Effect of aging on pain relief in the older cancer patients: pharmacokinetic and pharmacodynamic aspects

1. Introduction

The prevalence of cancer rises with advancing age. A large number of cancer patients are aged over 65 years, and it is expected that even more patients will develop cancer as a consequence of the growing aging population. Pain is a common complaint of cancer patients and is considered one of the most distressing symptoms. Older patients more often present complex clinical problems than younger people. As a consequence, assessing and managing pain in older people with cancer commonly pose significant challenges [1].

Regrettably, older patients often are undertreated for cancer pain, despite available analgesics could be effective in most cases. Ageism has been considered a limitation for the optimal management of cancer pain and existing studies indicate that older people with cancer pain are poorly managed [2].Pain is often considered an expected concomitant of aging so that physicians are reluctant to report pain as a problem. Several studies have shown that older patients are less likely to receive appropriate analgesic treatments [3].The risk for undertreatment in this population depends on multiple factors, including the assumption that they tolerate pain well, misconceptions and fears about the use of opioids, elderly’s ability to benefit from them, and poor knowledge of pain treatment options. Pain seems to be an inevitable consequence of aging, and inadequate training and reluctance to prescribe opioid medications has been frequently reported. Moreover, the older patient is considered to be more susceptible to opioid-related adverse effects, and concomitant medications used for chronic disease may render the treatment more difficult [4].

2. Pharmacodynamic aspects

The question of the different pain perception in the elderly has been debated in literature. Possibly, the elderly may experience more pain than younger people, but they are less likely to complain of it. Several medical problems, including the presence of depression or cognitive impairment, and language barriers in minority patients, all contributing to under-reporting of pain, may render the assessment more complicated and specialistic advice should be required. Pharmacodynamic data in the elderly have rarely been explored. A tendency for tolerance to be more prominent in the young than elderly groups has been claimed, according to animal studies due to enhanced molecular and cellular neuroplasticity in younger neurons [5]. Some investigations have reported age-related differences in endogenous pain modulation and diminished tolerance for certain types of experimental pain models among elderly. Older adults demonstrated facilitation rather than inhibition during painful stimulation, suggesting decrements in endogenous analgesic response [6]. However, in studies dealing with the pharmacodynamic effects of opioids in elderly, the rate of drug delivery rather than the absolute dose over time may influence both analgesia and adverse effects [7]. In cancer patients, the relationship between the progression of disease, changes in neuroplasticity, and opioid receptor activity is more complex than in animals or non-cancer population. Moreover, the complex network of factors involved in the opioid response make the evaluation of a single element, such as age, more difficult. At moment, no consistent proofs of a pharmacodynamics influence exist in the elderly [5].

3. Pharmacokinetic aspects

Acetaminophen and nonsteroidal anti-inflammatory drugs are frequently used alone or in combination with opioids. The analgesic activity of these drugs is characterized by a ceiling effect so that increases in the dose will result in no further improvement of analgesia. While these drugs may be effective and have no habit-forming properties, they have been associated with a variety of adverse effects in the elderly, including gastric damage, renal failure, and coagulation disorders. Their use should be cautious in elderly cancer patients, particularly in frail elderly patients affected by several comorbidities [5].

Opioids that are commonly used for the management of acute and chronic pain have different physicochemical and pharmacokinetic characteristics, which explain the profound changes in the clinical effect in several clinical conditions. Age, other than genetic background of the metabolic enzymes involved in opioid metabolism, comorbid medical conditions, and the presence of other drugs that influence metabolism, can greatly vary the opioid response. Changes in drug metabolism, protein binding, distribution, and clearance associated with aging may result in a diminished rate of elimination, so amplifying the drug effects. The recognition of possible metabolic problems and the consideration of adverse drug–drug interactions are fundamental to optimize the use of opioids in clinical practice [8].Thus older people are potentially more likely to be affected by opioid toxicity, due to physiologic changes associated with aging.

Nevertheless, appropriate dosing may limit these risks. Despite the presumed vulnerability of older patients, several findings have shown that providing adequate and specialist palliative care, it is possible to achieve an adequate analgesia even at home. In a recent analysis of patients followed at home by a specialist palliative care team older patients were relatively similar to adults in terms of performance status and survival, and pain intensity was equally similar to that recorded in adult patients, with most patients having a well-controlled pain until death. Opioid-related adverse effects did not differ during opioid titration between older and adults patients. Similar figures regarding the routes of administration were found, as well doses of opioids used for opioid switching in case of unfavorable response, mostly due to the development of adverse effects. Interestingly, more than half of patients changed their opioid or their route of administration in the last 4 weeks, but older patients less frequently changed opioid or route of administration. This observation suggests that older patients have a better tolerability of opioid therapy, possibly also due to less opioid consumption. Elderly cancer patients experienced a similar level of pain intensity but required a lower amount of opioid analgesia than younger adults. It has been suggested that, because elderly patients are more likely to be affected by the acute and chronic toxicities of opioids, opioids should be initially administered at a lower dose and titrated cautiously in these patients [9]. In another retrospective study, an inverse significant association between age group and dose was found [10]. Similarly, opioid requirements have been shown to decrease with age in a regular pattern and from early adult life [11].In a home palliative care setting, very old patients reported a lower intensity of some symptoms, while presenting similar pain relief obtained with lower doses of opioids[12].

Cancer patients with pain who do not respond to increasing doses of opioids because they develop adverse effects before achieving an acceptable analgesia may be switched to alternative opioids. Unfortunately, data regarding the influence of aging on opioid switching and doses, particularly with methadone, are poor. In a retrospective analysis of clinical records, no differences between older patients and adults were found [13]. Opioid switching remains an unmet aspect which deserves further studies.

Data regarding breakthrough pain (BTP) are lacking. It has been reported that the oldest patients less frequently reported BTP, although BTP medication were similarly given in the age subgroups, confirming the appropriateness of opioid prescription. Age subgroup analysis of efficacy or adverse effects of BTP medications has never been reported in literature and deserve further interest for researchers [14].

4. Expert opinion

Regrettably, existing data regarding the effects of analgesic drugs in older people with cancer pain are poor. Despite the well-known metabolic aspects that may render the treatment of the elderly difficult, a careful use of analgesics may be effective in most cases. Poor pain relief is due to misconceptions, beliefs, or inappropriate assessment rather than a poor response to analgesics. These patients require lower doses of opioid analgesics to achieve in adequate analgesia with an acceptable adverse effect rate. Indeed, when these patients are followed by expert teams, the outcome of a pharmacological pain treatment is favorable, exactly like with adult patients. A careful assessment of the metabolic consequences of administering particular drugs in a patient with reduced metabolic capacity and with more chances to receive concomitant therapies is of paramount importance to optimize the treatment and to achieve an adequate pain relief, while minimizing the occurrence of adverse effects. A slow opioid dose titration may help in personalizing the treatment that requires to be followed in time through a continuous care, including the monitoring and the treatment of opioid-induced adverse effects or symptoms associated to advanced cancer. Some specific fields of research sic as breakthrough pain and opioid switching should be assessed in older patients in future studies.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.