Health Articles

Opioid analgesics are indicated primarily to relieve moderate to severe acute pain and chronic pain due to cancer. Response to these drugs is enhanced in the elderly, partly because of elevated plasma levels and prolonged clearance and partly because of increased tissue sensitivity. Therapeutic guidelines for this population are summarized as follows.
Ensure that the indication is appropriate. Severe acute pain, such as that ompanying fractures, is the clearest indication. For chronic cancer pain, a so-called nalgesic ladder has been advocated; mild pain is managed with acetaminophen or an NSAID,rate pain with the addition of an opioid conventionally used for this indication (eg,e), and severe pain with an opioid usually used to treat intense pain (eg, morphine). or nonmalignant pain, chronic opioid therapy is controversial and should be considered only after all other reasonable attempts at analgesia have failed.
Choose an appropriate drug. Opioid selection is based on empiric factors such as avorable prior experience, cost, availability of a certain formulation, and specific pharmacologic properties. Pharmacologic issues include the class of opioid, sidects of specific drugs, and pharmacokinetic differences among drugs.
The opioid analgesics can be divided into pure agonists and agonist-antagonists (see TABLE 12-4). The latter are characterized by a balance of agonism and competitive antagonism at one or more types of opioid receptor site. Clinical characteristics of the agonist-antagonist opioids include a ceiling effect for respiratory depression, a lesser tendency to cause physical dependence, a relatively high incidence of psychotomimetic effects in the mixed agonist-antagonist subclass, and the ability to reverse opioid agonist effects and precipitate withdrawal in physically dependent patients. Because they reverse agonist effects, agonist-antagonists should be given only to patients not already receiving opioid drugs (ie, as first-line agents only). The only drug in this class available in the USA in an oral formulation is pentazocine, which is relatively likely to cause psychotomimetic effects.
Agonist-antagonist drugs are not currently recommended for the treatment of chronic cancer pain and should be used for severe acute pain only when parenteral administration is necessary. None has compelling advantages over the agonists. The clinical usefulness of a new intranasal formulation of butqrphanol has not yet been determined. Older patients with pain requiring opioid analgesics usually can be adequately managed with pure agonists.
Of the agonist drugs, meperidine causes a relatively high incidence of CNS hyperexcitability, including agitation, tremulousness, myoclonus, seizures, and dysphoria. This effect is caused by the accumulation in plasma of normeperidine, a toxic metabolite with a long half-life. Renal insufficiency is the major predisposing factor for this effect, suggesting that the elderly may be at particular risk. Thus, meperidine should generally be avoided.
The most important pharmacokinetic consideration is half-life. The preferred opioids are those that rapidly approach steady state and, therefore, are more easily monitored (eg, morphine, hydromorphone, and oxycodone).
Begin with the lowest dose that produces analgesia. In the nontolerant older patient, initial doses should be lower than those prescribed in younger patients. For example, opioid-naive patients with postoperative pain can be given morphine 5 mg or hydromorphone 0.75 mg IM q 3 to 4 h. Patients already receiving opioids require an initial dose based on prior opioid exposure and converted to an equianalgesic dose as described below.
Titrate the dose to desired analgesic effect or to intolerance of side effects.
If analgesia is entirely inadequate after the initial dose in the naive patient, the next dose should be doubled. If partial analgesia follows the initial dose of an opioid with a short half-life, succeeding doses should be increased by a smaller amount q 12 to 24 h, as steady-state plasma levels are approached. A useful technique for dose titration involves the concurrent prescription of a fixed dose and a “rescue dose” as needed (q 2 or 3 h). The latter should be a drug with a short half-life, the same as the drug used for fixed dosing, if possible. This technique gives the patient some control over pain, allows transitory exacerbations of pain to be managed expeditiously, and can be the basis for upward titration of the fixed dose. The increment can equal the total of the rescue dose administered during the previous period or can be empirically chosen to be 25% to 50% of the current fixed dose. Analgesia provided by agonist opioids has no ceiling effect; upward titration of doses should continue until analgesia occurs or limiting side effects develop.
Be aware Of analgesic duration. Although methadone is sometimes effective with dosing q 6 to 8 h, other opioids usually require dosing q 4 h. The controlled-release oral morphine formulation can be administered q 8 to 12 h, and the new fentanyl transdermal system can be administered q 48 to 72 h.
Administer analgesics regularly. Generally, opioid drugs should be administered around the clock to provide consistent analgesia and to reduce anticipatory anxiety and clock watching. Exceptions to this are as follows: (1) In patients requiring long-term opioid use, several days of dosing on an as-needed basis can determine the analgesic requirement. (2) With drugs possessing a long half-life, particularly methadone, dosing could be initiated on an as-needed basis to reduce the risk of accumulation and toxicity as steady state is approached. (3) When the degree of nociception is likely to change rapidly (eg, following certain operations or radiotherapy), dosing as needed allows the patient to adjust the amount of analgesic needed. (4) A rescue dose as needed is combined with a fixed dose during chronic opioid administration.
Choose an appropriate route of administration. Opioids have a wide range of potential routes of administration (see TABLE 12-5). The oral route is preferred for safety, ease of administration, and longer duration of action. If this route is unavailable or if pain is very severe and rapid titration of doses is desired, a parenteral route should be used. Parenteral administration is not more effective than oral administration; if equianalgesic doses are used and all orally administered drug is absorbed, efficacy is the same although onset of action is faster via the parenteral route.
Be aware of equianalgesic doses. TABLE 12-4 lists the equianalgesic doses for most opioid analgesics, relative to morphine 10 mg IM. This information must be used when switching drugs or routes of administration. For example, in switching a postoperative patient from 50 mg of meperidine IM to 50 mg orally, analgesic potency is abruptly reduced by 75%, resulting in undermedication. Conversely, if a patient with cancer pain receiving oral hydromorphone 8 mg q 3 h develops a bowel obstruction and 8 mg IM is prescribed, potency is increased live times, with a serious risk of toxicity. Similar considerations apply when switching from one drug to another. Because cross-tolerance between drugs is incomplete, the equianalgesic dose should be reduced by 30% to 50%, and clinical experience indicates that a switch to methadone should be accompanied by a 75% reduction of the equiaiialnesic close.
Anticipate and treat side effects. Constipation and sedation or confusion are the most common opioid side effects in older persons Constipation should be addressed at the start of therapy and can be managed by (1) an osmotic (saline) laxative q 3 days (eg, magnesium citrate, magnesium sulfate, sodium citrate); (2) a daily contact laxative (senna, bisacodyl, or phenolphthalein); (3) a daily dose of stool softener (docusate); and (4) daily administration of lactulose or sorbitol 15 to 30 mL bid initially. Doses of these drugs and the use of combinations may be necessary in patients receiving chronic therapy. Sedation and confusion are often transient and may improve if other contributing factors (eg, the use of nonopioid drugs with sedative effects) are reduced; if they persist, a switch to an alternative opioid may be salutary. Using a psychostimulant (eg, methylphenidate or dextroamphetamine) to manage opiqid-induced sedation may be relatively more risky in the elderly, but clinical experience is generally sanguine. Both drugs should be started at 2.5 to 5 mg orally once or twice daily, and the dose should be escalated every other day as needed.
Although respiratory depression is a serious potential adverse effect, tolerance to it develops rapidly, and it is rarely a problem if doses are increased cautiously. If respiratory depression does develop, an alternative cause such as pulmonary embolism or pneumonia should be sought. Nausea may be treated with antiemetic drugs (metoclopramide 10 mg orally qid or prochlorperazine 10 mg orally qid or 25 mg rectally bid, followed by dose escalation, if needed). Side effects such as dry mouth, urinary retention, and accommodation difficulties occur occasionally, particularly in patients receiving other drugs with similar effects. Nonessential drugs should be discontinued and a switch to an alternative opioid considered. Pruritus, an uncommon side effect, usually responds to antihistamines (eg, hydroxyzine 25 mg orally qid).
Use analgesic combinations cautiously. Drug combinations can enhance pain relief. If there are no contraindications, an NSAID may be added to the opioid. One or more of the adjuvant analgesics may also be appropriate, depending on the nature of the pain. However, because the older patient is at increased risk for side effects, particularly sedation or confusion, these drugs should be added cautiously, at low initial doses and one drug at a time. Guidelines for their use are listed below.
Watch for the development of tolerance, the need for increasing doses to maintain the same analgesic effect. This phenomenon is poorly understood. Although it can be reproducibly demonstrated in animals, tolerance has a far more variable course in humans. The need to escalate doses usually signals progressive disease or increased distress rather than the development of pharmacologic tolerance per se. The earliest indication of tolerance is the complaint of decreasing duration of analgesia after a dose. Clinically, tolerance is seldom a problem, since pain relief recurs with an increase in dose or a reduction in the dosing interval. If rapid escalation of doses becomes problematic, a switch to an alternative drug or route of administration may be useful.
Observe for signs of physical and psychologic dependence. Physical dependence is a pharmacologic phenomenon in which a specific abstinence (withdrawal) syndrome occurs after abrupt discontinuance of an opioid drug or administration of an opioid antagonist. Clinically, physical dependence poses no problem unless withdrawal is produced by noncompliance or inadvertent administration of a drug with antagonistic effects. In contrast, psychologic dependence or addiction is a psychologic and behavioral syndrome in which there is drug craving and aberrant drug-related behaviors characterized by loss of control, compulsive use, and continued use despite harm. Although psychologic dependence is a risk with opioid drugs, the overwhelming majority of patients with acute pain and pain due to cancer do not develop such aberrant behaviors.
Chronic opioid therapy in patients with chronic nonmalignant pain syndrome is controversial, but some patients benefit substantially from long-term use of opioids without developing clinically significant tolerance, toxicity, or psychologic dependence.

Although there is evidence for a central mechanism as well, NSAIDs are generally believed to act peripherally, with varying and possibly disproportionate anti-inflammatory and analgesic effects. They can be classified into a weak acidic group and a nonacidic group (see TABLE 12—3). Acetaminophen is usually considered together with these drugs, despite minimal anti-inflammatory effects and a mechanism of action that is presumably central. All of these drugs share a ceiling effect, as noted above. Except for acetaminophen, all are anti-inflammatory, with variable potency. Although all are used empirically for pain, only some (eg, acetaminophen, aspirin, diflunisal, ibuprofen, naproxen, and several others) are currently approved as analgesics in the USA. Little data are available on NSAID use in the elderly. Therefore, proper use depends on understanding their pharmacologic implications and clinical experience, as follows.
Ensure that the indication is appropriate. The NSAIDs are generally used to treat mild to moderate pain, particularly that caused by an inflammatory lesion. An NSAID also provides additive analgesia to chronic opioid therapy. The NSAIDs should be prescribed cautiously in patients with preexisting renal disease, heart failure, hypertension, gastroduodenopathy, and bleeding diatheses because of the risks of interstitial nephritis, sodium retention, peptic ulcer disease, and platelet dysfunction shared to some degree by most of these drugs.
Choose an appropriate drug. Patient response to an individual agent varies widely, and the initial choice of NSAID is largely empiric. However, several factors influence this choice. For the elderly, a drug with a short half-life is generally preferred, although this guideline is less applicable to these analgesics than to others. A better guide is favorable prior experience with a specific drug. A history of ulcer disease or risk of ulcer or bleeding from any cause is an indication for selecting a drug that least affects the gastric mucosa and platelet function (ie, acetaminophen, or if anti-inflammatory effects are desirable, choline magnesium trisalicylate or salsalate).
Begin with a low initial dose and titrate to ceiling. This approach is described under the general principles of pharmacologic management, above. Intervals between dose escalations should be long enough to ensure that steady-state effects can be observed at one dose before a higher dose is administered. Dose escalation before steady state is approached may lead to delayed toxicity as plasma drug concentration continues to rise beyond the targeted therapeutic range. The risks of rapidly titrating long-acting drugs are particularly great in populations predisposed to adverse effects, such as the elderly.
Switch to another NSAID if the response is unsatisfactory. Patients who fail to respond to a 2- to 3-wk trial of one drug at adequate doses should be switched to another. The selection of subsequent drugs during these sequential trials is empiric.

Pharmacotherapy, the mainstay of analgesia, involves three categories of drugs: nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, and the so-called adjuvant analgesics (see TABLE 12-2).
The aging process may dramatically alter the clinical pharmacologic dynamics of all classes of analgesic drugs (see Ch. 21). Studies of several opioids have emonstrated some combination of diminished volume of distribution, prolonged half-life, and uced clearance for each, in every case leading to higher plasma levels than the same dose given to a younger patient. Although the data on NSAIDs are less conclusive and hose on adjuvant analgesics almost nonexistent, similar observations have been made about several compounds in each class.
Increased sensitivity to the adverse effects of all classes of analgesic drugs has been noted among the elderly. The relative contributions of pharmacokinetic factors (leading to higher plasma drug levels) and pharmacodynamic factors (increasedtivity to drug effects independent of plasma level, presumably involving changes at a eptor level) remain undetermined.
General principles of pharmacologic management are as follows.
Choose an appropriate drug. Such choice depends on the severity and type of pain. In cancer pain, for example, mild pain is treated with an NSAID, moderate pain usually requires the addition of an opioid conventionally used to treat mild to moderateain (eg, codeine), and severe pain mandates the selection of an opioid conventionallyed in this setting (eg, morphine)—see Pain in Ch. 19. Patients with neuropathic pain ay be less likely to respond to NSAIDs or opioids and should be treated early with vant drugs, often beginning with a tricyclic antidepressant. Patients with pain ssociated with marked inflammation should be treated with an NSAID.
Choose a short-acting drug. Four to five half-lives are required to achieve steady-state plasma drug levels. This applies to initiation, discontinuance, or change in dosage. A drug with a long half-life thus has a longer period before its effects stabilize. For example, steady-state plasma levels are approached after 12 to 24 h with morphine, but more than a week may be required with methadone, which therefore has a far greater risk of delayed toxicity.
Prescribe one drug at a time. When combinations of drugs are needed, they should be started one at a time to avoid cumulative toxicity and to allow identification of the offending agent if an adverse effect occurs.
Increase the dose incrementally until therapeutic effects or side effects occur, or until some upper limit based on the drug’s known pharmacology is reached. Dose ation to efficacy or toxicity is fundamental for opioid drugs. Given the ceiling effecte, a dose beyond which incremental increases fail to provide additive analgesia) and dose-related toxicity of the NSAIDs, upward titration of doses is finite. A useful empiric guideline for the NSAIDs is that the maximum reasonable dose is 1.5 to 2 mes the starting dose; if analgesia is not achieved after an adequate trial at this vel, an alternative drug should be considered.
Continue drug trials for an adequate duration. Virtually all nonopioid analgesic drugs require a minimum trial of 2 wk at an adequate dose to judge efficacy.

The general principles of pain treatment—pharmacologic and non-pharmacologic—are outlined briefly below.
1.Treat the underlying problem, if possible. Particularly in cancer pain, recognition of the pain syndrome can lead to diagnosis of the cause and, possibly, to effective primary therapy. Although elimination of the underlying cause in nonmalignant pain syndromes is seldom feasible, primary treatment is often available for nociceptive pain (eg,prosthetic joint replacement for intractable hip or knee pain from osteoarthritis).
2.Address psychologic factors and functional impairment concurrently. This requires an accurate diagnosis.
3.Consider a multimodal approach. While some patients respond to only one form of therapy (eg, > 80% of patients with trigeminal neuralgia respond to carbamazepine), many require several concomitant analgesic approaches. Therapeutic modalities can be categorized as pharmacologic, neurostimulatory, anesthetic,surgical, physiatric, and psychologic.

The history is central. However, stoicism or slowness to respond, at times compounded by mild cognitive deficits, compromises its reliability. The clinician must be alert to this, spend adequate time with the patient, and obtain additional information from others.
The assessment of pain includes its location, severity, quality, duration and course, palliative and provocative factors, and associated somatic and psychosocial symptoms. A medical and drug history should attempt to evaluate compliance. A family history of chronic pain may provide insight into the patient’s complaints. The patient’s level of cognitive, psychologic, and social functioning must also be assessed.
Nociception should be distinguished from pain, a perception only loosely related to nociception. The nociceptive focus (eg, an arthritic joint) must be identified so primary therapy can be instituted. However, pain can exist without a nociceptive focus, and conversely, profound tissue damage can be present without the perception of pain. An attempt should be made to identify all the salient factors, both nociceptive and nonnociceptive, that contribute to the pain. Nonnociceptive factors can be pathophysiologic (eg, neuropathic mechanisms that persist without ongoing tissue damage) or psychopathologic processes. Another subtype of neuropathic pain is related to the reorganization of nociceptive information processing by the CNS; it persists without ongoing activation of pain-sensitive fibers. This type of pain, known collectively as the deafferentation syndromes, includes postherpetic neuralgia, central pain (which can result from a lesion at any level of the CNS), phantom limb pain, and others. A third subtype of neuropathic pain, often called sympathetically maintained pain, can be ameliorated by interruption of sympathetic nerves to the painful area; the prototypic disorder is reflex sympathetic dystrophy. The precise mechanisms involved in these disorders are conjectural, but all can produce an unfamiliar pain, often described as burning and stabbing. They may respond poorly to analgesics.
Some patients have persistent pain without either nociceptive foci or evidence of a neuropathic mechanism for the pain. Many others have nociceptive lesions that do not sufficiently explain the degree of pain and disability. Psychopathologic processes account for these complaints in some patients. If no evidence for a psychologic cause is found, the pain should be called idiopathic.
Many patients have an idiopathic pain syndrome that is best described by the generic diagnosis chronic nonmalignant pain syndrome, a term denoting pain and disability disproportionate to an identifiable somatic cause and usually related to a more pervasive set of abnormal illness behaviors. Some of these patients may be labeled by the more formal psychiatric diagnosis of somatoform pain disorder. Others have complaints that constitute a specific pain diagnosis, most commonly the failed low back syndrome or atypical facial pain. Still others have significant organic lesions (eg, lumbar arachnoiditis) but also have a clear psychologic contribution associated with excessive disability. Diagnosis may be difficult, but the relative contributions of both organic and psychologic components of the pain must be defined.
The chronic nonmalignant pain syndrome appears to be relatively rare in the elderly, whose persistent pain is usually associated with an organic lesion, either nociceptive (eg, osteoarthritis) or neuropathic (eg, postherpetic neuralgia). Nonetheless, profound psychosocial impairment is common and can have a devastating impact on function, regardless of whether it causes or is a reaction to the pain.
Another clinically useful classification of chronic pain is broadly syndromic. For example, chronic pain may be part of a medical illness (eg, cancer or arthritis). A mixture of pathophysiologic mechanisms may be involved; eg, tumor invasion of nerve and bone may cause neuropathic and somatic nociceptive pains, respectively, and psychologic factors may be prominent. The relationship between the pain and the underlying disease must be clarified to permit optimal management. Alternatively, specific organic syndromes exist that are characterized only by pain (eg, postherpetic neuralgia). Each diagnosis suggests specific therapeutic options.

Although one study reports a threefold increase in persistent pain between 18 and 80 yr of age, another larger study reveals an age-related reduction in pain at all anatomic sites other than joints. Other studies have shown that analgesic use declines with age, the elderly constitute a relatively small proportion of pain-clinic admissions, and fewer pain complaints are recorded in older than in younger patients with myocardial infarction.
A shift occurs in the relative frequency of disorders commonly associated with pain. Osteoarthritis is by far the most common painful disorder in the elderly. Some types of neuropathic pain, notably trigeminal and postherpetic neuralgia, occur often; and some common, chronic nonmalignant pain syndromes (eg, atypical facial, failed low back, and myofascial pain) appear to occur infrequently.
The age-related reduction in pain prevalence is unexplained but may be associated with alterations in neural pathways involved in nociception (ie, the sensory processing initiated by a noxious stimulus) or with differences in the psychologic disposition to report pain. The latter may reflect either reticence in responding to any stimuli or stoicism toward pain. If neural changes are the cause, the lower prevalence of pain may accurately represent the experience of these patients. If less frequent pain reporting occurs, however, pain may be underrecognized and inadequately assessed and treated. The latter conclusion is supported by studies suggesting that the neural apparatus involved in nociception does not decline with age. Comprehensive pain assessment is necessary to ensure that pain is not undertreated and underlying conditions are not missed.
Chronic pain has a major impact on quality of life, and associated affective and behavioral disturbances may become particularly problematic. Depression often complicates pain in these patients, who may deny overt mood disturbance but manifest profound vegetative signs (eg, sleep abnormalities and lassitude). The terms abnormal illness behavior and chronic pain syndrome are used to characterize the behavioral changes commonly accompanying chronic pain (including social isolation, loss of interest in avocations, and inability to perform activi ties of daily living). Such consequences of chronic pain are especially important in older persons, who can rapidly become hopeless and disabled.

Traditionally, little attention has been given to the influence of aging on the incidence, clinical manifestations, and treatment of pain. However, information is now available to provide a framework for rational nosology and therapeutic strategy.