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SPECIAL ARTICLE Pharmacological Management of Persistent Pain in Older Persons American Geriatrics Society Panel on the Pharmacological Management of Persistent Pain in Older Persons Pain is a complex phenomenon caused by noxious sen-sory stimuli or neuropathological mechanisms. An in- dividual’s memories, expectations, and emotions modify the experience of pain.1 Persistent pain, by definition, con- tinues for a prolonged period of time and may or may not be associated with a well-defined disease process. In the med- ical literature, the terms ‘‘persistent pain’’ and ‘‘chronic pain’’ are often used interchangeably, but the newer term, ‘‘persistent pain,’’ is preferred, because it is not associated with the negative attitudes and stereotypes that clinicians and patients often associate with the ‘‘chronic pain’’ label.2 In the definition of persistent pain, authors have used var- ious durations of painful sensation, including pain longer than 3 months, 6 months, or more. Some reports make the assumption that patients with certain diagnoses, such as postherpetic neuralgia, low back pain, or cancer-related pain, must also experience persistent pain. In the final anal- ysis, readers must evaluate new additions to the medical literature carefully and consider how these sometimes ar- bitrary definitions apply to each clinical situation and in- dividual patient. Demographers, insurers, and employers have defined older persons as aged 65 and older. By age 75, many persons exhibit some frailty and chronic illness, with many having multiple chronic illnesses. In the population aged 75 and older, morbidity, mortality, and social problems increase rapidly, resulting in substantial strains on the healthcare system and social safety net.3,4 The American Geriatrics Society (AGS) Panel on Pharmacological Management of Persistent Pain in Older Persons focused its attention on this older frail population in preparing this update. Persistent pain commonly affects older people5–7 and is most frequently associated with musculoskeletal disorders, such as degenerative spine conditions and arthritis. Night- time leg pain (stemming from muscle cramps, restless legs, or other conditions) and pain from claudication are also common. As many as 80% of older persons diagnosed with cancer experience pain during the course of their illness,8 and pain that occurs as a consequence of cancer treatment is increasingly recognized as a form of persistent pain.9 The distress of cancer pain creates an obligation for clinicians to provide effective pain management, particularly near the end of life. Persistent pain is also frequently encountered in nursing homes. Many nursing home residents have multiple complaints and numerous potential sources of pain.10,11 Neuralgia secondary to diseases such as diabetes mellitus, infections such as herpes zoster, peripheral vascular disease, and trauma, including surgery, amputation, and other nerve injuries, is somewhat less frequent. Persistent pain or its inadequate treatment is associated with a number of adverse outcomes in older people, in- cluding functional impairment, falls, slow rehabilitation, mood changes (depression and anxiety), decreased social- ization, sleep and appetite disturbance, and greater health- care use and costs.12 Although appropriate treatment can reduce these adverse events, the treatments themselves may incur their own risks and morbidities. Persistent pain can also be as distressing for the caregiver as for the patient. Caregiver strain and negative caregiver attitudes can sub- stantially affect the patient’s experience of pain and should be evaluated and discussed during the clinical encounter, if present. Guideline Development Process and Methods The American Geriatrics Society (AGS) provided the first Clinical Practice Guideline on management of chronic pain in older persons in 1998.13 This landmark publication be- came a call to arms for improving pain management, qual- ity of life, and quality of care for older patients. In 2002, the publication was revised to include new pharmacological and other strategies for improving patient care, as well as new information on the assessment of pain in patients with cognitive impairment.12 The focus of these efforts has been to provide education and guidance to primary care clinicians, researchers, and other health professionals as they encounter patients with persistent pain and its complications. The current Guideline aims to update the evidence base of the 2002 Guideline and provide recommendations re- garding the use of newer pharmacological approaches to managing persistent pain in the older population. Since the development of the two previous AGS publications, sub- stantial progress has been made in this area. New drugs AGS Panel on Pharmacological Management of Persistent Pain in Older Persons. This guideline was developed and written under the auspices of the AGS Panel on Pharmacological Management of Persistent Pain in Older Persons and approved by the AGS Executive Committee on April 21, 2009. Address correspondence to Elvy Ickowicz, MPH, Assistant Deputy Executive Vice President, American Geriatrics Society, 350 Fifth Avenue, Suite 801, New York, NY, 10118. E-mail: eickowicz@americangeriatrics.org DOI: 10.1111/j.1532-5415.2009.02376.x American Geriatrics Society, New York, New York. JAGS 57:1331–1346, 2009 r 2009, Copyright the Authors Journal compilationr 2009, The American Geriatrics Society 0002-8614/09/$15.00 aries.xu 高亮 aries.xu 高亮 have been introduced, management strategies have been more fully evaluated, and new treatment approaches are now available. In particular, many recent reports describing novel pharmacological approaches to management warrant an appropriate revision to the 2002 publication at this time. Because the most common strategy for management of persistent pain in older persons is the use of pharmacolog- ical agents, and because this is also the area of greatest risk, it was decided to focus on pharmacotherapy in this update. This document is not an exhaustive treatise; rather, it is offered as a synthesis of existing literature and the consen- sus of experts familiar with clinical pain management, re- search in older persons, and the diverse settings in which care is often provided, including ambulatory care settings and nursing homes. As such, it is hoped that this guideline update proves helpful to clinicians, researchers, and policy makers alike. Ultimately, it is hoped that the beneficiaries of this work will be older patients who often require effective pain management to maintain their dignity, functional ca- pacity, and overall quality of life. The development of this guideline update was begun by convening a panel comprising members from the previous panels and new members with substantial knowledge, ex- perience, and publications in pain management and care of older patients. Panel members included experts in geriatric pain management, pharmacology, rheumatology, neurol- ogy, nursing, palliative care, and geriatric clinical practice. Beginning with a review of previous guidelines from the AGS, American Pain Society, American College of Rheum- atology, and others, the panel conducted a review of evi- dence-based literature published since the preceding AGS guidelines appeared and then drafted new recommenda- tions. An independent researcher was commissioned to conduct a literature search. More than 24,000 citations were identified from sources such as computerized key word searches for each recommendation, personal citation libraries of the panel members, and references from texts of some individual articles. Of these, approximately 2,400 abstracts were screened for evidence-based content. De- tailed summaries were created along with the full-text articles for more than 240 full-text English-language arti- cles. Data from these articles (formal meta-analyses, ran- domized controlled trials, other clinical trials) were reviewed to determine the strength and quality of evidence for the recommendations based on a modified version of the Grading of Recommendations Assessment, Development, and Evaluation Working Group14,15 that the American College of Physicians developed for their Guideline Grading System.16 Through a consensus process, panel members assigned strength and quality of evidence to each recom- mendation. Table 1 provides a key to the designations used. Current evidence-based literature does not serve as an adequate guide in many decision-making situations that are routinely encountered in clinical practice. For example, much existing evidence is focused on disease-specific con- ditions or on younger populations with limited generaliz- ability. Also, the number of controlled studies involving only patients aged 75 and older remains low. Furthermore, high-quality studies involving elderly patients from differ- ent ethnic groups are rare. Therefore, some of the recom- mendations are based on the clinical experience and the consensus of panel members, as well as the existing weak scientific evidence. When appropriate, the panel drew on studies of younger subjects that could be extrapolated to older individuals, but extrapolation to the oldest old or to care settings where older persons often reside was not al- ways reasonable. Once the literature review was completed, evidence was rated, and the document was disseminated for external review by experts from a variety of other organi- zations with interest in this subject. (See Acknowledgments for listing of review organizations.) Each expert panel member completed a disclosure form at the beginning of the guideline process that was shared with the entire expert panel at the start of its two expert panel meetings. Conflicts of interest in this guideline have been resolved by having the guideline independently peer reviewed and then edited by the Expert Panel Chair, who had no conflict of interest with the medications being dis- cussed. Expert panel members who disclosed affiliations or financial interests with commercial interests involved with the products or services referred to in the guideline are listed under the disclosures section of this article. Some matters involving pharmacological management of persistent pain in older persons were beyond the scope of this publication. For example, the use of anesthetic agents, chronic infusions, and neurostimulatory and implantable pump technologies were not addressed. It is hoped that this update will stimulate others to focus on solutions to the significant issues not addressed here. The update begins with a review of pain assessment principles. The recommendations that follow have been grouped under the following headings: nonopioids, includ- Table 1. Key to Designations of Quality and Strength of Evidence Quality of evidence High Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes (�2 consistent, higher-quality randomized controlled trials or multiple, consistent observational studies with no significant methodological flaws showing large effects). Moderate Evidence is sufficient to determine effects on health outcomes, but the number, quality, size, or consistency of included studies; generalizability to routine practice; or indirect nature of the evidence on health outcomes (�1 higher quality trial with 4100 subjects; �2 higher- quality trials with some inconsistency; �2 consistent, lower-quality trials; or multiple, consistent observational studies with no significant methodological flaws showing at least moderate effects) limits the strength of the evidence. Low Evidence is insufficient to assess effects on health outcomes because of limited number or power of studies, large and unexplained inconsistency between higher- quality studies, important flaws in study design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes. Strength of recommendation Strong Benefits clearly outweigh risks and burden OR risks and burden clearly outweigh benefits. Weak Benefits finely balanced with risks and burden. Insufficient Insufficient evidence to determine net benefits or risks. 1332 ICKOWICZ AUGUST 2009–VOL. 57, NO. 8 JAGS ing acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs); opioid analgesics; adjuvant drugs; and other medications. General principles are discussed first, followed by the panel’s specific recommendations for use of these medications. Readers should recognize that medical science is constantly evolving and that clinicians have a re- sponsibility to keep abreast of new developments. New and emerging evidence may have important implications for the implementation of specific recommendations contained in this document. These recommendations are intended as a guide. They should not substitute for critical thinking, sound judgment, clinical experience, and an open-minded approach to the unique individual circumstances of each clinical encounter. ASSESSMENT AND MANAGEMENT OF PERSISTENT PAIN General Principles The approach to pain management in older persons differs from that for younger people. Clinical manifestations of persistent pain are often complex and multifactorial in the older population. In addition, older people may underre- port pain. Concurrent illnesses and multiple problems make pain evaluation and treatment more difficult. Also, older persons are more likely to experience medication-related side effects and have a higher potential for complications and adverse events related to diagnostic and invasive pro- cedures. Despite these challenges, pain can usually be ef- fectively managed in this age group. Moreover, clinicians have an ethical and moral obligation to prevent needless suffering and do their best to provide effective pain relief, especially for those near the end of life. An effective pharmacological approach to the treat- ment of persistent pain requires accurate pain assessment. Routine screening and careful assessment of all older pa- tients is crucial, because even pain that is causing severe impairment may not be spontaneously revealed for a variety of personal, cultural, or psychological reasons.12 Not only do many older persons underreport pain, but there are also inherent difficulties in recognizing pain experienced by pa- tients with cognitive impairment. A thorough initial assess- ment and appropriate diagnostic evaluation are always necessary and may reveal disease-modifying interventions that can potentially relieve pain at the source.17 Interdis- ciplinary assessment during the evaluation process may help identify all such treatable contributing factors. For patients whose underlying pain source is not remediable or only partially treatable, an interdisciplinary assessment and treatment strategy is the best approach.18,19 When special- ized services or skilled procedures are indicated, referral to an appropriate specialist is necessary. For example, patients with debilitating psychiatric complications, problems of substance abuse, or life-altering intractable pain require re- ferral to specialists with relevant expertise.12 The current best indicator of the pain experience is the patient’s own report, which must include an assessment of the pain intensity and an evaluation of the effect of the pain on daily function.20 Even in the presence of mild or mod- erate cognitive impairment, an assessment can be made us- ing simple questions and screening tools, including a variety of pain scales that have been developed specifically for this purpose.21–25 Approaches for recognizing and evaluating pain in nonverbal older persons are also available.26 Readers are referred to a recent systematic review for details of the current state of the art in assessment of pain in older persons27 and to previous AGS guidelines (http://www.americangeriatrics.org) for specific recommen- dations for pain assessment in older persons that remain relevant.12,13 General Principles of Pharmacological Management Any pain complaint that affects physical function or quality of life should be recognized as a significant problem. Older patients with functional impairment or diminished quality of life are candidates for pharmacological therapy, with in- tervention decisions based on careful weighing of risks and benefits. Positive outcomes are maximized when clinicians are knowledgeable about the drugs they prescribe and reg- ularly monitor patients for adverse effects, although it is unrealistic to imply, or for patients to expect, complete ab- sence of pain for some persistent pain conditions.12 Com- fort goals should be mutually established for managing pain to a level that allows the patient to engage in activities and achieve an acceptable quality of life. Although older patients are generally at higher risk of adverse drug reactions, analgesic and pain-modulating drugs can still be safe and effective when comorbidities and other risk factors are carefully considered. It must be assumed that there will be age-associated differences in ef- fectiveness, sensitivity, and toxicity and that pharmacoki- netic and pharmacodynamic drug properties will change in this population.28–31 Table 2 provides a summary of changes observed with normal aging that can affect dispo- sition, metabolism, and responses to analgesic medications. For some classes of pain-relieving medications (e.g., opioids), older patients have demonstrated greater analge- sic sensitivity, but older people constitute a heterogeneous population, making optimum dosage and common side ef- fects difficult to predict. Recommendations for age-adjusted dosing are not available for most analgesics. In reality, dos- ing for most patients requires initiation with low doses fol- lowed by careful upward titration, including frequent reassessment for dosage adjustments and optimum pain re- lief and for adverse effects. The least-invasive method of drug administration should be used. Some opioids, for example, can be admin- istered through a variety of routes, including oral, subcu- taneous, intravenous, transdermal, oral sublingual, intrathecal, and rectal. Most drugs are limited to only a few safe routes of administration, but new delivery systems are being developed each year. As a rule, the oral route is preferable because of its convenience and the relatively steady blood concentrations that result. Some drug effects are seen in 30 minutes to 2 hours after oral administration of analgesics; this may be inadequate for acute, rapidly fluctuating pain. Intravenous bolus provides the most rapid onset and shortest duration of action but requires more labor, technical skill, and monitoring than oral administra- tion. Although commonly used, subcutaneous and intra- muscular injections have disadvantages such as wider fluctuations in absorption and more rapid fall-off of action than the oral route. Transdermal, rectal, and oral transmu- PHARMACOLOGICAL MANAGEMENT OF PERSISTENT PAIN IN OLDER PERSONS 1333JAGS AUGUST 2009–VOL. 57, NO. 8 cosal routes may be essential for people with swallowing difficulties. Timing of medication administration is also important. Rapid-onset, short-acting analgesic drugs should be used for severe episodic pain. Medications for intermittent or episodic pain can usually be prescribed as needed, although the as-needed approach is not a good choice for patients with cognitive impairment who are not able to request medication appropriately. Scheduled administration before anticipated (or incident) pain episodes is recommended in these patients. For continuous pain, medications should be provided around the clock. In these situations, a steady- state analgesic blood concentration maintains comfort more effectively. Most patients with continuous pain who are receiving long-acting or sustained-release prepara