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      Pharmacotherapy of Pain in the Older Population: The Place of Opioids

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          Abstract

          Pain is a common symptom in older people. It is possible that pain is underreported in older persons due to an incorrect belief that it is an inevitable part of aging. Opioid analgesics are potent medications, with confirmed efficacy for the treatment of moderate to severe pain. These drugs are commonly used in older persons. However, there is insufficient evidence regarding safety of opioids in older patients. One of the reasons for this is the lack of randomized, controlled clinical trials. People of advanced age often have comorbidites and use other prescription drugs, as well as over-the-counter (OTC) compounds, thus making them more suceptible to the risk of interactions with opioids. Significant pharmacokinetic and pharmacodynamic changes that occur with advancing age increase the risk of adverse effects of opioids. There are also some discrepancies between guidelines, which recommend the use of lower doses of opioids in older patients, and the findings in the literature which suggest that pain is often undertreated in this age group. It seems that there are significant variations in the tolerability of different opioid analgesics in older people. Morphine, fentanyl, oxycodone, and buprenorphine are still the preferred evidence-based choices for add-on opioid therapy for these patients. However, the safety and efficacy of other opioids in older patients, especially if comorbidities and polypharmacy are present, is still questionable. This review addresses the most important aspects of the use of opioids in older persons, focusing on pharmacokinetics, pharmacodynamics, adverse effects, and interactions.

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          Opioids and the management of chronic severe pain in the elderly: consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).

          SUMMARY OF CONSENSUS: 1. The use of opioids in cancer pain: The criteria for selecting analgesics for pain treatment in the elderly include, but are not limited to, overall efficacy, overall side-effect profile, onset of action, drug interactions, abuse potential, and practical issues, such as cost and availability of the drug, as well as the severity and type of pain (nociceptive, acute/chronic, etc.). At any given time, the order of choice in the decision-making process can change. This consensus is based on evidence-based literature (extended data are not included and chronic, extended-release opioids are not covered). There are various driving factors relating to prescribing medication, including availability of the compound and cost, which may, at times, be the main driving factor. The transdermal formulation of buprenorphine is available in most European countries, particularly those with high opioid usage, with the exception of France; however, the availability of the sublingual formulation of buprenorphine in Europe is limited, as it is marketed in only a few countries, including Germany and Belgium. The opioid patch is experimental at present in U.S.A. and the sublingual formulation has dispensing restrictions, therefore, its use is limited. It is evident that the population pyramid is upturned. Globally, there is going to be an older population that needs to be cared for in the future. This older population has expectations in life, in that a retiree is no longer an individual who decreases their lifestyle activities. The "baby-boomers" in their 60s and 70s are "baby zoomers"; they want to have a functional active lifestyle. They are willing to make trade-offs regarding treatment choices and understand that they may experience pain, providing that can have increased quality of life and functionality. Therefore, comorbidities--including cancer and noncancer pain, osteoarthritis, rheumatoid arthritis, and postherpetic neuralgia--and patient functional status need to be taken carefully into account when addressing pain in the elderly. World Health Organization step III opioids are the mainstay of pain treatment for cancer patients and morphine has been the most commonly used for decades. In general, high level evidence data (Ib or IIb) exist, although many studies have included only few patients. Based on these studies, all opioids are considered effective in cancer pain management (although parts of cancer pain are not or only partially opioid sensitive), but no well-designed specific studies in the elderly cancer patient are available. Of the 2 opioids that are available in transdermal formulation--fentanyl and buprenorphine--fentanyl is the most investigated, but based on the published data both seem to be effective, with low toxicity and good tolerability profiles, especially at low doses. 2. The use of opioids in noncancer-related pain: Evidence is growing that opioids are efficacious in noncancer pain (treatment data mostly level Ib or IIb), but need individual dose titration and consideration of the respective tolerability profiles. Again no specific studies in the elderly have been performed, but it can be concluded that opioids have shown efficacy in noncancer pain, which is often due to diseases typical for an elderly population. When it is not clear which drugs and which regimes are superior in terms of maintaining analgesic efficacy, the appropriate drug should be chosen based on safety and tolerability considerations. Evidence-based medicine, which has been incorporated into best clinical practice guidelines, should serve as a foundation for the decision-making processes in patient care; however, in practice, the art of medicine is realized when we individualize care to the patient. This strikes a balance between the evidence-based medicine and anecdotal experience. Factual recommendations and expert opinion both have a value when applying guidelines in clinical practice. 3. The use of opioids in neuropathic pain: The role of opioids in neuropathic pain has been under debate in the past but is nowadays more and more accepted; however, higher opioid doses are often needed for neuropathic pain than for nociceptive pain. Most of the treatment data are level II or III, and suggest that incorporation of opioids earlier on might be beneficial. Buprenorphine shows a distinct benefit in improving neuropathic pain symptoms, which is considered a result of its specific pharmacological profile. 4. The use of opioids in elderly patients with impaired hepatic and renal function: Functional impairment of excretory organs is common in the elderly, especially with respect to renal function. For all opioids except buprenorphine, half-life of the active drug and metabolites is increased in the elderly and in patients with renal dysfunction. It is, therefore, recommended that--except for buprenorphine--doses be reduced, a longer time interval be used between doses, and creatinine clearance be monitored. Thus, buprenorphine appears to be the top-line choice for opioid treatment in the elderly. 5. Opioids and respiratory depression: Respiratory depression is a significant threat for opioid-treated patients with underlying pulmonary condition or receiving concomitant central nervous system (CNS) drugs associated with hypoventilation. Not all opioids show equal effects on respiratory depression: buprenorphine is the only opioid demonstrating a ceiling for respiratory depression when used without other CNS depressants. The different features of opioids regarding respiratory effects should be considered when treating patients at risk for respiratory problems, therefore careful dosing must be maintained. 6. Opioids and immunosuppression: Age is related to a gradual decline in the immune system: immunosenescence, which is associated with increased morbidity and mortality from infectious diseases, autoimmune diseases, and cancer, and decreased efficacy of immunotherapy, such as vaccination. The clinical relevance of the immunosuppressant effects of opioids in the elderly is not fully understood, and pain itself may also cause immunosuppression. Providing adequate analgesia can be achieved without significant adverse events, opioids with minimal immunosuppressive characteristics should be used in the elderly. The immunosuppressive effects of most opioids are poorly described and this is one of the problems in assessing true effect of the opioid spectrum, but there is some indication that higher doses of opioids correlate with increased immunosuppressant effects. Taking into consideration all the very limited available evidence from preclinical and clinical work, buprenorphine can be recommended, while morphine and fentanyl cannot. 7. Safety and tolerability profile of opioids: The adverse event profile varies greatly between opioids. As the consequences of adverse events in the elderly can be serious, agents should be used that have a good tolerability profile (especially regarding CNS and gastrointestinal effects) and that are as safe as possible in overdose especially regarding effects on respiration. Slow dose titration helps to reduce the incidence of typical initial adverse events such as nausea and vomiting. Sustained release preparations, including transdermal formulations, increase patient compliance.
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            Management of pain in elderly patients with cancer. SAGE Study Group. Systematic Assessment of Geriatric Drug Use via Epidemiology.

            Cancer pain can be relieved with pharmacological agents as indicated by the World Health Organization (WHO). All too frequently pain management is reported to be poor. To evaluate the adequacy of pain management in elderly and minority cancer patients admitted to nursing homes. Retrospective, cross-sectional study. A total of 1492 Medicare-certified and/or Medicaid-certified nursing homes in 5 states participating in the Health Care Financing Administration's demonstration project, which evaluated the implementation of the Resident Assessment Instrument and its Minimum Data Set. A group of 13 625 cancer patients aged 65 years and older discharged from the hospital to any of the facilities from 1992 to 1995. Data were from the multilinked Systematic Assessment of Geriatric Drug Use via Epidemiology (SAGE) database. Prevalence and predictors of daily pain and of analgesic treatment. Pain assessment was based on patients' report and was completed by a multidisciplinary team of nursing home personnel that observed, over a 7-day period, whether each resident complained or showed evidence of pain daily. A total of 4003 patients (24%, 29%, and 38% of those aged > or =85 years, 75 to 84 years, and 65 to 74 years, respectively) reported daily pain. Age, gender, race, marital status, physical function, depression, and cognitive status were all independently associated with the presence of pain. Of patients with daily pain, 16% received a WHO level 1 drug, 32% a WHO level 2 drug, and only 26% received morphine. Patients aged 85 years and older were less likely to receive morphine or other strong opiates [corrected] than those aged 65 to 74 years (13% vs 38%, respectively). More than a quarter of patients (26%) in daily pain did not receive any analgesic agent. Patients older than 85 years in daily pain were also more likely to receive no analgesia (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.13-1.73). Other independent predictors of failing to receive any analgesic agent were minority race (OR, 1.63; 95% CI, 1.18-2.26 for African Americans), low cognitive performance (OR, 1.23; 95% CI, 1.05-1.44), and the number of other medications received (OR, 0.65; 95% CI, 0.5-0.84 for 11 or more medications). Daily pain is prevalent among nursing home residents with cancer and is often untreated, particularly among older and minority patients.
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              Pain management in the elderly population: a review.

              The elderly population comprises the fastest growing segment of the world's population. As patients age, the incidence and prevalence of certain pain syndromes increase. Pain may be underreported as some elderly patients incorrectly believe that pain is a normal process of aging. A comprehensive pain assessment includes a thorough medical history and physical examination, review of systems and pertinent laboratory results, imaging studies, and diagnostic tests. Pain physicians should have a broad range of understanding of the pharmacologic and physiological changes that occur in the geriatric population. The present review on pain management in the elderly focuses on relevant information for the pain clinician. Included are appropriate pain assessment, physical examination, pathophysiologic changes in the elderly, pharmacokinetic and pharmacodynamic changes, and present pain management modalities. Elderly patients present with increased fat mass, decreased muscle mass, and decreased body water, all of which have important ramifications on drug distribution. Hepatic phase I reactions involving oxidation, hydrolysis, and reduction appear to be more altered by age than phase II conjugation such as acetylation, glucuronidation, sulfation, and glycine conjugation. There is a predictable age-related decline in cytochrome P-450 function and, combined with the polypharmacy that much of the elderly population experiences, this may lead to a toxic reaction of medications. One of the newer opiates, oxymorphone, has recently been studied as it is metabolized in a non-cytochrome P-450 pathway and therefore bypasses many of the drug-drug interactions common to the elderly. A multidisciplinary approach is recommended to investigate all possible options for optimal management, including pharmacotherapy, interventional procedures, physical rehabilitation, and psychological support.
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                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                16 June 2016
                2016
                : 8
                : 144
                Affiliations
                [1] 1Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade Belgrade, Serbia
                [2] 2Hospital for ENT, KBC Dragiša Mišović Belgrade, Serbia
                [3] 3Institute for Gerontology and Palliative Care Belgrade, Serbia
                [4] 4Clinic for Otorhinolaryngology and Maxillofacial Surgery, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade Belgrade, Serbia
                [5] 5Clinic for Neurology and Psychiatry for Children and Youth, Faculty of Medicine, University of Belgrade Belgrade, Serbia
                Author notes

                Edited by: Rodrigo Orlando Kuljiš, University of Miami School of Medicine, USA

                Reviewed by: Tzvi Dwolatzky, Rambam Health Care Campus, Israel; Chandra Sekhar Kuruva, Texas Tech University of Health Sciences, USA

                *Correspondence: Milica Prostran mprostran@ 123456doctor.com
                Article
                10.3389/fnagi.2016.00144
                4909762
                27378916
                d9496350-0322-4dd8-a828-6d3c6e4146cd
                Copyright © 2016 Prostran, Savić Vujović, Vučković, Medić, Srebro, Divac, Stojanović, Vujović, Jovanović, Jotić and Cerovac.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 05 February 2016
                : 02 June 2016
                Page count
                Figures: 0, Tables: 3, Equations: 0, References: 50, Pages: 7, Words: 5279
                Funding
                Funded by: Ministarstvo Prosvete, Nauke i Tehnološkog Razvoja 10.13039/501100004564
                Award ID: 175023
                Categories
                Neuroscience
                Review

                Neurosciences
                pain,opioids,older persons,aging,polypharmacy,adverse effect
                Neurosciences
                pain, opioids, older persons, aging, polypharmacy, adverse effect

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