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Tolerance and Aging: Optimizing Analgesia in Pain Management

Section Editor(s): Stein, ChristophAgin, Carole W. MD; Glass, Peter S. A. MB, ChB

doi: 10.1213/01.ANE.0000152203.17541.16
Pain Medicine: Editorial
Chinese Language Editions

Chronic Pain Management Center, Department of Anesthesiology, State University of New York at Stony Brook

Accepted for publication November 16, 2004.

Address correspondence and reprint requests to Peter S. Glass, MB, ChB, FFA (S.A.), University Medical Center at Stony Brook, Department of Anesthesiology, Nicolls Rd., HSC Level 4, Rm 060, Stony Brook, NY 11794-8480. Address e-mail to

In this month’s issue of Anesthesia & Analgesia, Wang et al. (1) present the results of their study concerning the need to escalate opiate dose (as a measure of the development of tolerance) in four different age groups of rats. In the companion article, Buntin-Mushock et al. (2), from the same institution, present their findings of retrospectively reviewed charts of pain center patients. The patients were separated by age, and the need to escalate their opiate doses was reviewed. In both articles, the authors claim a tendency for tolerance to be more prominent in the young than the elderly groups. These results certainly have important clinical implications. However, before they are accepted, it is important to examine how the data were determined.

Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time (3). Addiction is a human condition with genetic, psychosocial, and environmental factors (3,4). When treating chronic pain patients, doses of opiates often are increased in an attempt to achieve palliation from pain. The development of tolerance or addiction can contribute to the escalation of opiate doses. By definition, addiction requires a conscious effort. Addiction occurs when a patient intentionally seeks out an opiate with little concern for the negative impact on their health or well-being or that of their loved ones. In the clinical study by Buntin-Mushock et al. (2), the impact of addiction versus tolerance is difficult to separate. Rats cannot develop an addiction to opiates, and thus the study by Wang et al. (1) by definition examines tolerance. Their study design is elegant in that it examines a spectrum of ages and controls for the pain stimulus and the impact of pharmacokinetics confounding the dynamic responses. Unfortunately, the pain model does not truly replicate the clinical environments where pain is a continuous rather than an intermittent stimulus. As shown with other G protein receptors, such as those of the adrenergic system, the balance between agonist and antagonist is important in the evolution of tolerance. Tolerance is a physiologic occurrence. Wang et al. (1) ascribe the role of cellular plasticity and modulation of N-methyl-d-aspartic acid receptors and translocation of protein kinase in the development of tolerance to morphine in rats. The claim is that these cellular changes occurred more rapidly in the younger rats, leading to tolerance developing sooner when compared with older rats. That the adaptation of cellular processes occurs more readily in the young is an interesting hypothesis.

In the companion article, Buntin-Mushock et al. (2) describe the pattern of opiate prescribing in younger versus older patients being treated for nonmalignant pain in their pain center. Is tolerance the only reason that the elderly did not experience dose escalation comparable to the younger patients? One needs to question whether there are factors other than tolerance that affected the changes in dose escalation noted. Cutler et al. (5) evaluated the response of geriatric (>65 yr old), middle-aged (45–64 yr old), and younger (21–44 yr old) patients to treatment at pain centers. They determined that the geriatric chronic pain patients respond to treatment differently than younger chronic pain patients. Other possible explanations are: (a) the starting doses were uniform across the groups not because requirements were the same, but rather physicians tend to use the same starting dose; (b) underlying disease and progression of the disease was different by age group; and (c) in younger patients, if the initial doses of opiates relieved enough pain so that the patient could increase their activity level, this may have resulted in a return of his or her pain and subsequent need for an increase in opiate dose. These are a few potential explanations that may explain these results other than tolerance.

The under-treatment of pain results in physiological, psychosocial, and economic consequences. This continues to occur despite targeted approaches to improve the treatment of chronic pain (6). The specific under-treatment of pain in the elderly is a continuing problem. Ferrell et al. (7) described the management of pain at the end of life, the general under-treatment of pain, and the under-treatment of pain in the elderly as “the most frequently encountered dilemmas” faced by the physicians they studied.

Many barriers to adequate treatment of pain in the elderly have been identified. These include patient issues such as fear of addiction, concerns over side effects (in particular cognitive impairment), fear of angering the physician, and fear that an increase in opiate dose may mean that their medical condition is worsening. There are also barriers affecting opiate prescribing for the health care provider. These include fear of causing addiction and the fear of regulatory actions by government agencies. The lack of education about the appropriate use and reasonable risks of chronic opiate therapy contribute to the problem (8).

The health care provider may be limited in increasing the opiate dose in elderly patients by the frequent incidence of side effects, such as urinary retention, constipation, respiratory depression, forgetfulness, and cognitive impairment. Tolerance will develop to these adverse effects, usually within the first few days to weeks of initiating opiate therapy. Physical function often improves once pain relief is adequate and tolerance to these adverse effects has developed. Opioids frequently cause constipation. Unfortunately, tolerance to this adverse effect does not occur. As the authors point out, the older patient and, in particular, the elderly (patients older than 75 yr) are rarely studied with respect to chronic opiate therapy for nonmalignant pain. This adds to the risk of under-treatment in this patient population.

The visual analog scale (VAS) as a measurement instrument of pain has been shown to be a reliable, valid, and responsive tool when compared with multi-item questionnaires (9). There may be multiple explanations as to why the VAS in the elderly patients changed more than those of the younger patients studied. Is it possible that the older patients had fewer expectations? The expectations of the older patients (and those of their treating physicians) may have influenced the reporting (10).

The activity level and the level of interference in the patient’s daily activities were not discussed. As mentioned above, as the patient’s activity level increased, so may have the need for opiates. The activity level of the older patient may be more limited overall. Previous functional status of the elderly patients is important and needs to be considered when determining outcome of treatments (11).

Knowledge is power. Any knowledge that helps demystify tolerance and addiction and enhance the appropriate prescribing of opioids in medical practice is welcome. The combination of both a well-controlled animal study and supportive clinical evidence make the presented argument compelling, but like any good research, that of Wang et al. (1) has broached an area where more research is required, particularly as the use of opiates in the treatment of chronic nonmalignant pain increases. The knowledge that the elderly are less likely to require escalation of opiate doses secondary to the development of tolerance may also empower more physicians to be willing to use this important modality in the treatment of pain in this population.

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