Pain is the most common presenting symptom of disease. It is defined as an unpleasant sensory and emotional experience, associated with actual or potential tissue damage. There are sound medical and legal reasons to treat pain aggressively in hospitalized patients. The Joint Commission, which certifies health care institutions in the United States, mandates that all patients have the right to adequate pain assessment and management (Table 48-1).
TABLE 48-1Joint Commission Pain Assessment and Management Standards for Hospitals ||Download (.pdf) TABLE 48-1 Joint Commission Pain Assessment and Management Standards for Hospitals
The hospital respects the patient’s right to pain management.
The hospital educates all licensed independent practitioners on assessing and managing pain.
The hospital assesses and manages the patient’s pain. The hospital conducts a comprehensive pain assessment that is consistent with its scope of care, treatment, and services and the patient’s condition.
The hospital uses methods to assess pain that are consistent with the patient’s age, condition, and ability to understand.
The hospital assesses and reassesses its patients. The hospital defines, in writing, criteria that identify when additional, specialized, or more in-depth assessments are performed for pain.
Based on the patient’s condition and assessed needs, the education and training provided to the patient by the hospital include any of the following: discussion of pain, the risk for pain, the importance of effective pain management, the pain assessment process, and methods for pain management.
In the inpatient setting, patients may be more concerned about pain relief than the outcome of their underlying illness. Poor pain control has adverse physiologic consequences that lead to worse outcomes (Table 48-2).
TABLE 48-2Physiologic Consequences of Uncontrolled Pain ||Download (.pdf) TABLE 48-2 Physiologic Consequences of Uncontrolled Pain
|Cardiovascular ||Tachycardia, hypertension, increased cardiac workload |
|Pulmonary ||Hypoxia, hypercarbia, atelectasis, decreased cough |
|Gastrointestinal ||Decreased gastric emptying, nausea/vomiting, ileus |
|Renal ||Urinary retention |
|Endocrine ||Increased adrenergic activity, catabolic state, sodium/water retention |
|Immunologic ||Impairment, slowed wound healing |
|Musculoskeletal ||Splinting, contractures, decreased mobility (deep vein thrombosis) |
|Hematological ||Increased coagulability |
|Neurological ||Anxiety, fear, anger, fatigue, delirium |
In postoperative patients, better analgesia improves cardiovascular, respiratory, endocrine, immunologic, gastrointestinal, and hematologic status. Following many common surgeries, acute pain that is not satisfactorily treated may become persistent.
PATHOPHYSIOLOGY: NOCICEPTIVE AND ANTI-NOCICEPTIVE PATHWAYS
Nociception, the perception of noxious stimuli, is a preconscious neural activity that is normally necessary, but not sufficient, for pain. It is more accurate to refer to nociceptive pathways, rather than pain pathways. The peripheral nerve fibers acting as nociceptors are lightly myelinated A-delta and unmyelinated C fibers, which are triggered or sensitized (peripheral sensitization) by several substances, including adenosine triphosphate (ATP), prostanoids, bradykinin, serotonin, histamine, and hydrogen ions. Heat, pressure, or nerve damage also results in activation.
The primary nociceptors synapse in the dorsal horn of the spinal cord (Figure 48-1), where the excitatory amino acids glutamate and aspartate and peptides such as substance P serve as neurotransmitters. Noxious impulses ascend in the lateral spinothalamic tract to the medial and lateral thalamus and spread to sensory regions of the cerebral cortex. Parts of the limbic system are also activated; most likely, this is where nociception is associated with emotion and arousal and is then perceived as pain.
Nociception transmission and pain modulatory pathways. (A) Transmission system for nociceptive messages. Noxious stimuli activate the sensitive peripheral ending of the primary afferent nociceptor by the process of transduction. The message is then transmitted over the peripheral nerve to the spinal cord, where it synapses with cells of origin of the major ascending pain pathway, the spinothalamic tract. The message is relayed in the thalamus to the anterior cingulate (C), frontal insular (F), and somatosensory cortex (SS). (B) Pain-modulation network. Inputs from frontal cortex and hypothalamus activate cells in the midbrain that control spinal pain-transmission cells via cells in the medulla. (Reproduced with permission from Fauci AS, Braunwald E, Kasper DL, et al. Harrison’s Principles of Internal Medicine, 17th ed. New York: McGraw-Hill; 2008, Fig. 12-4.)
The nociceptive system has built-in positive and negative feedback loops. Prolonged firing of nociceptors enhances synaptic transmission to dorsal horn neurons. This process of central sensitization involves glutamine and a host of other mediators. Central sensitization is an adaptive response that prevents further injury during a vulnerable period of tissue healing. This heightened sensitivity generally returns to baseline over time. However, if central sensitization is prolonged beyond the healing phase, chronic pain may result.
Substance P–mediated nociception is antagonized by local production of endogenous opiates, such as enkephalins and endorphins, in the dorsal horn and the brain stem. Binding of opioids to opiate receptors in these locations may account for the analgesic effects of these drugs. As well, powerful top-down, endogenous mechanisms of pain modulation originate in the cortex and travel through brain stem and midbrain structures en route to the spinal cord. These descending pain control pathways are mediated by nor-adrenergic and serotonergic transmission, as well as endogenous opiates.
CHARACTERIZING PAIN INTENSITY
The most commonly used measures of pain intensity in the acute setting are single-dimension scales (Table 48-3). A numerical rating scale has the numbers 0 to 10 spaced evenly across a page, where 0 is “no pain at all” and 10 is “the worst pain imaginable.” Patients are instructed to circle the number that represents the amount of pain they are currently experiencing. A common variation is the verbal numeric scale, where patients are asked to verbally state a number between 0 and 10 to correspond to their present pain intensity. Some people prefer to use words to describe the intensity of their pain; these are termed verbal descriptor scales. Another variant that may be useful in the elderly or cognitively impaired are scales with drawings of faces, ranging from a contented smiling face to a distressed-looking face.
TABLE 48-3Single-Dimension Pain Scales ||Download (.pdf) TABLE 48-3 Single-Dimension Pain Scales
|Numerical Rating Scale |
|0 ||1 ||2 ||3 ||4 ||5 ||6 ||7 ||8 ||9 ||10 |
|Verbal Descriptor Scales |
Worst pain imaginable
Single-dimensional scales are quick and simple to use, an important benefit in the acute setting when repeated measures are needed over a brief period of time. One disadvantage is that they attempt to assign a single value to a complex, multidimensional experience. Another is that patients can never know if the present experience is the “worst.” If a value of “10” is chosen and the pain worsens, the patient has no official means to express this; in practice many patients state a number over 10.
Several multidimensional scales exist that attempt to assess various aspects of the patient’s pain experience (eg, McGill Pain Questionnaire, Brief Pain Inventory). These multidimensional scales attempt to take into account the complex nature of pain. However, in the inpatient setting, they are too time consuming for rapid or repeated use. One compromise is to address a limited number of the dimensions of pain, using a few single-dimensional scales to address issues that are important to hospitalized patients—for example pain, anxiety, depression, anger, fear, and interference with physical activity.
The history of the patient in pain includes the pain’s location and the presence, or absence, of radiation from the primary site. Intensity should be determined using appropriate scales, as already described. The patient should describe the pain’s character (eg, aching, burning, dull, electric-like, sharp, shooting, stabbing, tender, and throbbing). This may provide clues to help diagnose the generator of the pain which aides in deciding the correct therapy (Table 48-4). Does the pain have a pattern (constant, intermittent, or better or worse at certain times of day) and aggravating and alleviating factors? Does the pain have an impact on functional status? Are the patient’s activities of daily living affected as an outpatient, or is it hampering their ability to cough, get out of bed, and ambulate while in the hospital? The patient’s prior analgesic history, in particular, what therapies have either worked or not worked in the past, helps to decide what agents may be effective now. Exact doses of ongoing analgesics should also be determined.
TABLE 48-4Determining the Mechanism and Treatment of Pain ||Download (.pdf) TABLE 48-4 Determining the Mechanism and Treatment of Pain
|Pain Mechanism ||Character ||Examples ||Treatment Options |
|Somatic || |
Usually well localized and constant
Aching, sharp, stabbing
| || |
|Visceral || |
Not well localized—constant or intermittent
Generalized ache, pressure or cramping, can be sharp
| || |
|Neuropathic || |
Can be localized (ie, dermatomal) or radiating, can also be generalized and not well localized
Burning, tingling, electric shock, lancinating
The patient’s medical history should be obtained. Medical conditions that cause pain include cancer, diabetes, osteoarthritis, rheumatoid arthritis, herpes zoster (shingles), and spinal cord injury. Psychological conditions may adversely impact a patient’s pain experience and need appropriate diagnosis and therapy. These include anxiety (especially in acute pain states), depression (most prevalent in persistent pain states), fear, catastrophizing (assuming the worst-case scenario), and personality disorders. A family history that is positive for substance abuse in the patient’s relatives is a risk factor for addiction in the patient. A social history positive for alcohol, tobacco, or other drugs may indicate a need to prescribe agents to prevent withdrawal (ie, benzodiazepines or nicotine patches). Even patients with a history of addiction still need to be appropriately treated for pain in the acute setting. In this setting, it may be useful to enlist the help of a psychiatrist or psychologist trained in addiction management.
A directed physical examination of the painful site, and a generalized physical exam of the patient as appropriate, should be performed. Pain (especially acute) may be associated with tachycardia, hypertension, diaphoresis, and tachypnea. However, since sympathetic activation is a common and nonspecific finding in hospitalized patients, it offers little help in the diagnosis and treatment of pain in an awake, competent patient. These measures may be used as surrogates in patients who cannot express their pain experience.
Diagnostic tests to determine the etiology of pain may be useful in some situations (eg, radiographs to assess for fracture, magnetic resonance imaging [MRI] to diagnose nerve impingement in the spinal cord, or electromyography [EMG] to diagnose a neuropathy). However, normal test results should not be used to discount a patient’s report of pain.
CARDINAL PRINCIPLES OF PAIN MANAGEMENT
Pain is a subjective phenomenon, resulting from the processing, filtering and modulating of nociceptive input through the affective (limbic system) and cognitive processes unique to each individual. The patient’s report of pain must be respected and believed. As pain is an affective and cognitive experience, the placebo response to analgesics is real and may be helpful. However, using the placebo response does not mean misleading patients, or administering an inactive substance to determine whether they are lying or to punish them. Rather, the placebo effect in contemporary medicine is that patient belief in a particular therapy makes it more likely to work. Physician attempts to truthfully “talk up” genuine attempts at analgesia are thus likely to enhance the effects. The reverse is also true. If a patient states that a particular therapy “never works for them,” it is less likely to be effective.
The patient’s pain level and degree of pain relief should be assessed appropriately and regularly. Pain should be treated quickly. Therapy should not be withheld while the diagnosis is unclear; pain treatment does not impede the ability to diagnose disease. A comprehensive plan should be used that addresses the multidimensional aspects of pain. This may require an interdisciplinary team approach (eg, hospitalist, pain specialist, anesthesiologist, surgeon, psychiatrist or psychologist, and physical therapist), especially for patients with persistent pain.
The analgesic plan should be discussed with the patient and, when appropriate, the patient’s family. The patient’s expectations for pain management should be understood, and patients should be offered reasonable goals for the outcomes of therapy.
A multimodal approach for managing pain, employing both pharmacologic and nonpharmacologic measures, is better than using just one modality. This approach allows for optimal analgesia with the lowest incidence of side effects. In the absence of a contraindication, all patients in pain should be prescribed a nonopioid analgesic. Clinicians should be familiar with several agents within each class of analgesics, including possible side effects, because individual responses vary greatly.
If pain is present most of the time or expected to last for an extended period of time (eg, more than a few weeks), long-acting agents or round-the-clock dosing of short-acting agents should be used. When long-acting drugs are used, immediate-release agents will also be needed for breakthrough pain. When pain is intermittent or expected to be of brief duration (eg, less than a few weeks), then as-needed dosing of immediate release agents can be used alone.
Pharmacologic and nonpharmacologic treatment measures are often used together. Pain medication falls into three categories: nonopioid analgesics, opioids, and adjuvant analgesics. Therapy should be individualized in a multimodal, stepwise approach, adding or changing agents when pain control is inadequate, and withdrawing agents as pain resolves (Table 48-5).
TABLE 48-5Suggested Pain Management Schemes ||Download (.pdf) TABLE 48-5 Suggested Pain Management Schemes
|The World Health Organization devised the analgesic ladder for the treatment of cancer pain. The concepts behind its use are helpful in the management of all types of pain, both persistent and acute. |
|The World Federation of Societies of Anesthesiologists devised another analgesic ladder to use for the treatment of acute/postoperative pain. |
Although scientific data on nonpharmacologic measures are limited, most have little risk. At a minimum, they may have placebo benefit, due to the cognitive and affective influence on pain. Application of cold (to reduce inflammation) or heat (to reduce spasms) to muscles or joints are commonly used, but the evidence for an analgesic benefit is mixed. Hypnosis has been shown to reduce pain associated with procedures. However, it requires specific training and time to administer. In the acute setting, the results with transcutaneous electrical nerve stimulation (TENS) are conflicting, with somewhat better evidence of effectiveness in the setting of chronic pain, particularly painful diabetic neuropathy. Relaxation and guided imagery have shown little benefit in the acute setting. Attention techniques can be complicated in that one needs to determine which approach is better for a particular patient. Some patients do better when instructed to shift attention away from the pain, whereas others do better if instructed to attend to a particular portion of the pain (eg, the sensory component, as opposed to the emotional component). Acupuncture and electroacupuncture have been shown to be beneficial in the acute setting, reducing both pain and common side effects from opioid analgesics. However, these are labor intensive, and specific training is required. The use of virtual reality has been shown to reduce levels of pain and unpleasantness for burn care procedures, common painful cancer procedures and treatments, and routine medical procedures. The major hindrance to its use is the cost and availability of the equipment.
In the absence of a contraindication, all patients in pain should be prescribed a nonopioid analgesic. These agents have analgesic effects and are opioid sparing, leading to decreased side effects. They are the primary analgesics for low-intensity pain associated with headache or musculoskeletal disorders and are useful adjuncts in moderate to severe pain. These agents have a plateau effect, such that doses beyond the recommended range increase the incidence of side effects but do not improve analgesia.
Acetaminophen does not inhibit peripheral prostaglandin synthesis. This explains its lack of side effects on gastric mucosa and platelets, but it also means that it is not active at peripheral sites of inflammation. In diseases where inflammation plays a major role in generating pain (eg, rheumatoid arthritis), acetaminophen is of minimal benefit. The analgesic mechanism of acetaminophen is not well characterized but may involve facilitation of central antinociceptive pathways via serotonin, increasing levels of endogenous cannabinoids, or inhibition of nitric oxide synthesis in the spinal cord, which may interfere with substance P–related nociception.
The nonacetylated salicylates (eg, choline magnesium trisalicylate) have a relatively low incidence of gastrointestinal bleeding, perhaps related to their lack of inhibition of platelet aggregation. The nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are potent anti-inflammatory analgesics with significant risk for gastrointestinal bleeding and renal insufficiency. No single NSAID appears to be more effective as an analgesic than any other, but as there is great interpatient variability in response, thus changing agents may be of benefit if one does not seem to be effective. The COX-2 selective NSAIDs have a reduced risk of peptic ulceration compared to nonselective NSAIDs, but an equivalent chance of renal toxicity. Celecoxib is currently the only COX-2 selective NSAID available in the United States. It should not be considered a first-line agent given it’s cost, and should not be used long term at high doses, as it increases the risk of major cardiovascular events. Table 48-6 lists the dosing regimens and adverse effects of selected nonopioid analgesics.
TABLE 48-6Select Nonopioid Analgesics ||Download (.pdf) TABLE 48-6 Select Nonopioid Analgesics
|Agent ||Adult Dosing ||Maximum Daily Dose ||Comments |
|Acetaminophen ||650-1000 mg every 6 h ||4000 mg ||Single doses above 1000 mg do not improve analgesia |
|Choline magnesium trisalicylate ||1000-1500 mg twice a day ||3000 mg ||Caution in liver disease, avoid in severe liver disease |
|Diclofenac ||50 mg twice a day-four times a day ||200 mg ||Low GI effect incidence, but possible increased renal effects, recent data suggest increased negative CV effects |
|Etodalac ||200-400 mg every 6-8 h ||1000 mg ||Low GI and renal effect incidence, safest NSAID in liver disease |
|Ibuprofen ||400-600 mg every 4-6 h ||3000 mg ||<1500 mg daily has low risk of GI effects, possible increased renal effects, inhibits CV benefits of aspirin when given concomitantly |
|Ketorolac ||30 mg every 6 h ||120 mg ||High risk of renal and GI complications; use for no more than 5 d; 15 mg every 6 h in renal impairment, age >65, weight <50 kg |
|Nabumetone ||750-1500 mg daily or twice a day ||1500 mg ||Low GI effect incidence |
|Naproxen ||250-500 mg every 6-12 h ||1500 mg ||Possible increased liver and renal effects, probably least negative CV effects |
|Celecoxib ||100-200 mg daily ||200 mg ||Use 100 mg dose if possible; long-term use has increased negative CV effects |
Tolerance is the diminished response to a drug over time, such that, in order to maintain the same effect, the drug dose needs to be increased. Dependence is a state of physiologic adaptation that develops with continued use of a drug, presenting as a withdrawal syndrome if the drug is abruptly stopped, the dose is dramatically reduced, or an antagonist is given. Addiction is a primary, chronic, neurobiologic disease with many factors influencing its development. It manifests as drug-seeking behaviors, impaired control over the drug, and continued use despite negative effects. Tolerance to and dependence on opioids do not equal addiction! Pseudoaddiction denotes iatrogenically induced patient behaviors that mimic drug seeking, due solely to the under treatment of pain. When pain is adequately managed, the behaviors resolve.
When treating moderate to severe pain, pure agonists should be used, as opposed to agonist/antagonists. The commonly used agonists are shown in Table 48-7.
TABLE 48-7Opioid Classification
The optimal analgesic dose varies widely among patients, even the opioid naïve. Side effects from opioids also vary widely between patients. It is, therefore, helpful to be familiar with the characteristics of several different agonists (Table 48-8).
TABLE 48-8Opioid Characteristics
Patients should be asked which opioids have worked or not worked in the past, or have given them intolerable side effects.
Whenever possible, the enteral route of administration is best, as it is the easiest route with the most stable pharmacokinetics. If a patient cannot take anything by mouth or adequate analgesia cannot be obtained in a timely manner, then intravenous (IV) administration should be used. Intramuscular administration should be avoided.
If pain is present most of the time or expected to last for an extended period of time (ie, more than a few weeks), long-acting agents or round-the-clock dosing of short-acting agents should be used. When long-acting drugs are used, immediate-release agents will also be needed for breakthrough pain.
Patients should be monitored closely for effectiveness and adverse events whenever there is a change of agent or route of administration.
When pain is intermittent or expected to be of brief duration (eg, less than a few weeks), then as-needed dosing of immediate release agents can be used alone.
When a patient is competent, the use of an IV patient-controlled analgesia (PCA) offers the best overall pain management option for postoperative hospitalized patients.
Codeine is not a good first choice due to the fact that 10% to 20% of the population lacks an active form of the enzyme (cytochrome P450 2D6) necessary to convert codeine into an active drug in the body (ie, morphine). All opioids should be used with caution in patients with renal or hepatic insufficiency; lower doses or longer dosing intervals are wise in this setting. Morphine is relatively contraindicated in patients with severe renal insufficiency due to the accumulation of the metabolite, morphine-6-glucuronide, which can lead to sedation and respiratory depression.
Meperidine (Demerol) is not recommended for pain management. Its active metabolite, normeperidine, can accumulate in 24 to 48 hours to levels that produce nervous system excitation (tremors, muscle twitching, convulsions). Meperidine causes a strong euphoric feeling, especially when given by intravenous push. It is a weak agonist that is usually ineffective for more than mild pain, and it causes more nausea than other agents. Hydrocodone should be used with caution. In the United States, it is often coformulated with acetaminophen, aspirin, or ibuprofen, and adverse events and toxicity may result from these other agents, in addition to the hydrocodone itself. Hydrocodone has also become a favored drug of abuse in the United States.
Whenever possible, the enteral route of administration is best, as it is the easiest route with the most stable pharmacokinetics. If a patient cannot take anything by mouth or adequate analgesia cannot be obtained in a timely manner, then intravenous (IV) administration should be used. Intramuscular administration should be avoided for several reasons: It is painful; there are wide fluctuations in absorption; it takes a long time to reach peak effect; there is a rapid fall-off of action thereafter. When a patient is competent, the use of an IV patient-controlled analgesia (PCA) offers the best overall pain management option (see later discussion).
Recommended starting doses for moderate to severe pain in the opioid-naïve are listed in Table 48-9. If a patient is not receiving enough pain relief at a given dose, subsequent doses should be increased by 25% to 50%. If a patient is having pain before the next dose is due, the dosing interval should be reduced, or the dose increased.
TABLE 48-9Recommended Starting Doses of Opioids for Adults Over 50 kg ||Download (.pdf) TABLE 48-9 Recommended Starting Doses of Opioids for Adults Over 50 kg
A switch to another opioid may be necessary in several circumstances. First, patients on therapeutic opioid doses who are not receiving any pain relief may not have a receptor population at which that particular opioid is effective. A different opioid may provide better analgesia. Second, if a patient is having intolerable side effects, rotation to a different opioid may provide relief. In this case, the patient’s receptor population may bind a particular opioid in regions that cause side effects. Third, if a particular opioid cannot be given by the route of administration required, then changing to another opioid will be necessary. Finally, if a patient has been on an opioid for a long time and has developed tolerance, rotation to a different opioid may provide better analgesia, usually at less than the expected equianalgesic dose. A similar effect may also be seen in patients on long-term opioid therapy for chronic pain who have an episode of acute pain; better analgesia may also be experienced in this setting with a switch to a different opioid.
Equianalgesic-dosing charts (see Table 48-8) are based on the relative potency of opioid agonists, as determined by single-dose clinical studies and experience. These calculations are estimates only, and clinical judgment is always required for use. Incomplete cross-tolerance exists between the various opioids. This means patients will not be as tolerant to a new opioid agonist as they are to the one they were on previously. Thus, when converting between opioids, the calculated equianalgesic dose of the new agent must be reduced by 25% to 75% to prevent over sedation and respiratory depression. Table 48-10 shows an example of opioid conversion.
TABLE 48-10Example of Opioid Conversion ||Download (.pdf) TABLE 48-10 Example of Opioid Conversion
Patient used 15 mg of IV hydromorphone in the past 24 h.
According to the equianalgesic table:
Taking into account incomplete cross-tolerance, decrease the total daily opioid dose by 25%-75%:
200 – (0.25 × 200) = 150 mg of oral oxycodone
200 – (0.75 × 200) = 50 mg of oral oxycodone
Dose initially every 4 h:
Therefore, order: oxycodone 10-25 mg every 4 h as needed for pain.
Sustained-release or long-acting opioids
Episodic pain or pain expected to be of a brief duration should be treated with immediate-release agents alone. Sustained-release formulations should be initiated in the acute setting if pain is present most of the time, and pain is expected to last for an extended period of time (2-3 weeks or more). When using a sustained-release opioid, an immediate-release opioid equivalent to 10% to 15% of the 24-hour total every few hours on an as-needed basis should also be prescribed. If more than four to five rescue doses of immediate-release opioid are needed in 24 hours, the dose of sustained-release agent should be increased by 50% to 100% of the total 24-hour breakthrough dose used.
Transdermal fentanyl is not appropriate to treat acute pain, especially in the opioid-naïve. Its use in the acute setting may lead to severe respiratory depression from the delayed peak effect of the drug. It should only be used in patients already tolerant to opioids of comparable potency. Table 48-11 gives recommendations for conversion from other opioids to transdermal fentanyl.
TABLE 48-11Dose Conversion Guidelines from Another Opioid to Transdermal Fentanyl ||Download (.pdf) TABLE 48-11 Dose Conversion Guidelines from Another Opioid to Transdermal Fentanyl
|24-h Oral Morphine Equivalent Dose (mg/d)* ||Transdermal Fentanyl Initial Dose (mcg/h) |
|60-134 ||25 |
|135-224 ||50 |
|225-314 ||75 |
|315-404 ||100 |
|405-494 ||125 |
|495-584 ||150 |
|585-674 ||175 |
|675-764 ||200 |
|765-854 ||225 |
|855-944 ||250 |
|945-1034 ||275 |
|1035-1124 ||300 |
Methadone is also not appropriate as a first-line agent in the acute setting, especially in the opioid-naïve. Its use requires an understanding of the unique pharmacology of the drug, especially its extended duration of action and its dose-dependent potency. Also, as it takes several days to reach a stable plasma concentration, patients need to be monitored closely for efficacy and side effects. As methadone is a racemic mixture of a mu agonist and an N-methyl-d-aspartate (NMDA) antagonist (see later discussion), patients develop less analgesic tolerance. Patients must be made aware of the long duration of action of methadone, be warned not to take extra doses or mix it with other medications, and be familiar with signs of overdose.
PATIENT-CONTROLLED ANALGESIA BASICS
PCA is intended as maintenance therapy. If the patient is in moderate to severe pain when it is begun, IV loading doses must be given to achieve comfort, because the incremental dosing of the PCA will not be effective in a reasonable period of time. The use of a PCA helps overcome the wide interpatient variation in opioid requirements by allowing the patient to control the dosing regimen. Morphine is the most common first-line agent. It is not the best choice in patients with renal insufficiency, due to accumulation of the active metabolite. Fentanyl has a quicker onset and shorter duration of action than morphine. This decreases the likelihood of oversedation, but the patient must activate the PCA more often, making it difficult for some patients to sleep at night. Hydromorphone is generally more effective in opioid-tolerant patients and given its pharmacokinetics is an excellent choice for use in PCAs. Recommended starting doses in the opioid-naïve patient are listed in Table 48-12, along with suggestions for dose titration.
TABLE 48-12Suggested Starting Patient-Controlled Analgesia Dose and Dose Changes ||Download (.pdf) TABLE 48-12 Suggested Starting Patient-Controlled Analgesia Dose and Dose Changes
The lockout interval, or minimum time between doses, is typically set at 5 to 10 minutes. Even though the time to peak effect may be longer than this, in practice no major differences are seen with longer lockouts. There have also been no good studies to suggest that a particular lockout interval is better than any other.
A basal rate on the PCA may be needed in opioid-tolerant patients or in patients receiving fentanyl, given its short half-life. Basal rates are not recommended in the opioid-naïve, elderly, or patients with obstructive sleep apnea or morbid obesity. Some people advocate use of basal rates at night however this is not recommended as there is no data that basal rates help patients get more sleep at night, pain scores are not improved and the risk of respiratory depression is increased. Basal rates should be decreased or discontinued if a patient is not activating the PCA, or if the patient is becoming excessively sedated.
COMPLICATIONS/OPIOID-INDUCED SIDE EFFECTS
Nausea, vomiting, pruritus, constipation, sedation, and respiratory depression are common opioid-related side effects. They occur more often in opioid-naïve patients, as tolerance eventually develops to all these effects, except constipation. Adverse effects can be ameliorated by changing the drug dose or schedule, switching to a different agent (side effects of different opioid agonists vary among patients), using specific therapy to counteract the side effect, or adding another analgesic or adjuvant to allow a lower opioid dose.
Constipation should always be expected with opioids. Prophylactic use of stool softeners, such as docusate, and stimulant laxatives, such as senna preparations, is recommended. Nausea and vomiting can be treated with any of the available agents (eg, prochlorperazine, ondansetron, metoclopramide, and promethazine), as none has been shown to be more or less effective. Metoclopramide is a promotility agent with limited antinausea effects and is most effective if there is vomiting. Promethazine or possibly a scopolamine patch (especially if used before the symptoms onset) may be effective if the patient has a history of motion sickness, or if nausea is provoked by movement, as opioids sensitize the inner ear labyrinthine system. Extreme caution must be used with promethazine because of its possibility to cause severe tissue damage if extravasation occurs. Pruritus is thought to be a central mu opioid receptor-related phenomenon. Diphenhydramine is only effective if the etiology is definitely due to histamine release, which is usually only the case for large doses of morphine given quickly, or a true allergic reaction. Nalbuphine 5 mg IV every 4 hours as needed is more effective in that it treats the cause, by antagonism of the central mu receptors. Sedation may be a troublesome side effect, particularly when using opiates to alleviate persistent pain in terminal illness. The proper treatment of respiratory depression from opioid agonists is described in Table 48-13.
TABLE 48-13Treatment of Suspected Opioid-Induced Respiratory Depression ||Download (.pdf) TABLE 48-13 Treatment of Suspected Opioid-Induced Respiratory Depression
Suggested definition of respiratory depression
Primary, nonpharmacologic treatments of respiratory depression
Naloxone should only be considered in the following situations
Proper naloxone dilution and dosing
1 ampule (0.4 mg) of naloxone must be diluted with 9 mL saline to yield 0.04 mg/mL.
Administer to patient in 1-2 mL increments (0.04-0.08 mg) at 2-3 min intervals until response.
If no change in respiratory depression after 0.4 mg naloxone has been titrated, consider another etiology other than opioid induced.
If there is some, but not enough, improvement after 0.4 mg of naloxone has been titrated, continue titration.
Naloxone’s half-life is less than most of the opioid agonists, so be aware that rebound respiratory depression may recur. Therefore, be prepared for the need to readminister naloxone boluses or consider use of a naloxone infusion.
Adjunctive agents are useful for additional analgesia especially in opioid-tolerant patients, and have a particular role in the treatment of neuropathic symptoms and chronic pain. Examples of adjuvant analgesics with dosing guidelines and common side effects are listed in Table 48-14.
TABLE 48-14Select Adjuvant Analgesics ||Download (.pdf) TABLE 48-14 Select Adjuvant Analgesics
|Class ||Agent ||Adult Dosing ||Side Effects/Comments |
|Antiepileptics ||Gabapentin ||Start with 300 mg orally every 8 h, increase by 300 mg daily after a few days to a max of 3600 mg/d in divided doses ||Dizziness and somnolence; do not stop abruptly |
| ||Pregabalin ||Start with 50 mg orally every 8 h or 75 mg orally every 12 h; in 1 wk increase to max of 300 mg/d in divided doses |
|Tricyclic antidepressants || |
|25 mg orally every night at bed time; increase to max of 150 mg/d in a single or divided doses ||Anticholinergic symptoms (eg, dry mouth, confusion, sedation, and hypotension) |
|Local anesthetics ||Lidocaine 2.5% and prilocaine 2.5% cream ||2-2.5 g per 10-25 cm2 skin for 1-2 h before procedure ||Localized skin reactions; rare cardiovascular and/or CNS toxicity; prilocaine may contribute to methemoglobinemia in patients treated with other agents known to cause this |
| ||Lidocaine patch 5% ||Up to three patches for up to 12 h within a 24-h period ||Localized skin reactions; rare cardiovascular and/or CNS toxicity; only FDA indication is for treatment of postherpetic neuralgia |
|Glucocorticoids ||Dexamethasone ||4-8 mg orally every 8-12 h ||Typical steroid-induced side effects from long-term use (>2-3 mo) usually outweigh benefits; concomitant use with NSAIDs not recommended |
|Skeletal muscle relaxants ||Cyclobenzaprine ||5-10 mg orally every 8 h ||Long-term use can lead to the development of dependence |
| ||Tizanidine ||4-8 mg orally every 6-24 h |
| ||Orphenadrine || |
100 mg orally every 12 h
60 mg IV every 12 h
|Antispasmodic ||Baclofen ||10 mg orally every 8 h, titrate slowly to max of 80 mg/d in divided doses ||Drowsiness; may impair renal function; abrupt discontinuation may cause seizures |
|NMDA antagonists ||Ketamine ||0.1-0.2 mg/kg/h IV ||Sedation, dreams, and hallucinations possible but infrequent at analgesic (low) dose, treat with the addition of benzodiazepine or dose-reduction |
| ||Dextromethorphan ||Start with 30-90 mg orally every 8 h, increase to max of 360 mg/d in divided doses ||Best dose and regimen not well defined |
|Alpha-2 agonist ||Clonidine ||0.2 mg/d via a transdermal patch, left on for 1 wk ||Hypotension and sedation; monitor for rebound hypertension on discontinuation if used for >1 wk |
The most commonly used antiepileptic agents are gabapentin and pregabalin. They are effective for neuropathic pain and may have benefits in the acute setting as well. Antidepressants are also effective in neuropathic pain. Analgesic doses are lower than those for depression treatment, and the onset of analgesia is faster (days) than the antidepressant effects (weeks). Skeletal muscle relaxants are useful for muscle injury or spasms. The antispasmodic baclofen is useful for the treatment of pain with a spastic component or in certain neuropathic pain states. Antagonism of the NMDA receptor has no primary analgesic effect, but it has opioid-sparing, opioid tolerance-reversing, and antihyperalgesic effects. Ketamine, in addition to being an NMDA antagonist, interacts with opioid and other receptors, and thus it has true analgesic properties in addition to the NMDA class effects. Ketamine use improves pain scores and has an opioid-sparing effect of up to 50% although there are equivocal benefits in reduction of opioid side effects. The alpha-2 agonist, clonidine, has analgesic and opioid-sparing effects. Dexmedetomidine has documented opioid-sparing effects when given by IV infusion. It may have analgesic effects as well, although this effect may only occur at sedating doses, restricting its use to sedated intensive care patients. Glucocorticoids are used in cancer pain management to reduce inflammation from tumor invasion of nerves.
Benzodiazepines may reduce the insomnia and anxiety that often accompany acute pain. However, these agents do not have analgesic properties. They must be used with extreme caution in acute pain, especially when high doses of opioids are required, as significant sedation and respiratory depression can occur in the benzodiazepine-naïve patient. In the anxious patient with pain, adequate titration with analgesics should occur before the addition of a benzodiazepine.
ACUTE PAIN IN THE OPIOID TOLERANT
When opioid-tolerant patients experience an event resulting in pain escalation, opioid use is expected to be higher than mere replacement of what the patient was receiving before. The additional doses of opioids required may be much higher than in opioid-naïve patients. More complaints of pain and high pain scores should be expected. Discussion of reasonable goals and expectations of analgesic therapy with the patient is crucial. Multimodal therapy in this patient population is helpful to achieve the best pain control, and have the least escalation of home opioid dose as possible.
Involvement of a pain specialist may be appropriate in the patient with severe pain that remains uncontrolled after several escalations of drug doses and use of multiple classes of agents. Concomitant psychiatric illness may warrant input from a psychiatrist or psychologist. Certain diagnostic tests, such as diagnostic epidural injections, require an interventional pain physician. Physical therapy, surgery, complementary therapies, or invasive treatment modalities, such as epidural injections, intrathecal pumps, and spinal cord stimulators, will require referral to the appropriate provider.
Communication with the patient’s primary care provider about the discharge analgesic plan is essential, especially if the prior analgesic regimen has been changed. Follow-up should be arranged to ensure effectiveness of the analgesic regimen, monitor for side effects after discharge, and taper the patient off analgesics, or reduce doses to baseline if the patient was on chronic analgesics before.
If the cause of pain is gone, patients need discontinuation of opioids in a manner that prevents the occurrence of withdrawal symptoms, such as abdominal pain, diarrhea, tachycardia, vomiting, diaphoresis, runny nose, muscle cramps, piloerection, anxiety, and irritability. When weaning a patient from long-acting agents, the dose of the long-acting agent should be decreased by 25% to 50% every 2 days. Once the patient is off the sustained-release form, the immediate-release agent can also be weaned. In weaning a patient from immediate-release agents, the opioid dose should be reduced by 50% for 2 days, and then reduced by 25% every 2 days thereafter until the total dose in oral morphine equivalents is 30 mg/d. The drug may be discontinued after 2 days on the 30 mg/d dose.
Data on pain management quality should be collected periodically to assess the quality of care, to establish baseline data, and to identify areas in which care can be improved. The American Pain Society has proposed the following six quality indicators for hospital-based pain management: (1) pain intensity is documented with a numeric or descriptive rating scale; (2) pain intensity is documented frequently; (3) pain is treated by a route other than intramuscular; (4) pain is treated with regularly administered analgesics, and whenever possible, a multimodal approach is used; (5) pain is prevented and controlled to a degree that facilitates function and quality of life; and (6) patients are involved in the treatment plan and are informed and knowledgeable about pain management.
American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, 6th ed. Glenview, IL: American Pain Society; 2008.
SD, eds. Pain Control in the Primary Care Setting. Glenview, IL: American Pain Society; 2006.
United States Food and Drug Administration/Center for Drug Evaluation and Research website. http://www.fda.gov/Drugs/
. Accessed May 26, 2015.