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9 Articles in Volume 8, Issue #4
Chronic Daily Headache
Confidentiality, Choice, and the Question of Autonomy
Head and Neck: Temporal Arteritis and Temporal Tendonitis Co-morbidity
Laser Acupuncture as a Pain Relief Modality
Long-term Therapy Using Short Acting Opioids for Chronic Non-cancer Pain
New Daily Persistent Headache (NDPH)
Opioids in Patients with Renal or Hepatic Dysfunction
Pain Management and Terminal Illness
The Biopsychosocial Approach

Pain Management and Terminal Illness

The prevalence of pain in terminally ill patients requires that physicians acquire the skills necessary to provide palliative pain treatment at end of life.

It is challenging to face a potentially terminal illness: hoping for the best, while planning for the worst. The importance of pain management at the end of life is a professional, moral, and ethical obligation. Although pain may not be the most prevalent symptom at the end of life, it is the most feared. Pain steals both the quality and satisfaction of remaining life, contributes to anxiety, depression, despair, loss of self-efficacy, and interferes with medical decision-making. For many families, the last memory of their loved one may either be that of a “peaceful” and comfortable transition or that of a painful and agonizing end.

Prevalence of End-of life Pain

Pain at end of life is most often equated with the medical consequences of significant illness such as cancer, late HIV disease, degenerative diseases, but it occurs not simply because of the underlying diagnosis, but rather as a consequence of the underlying pathology. Most people equate pain at the end of life with cancer. Surveys of adult cancer patients with advanced disease—often performed in a hospice or palliative care setting—indicate that the prevalence of pain ranges from 50% to 90%.1 It is said that 40-50% of those with pain from cancer report it to be severe while 25-30% describe it to be very severe.2

With cardiovascular disease, as many as 75% of those with heart failure may experience pain in the last six months of life.3 Many of these patients with advanced cardiovascular disease also have painful co-morbidities (e.g. osteoarthritis, neuro-pathy from diabetes).

About 50% of those with AIDS experience pain either related to the virus or the treatment. Pain at the end of life for those with AIDS has been seen in up to 93% of a patient population observed in an inpatient setting.4

Patients with neurological diseases such as multiple sclerosis, Parkinson’s disease, and central pain related to cerebral vascular disease or spinal cord injury often experience pain.5-7 The extent of pain experienced by those with dementia is unclear due to the difficulty of assessing their pain late in the disease. However, at the end of life, functional decline, weight loss, development of skin breakdown, and contractures are known sources of pain.

Care Setting at the End of Life

The care setting, availability of resources, and the level of expertise of the care provider influences pain management at the end of life. Although surveys suggest that most people prefer to die at home, only 25% die there—with 50% dying in hospital settings and 25% dying in nursing homes or other long-term care facilities.8 About 50% of nursing home patients at end of life have daily pain, with about 85% of them experiencing moderate intensity pain.9 With the advent of the hospice Medicare benefit, people have the opportunity to receive pain management services at the end of life. However, only 36% utilize their benefit with a median length of stay of about three weeks.10

Pain Assessment in Advanced Disease

Ideally, pain should be assessed utilizing a thorough pain assessment—including location, duration, onset, characteristics, severity, alleviating/relieving factors, and associated symptoms. Identifying the underlying pain mechanisms (nociceptive versus neuropathic) should direct appropriate treatment. As the end of life nears, and cognition decreases, it becomes important to utilize behavioral pain tools; e.g., Pain Assessment in Advanced Dementia (PAINAID),11 Behavioral Pain Scale (BPS),12 Critical Care Pain Observation Tool (CPOT).13

There has been a reluctance to use surrogates (individuals who make medical decisions when patients cannot do so) to report patients’ pain because of their emotional attachment to these patients and their potential for overestimating pain. In a large study of seriously ill hospitalized patients, surrogates correctly identified the existence of pain 73% of the time, but estimated its severity with only 53% accuracy.14 Although surrogates may be less accurate about estimating pain’s severity, they are able to assist with pain’s assessment when patients cannot give self-reports.

If unable to adequately assess pain due to cognitive impairment, clinicians should ask themselves “Would I be in pain in this situation?” If the answer is “Yes,” or if the condition is known to predictably cause pain, it is best to assume that pain is present and treat accordingly.

Pharmacotherapy for Pain in Advanced Disease and at the End of Life

Pharmacotherapy remains the mainstay of treatment for pain at the end of life. The first step in treating cancer pain according to the World Health Organization guidelines is to use nonsteroidal anti-inflammatory drugs (NSAIDs). However, NSAIDs are not always used at the end of life because of their many side effects and need for oral route of administration. One parenteral NSAID, ketorolac, may be used for pain relief at the end of life. While it is only indicated for a maximum of 5 days of acute administration, there have been discussions at end of life meetings regarding longer periods of “off label” administration.

Adjuvant analgesics are routinely used in pain management for many types of pain. However, commonly used agents—antidepressants and anticonvulsants—are generally not available as intravenous preparations and thus potentially limits their use at the end of life. In advanced disease, the use of these adjuvants may be beneficial for neuropathic pain, pain related to bony metastases, and pain related to bowel obstruction.

Opioids are the principal class of analgesics used at the end of life because of their potency, concomitant mild sedative and anxiolytic properties, and ability to be administered by multiple routes. Some say that only lack of imagination on the part of healthcare practitioners prevents them finding routes of administration for patients needing opioid medications. Opioid therapy fortunately provides adequate pain relief for greater than three quarters of patients with cancer pain.2 Opioids—specifically excluding meperidine—that are typically utilized in end-of-life settings include:

  • Morphine
  • Fentanyl
  • Hydromorphone
  • Methadone
  • Oxycodone

Caution: Meperidine use must be avoided due to accumulation of its metabolite normeperidine, which is not reversed by naloxone and produces neurotoxicity (e.g., seizures, hallucinations, and delirium).20 There is no recommended long term use of meperidine.

Morphine has been the most widely used medication for cancer pain and is considered a mainstay in end of life care. It is the standard by which other opioids are compared. Morphine does have active metabolites of concern, including morphine-3-glucuronide (M-3-G) and morphine-6-gluconoride (M-6-G). Accumulation of M-6-G in those with renal insufficiency enhances morphine’s analgesic potency, and may cause worsening nausea, sedation, and respiratory depression. Accumulation of M-3-G may lead to CNS irritability, myoclonus, and delirium.15-17 Morphine use should be avoided for patients with known renal insufficiency or failure.

Fentanyl, a synthetic opioid 100 times more potent than morphine, lacks active metabolites, and may be better tolerated at end of life when renal function is declining. The fentanyl transdermal patch can be used for those at home and in nursing home settings, but it may be more difficult to titrate at the end of life when pain escalates. Breakthrough pain may be treated with buccal transmucosal fentanyl if the patient is cognizant enough to use it. However, as cognition decreases, other opioids may be necessary to treat breakthrough pain unless intravenous access is available.

Hydromorphone is a semisynthetic opioid five to six times more potent parenterally than morphine. Hydromorphone does not significantly accumulate in patients with renal failure so it may not cause neuroexcitability and cognitive impairment. Hydromorphone, in a concentratation of 10 mg per mL, is an ideal agent for subcutaneous administration. In the home or nursing home setting, hydromorphone in the form of tablets, liquids, or suppository forms may be used. At the present time, there is no long acting form of oral hydromorphone available in the U.S.—although at least two companies are working on it.

Methadone, an inexpensive synthetic opioid with very high oral bioavailability, may produce dramatic improvement in pain when patients are rotated to it.18 In vitro studies have shown methadone to be a relatively potent N-methyl-D-aspartate (NMDA) inhibitor and has been postulated to decrease development of tolerance and increase analgesia.19 Methadone has a rapid distribution phase, but a very slow elimination phase. Its relative potency, combined with its slow elimination phase, has the potential for over-sedation occurring several days after initiation or titration. This makes prescribing methadone challenging for clinicians. An effective strategy for converting to methadone from other opioids is to first determine the total daily oral equianalgesic dose of morphine. If it is less than 1000 mg daily, start methadone at 10% of that dose, given every eight hours. If the equianalgesic daily dose is more than 1000 mg, start methadone at 5% of the calculated daily dose, given every eight hours. Generally it is not advisable to use methadone as the breakthrough medication—instead, a second immediate-release opioid should be prescribed.

Oxycodone is a semi-synthetic opioid available in long acting, controlled release and short acting, immediate release preparations. Although used extensively for cancer-related pain, it may be difficult for patients to use at the end of life when they are no longer able to swallow oral medications. Its elimination is primarily through the kidneys. Dose reduction may be necessary for those with changing hepatic and renal function. Rotation to transdermal or intravenous/ subcutaneous opioids may be necessary to control pain at the end of life.

Route of Administration

Oral, sublingual, and buccal administration of opioids is preferred for those able to swallow, and for whom pain can be controlled by these routes. However, as disease progresses and pain increases, rotation to transdermal, rectal, vaginal, intravenous, subcutaneous, and neuraxial opioid administration may become necessary. In a study of cancer patients at the end of life, less than 50% were able to use the oral route of analgesia in the last week of life and more than 50% required more than one route of medication.21

Neuraxial infusion may provide the most benefit for those with refractory pain and/or intolerable side effects. A variety of techniques for intraspinal opioid delivery have been adapted to long-term treatment, and from which properly selected patients can benefit greatly.22 The clearest indication for neuraxial administration is for the management of intolerable somnolence or confusion in patients not experiencing adequate analgesia during systemic opioid treatment of a pain syndrome located below the level of mid-chest.

“It is imperative that physicians acquire skills necessary to treat pain at the end of life, and to support their patients and family members through the dying process.”

For patients with limited prior opioid exposure (e.g. the use of an acetaminophen-hydrocodone or -oxycodone combination product several doses per day), the starting dose of an opioid conventionally used for severe pain is usually equivalent to morphine sulfate 5-10 mg intravenously every 4 hours. As end of life approaches, there may become the need for rapid titration of intravenous opioids even for the previously opioid naïve.

Trials of different opioids, a technique known as opioid rotation, may be used to attain the most favorable balance between analgesia and side effects.23 When it is necessary to rotate opioids or use different routes of administration, the sum of opioids given during the previous 24 hour period in units of oral morphine equivalents is calculated. From this calculation, the new agent can be dosed up to 50-80% of the new agent’s equivalent dose, given as continuous or intermittent dosing.24

Patients at the end of life often need around the clock analgesia. Use of intermittent, as needed (PRN) medication administration may lead to inadequate pain control and is not recommended unless pain is only incidental to a certain activity—such as repositioning or performing wound care. In general, continuous IV infusion is the preferred route of administration to provide consistent analgesia for dying patients in the hospital setting. Sufficient breakthrough medication (at least 10% of the total daily dose) should be given on a PRN basis, especially during times when patients are stimulated or moved (eg, bathing, turning, suctioning). Patient-controlled analgesia (PCA) is optimal when patients are able to participate because it can provide a background continuous infusion for those who need continuous opioids and/or can provide controlled bolus doses with short lockout periods for breakthrough or incidental pain.

Selected End-of-Life Pain Syndromes

Bone pain related to malignancy is the most common cause of pain in those with cancer. Pharmacotherapeutic options include NSAIDs, corticosteroids, and osteoclast inhibitors. Corticosteroids, administered by oral, intravenous and subcutaneous routes, are often utilized for pain related to bony metastases. For people at the end of life, steroids may not only provide analgesia but may also control nausea and improve appetite.25 Dexamethasone is a preferred agent due to the longer duration of action, less mineralocorticoid effects, and can be used at low doses (2-4 mg daily) in those with advanced cancer who have pain that is not optimally controlled with opioids. Although there is the long term risk of side effects related to steroid use, this is usually not an issue at the end of life.

Patients with malignant bowel obstruction who are not candidates for surgical decompression require intensive palliative interventions to reduce pain and other obstructive symptoms—including distention, nausea, and vomiting.26 Surveys of patients with far advanced disease suggest that the use of opioids, corticosteroids, anticholinergic drugs, and octreotide provide good symptom control and obviate the need for tube drainage. Scopolamine (1.5mg)—available transdermally—is often tried first; hyoscyamine and glycopyrrolate cause less central nervous system toxicity. Octreotide inhibits the secretion of gastric, pancreatic, and intestinal secretions, and reduces gastrointestinal motility. Its use in the symptomatic treatment of bowel obstruction is supported by favorable anecdotal experience.27

Pharmacotherapeutic Approaches for Refractory Pain

Parenteral lidocaine has been utilized at end of life for pain refractory to opioid therapy. There have been different approaches to therapy including one time boluses and continuous infusion.28 If technology and nursing support is available, lidocaine can be safely administered in the home and long term care setting via intravenous or subcutaneous routes at a dose of 0.5-1 mg/kg/hr either continuously or as a short-term infusion without significant cardiotoxicity.

Ketamine, a NMDA antagonist, has been utilized by some in the setting of severe, refractory pain in far advanced disease. There is substantial evidence that ketamine is analgesic, but its side effect profile limits use.29,30 Ketamine can be started at 0.1 mg/kg/hr by continuous infusion and titrated slowly to 0.5mg/kg/hr. Due to psychotomimetic side effects it may be prudent to pre-treat with a low dose of a neuroleptic agent prior to initiation of ketamine and, as needed, during the infusion.

Interventional Strategies

Neural blockade with alcohol, phenol, or glycerol, are often used to denervate painful areas of the body. Risks associated with these injections suggest that these techniques should be reserved for patients with refractory pain in the setting of advanced cancer or with an appropriate risk-to-benefit ratio. In patients with pancreatic cancer, the favorable response to neurolytic celiac plexus blockade warrants its use for refractory pain.31

Intractable Pain and Suffering at the End of Life: Palliative Sedation

People with advanced disease may experience more than just physical pain. Dame Cicely Saunders, founder of the hospice movement introduced the term “total pain.”32 “Total pain” may not be easily treated with pharmacologic or interventional therapy. There are certain circumstances when pain is not able to be controlled despite the best efforts of trained professionals. For a select group of persons, the use of palliative sedation may be the only means to relieve suffering at the end of life. Sedation at the end-of-life may be controversial, especially if the ethical foundation is not adequately understood. It should not be confused with euthanasia, and from an ethical perspective, it is founded on the patient’s right to be free of suffering. A recent review of the literature includes recommendations for standards in this area where there are a variety of approaches with minimal research.33 There is considerable discussion among palliative care specialists about the role and practical strategies for sedation in the imminently dying. It is recommended that palliative specialists knowledgeable in this area be consulted if palliative sedation is to become a part of the institution’s practice.


Since the days of Hippocrates, physicians have tried to relieve the pain of the dying. Today, there are many options available to provide terminally ill people with “good deaths.” It is imperative that physicians acquire skills necessary to treat pain at the end of life, and to support their patients and family members through the dying process. This is the essence of being a good physician.

Last updated on: December 20, 2011
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