Pain is a complex biopsychosocial event. Studies have shown that all types of pain (acute, chronic, and cancer pain) are undertreated, and poorly controlled pain has been identified consistently as one of the major problems in end-of-life care. In North America, pain is a major reason for referral to palliative care programs. However, adequate pain control can be achieved in most patients at the end of life by using a comprehensive approach that includes analgesics, adjuvants, education, support, and monitoring.
Pain Classification
Pain can generally be classified as nociceptive, neuropathic, or mixed.
Nociceptive Pain
Nociceptive pain is caused by the activation of nociceptive nerve fibers by physical tissue destruction or by chemical, pressure, or thermal processes. Nociceptive somatic pain can result from injury to skin, muscle, soft tissue, or bone and can have a strong incident- or movement-related component. It is usually well localized, can be constant or intermittent, and is often described as gnawing or aching pain that may become sharp with movement. Nociceptive visceral pain is typically less well localized, is usually constant, and may be referred (e.g., diaphragmatic pain may be manifested as shoulder pain). It is often described by a variety of terms such as aching, squeezing, and cramping. Pain arising from liver metastases is an example of nociceptive visceral pain.
Neuropathic Pain
Neuropathic pain is caused by injury to nerve tissue, including the central or peripheral nervous system and even the autonomic system. Neuropathic pain is frequently described as burning and often radiates along nerves or nerve roots. It can also be associated with dysesthesia (numbness and tingling), hyperalgesia (exaggerated response to a painful stimulus), lancinating pain, and allodynia (pain experienced from a stimulus that does not normally produce pain).
Mixed Pain
Mixed nociceptive and neuropathic pain is common in illnesses like cancer. As knowledge about pain has advanced, health care professionals have become increasingly aware of the need to develop a more mechanism-based approach to pain control. Pain is often a combination of physical and inflammatory processes. Cancer pain is an example of pain that may result from tissue damage and destruction and stimulation of nerves by inflammatory mediators that are produced by the tumor and also by the body in response to tumors. The clinical usefulness of pain classification relates to the use of certain adjuvant medications for specific pains, particularly for neuropathic pain.
Assessment of Pain
Pain is a subjective sensation, and there is no truly objective method for measuring it. Understanding the multidimensional nature of the physical, psychosocial, and spiritual components of pain is integral to the assessment of pain. Pain assessment should include a detailed history, relevant psychosocial and spiritual evaluation, physical examination, and relevant investigations. It is useful to assess pain in the physical, psychological, and social domains in sequence.
Physical Domain
A complete assessment of pain includes the following:
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Location
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Pattern of occurrence
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Quality (e.g., sharp, dull, burning)
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Aggravating or relieving factors
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Radiation of the pain
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Severity and variation in severity
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Interference with activities of daily living that may reflect the severity of pain
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Report of skin hypersensitivity or numbness, for example, that may suggest an underlying neuropathic component of the pain
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Pain treatment and analgesic history: what worked and what failed, dosage, adverse effects, compliance
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Breakthrough pain (e.g., incident or spontaneous)
The Brief Pain Inventory is a useful tool to quantify pain; alternatively, various types of validated and reliable visual, verbal, or numerical analogue scales can also be used ( Figure 7-1 ).
A history of present and past medical conditions is useful because some conditions complicate pain expression and subsequent management. Inquiry should cover the following:
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Presence of underlying delirium, cognitive failure, or dementia that could alter pain expression and the accuracy of pain history
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Presence of preexisting chronic pain or a history of pain, such as osteoarthritis or diabetic neuropathy
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Previous exposure to neurotoxic antineoplastic agents
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Presence of complicated cancer pain syndromes, such as malignant leptomeningeal spread, plexus involvement, or pathologic fractures
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Location of tumors, such as large retroperitoneal lymph nodes that cause back pain
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Presence of concomitant infection or abscess
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Presence of general medical conditions that could affect management and analgesic dosing, such as significant hepatic or renal impairment
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Current medications that may interact with analgesics or adjuvants
Psychological Domain
An assessment of psychological factors adds to the understanding of a patient’s suffering and pain expression. Issues in these domains that could affect pain assessment and management include the following:
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Depression and anxiety
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Limited understanding of the illness
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Patient’s fears of opioid use
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Anger toward the health care system or health care workers
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Underlying personality disorder or psychiatric disorder
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Loss of body image related to various surgical procedures
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Poor coping mechanisms
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Patient denial
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History of drug abuse or alcohol abuse
Social Domain
An assessment of the social factors that may have a bearing on the patient’s pain expression is also useful. Some factors include the following:
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Fears of opioids
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Family discord and dysfunction
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Guilt within the family
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The family’s lack of knowledge and understanding of the disease and prognosis
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Denial or unrealistic expectations of the family
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Financial issues
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Cultural and religious factors
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Drug and alcohol abuse
Complicated Cancer Pain Assessment and Classification
A number of factors may complicate cancer pain assessment and may cause difficulty in achieving stable pain control or require consideration of a referral for the support of a pain specialist. Therefore, assessment of pain should include problems that may complicate pain management or be a poor prognostic factor for pain control. Research to develop an international classification system for cancer pain has highlighted potential poor prognostic factors predictive of increased time to achieve stable pain control, higher opioid doses, and more requirements for adjuvant analgesics:
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Younger patients
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Neuropathic pain
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Incident or episodic pain
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Psychological distress potentially impacting increased expression of pain intensity
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Substance abuse disorder potentially predicting inappropriate opioid use or tolerance to opioids
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Severe pain intensity on initial presentation
For further elaboration and definitions used in the international classification system for cancer pain, see Knudsen and colleagues.
Pain Assessment in the Cognitively Impaired
Pain in those with cognitive impairment (e.g., dementia patients) can be particularly challenging. Some of the behavioral domains to assess pain in the cognitively impaired include facial expressions (e.g., grimacing, distorted), verbalizations/vocalizations (e.g., moaning, calling out), body movements (e.g., rigid, tense), changes to interpersonal interaction (e.g., aggression), and activity patterns and mentation. None of these behaviors are always indicators of pain. Assessment scales are available, but few of them have been tested widely for validity or reliability. The FACES Scale, which is often used for those who are cognitively impaired, has little proven validity or reliability in this population.
Principles of Pain Management
Educate the Patient and Family
It is essential to explain to the family and the patient the origin of the pain, the type of pain, the initial management plan (including the role of titration), expected adverse effects and how they will be managed, how the pain will be monitored, and how to access the professional care team. Fears concerning opioid use also need to be addressed.
Prevent and Minimize Adverse Effects
Common adverse effects such as sedation, constipation, and nausea should be anticipated and prevented through a combination of education and the regular use of drugs that will address these issues. By minimizing adverse effects, additional patient suffering can be avoided, compliance may be enhanced, and anxiety can be reduced.
Match Pain Severity to Analgesic Potency
The three-step ladder approach for pain control by the World Health Organization (WHO) remains a useful educational tool, but aspects of clinical application have been questioned. Evidence indicates that for mild to moderate pain, nonopioid analgesics can be effective either alone or in combination with weak opioids. For moderate pain, the recommendation is to consider starting with small doses of a strong opioid. For severe pain, a strong opioid is the initial drug of choice. Adjuvant analgesics can be used for all types of pain if clinically indicated. For a summary of prescribing principles, see Table 7-1 .
| Type | Typical Analgesics | Adjuvant Analgesics |
|---|---|---|
| Nociceptive pain: mild | Nonopioids + / – weak opioids | NSAIDs (brief trial) |
| Nociceptive pain: moderate to severe | Strong opioids | NSAIDs Radiotherapy Surgery |
| Neuropathic pain: mild | May not be indicated | Tricyclic antidepressants Typical and atypical anticonvulsants |
| Neuropathic pain: moderate to severe | Strong opioids | Tricyclic antidepressants Typical and atypical anticonvulsants Radiation Surgery |
Titrate to Pain Control
Each patient has different analgesic requirements, depending on the source of the pain and as a result of pharmacokinetic and pharmacodynamic differences among patients and the interplay of other factors, all of which produce the “total pain” experience. Thus, dosages have to be tailored and titrated to the patient’s individual pain needs.
Prescribe Around-the-Clock Dosing
Patients with constant pain require around-the-clock dosing at regular intervals to suppress the pain. There is rarely a role for “as necessary” administration of medication for constant pain except as breakthrough dosing.
Prescribe Rescue or breaKthrough Doses
Pain is rarely completely stable, and extra pain should be treated with breakthrough or rescue doses. Always prescribe rescue dosing.
Always Consider Using Adjuvants
For neuropathic pain, consider starting adjuvant analgesics before opioids for mild pain, or at the same time as opioids for moderate or severe pain. Recommended first-line agents include tricyclic and other antidepressants, anticonvulsants such as gabapentin or pregabalin, and transdermal lidocaine. For bone pain from cancer, the option of radiotherapy must always be explored. For all types of pain, nonopioids such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) may be helpful. Brief trials of these nonopioids along with opioids may prove to be beneficial to some patients. Surgery may also be indicated for bone pain or neuropathic pain. These points are summarized in Table 7-1 .
Monitor Continuously
Constant and frequent review of the patient’s response to the prescribed regimen of analgesics, adjuvants, and other interventions is important. The patient’s medical status must be monitored for conditions that could affect the dose of the analgesic regimen, such as the development of renal failure. Patients, family members, and all health care professionals can be involved in this process.
Ask For Help
Pain specialists and palliative care specialists are available to assist in more complicated cases. Do not hesitate to call and ask them for an opinion.
Addiction, Diversion, Physical Dependence, and Tolerance
Physicians who prescribe opioids need to differentiate the issues of physical dependence, drug abuse and diversion, addiction, and tolerance. However, a history of substance abuse does not exclude someone from having pain. Definitions of addiction, physical dependence, tolerance, and pseudoaddiction are listed in Table 7-2 .
| Addiction |
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| Physical dependence | A state of adaptation manifested by a drug class–specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist |
| Tolerance | A state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time |
| Pseudoaddiction | Syndrome of behavioral symptoms that mimic those seen with psychological dependence, including an overwhelming and compulsive interest in the acquisition and use of opioid analgesics |
| An iatrogenic syndrome (unlike true psychological dependence) caused by undermedication of pain; symptoms and aberrant behaviors resolve once pain is effectively controlled |
Steps the clinician can take to address these issues include adopting a risk management approach that includes universal precautions and using various risk assessment tools.
When prescribing opioids for pain in a person with a history of substance abuse, consider the following:
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Patients who have abused and developed tolerance to opioids may require higher than usual doses of opioids for pain control.
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Patients who are at higher risk of substance abuse can be identified, and questionnaires such as the CAGE substance abuse screening tool may indicate abuse potential.
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Common abuse behaviors include reports of “lost” or “stolen” prescriptions, a history of multiple prescribers, obtaining prescription drugs from nonmedical sources, and repeated dose escalations or similar instances of noncompliance despite multiple warnings.
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Emotional, social, and even spiritual issues may complicate and magnify pain expression.
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The patient’s behavior may contribute to the difficulty in treating pain, and mistrust between the patient and health care provider can be a barrier.
Simple strategies to prevent abuse may include dispensing a limited amount of opioids at a time, having only one designated prescriber and one designated pharmacy to fill the prescription, and allowing no refills for “lost” or “stolen” prescriptions. Consider using opioids that have less street value (this can vary in different geographic locations). Be aware of analgesic combinations that have potentially hepatotoxic components, such as acetaminophen in drug abusers, who are at high risk of liver damage.
Pharmacologic Options for Pain Management
Analgesics can be classified as nonopioid analgesics, opioid analgesics, and adjuvant drugs.
Nonopioid Analgesics
Nonopioid analgesics are appropriate as single agents for mild pain.
Acetaminophen
Acetaminophen is the most common over-the-counter analgesic drug. Its exact mechanism of action is not completely understood, but it does have peripheral and central actions. Dosage is limited to less than 4 g/day to minimize potential hepatotoxicity. This drug should be used with caution in patients with active hepatitis or hepatic dysfunction, in patients who abuse alcohol, and in those with jaundice. It may also be effective as an adjuvant when added to strong opioids.
Acetaminophen is often combined with codeine or oxycodone. This combination may prove useful in patients who have mild to moderate pain, but the amount of acetaminophen limits the dosages.
Nonsteroidal Anti-Inflammatory Drugs
NSAIDs have peripheral and central actions perhaps related but not totally limited to inhibition of cyclooxygenase enzymes (COX-1 and COX-2). Gastrointestinal and renal toxicity can be a problem with NSAIDs. Some of the newer, specific COX-2 inhibitors may have less severe or fewer gastrointestinal and renal side effects. There are a number of concerns concerning the use of NSAIDs in certain patients.
For patients taking corticosteroids, NSAIDs will increase the risk of gastrointestinal erosion and bleeding. In patients on anticoagulants for deep vein thrombosis or who may even have a coagulopathy secondary to hepatic impairment or platelet problems, the use of NSAIDs puts them at higher risk of upper gastrointestinal bleeding. Clearance of the first-line strong opioids such as morphine and hydromorphone depends on kidney function. NSAIDs may affect renal function and may lead to decreased renal clearance and an increased risk of opioid toxicity. Gastric protection with misoprostol and proton pump inhibitors such as omeprazole can be considered for high-risk patients.
No clear evidence indicates that one NSAID is superior to another. If the patient has no obvious response to an NSAID, the drug should be discontinued. This applies whether the drug is used alone or as an adjuvant.
Tramadol
Tramadol is a unique, synthetic, centrally acting analgesic with both opioid and nonopioid properties. It has some action at the mu opioid receptor, but it also has other actions, including possible anti-inflammatory effects. In addition, it stimulates neuronal serotonin release and inhibits the presynaptic reuptake of both norepinephrine and serotonin at synapses. Naloxone only partially reverses the analgesic effect of tramadol. Its bioavailability is twice that of codeine. It is a pro-drug and relies in part on an active metabolite for its analgesia. It is converted in the liver in the cytochrome P450 system to O-desmethyltramadol, which is itself an active substance, two to four times more potent than tramadol. Further biotransformation results in inactive metabolites that are excreted by the kidneys. Approximately 5% to 10% of the population lacks the isoenzyme to metabolize tramadol, and in such persons tramadol has limited analgesic effect. CYP2D6 inhibitors (e.g., chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole) may decrease the effects of tramadol. Carbamazepine decreases the half-life of tramadol by 33% to 50%. The concomitant use of monoamine oxidase inhibitors is contraindicated. Tramadol must be used with caution with any central nervous system depressant such as phenothiazines and barbiturates.
By injection, tramadol is one tenth as potent as parenteral morphine. Orally, because of much better bioavailability, it is one fifth as potent. Tramadol can be regarded as double-strength codeine.
Tramadol is available in the United States and Canada as a fixed combination with acetaminophen or in a sustained-release formulation. The ceiling recommended dose is 400 mg/day.
The most common adverse effect is constipation, but this seems to occur less often than with equianalgesic doses of morphine. The risk of seizures is increased with high dose tramadol (e.g. >400 mg/day), and therefore tramadol should probably not be used in patients with a history of seizures.
Opioids
Opioids are the mainstay of pain management in palliative care.
General Properties
Opioids are variably absorbed from the gastrointestinal tract. Morphine and codeine are absorbed relatively poorly (30% to 50%), and methadone has a good oral bioavailability of about 80% (ranges from 41% to 99%). Bioavailability is further reduced by metabolism in the gut wall and the liver (the first-pass effect). Absorption may be genetically determined and may decrease with increasing age.
All opioids are bound to plasma proteins, generally to albumin and alpha-1-acid glycoprotein. However, the extent of binding varies from less than 10% for codeine to 80% to 86% for fentanyl. Morphine is about 20% to 35% protein bound.
Most opioids have a large volume of distribution, depending on the lipophilicity of the parent compound and metabolites. Fentanyl and methadone are the most lipophilic.
Opioids are metabolized to more hydrophilic compounds, predominantly by glucuronidation in the liver, although some extrahepatic metabolism may occur. Most of the metabolites are less active than the parent opioid and may not have much clinically relevant pharmacologic action. However, some metabolites are as potent or more potent opioid agonists than the parent drug (e.g., morphine as a metabolite of codeine, morphine-6-glucuronide derived from morphine). Some metabolic byproducts (particularly morphine-3-glucuronide, hydromorphone-3-glucuronide, and normorphine) may be responsible for the neurotoxic side effects of confusion and myoclonus. Because they are excreted by the kidneys, these metabolites accumulate in patients with renal failure. Methadone and, to some extent, fentanyl are exceptions because they are metabolized in the liver through the cytochrome P450 system and the major route of excretion is fecal. Methadone and fentanyl are therefore more prone to drug interactions with agents that affect that metabolic system. Oxycodone, fentanyl, and methadone have no active final metabolites.
Opioids bind to opioid receptors that are spread throughout the body. In the central nervous system they are concentrated in the thalamus, the periaqueductal gray matter, and the dorsal horn of the spinal cord. Receptors are also present in the lungs, in the myenteric plexuses of the gastrointestinal tract, and in other areas where their exact function remains unclear. The mu receptor is the one most strongly associated with analgesia. Other receptors include kappa and delta receptors. Recent work on opioid receptors suggests that genetic polymorphism may be responsible for the varied interindividual response to the same doses of an opioid.
Opioids can be divided into pure agonists, partial agonists, mixed agonists, and antagonists ( Table 7-3 ) based on their interactions with the various receptor subtypes (mu, kappa, and delta). Partial agonists (e.g., buprenorphine) and the mixed agonists and antagonists (e.g., butorphanol and pentazocine) have the disadvantage of a ceiling effect. The mixed agonist and antagonists are noted to have more psychotomimetic side effects, and partial agonists have the potential to cause withdrawal problems when added to pure opioid agonists. Hence, pure agonist opioids are the most useful medications in the management of pain.
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