life can be prolonged and a reduction in dose and dura-tion is recommended57. A number of factors that increase the risk of hepatotoxicity have been identified, including chronic alcoholism, dosing in excess of 4 g day−1, pre-existing liver disease, concomitant use of microsomal enzy-me inducers and malnourishment57. Given the physiological changes characteristic of frailty, in particular malnourishment, frail older peo-ple may be more susceptible to the adverse ef-fects of paracetamol than their healthy counter-parts.

Paracetamol’s opiate-sparing properties are well established in the postoperative setting54. Paracetamol reduces opioid consumption com-pared with placebo in a variety of postoperati-ve settings including total hip replacement, to-tal knee replacement, hysterectomy and tonsil-lectomy11. Despite consistent reduction in 24 h postoperative morphine consumption, no appa-rent reduction has been found in opioid-related side effects after major surgery54.

There has been increasing interest in the use of routine paracetamol in patients with dementia, even in the absence of overt signs of pain. A randomized, placebo-controlled study of 25 nursing home residents with moderate to seve-re dementia found regular administration of paracetamol (3 times daily) resulted in increa-sed social interaction, work-like behavior and self-talk57. It appears that the regular admini-stration of paracetamol can reduce the sequel of untreated pain and improve functioning in patients with dementia, although an optimal dose has not yet been ascertained. Maybe the routine administration of paracetamol can be applied also to postoperative geriatric patients with dementia.

Anticonvulsants

Gabapentin is an anti-epileptic drug that has demonstrated analgesic effect in diabetic neu-ropathy, post-herpetic neuralgia, and neuropa-thic pain. Gabapentin does not bind to GABA A or GABA B receptor but to the alpha-2 delta subunit of the presynaptic voltage gated-calci-um channels. The inhibition of calcium release prevents the release of excitatory neurotrans-mitters involved in the pain pathways. Most of the studies of gabapentin (and occasionally its structural analog pregabalin) in the perioperati-ve setting have been published in the last 8 years, and several systematic reviews availa-ble58.Gabapentin and its successor pregabalin proved to decrease perioperative pain and limit long-term wound hypersensitivity11. This latter property is particularly important with those surgeries that have high rates of chronic wound pain: mastectomy, hysterectomy, ingui-nal hernia repair and thoracotomy. All of these types of surgery involve cutting peripheral ner-ves and inducing wound hypersensitivity11. Most of the reviews and meta-analyses concur that perioperative gabapentin helps to produce a significant opioid-sparing effect and proba-bly improves postoperative pain score relative to control group58. Gabapentin and similar drugs seem to have a strong potential for peri-operative use as an analgesic adjuvant and an-ti-hyperalgesic agent when used in conjunction with opioids58.

Adverse effects associated with perioperative administration of the gabapentinoids are infre-quent. An increased incidence of sedation and a trend towards more patient dizziness may li-mit their use in the ambulatory surgical setting. Gabapentinoids are not metabolized prior to renal elimination; therefore, dose adjustments are required for patients with renal insufficien-cy11. The choice of anticonvulsants for the tre-atment of acute pain in the elderly will depend on further research.

N-methyl-D-aspartate Receptor Antagonists (NMDA)

NMDA receptor antagonists and specifically ketamine, which commonly used in clinical practice, have been used in perioperative pain management of elderly patients59. Routes of ketamine administration include intravenous, subcutaneous, epidural, transdermal, and intra-articular. At low sub anesthetic doses (0.15–1 mg/kg), ketamine exerts a specific NMDA blo-ckade and, hence, modulates central sensitiza-tion induced both by the incision and tissue da-mage and by perioperative analgesics such as opioids58. Subanesthetic ketamine dosing was found to lower pain scores, reduce morphine consumption and shorten postoperative i.v PCA dependence in orthopedic patients with malignancy11. There is a definite role of keta-mine in preventing opioid-induced hyperalge-sia in patients receiving high doses of opioid for their postoperative pain relief58. However, clinical use of ketamine can be limited due to psychotomimetic adverse effects such as hallu-cinations and bad dreams. Other common ad-verse effects are dizziness, blurred vision, nau-sea and vomiting11. Clinicians concern over ketamine’s side effect profile has limited its u-se, however, low-dose ketamine can be safely used, in elderly patients11.

Other agents

Incorporation of antidepressant medications into perioperative pain management also has advantages that compliment analgesic techni-ques used in the elderly. In addition to their value as an analgesic, antidepressants improve a patient’s sense of well-being, reduces fatigue, and do not disrupt the normal sleep cycle55. Certain antidepressants (treatment of neuropa-thic pain characterized by damage/dysfunction of CNS and/or PNS) have become popular as a non-opioid medication in the treatment of po-stoperative pain as a multimodal component in combination with regional anesthesia55. Anxio-lytics can be included in a multimodal periope-rative pain management regimen. Pain can cause anxiety and, in turn, anxiety often exa-cerbates the perception of pain. Therefore, an-xiolytics may provide a mechanism to break this cycle and indirectly help to relieve pain, in elderly patients, in combination with regional anesthesia/analgesia55.

Other non-opioid analgesic adjuvants that can be used for postoparerative pain relief, are clo-nidine, dexmetomidine, neostigmine and ade-nosine58.Further research is necessary to esta-blish their clinical efficacy in geriatric surgical population.

Conclusion

In our days, pain care providers have a variety of choices of analgesic pharmacotherapy and techniques to choose from, in order to provide adequate postoperative pain relief for the geri-atric surgical patient. However, many factors should be takeninto account before deciding on the type of pain therapy, such as the physio-logical changes of aging, the drug dosing, the drug toxicity, the altered pain perception, the need to individualize pain assessment tools and the frequent incidences of depression and altered cognition on painful states. Perhaps the greatest challenge of postoperative pain mana-gement in the elderly is the education of clini-cians on the need to adjust their approach to pain management, in this special population. Pain management therapy, including multimo-dal analgesia, along with regional anesthesia, may help reduce the risk of negative influences in the elderly patient. Analgesic techniques that provide optimal pain control and low side effect profiles with minimal opioid exposure should always be considered for elderly pati-ents and especially for cognitively impaired patients. Improvements in analgesic efficacy with regional anesthesia may attenuate patho-physiological surgical responses, reduce the length of hospitalization, and accelerate patient rehabilitation and recovery. Careful monitor-ing and frequent assessment remain a priority. Confusional states often develop insidiously in elders following surgery, and frequently is un-detected without careful assessment. Additio-nally, performing minimal invasive surgery can decrease surgical stress, the need for anal-gesics and contributes to early mobilization, a-limentation and to reduced mortality in the ge-riatric surgical population.

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