Pharmacological Treatment of Pain in Dementia

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Pain is common in older individuals [3]: acute painful conditions are very frequent, as older persons have the highest rates of surgery, procedural pain, and complications [30], and chronic conditions disproportionately affect older adults [42]. Age-related factors influence the pharmacology of drugs and their efficacy/safety ratio, the frequency of comorbidities, the polymedication, drug–drug and drug–disease interactions, the high variability of pharmacological changes, and ensuing analgesic requirements [5]. Over recent years, treatment guidelines for managing pain and prescribing analgesics to older persons have been developed worldwide [2, 4, 6, 9, 37, 57]. They support a more tailored approach based on the patients’ individualized risks, an optimization of the treatment strategy, an anticipation of potential medication-related problems (falls, hospitalization) [14], and a multimodal therapeutic regimen. However, pain treatment in older persons with cognitive disorders, communication problems, and especially dementia is a real challenge for a number of reasons: pain assessment is particularly difficult in this population, titration of action and dosage finding are cumbersome, behavioral and psychological symptoms of dementia (BPSD) are easily confused with pain, psychotropic drugs are frequently prescribed and medications, sometimes inappropriate, display their cohort of side effects including delirium. This chapter will review the sequels of dementia on adequate pain management.

PHARMACOLOGICAL CHANGES WITH AGING

Aging is associated with a number of pharmacokinetic and pharmacodynamic changes, and although most published studies were performed in healthy older subjects, a few reports suggest even greater significant pharmacokinetic and pharmacodynamic alterations in frail compared to healthy elderly [49].

Pharmacokinetic Changes

Absorption may be influenced by several factors including comorbidities, medications slowing the gastrointestinal transit, chronic constipation, chronic laxative use, gastroesophageal reflux, and dysphagia [49, 54]. Concerning transdermal absorption, bioavailability of medications in plasters is often unpredictable in older patients, and associated with significant interindividual variability [19].

The consequences of age-related changes in distribution are significant. Aging is associated with decreased lean mass, increased fat mass, and decreased total water volume, and consequently changes the distribution of medications in the body [19, 25]. The distribution volume of hydrophilic medications (like morphine) is decreased, which increases the plasmatic concentrations and requires a lower dosing. Inversely, the distribution volume of lipophilic medications (like fentanyl) is increased, and this decreases their plasmatic concentrations and increases their half-life, often resulting in an accumulation of drugs [19]. Advanced age is also often associated with decreased serum albumin [36]: this is more frequent in the presence of chronic disease or malnutrition, and results in an increased free fraction of the medication. These changes are, however, only clinically significant for medications with a protein binding higher than 90%, a small distribution volume and a narrow therapeutic index [18].

Concerning the metabolism of drugs, liver mass and hepatic blood flow decrease with aging, which impairs drug clearance for flow-limited (high-clearance) drugs, and some authors suggest a 20–60% impairment of the intrinsic metabolic drug clearance [10]. The activity of phase I enzymatic reactions seems to be reduced, whereas activity of phase II enzymatic reactions is usually not modified [47]. Concerning renal elimination, renal mass and tubular secretion decrease significantly with age. There is a 30–50% decrease of glomerular filtration at 80 years old, which results in accumulation of renally excreted medications. Renal function and creatinine clearance can be estimated with the Cockroft–Gault formula, taking into account age, weight, serum creatinine, and gender [12]. In older malnourished patients with decreased muscle mass, this formula overestimates creatinine clearance.

Pharmacodynamic Changes

Age-related pharmacodynamic changes often result in increased sensitivity of older patients to medications and, consequently, increased occurrence of adverse effects (AEs) [34]. More specifically, increased sensitivity of cholinergic receptors makes older patients more sensitive to AEs from anticholinergic medications, including tricyclic antidepressants.

Decreased homeostasis can explain the delayed recovery of basal state following impairment of a physiological function in older patients, including development of acute renal failure or gastrointestinal bleeding with nonsteroidal anti-inflammatory drugs (NSAIDs) administration or sedation associated with opioids.

ANALGESICS AND RED FLAGS OF PAIN TREATMENT IN THE ELDERLY

Pain evaluation is particularly difficult in patients with dementia, and this central point is largely discussed in other chapters (see Chapters 9–11). Suspicion of pain in demented patients may be raised by behavioral changes like agitation and aggression, and assessment of the efficacy of an analgesic relies on a systematic reevaluation of pain and on the reliability of the scale. While agitation and aggression may be symptoms of pain in noncommunicative patients, they may also be symptoms of dementia. These Behavioural and Psychological Symptoms of Dementia (BPSD) may orientate treatment toward psychopharmacological rather than analgesic treatment or may increase the risk of serious side effects with analgesics.

In older patients with polymedication and age-related pharmacological changes, treatment of pain will bring an additional pharmacological burden and the choice of the analgesic should follow recommendations and be individualized. The frequent polypharmacy in older patients leads to an increased risk of drug–drug interactions and related toxicity [38].

Paracetamol is widely used in older patients because of the high prevalence of joint pathologies and recommended as the first-line oral analgesic [3, 4]. Adverse Effects (AEs) are rare, with hepatotoxicity being the main safety concern in the context of depleted glutathione stores associated with malnutrition, prolonged fasting, underweight, poor nutritional status or alcoholism, age-related changes of antioxidant status, or dehydration [39, 44, 45].

NSAIDs and the cyclooxygenase-II selective inhibitors (coxibs) have a proven efficacy but a well-defined toxicity profile (gastrointestinal, renal, and cardiovascular), and NSAIDs may only be considered rarely, and with extreme caution, in highly selected older patients who have failed other safer therapies [4]. Studies have demonstrated that there is a high prevalence of inappropriate NSAIDs and coxibs usage in the elderly population [1, 55, 56]. Inappropriate medication prescription (especially the type of drug rather than the dosage) is frequent in older patients, and patients taking NSAIDs should be reassessed on a regular basis to ensure ongoing benefits, absence of toxicity, and drug–drug or drug–disease interactions [4]. A systematic literature review has recently suggested that an increased risk for accidental falls is probable when older persons are exposed to NSAIDs [21]. Topical NSAIDs have demonstrated efficacy similar to oral NSAIDs, with a low incidence of adverse events [8].

Opioid analgesics are recommended for the treatment of chronic pain of moderate to severe intensity with pain-related functional impairment or diminished quality of life [4, 37]. A review on the use of opioids in chronic pain in the elderly, with a focus on buprenorphine, fentanyl, hydromorphone, methadone, morphine, and oxycodone, stresses that older patients respond to opioid treatment as well as younger patients, but tolerability is often a limiting factor. It is not possible to recommend the use of a specific opioid [37], and the benefit–risk ratio of each opioid should be considered as well as comorbidities and concomitant medications. The general rule, applied in geriatrics but very strongly with opioids, is to start with the lowest dose possible, and titrate according to the analgesic response and AEs. Over the last two decades, opioid prescription has exploded leading to an opioid epidemic with adverse consequences [32]. Elderly patients have not escaped this epidemic. It is linked to a number of causes including liberalization of laws governing the prescribing of opioids for the treatment of chronic noncancer pain, allegations of undertreatment of pain and underuse of opioids in the elderly, increased prevalence of chronic pain, and longer life expectancy. From 1997 to 2007, hydrodrocodone usage has increased by 280% whereas oxycodone usage has increased by 866% [32]. In older persons opioids are prescribed for cancer pain treatment but also for noncancer pain and osteoarthritis. Osteoarthritis is one of the most common diseases of old age and a leading cause of disability and of chronic pain worldwide. Benefits and harms of opioids in the elderly are largely reviewed in the literature and are associated with a much higher risk of fracture [51, 52] than other treatments [17, 29].