Educational Objectives
1. To appreciate the barriers to optional pain management at the end of life
2. To understand the importance of assessment and reassessment of pain for patients at the end of life
3. To be knowledgeable of the unique approaches to assessment and management of pain in the elderly
4. To be able to utilize the Three-Step Analgesic Ladder approach of the World Health Organization in the management of pain at the end of life

ACCREDITATION
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 1.0 category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Valid April 1 - June 30, 2005. Estimated time: 1 hour

FULL DISCLOSURE POLICY AFFECTING CME ACTIVITIES
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or provider has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The presenting faculty reported the following: Dr. Cavalieri has indicated that he has not received financial support for consultation, research or evaluation or has a financial interest relevant to this article. No faculty member has indicated that their presentation will include information on off-label products.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings and adverse effects before administering pharmacologic therapy to patients.

The management of pain at the end of life can be very challenging and rewarding in clinical practice. Pain at the end of life may have several origins, but frequently the pain is due to a cancer diagnosis. Effective pain management at the end of life calls for an interdisciplinary approach, and the physician is central to coordinating and determining effective management strategies. Pain in the older patient, especially at the end of life, is often not treated or recognized effectively. From 20-50% of community-dwelling older persons have important pain problems, and in the nursing home, 70% of residents have pain that is underrecognized and undertreated.1

From 60-90% of patients with advanced malignancies experience significant pain and most die without adequate pain relief.2 The elderly account for most deaths caused by cancer. Cancers of the lung, colon, breast, and prostate are most common in older persons and are frequently associated with significant pain in the advanced stages of disease.3 Several studies have documented that cancer pain is often undertreated.4 Unrelieved pain can have profound consequences for the patient and his or her family. It can lead to depression, loss of sleep, and poor appetite; prevent the dying patient from experiencing enjoyment; and create a sense of hopelessness. It has frequently been cited as a major justification for those who seek legalization of physician-assisted suicide and euthanasia. Yet, most pain at the end of life can be treated with simple measures.4 The physician needs to be not only skillful in effective pain management at the end of life but must also appreciate the special approaches to pain management and drug prescribing in the older patient.5

BARRIERS TO PAIN MANAGEMENT
In the past, the recognized lack of effective strategies for pain management at the end of life had led the Agency for Healthcare Policy and Research to issue Clinical Practice Guidelines on the Management of Cancer Pain.6 More recently, the American Geriatrics Society has also issued guidelines for effective pain management in the older patient.7 What are the barriers that hamper adequate pain management at the end of life? Inadequate knowledge about pain assessment and pharmacologic management, in addition to excessive concerns about addiction and opioid side effects, may represent barriers for appropriate management by health professionals.

On the part of patients and their families, there may be a myth that cancer pain is inevitable or that suffering is deserved. There may also be fears about addiction or that disabling side effects will result. The elderly, in particular, may exhibit stoicism, may be victims of ageism, or may not be able to express their pain due to dementia or aphasia. Finally, health care and regulatory systems may represent barriers to effective pain management. These include the emphasis of an acute-care and disease-oriented health system model, limitations on the services provided by hospice, and the concerns about prescribing requirements for opioids. With effective educational programs and health policy changes, the barriers to effective pain management can be avoided.4,8

TYPES OF PAIN
Although it is often the cancer itself that is the cause of pain in most patients with advanced disease, frequently, and particularly in the elderly, there may be more than one cause. About 70% of patients will manifest pain directly from the cancer itself, whereas approximately 25% will develop pain syndromes from cancer therapy. Pain in the remaining 5% may be due to other causes such as musculoskeletal disorders (Table I).4,5,9

Pain can be classified as either nociceptive or neuropathic. The two types of pain differ by how they present, the cause, and their response to therapy. Nociceptive or somatic/visceral pain arises from afferent nerve stimulation, either from tumor infiltration or other causes, involving the skin, soft tissue, or the viscera. Visceral pain is poorly localized and may arise from liver metastasis or biliary, bowel, or ureteral obstruction. Somatic pain is well localized and includes both bone and soft tissue metastasis.2,10 Nociceptive pain will respond to both non-opioid and opioid analgesics.

Neuropathic pain is due to injury to the nervous system. This may include direct invasion to nerves by the tumor, such as invasion to the brachial or lumbar plexuses, or other causes such as herpes zoster, an effect of chemotherapy, or surgical injury. Neuropathic pain is sharp, burning, or shock-like. It is often unresponsive to opioids but responds to antidepressant and anticonvulsant medications.4 Pain often may be both of nociceptive and neuropathic origins (Table II).

ASSESSMENT OF PAIN
The importance of effective pain assessment is critical to appropriate pain management. Of physicians surveyed, 70% revealed that they identified poor pain assessment as the major barrier to effective cancer pain management.11 This is especially true for older patients and nursing home residents. A thorough pain assessment should include onset, duration, intensity, location, factors that exacerbate the pain, and the effect of pain on sleep, mood, and appetite.4 Not only is initial pain assessment important to effective management but also frequent reassessment is important to assess the efficacy of our interventions.1

Many tools to assess pain are available. These include visual analog scales and numeric and pain intensity scales. Pain intensity can be assessed by a numerical rating scale where 0 represents no pain and 10 is the worst possible pain; 1-4 represents mild pain, 5-6 represents modest pain, and 7-10 represents severe pain. The higher scores correlate with a poor quality of life and reduced functional status.12 It is important to use an assessment scale that is meaningful to the patient and is reproducible. For example, in an elderly patient with aphasia or dementia, a scale utilizing “pain faces” may be appropriate.6

Pain management in the older person may be particularly challenging. Pain in elderly patients with dementia or other communication difficulties may be manifested by a decline in their functional status, mood changes leading to depression, increased agitation and confusion, or an altered appetite. Assessment tools to evaluate mood and function in the elderly are readily available and are a valuable aid in the assessment of pain.5,9

PHARMACOLOGIC MANAGEMENT OF PAIN AT THE END OF LIFE
Although the approach to pain management at the end of life includes both pharmacologic and nonpharmacologic interventions, analgesics are the cornerstone to management. It is important for the clinician to select the proper analgesic according to the type and intensity of the pain. Analgesics may be classified into three categories that can be used to treat different types and intensity of pain. These include non-opioids such as tramadol for mild-to-moderate pain, opioids for moderate-to-severe pain, and adjuvant therapy for neuropathic pain (Table III).6 The World Health Organization has proposed a Three-Step Analgesic Ladder approach to the treatment of pain. Mild pain (step 1), with an intensity of 1-4, is treated with non-opioids and/or adjuvant agents. Moderate pain (step 2), with an intensity of 5-6, is treated with the addition of a step 2 opioid analgesic, tramadol, and/or an adjuvant. Severe pain (step 3) is treated with a step 3 opioid and/or an adjuvant. This approach can relieve pain in up to 90% of patients (Figure).13

Non-opioid analgesics
These agents consist of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and tramadol. They are used to treat step 1 mild-to-moderate nociceptive pain. NSAIDs are effective in treating pain that is inflammatory in origin, as well as postoperative pain. Although NSAIDs can be effective in the management of pain from metastasis to bone or soft tissue, they are unlikely to be adequate in the management of pain due to advanced cancer alone. NSAIDs block the production of prostaglandin by inhibiting cyclo-oxygenase and do not activate opioid receptors; thus, NSAIDs and opioids may be synergistic. The NSAIDs vary in half-life but are comparable in effectiveness and toxicity. NSAIDs do have a ceiling effect, so their analgesic effect peaks at a certain level.14 It is important to give NSAIDs an adequate therapeutic trial as their maximal analgesic effect may be delayed. As there are several classes of NSAIDs, lack of response to one class does not mean NSAIDs of another class would lack effectiveness. Dosages and dosing intervals need to be tailored to the individual.6

NSAIDs may manifest severe side effects, particularly in the elderly. Whereas gastrointestinal bleeding is common, H2-histamine receptor antagonists, antacids, or sucralfate have been disappointing for prevention. Although misoprostol has been shown to be effective to prevent gastrointestinal bleeding, its frequent side effects, particularly diarrhea, have hampered its use to some effect. A proton pump inhibitor is important for most elderly persons taking NSAIDs. These drugs can impair renal function, especially in those who already have compromised renal function due to disease or aging.15 Inhibition of platelet aggregation by NSAIDs may be problematic, especially for patients on warfarin or with a coagulopathy. Although NSAID side effects have been similar, it was believed that the newer cyclo-oxygenase-2 (COX-2) inhibitors lacked some of the toxicities of other NSAIDs, particularly gastrointestinal side effects.1 However, new data regarding rofecoxib, indicating an enhanced risk of myocardial infarction and stroke with this agent, have raised serious concern about the use of COX-2 inhibitors.16 In general, because of the enhanced risk associated with NSAIDs, these agents should be avoided whenever possible when treating older patients.17

Acetaminophen is another step 1 analgesic that is equally effective to aspirin as an analgesic but will not be as effective for pain that is inflammatory or bone in origin. It lacks many of the toxicities of the NSAIDs but may cause hepatoxicity at doses over 4 g per day, particularly in those with liver disease or a history of alcoholism.4 It is safe and effective for most elderly persons and should be the drug of choice for patients with mild-to-moderate pain of musculoskeletal origin. There seems to be a ceiling effect at doses above 2.6 g per day. A common clinical error is the failure to use high enough dosages.17

Tramadol is a step 2, orally administered analgesic for moderate pain. It is centrally acting and has some opioid properties. It is comparable in effectiveness to codeine but does not cause constipation. It is advantageous over NSAIDs because it lacks the gastrointestinal and renal side effects. It may cause dizziness, nausea, and headache; therefore, it should be initiated at low doses in the elderly and titrated slowly. Unlike opioids, tramadol is not a controlled substance.5,13

Opioid analgesics
Opioid analgesics are clearly the drug of choice for moderate-to-severe nociceptive pain.6,18 Several types of opioids may be appropriate as step 2 or step 3 opioids. Step 2 opioids to treat moderate pain include codeine, dihydro- codeine, hydrocodone, oxycodone, and propoxyphene (Table III). These agents are usually used with non-opioid analgesics and have side effects that limit their dose. Codeine and dihydrocodeine are commonly used opioid analgesics and have side effects that limit their dose. They are frequently administered with aspirin and acetaminophen. Hydrocodone is also administered in combination with aspirin and is more potent with fewer side effects than codeine. Oxycodone is available as a single entity either as a tablet or as a solution. A slow-release formulation is available.13

Step 3 opioids used for severe pain include morphine, hydromorphone, oxycodone, fentanyl, and methadone. Morphine is the most widely used and versatile opioid.4 It is available by tablet, liquid, intramuscularly, intravenously, subcutaneously, or per rectum. A long-acting formulation of 8-12 hours has been the mainstay for control of chronic cancer pain because of its ease of administration and titration. Hydromorphone is similar to morphine but is four times more potent. It is very water-soluble and may have some advantages for parenteral use. Oxycodone has the advantage of a lower potential for accumulation of toxic metabolites, its pharmacokinetics are independent of age, and it has less potential to cause hallucinations in the older person. Fentanyl for transdermal administration has become widely used and can provide analgesia for 72 hours. Its onset is slow, so immediate-release opioids must be prescribed when the patch is initially applied. It should never be used in opioid-naive patients. Care must be used in the elderly as transdermal fentanyl delivery may be enhanced, particularly in the presence of hypo-albuminemia. Rescue doses of immediate-release opioids can be used for breakthrough pain.

Certain opioids should be avoided when possible. Meperidine is not recommended for chronic use because of the potential for accumulation of a metabolite, normeperidine, which can cause confusion or seizures. Partial and mixed opioid agonists such as buprenorphine, pentazocine, butorphanol, and nalbuphine, because of their limited efficacy and possible toxicity, should be avoided.19 In addition, propoxyphene should not be utilized, particularly in the elderly.7,17 Propoxyphene has a long half-life and a toxic metabolite that may accumulate. It is not recommended, especially for the older patient.7,17 Methadone is a potent opioid analgesic, but its long half-life may result in drug accumulation, particularly in the older patient and those with hepatic or renal diseases.7,14,17 Methadone should be avoided in the elderly.

Prevention and treatment of the side effects of opioids is important for care at the end of life. Nearly all patients receiving regular opioids need laxative therapy. Docusate sodium plus sennosides and lactulose are helpful for prevention. Opioid-induced nausea may be related to constipation or may need to be treated with prochlorperazine or metaclopramide.4 Sedation is common initially or when the opioid dosage is increased; however, this usually abates when tolerance occurs. On rare occasions, caffeine or methylphenidate can be used for opioid-related sedation.13 In the elderly, delirium is a common side effect of opioid therapy. Although antipsychotic agents could be used, lowering the opioid dose or switching to another opioid preparation would be a preferable first step. Respiratory depression is perhaps the most feared opioid side effect, and often the reason for reluctance to use opioids appropriately at the end of life. Tolerance develops rapidly; therefore, clinically significant respiratory depression develops rarely in patients with pain treated with opioids. If this does occur, treatment with a slow infusion of naloxone is appropriate.5,20

Reluctance to use opioids at the end of life is attributed to misconceptions about tolerance, dependence, and addiction. Tolerance can develop to the analgesic effects of the opioids, but more often the increased pain is due to worsening of the disease. Shortening of the duration of the analgesic effect is the typical manifestation of tolerance. Given that morphine and the opioids have no ceiling effect, it would be appropriate to increase the opioid dose. Patients who are on chronic opioid therapy will develop physical dependence. Should it be necessary to discontinue the opioid, tapering the opioid dose by 25% every 2 days should be adequate to avoid symptoms of withdrawal. When the equivalent dose of morphine 10-15 mg is achieved, the opioid can be stopped in 2 days. Addiction rarely occurs in patients who are treated with opioids for pain who have had no prior history of drug abuse.5,13,20

The practice of opioid dosing, administration, and titration are critical for effective pain control at the end of life. The appropriate opioid will control the patient’s pain without unmeasurable side effects. Although most patients with severe chronic pain can be controlled with the equivalent to 240 mg of oral morphine or less, dosages of 1200-1800 mg per day may be required. Although most patients with chronic pain receive oral analgesic therapy because of ease and expense, morphine concentrates can be administered sublingually. Both morphine and hydromorphone can be given rectally and fentanyl transdermally. For patients who cannot take oral opioids for short periods (24-72 hours) or for patients with frequent episodes of pain, subcutaneous or intravenous administration of morphine is preferable to fentanyl transdermally because of the need to rapidly increase the drug level. The parenteral morphine dose is three times more potent than oral morphine; therefore, the dosage must be changed when the route is switched from one to the other. Also, dosage adjustments must be considered when converting from one opioid to another (Table IV).13,21 Opioids can also be administered epidurally, but this intervention is usually reserved for patients in whom systemic analgesic therapy is not possible.5,6,19

The goal of the management of chronic pain should be to prevent the occurrence of pain. This can be achieved by the selection of the appropriate opioid at the proper interval. Short-acting opioids such as oxycodone, morphine, and hydromorphone begin after 30 minutes of oral administration and last for 4 hours. In slow-release preparations of morphine or oxycodone, the effect begins in 1 hour and lasts for 12 hours. In either case, if pain recurs before the next dose is due, the dosage should be increased.13 Transdermal fentanyl begins its effect in 12 hours, peaks in 24-48 hours, and lasts 72 hours. The dosage should be increased if the effect does not last 72 hours.22 Fentanyl continues to be released from subcutaneous fat for 24 hours after the patch is removed. Morphine given subcutaneously begins its analgesic effect in 15 minutes and lasts 3-4 hours; intravenously it begins in 5 minutes and lasts 1-2 hours.6

To achieve pain prevention throughout the day and night, the opioid must be administered at regular intervals. When breakthrough pain occurs due to activity or progressive disease, rescue doses of opioids should be administered.19 The rescue dose of an available opioid should equal the dose administered during that interval. For example, a patient receiving slow-release morphine at 90 mg every 12 hours should have immediate-release morphine 30 mg every 4 hours, as needed, for breakthrough pain.13

If repeated breakthrough pain occurs requiring rescue doses, an increase in the round-the-clock dosing of opioid is indicated. For patients with severe unrelieved chronic pain, the 24-hour dosage may be increased by 50-100% every day. For moderate unrelieved pain, it may be increased by 25-50%.6,19 If pain no longer is a problem, downward dose titration is appropriate. The opioid dose can be decreased daily by 25% of the previous day’s dosage to prevent physical withdrawal.5

Adjuvant analgesics
Adjuvant analgesics are used for specific pain problems. Neuropathic pain can be treated with anticonvulsants, antidepressants, and local analgesics. These agents may be used in conjunction with step 1, step 2, or step 3 analgesics.1 Amitriptyline and other tricylic antidepressants have been shown to be effective for diabetic neuropathy and other neuropathic pain.23 The sedative and anticholinergic effects may be particularly bothersome for the elderly; therefore, nortriptyline may be preferable for older patients if a tricyclic antidepressant is to be used. Pain relief may take up to 4 weeks to be initiated. Selective serotonin reuptake inhibitors have not been shown to be helpful for neuropathic pain.5

More recently, anticonvulsants gabapentin and carbamazepine have been used to treat neuropathic pain. Carbamazepine has been most widely used, and its initial dose should be low with gradual titration, monitoring plasma levels, and observing for side effects such as dizziness, lightheadedness, or tremors. However, gabapentin seems to be more effective and has the best side-effect profile but should be used with caution in the elderly because common adverse side effects include dizziness, somnolence, and ataxia. The dose is titrated slowly to achieve the best response.17

For chronic pain due to trigeminal neuralgia, postherpetic neuralgia, or diabetic neuropathy, topical capsaicin can be tried, but the results are often variable. Lidocaine patches may provide relief of regional pain without producing significant serum concentrations. Steroids may be indicated for pain due to tumor infiltration into nerve or bone, cerebral edema due to brain tumors, or for spinal cord compression. Although adverse effects of gastrointestinal bleeding and exacerbation of diabetes can be problematic, the euphoria, enhanced appetite, and sense of well-being often experienced with steroids may be beneficial.4,5,9,13,17

NONPHARMACOLOGIC MANAGEMENT OF PAIN
Whereas pharmacologic interventions are the mainstay for chronic pain management, nonpharmacologic approaches may be very beneficial and synergistic to drug treatments. Neurosensory stimulation techniques such as acupuncture and transcutaneous electrical nerve stimulation (TENS) can be helpful. Massage, exercise, heat and cold, and other interventions administered by a physical therapist can offer pain relief. Psychological approaches, such as counseling, music therapy, and biofeedback, as well as spiritual interventions, can be an aid to relieve pain.9,21 Osteopathic manipulative therapy offers an additional effective strategy to pain management.24 Effective pain management is truly interdisciplinary. It is important that the physician recognize the role that multiple health care professionals have in the management of pain at the end of life.5,7,17

CONCLUSION
Despite the fact that interventions and effective approaches to controlling pain have been well documented, health care professionals need to be diligent in the management of pain at the end of life. Un-relieved pain for the patient at the end of life is de-humanizing and an ethical issue.25 Although there are several barriers to effective pain management at the end of life, these can be avoided. Needed medications should not be withheld because of a fear that the patient may become an addict or that death may be induced by respiratory depression. Documented studies validate the exaggerated fear of addiction, particularly in patients at the end of life. Also, the likelihood of inducing respiratory depression in a patient with pain is minimal, but the ethical principle of the “double effect” allows for the administration of opioids to control pain even though the dying process may be hastened. Nearly all pain in patients who are dying can be controlled if current management strategies are utilized. Therefore, the inability to control pain at the end of life is not a valid argument for advocates of physician-assisted suicide and euthanasia. Physicians play a critical role in effective pain management at the end of life; incorporating these strategies for pain management in clinical practice can allow their patients to die in comfort and with dignity.5