Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

44. Pain Management

Terry J. Baumann, Chris M. Herndon, and Jennifer M. Strickland


 Images It is important, whenever possible, to ask patients if they have pain, to identify the source of pain, and to assess the characteristics of the pain.

 Images Doses must be individualized for each patient and administered for an adequate duration of time. Around-the-clock regimens should be considered for acute and chronic pain. As-needed regimens should be used for breakthrough pain or when acute pain displays wide variability and/or has subsided greatly.

 Images For chronic pain that has a neuropathic component, anticonvulsants, topical analgesics, tricyclic antidepressants, serotonin–norepinephrine reuptake inhibitors, and opioids should be considered based on evidence-based recommendations when available.

 Images Oral analgesics are preferred over other dosage forms whenever feasible, but it is important to adjust the route of administration to the needs of the patient.

 Images Equianalgesic doses are useful as a guide when converting from one agent to another, but further dose titration usually is required to achieve treatment goals.

 Images Patients taking analgesics should be monitored for response and side effects, particularly sedation and constipation associated with the opioids.

 Images Care should be taken to identify and avoid potential drug–drug interactions with analgesics when possible, as increased adverse effects may occur (e.g., opioids and benzodiazepines).

 Images Whenever possible, a multidisciplinary approach and nonpharmacologic strategies should be used.

 Images Etiology of pain may not always be identifiable.

If we know that pain and suffering can be alleviated, and do nothing about it, then we ourselves, become the tormentors.

Primo Levi1

Humans have always known and sought relief from pain.2 Today, pain’s impact on society still is great, and indeed pain complaints remain a primary reason patients seek medical advice.3

Regrettably, many healthcare providers do not receive adequate training in this area, and new information is not widely disseminated and/or understood. Clearly, pain management is enhanced when a multidisciplinary approach is applied. Thus, understanding the pathophysiology of pain therapy and maintaining a working knowledge of pain regimens are important factors in addressing pain control.


The accepted current definition of pain is: “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”4 Pain often is so subjective, however, that many clinicians define pain as whatever the patient says it is. The best care is achieved when the patient comes first.


Data presented in the recently released Institute of Medicine report, “Relieving Pain in America” suggests that greater than 100 million persons in the United States live with chronic pain.5 Given that greater than 50% of persons with low back pain in the previous 3 months reported interference with basic and complex activity, it is not surprising that the estimated economic burden of just chronic pain alone exceeds 500 billion dollars (US) annually.5 In 1 year, an estimated 25 million Americans will experience acute pain due to injury or surgery, and one third of Americans will experience severe chronic pain at some point in their lives.3 Unfortunately, despite much public attention, considerable focused education, and a number of consensus guidelines, pain often remains inadequately or inappropriately treated.3,510


The pathophysiology of pain involves a complex array of neural networks in the brain that are acted on by afferent stimuli to produce the experience we know as pain. It can be physiologic and protective (nociceptive) or pathophysiologic and harmful (e.g., neuropathic).11

Nociceptive Pain

Nociceptive pain, which can be considered protective and physiologic,11 typically is classified as either somatic (arising from skin, bone, joint, muscle, or connective tissue) or visceral (arising from internal organs such as the large intestine or pancreas).11 Whereas somatic pain often presents as throbbing and well localized, visceral pain can manifest as pain feeling as if it is coming from other structures (referred) or as a more localized phenomenon.11 We can think of nociception in terms of transduction, transmission, perception, and modulation.11


The first step leading to the sensation of pain is stimulation of free nerve endings known as nociceptors. These receptors are found in both somatic and visceral structures. They distinguish between noxious and innocuous stimuli, and they are activated and sensitized by mechanical, thermal, and chemical impulses.11 The underlying mechanism of these noxious stimuli (which in and of themselves may sensitize/stimulate the receptor) may be the release/activation of bradykinins, nerve growth factor, prostaglandins, histamine, interleukins, tumor necrosis factor α, serotonin, and substance P (among others) that sensitize and/or activate the nociceptors.11,12 Receptor activation (which also involves voltage-gated sodium channels) leads to action potentials that are transmitted along afferent nerve fibers to the spinal cord11,12 (Fig. 44-1).


FIGURE 44-1 Schematic representation of nociceptive pain. (Used with permission from, Pasero C, Portenoy R. Neurophysiology of pain and analgesia and the pathophysiology of neuropathic pain. In: McCaffery M, Pasero C, eds. Pain Assessment and Pharmacologic Management. St. Louis: Mosby, 2011:4–5, Figure 1-2.)


Nociceptive transmission takes place in A-δ and C-afferent nerve fibers.11 Stimulation of large-diameter, sparsely myelinated A-δ fibers evokes sharp, well-localized pain, whereas stimulation of unmyelinated, small-diameter C fibers produces aching, poorly localized pain.11

These afferent, nociceptive pain fibers synapse in various layers (laminae) of the spinal cord’s dorsal horn, releasing a variety of neurotransmitters, including glutamate, substance P, and aspartate.13 The complex array of events that influence pain can be explained in part by the interactions between neuroreceptors and neurotransmitters that take place in this synapse. For example, by stimulating sensory myelinated fibers that intraconnect in the dorsal horn with pain fibers, nonnoxious stimuli can have an inhibitory effect on pain transmission. These pain-initiated processes reach the brain through a complex array of ascending spinal cord pathways, which include the spinothalamic tract.13 Information other than pain is also carried along these pathways. Thus, pain is influenced by many factors supplemental to nociception and precludes simple schematic representation. It is postulated that the thalamus acts as a relay station, as these pathways ascend and pass the impulses to central structures where pain can be processed further.14


At this point in transmission, pain is thought to become a conscious experience that takes place in higher cortical structures. The physiology surrounding perception is complex and not well understood, but we know cognitive and behavioral functions can modify pain. Thus relaxation, distraction, meditation, and guided mental imagery may strongly influence pain perception11 and decrease pain. In contrast, a change in our neurobiochemical makeup that results in states such as depression or anxiety may worsen pain.


The body modulates pain through a number of complex processes. One, known as the endogenous opiate system, consists of neurotransmitters (e.g., enkephalins, dynorphins, and β-endorphins) and receptors (e.g., μδ, and κ) that are found throughout the central and peripheral nervous system (CNS and PNS).11,15 Like exogenous opioids, endogenous peptides bind to opioid receptor sites and modulate the transmission of pain impulses.11 Other receptor types also can influence this system. Blockade of N-methyl-D-aspartate (NMDA) receptors, found in the dorsal horn, may increase the μ-receptors’ responsiveness to opiates.15

The CNS also contains a highly organized descending system for the control of pain transmission. This system, which at least partially originates in the periaqueductal gray region of the midbrain, can inhibit synaptic pain transmission at the dorsal horn via modulation of the raphe nuclei in the brainstem.11,16 Important neurotransmitters here include endogenous opioids, serotonin, norepinephrine, and γ-aminobutyric acid (GABA).11,16

Pathophysiologic Pain

Pathophysiologic pain is distinctly different from nociceptive pain in that it becomes disengaged from noxious stimuli or healing11 and often is described in terms of chronic pain. This type of pain is a result of damage or abnormal functioning of the PNS and/or CNS.11 A number of pain syndromes (e.g., postherpetic neuralgia, diabetic neuropathy, fibromyalgia, irritable bowel syndrome, sympathetic induced pain, chronic headaches, and some noncardiac chest pain) fall into this category. These pain syndromes are often under-recognized and difficult to treat. In addition, the pain reported often is not commensurate with physical exam findings or imaging results.

The mechanism responsible for pain of this nature may be the nervous system’s endogenous dynamic nature. Nerve damage or certain disease states evoke both peripheral (e.g., alteration in nociceptive nerve fibers sensitivity, alterations in sodium channels, collateral sprouting of nerve fibers) and central (e.g., hyperexcitability of central neurons or central sensitization, NMDA receptor activation, central disinhibition) mechanisms leading to these changes.11,17 Pain circuits rewire themselves both anatomically and biochemically.18 This produces a mismatch between pain stimulation and inhibition and a potential progressive increase in the discharge of dorsal horn neurons.18

Clinically, patients present with episodic or continuous pain transmission (often described as burning, tingling, shock like, or shooting) exaggerated painful response to normally noxious stimuli (hyperalgesia), and/or painful response to normally nonnoxious stimuli (allodynia).3,18 This change over time may help to explain why this type of pain often manifests long after the actual nerve-related injury or when no actual injury is identified.


It is helpful in understanding pain to subdivide the presenting symptoms into acute pain, chronic pain, and cancer pain.

Acute Pain

Acute pain can be a useful physiologic process, warning individuals of disease states and potentially harmful situations. Unfortunately, severe, unremitting, undertreated acute pain, when it outlives its biologic usefulness, can produce many deleterious effects. Aside from unnecessary suffering, untreated and undertreated acute pain has also been shown to increase one’s risk for the development of chronic pain syndromes.19 Acute pain is usually nociceptive in nature with common causes, including surgery, acute illness, trauma, labor, and medical procedures.3

Chronic Pain

Under normal conditions, acute pain subsides quickly as the healing process decreases the pain-producing stimuli; however, in some instances, pain persists for months to years, leading to a chronic pathophysiologic pain state with features quite different from those of acute pain (Table 44-1).3 Chronic pain can be classified as either being associated with cancer (cancer pain) or from noncancer etiologies (chronic noncancer pain). It often is a result of changes to nerve function and transmission thus making treatment difficult.20

TABLE 44-1 Characteristics of Acute and Chronic Pain


Cancer Pain

Pain associated with potentially life-threatening conditions is often called malignant pain or in the case of cancer, cancer pain.3 This type of pain includes both chronic and acute (e.g., breakthrough pain) components and often has multiple etiologies. It is pain caused by the disease itself (e.g., tumor invasion, organ obstruction), treatment (e.g., chemotherapy, radiation, and surgical incisions), or diagnostic procedures (e.g., biopsy).3


A patient-oriented approach is essential, and evaluation methods should not differ from those used in other medical conditions.21

Images Therefore, a comprehensive history and physical examination are imperative to evaluate underlying diseases and possible other contributing factors.2 This includes asking if the patient has pain and identifying the source of pain when possible, however, the absence of a discreet etiology should not preclude pain treatment.2 A baseline characterization of pain can be obtained by assessing the attributes outlined in Table 44-2.22

TABLE 44-2 Pain Attributes



Acute Pain


    • Obvious distress (e.g., trauma), infants may present with changes in feeding habits, increased fussiness. Those with dementia may exhibit changes in eating habits, increased agitation, calling out. Attention also must be given to mental/emotional factors that alter the pain threshold. Anxiety, depression, fatigue, anger, and fear in particular, are noted to lower this threshold, whereas rest, mood elevation, sympathy, diversion, and understanding raise the pain threshold


    • Can be described as sharp, dull, shock like, tingling, shooting, radiating, fluctuating in intensity, and varying in location (these occur in a timely relationship with an obvious noxious stimuli)


    • Hypertension, tachycardia, diaphoresis, mydriasis, and pallor, but these signs are not diagnostic

    • In some cases there are no obvious physical signs

    • Comorbid conditions usually not present

    • Outcome of treatment generally predictable

Laboratory Tests

    • Pain is always subjective

    • There are no specific laboratory tests for pain

    • Pain is best diagnosed based on patient description and history

Chronic Pain


    • Can appear to have no noticeable suffering. Attention also must be given to mental/emotional factors that alter the pain threshold. Anxiety, depression, fatigue, anger, and fear in particular, are noted to lower this threshold; whereas rest, mood elevation, sympathy, diversion, and understanding raise the pain threshold


    • Can be described as sharp, dull, shock-like, tingling, shooting, radiating, fluctuating in intensity, and varying in location (these often occur without a temporal relationship with an obvious noxious stimuli)

    • Over time, the pain stimulus may cause symptoms that completely change (e.g., sharp to dull, obvious to vague).


    • Hypertension, tachycardia, diaphoresis, mydriasis, and pallor are seldom present

    • In most cases there are no obvious signs

    • Comorbid conditions often present (e.g., insomnia, depression, and anxiety)

    • Outcome of treatment often unpredictable

Laboratory Tests

    • Pain is always subjective

    • Pain is best diagnosed based on patient description and history

    • There are no specific laboratory tests for pain; however, history and/or diagnostic proof of past trauma (e.g., computed tomography) may be helpful in diagnosing etiology. General labs that may be considered include vitamin D, thyroid stimulating hormone (generalized or widespread pain), and B12 (neuropathic pain)

Data from Twycross,22 American Pain Society,29 Huang et al.,64 Hagen et al.,65 Matoushek et al.,66 Okumus et al.,67 and Porche.72


Desired pain management outcomes include both nonpharmacologic and pharmacologic strategies.

Desired Outcomes

The primary goal of pain treatment depends on the type of pain present and should be tailored to individual patients and circumstances.Images Images For example, in acute pain, rapid pain relief or reduction in pain intensity is usually the desired target. In comparison, the goal in chronic noncancer pain is to improve or maintain the patient’s level of day-to-day functioning, decrease the rate of physical deterioration, decrease pain perception, improve the patient’s sense of well-being, improve family and social relationships, and decrease dependency on drug therapy.2 And finally in cancer pain or other forms of malignant pain, the goal is to provide patients with adequate pain relief that allows them to tolerate diagnostic and therapeutic manipulation and permit the patient to function at a level that will allow freedom of movement and choice.23

Nonpharmacologic Therapy

Various nonpharmacologic therapies have been found to be beneficial in the management of acute and chronic pain, including physical manipulation, application of heat or cold, massage, biofeedback, cognitive behavioral therapy, relaxation, acupuncture, and exercise.2426 Spinal cord stimulators have also been found to be somewhat beneficial in some chronic pain conditions.27

Some commonly used nonpharmacologic therapies, including TENS (transcutaneous electrical nerve stimulation) and lumbar supports in back pain, have limited evidence or have been shown to be ineffective in the management of chronic pain.26

Simple interventions (e.g., education or introductory information about expected discomfort or pain after certain procedures) reduce patient distress and greatly reduce postprocedure suffering.28 Some psychological techniques, including cognitive-behavioral therapy, relaxation training, imagery, and hypnosis, have proven effective in numerous types of pain, including postprocedure pain, low back pain, and cancer-related pain.23,25,26,28 Nonpharmacologic therapies should be considered when possible.

Pharmacologic Treatment

Pharmacologic treatment is often considered the cornerstone of pain management.

Nonopioid Agents

Analgesia should be initiated with the most effective analgesic agent having the fewest side effects. Acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) often are preferred first-line therapies, in the treatment of mild-to-moderate pain (Table 44-3). The exact mechanism of acetaminophen is not completely understood. NSAIDs inhibit formation of varying prostaglandins produced in response to noxious stimuli, thereby decreasing the pain impulses received by the CNS.29 Acetaminophen is indicated as a first-line therapy in some pain-related disease states, such as osteoarthritis. NSAIDs may be particularly useful in the management of cancer-related bone pain and for short-term relief in the management of chronic low back pain.23,30

TABLE 44-3 Adult FDA-Approved Nonopioid Analgesics



Studies comparing the efficacy of individual NSAIDs have failed to identify greater efficacy of any NSAID compared to any other. Therefore, the choice of a particular agent often depends on availability, cost, pharmacokinetics, pharmacologic characteristics, and the side-effect profile. Because of the large interpatient variability in response to individual NSAIDs, it is considered rational therapy to switch to another member of this class if there is inadequate response after a sufficient therapeutic trial of any single agent.29 The duration of a sufficient trial has not been well defined; however, typically, a NSAID should be continued for a minimum of 1 month prior to evaluating the need to switch agents. Chronic use of NSAIDs, including selective inhibitors of cyclooxygenase 2 (COX-2 inhibitors), may be limited by adverse effects, including GI, renal, and cardiac effects. Topical NSAIDs may offer similar efficacy as oral NSAIDs in some patients with improved safety and tolerability.31 Patient selection is critical to ensure optimal benefit from NSAID therapy while minimizing potential adverse effects.

Opioid Agents

Opioids are often the next logical step in the management of acute pain and cancer-related chronic pain. They also may be an effective treatment option in the management of chronic noncancer pain; however, this continues to be somewhat controversial. Many times a trial of opioids is warranted, but such a trial should not be done without a complete assessment of the pain complaint, including an assessment of the patient’s functionality and risk factors for opioid misuse and abuse.32

The classification of these agents, their equianalgesic doses, relative histamine-releasing characteristics, pharmacokinetics, and dosing guidelines are outlined in Tables 44-4 and 44-5. Opioid choice should be based on patient acceptance; analgesic effectiveness; and pharmacokinetic, pharmacodynamic, and side-effect profiles (Tables 44-4 and 44-6).

TABLE 44-4 Opioid Analgesics, Central Analgesics, Opioid Antagonist


TABLE 44-5 Dosing Guidelines



TABLE 44-6 Analgesic Drug Monitoring


The pharmacologic activity of opioids depends on their affinity for and action at central and peripheral opiate receptors.33 Therapeutic activities and side effects range from those exhibited by the opiate agonists (e.g., morphine) to those seen with the opiate antagonists (e.g., naloxone). Partial agonists and antagonists (e.g., nalbuphine) compete with agonists for opiate receptor sites and, depending on the inherent agonist and antagonist properties, exhibit mixed agonist–antagonist activity.33 This may result in analgesia with fewer undesirable side effects. Efficacy and side effects also may further differ among agents because of receptor subtype variability.34 This μ-receptor subtype variability may explain why some patients respond differently to certain opioids, specifically μ-receptor agonists.34

The effects of the opioid analgesics are relatively selective, and at normal therapeutic concentrations, do not affect other sensory modalities.33 While sensations of touch and proprioception are preserved; undesirable side effects may increase as the dose is escalated (Table 44-6).33 Patients in severe pain may receive high doses of opioids with no unwanted side effects, but as the pain subsides, even very low doses may not be tolerated.35 Frequently, when opioids are administered, pain is not eliminated, but its unpleasantness is decreased.33 Patients report that although their pain is still present, it no longer bothers them.

Opioids share related pharmacologic attributes and exert a profound effect on the CNS and GI tract.33 Mood changes, sedation, nausea, vomiting, decreased GI motility, constipation, respiratory depression, dependence, and tolerance are evident in varying degrees with all agents.3,33 Tolerance to side effects (except to constipation) often develops over time.3 Some differences exist between the opioids in regards to incidence of side effects, which may assist in selection of the most appropriate agent. Images The route of administration depends on individual patient needs, with the oral route being preferred. However, the onset of analgesic effects for oral medications is approximately 45 minutes, and the peak effect usually occurs 1 to 2 hours after administration.29 This delay must be a consideration when immediate relief is needed in the management of acute pain. Therefore, in some scenarios, such as acute severe pain (e.g., pain crisis) or when the patient is unable to take oral medications, alternative routes of therapy (e.g., IV) may be preferred. The relative potency, defined by the equianalgesic dose, of opioids differs greatly (Table 44-4).Images Equianalgesic dose tables are often based on single-dose studies without regard for patient variability and should be used only as a guide.36

True opioid allergies are rare, but Table 44-4 also can be used when treating a patient who is allergic to opiates. Most reactions to opioids, such as itching or rash, are due to the associated histamine release from cutaneous mast cells, not a true allergic or immunoglobulin-E (IgE) or T-cell response.37 Although caution is always advised, a decrease in potential cross-sensitivity is thought to exist when moving from one opioid structural class to another.37 The classes are phenanthrenes (morphine-like agonists), phenylpiperidines (meperidine-like agonists), and diphenylheptanes (methadone-like agonists). When considering cross-sensitivity, the mixed agonist–antagonist and partial agonists class acts much like the morphine-like agonists.37

Images Images In the initial stages of acute pain, analgesics should be given around the clock. This should commence after administering a typical starting dose and titrating up or down, depending on the patient’s degree of pain and demonstrated side effects (e.g., sedation).29 As-needed schedules often produce wide swings in analgesic plasma concentrations that create wide swings in pain and sedation. This may initiate a vicious cycle where increasing amounts of pain medications are needed for relief.Images As the painful state subsides and the need for medication decreases, as-needed schedules may be appropriate. As-needed schedules also may be useful in patients who present with pain that is intermittent or sporadic in nature (Fig. 44-2). When opioids are used in the management of persistent chronic pain, around-the-clock administration schedules should be utilized. As-needed or prn opioids should be used in conjunction with around-the-clock regimens and when patients experience breakthrough pain. Breakthrough pain is a brief, transitory, exacerbation of moderate to severe pain typically occurring in patients with underlying persistent pain that may otherwise be controlled.36


FIGURE 44-2 Algorithm for acute pain. (Data modified from Omnicare, Inc., Acute Pain Pathway.)

Continuous IV methods of opioid infusion are effective for some postoperative pain, but the probability of unwanted side effects is high, and this technique should be reserved for opioid-tolerant patients.29 An alternative method is patient-controlled analgesia (PCA). With this technique, patients can self-administer a preset dose of an IV opioid via a pump electronically interfaced with a timing device. Compared with traditional as-needed opioid dosing, PCA yields better pain control, improved patient satisfaction, and relatively few differences in side effects.38,39

Administration of opioids directly into the CNS (e.g., epidural and intrathecal/subarachnoid routes) has shown considerable promise in the control of acute, chronic noncancer, and cancer pain (Table 44-7);33,40 and is common in both large and small institutions throughout the United States. Because of reports of respiratory depression, pruritus, nausea, vomiting, urinary retention, and hypotension,40 these methods of analgesia require careful monitoring and are best used by experienced practitioners. Respiratory depression is of concern and can occur within minutes with intrathecal fentanyl or manifest as late as 19 hours after a single dose of intrathecal morphine.40 Guidelines mandate respiratory monitoring for at least 24 hours after a single dose of intrathecal or epidural morphine with standing orders for naloxone (opioid antagonist) for full or partial reversal.41 Analgesia and side effects are evident at lower doses when opioids are administered intrathecally instead of epidurally. This form of analgesia is often administered as a continuous-infusion and/or on a patient-controlled basis. When given simultaneously with intrathecal or epidural local anesthetics such as bupivacaine, they have been proven safe and effective.40 All agents administered directly into the CNS should be preservative free.

TABLE 44-7 Intraspinal Opioids


Tolerance, Hyperalgesia, Physical Dependence, Addiction, and Pseudoaddiction A barrier that consistently causes clinicians to misjudge and mistreat pain is the misunderstanding of opioid tolerance, hyperalgesia, physical dependence, addiction, and pseudoaddiction. Tolerance is the reduction of drug effect over time as a result of exposure to the drug.35 It develops at different rates and with great patient variability. However, with stable disease, opioid use often stabilizes, and tolerance does not lead to addiction.35 Hyperalgesia is an increased sensitivity to pain secondary to increased opioid doses that can be seen with rapid opioid escalation or high dose administration.35 Opioid physical dependence is defined when an abstinence syndrome occurs following administration of an antagonist drug or abrupt dose reduction or discontinuation of an opioid.35 Clinicians must understand that physical dependence and tolerance are not equivalent to addiction; and with chronic opioid use, dependence is physiologic and is to be expected.29 Many definitions and classifications exist to describe the biopsychosocial phenomenon of addiction. While addiction represents a true neurological disorder characterized by changes in neurotransmitter expression, put simply this pattern of behaviors is typically characterized by ongoing substance use despite known harmful consequences to health or relationships (either professional or personal). Individually, these behaviors are often described as aberrant.35 When opioids are being used, these behaviors must be evaluated continually. However, caution is advised when using the term addiction because of its many negative connotations, which can lead to a compromised clinician–patient relationship and resulting ineffective pain control. Although, often very hard to diagnose, clinicians must be aware that an individual’s behaviors may suggest addiction, when in reality the behaviors noted are a reflection of unrelieved pain, this is termed pseudoaddiction.35 The incidence of addiction varies depending on the patient population. In patients with no history of addiction, the risk of addiction is relatively small.35 Higher risk for opioid misuse or abuse is associated with personal substance abuse, misuse, addiction, or diversion history, a significant family history of substance abuse, and underlying psychiatric diagnoses.32 Modifications, which should be stratified based on patient risk, include baseline and random drug screens, patient–provider treatment agreements, pill counts, a smaller prescription supply, and regular assessment of aberrant behaviors.32 Combining these approaches with regular and ongoing assessments of pain and functionality may result in improved outcomes.32

Morphine and Congeners Despite the availability of several newer agents, morphine remains the prototype opiate analgesic. As new opioid and nonopioid compounds are developed, their efficacy and side-effect profiles are typically compared against morphine as the standard. Many clinicians consider morphine the first-line agent when treating moderate-to-severe pain.

Side effects can be numerous, particularly when morphine is first initiated or when doses are significantly increased. Morphine causes nausea and vomiting through direct stimulation of the chemoreceptor trigger zone, decreased peristalsis, and probably through a vestibular mechanism.33 Opioid-induced nausea subsides over time.3 Although euphoria and dysphoria have been reported, morphine’s unpleasant effects are more prominent when administered to patients not experiencing pain.33 As doses of morphine are increased, the respiratory center becomes less responsive to carbon dioxide, causing progressive respiratory depression.33 This effect is less pronounced in patients being treated for severe or chronic pain.3 Respiratory depression often manifests as a decrease in respiratory rate (although minute volume and tidal exchange also are affected) and is further compounded because the cough reflex is also depressed.33 More recently, end-tidal capnography has become commonplace in larger institutions. Morphine-induced respiratory depression can be reversed by pure opioid antagonists, such as naloxone.33 In patients with underlying pulmonary dysfunction, caution must be used, as these patients are already using compensatory breathing mechanisms and are at risk for further respiratory compromise.33Images Caution is also urged when combining opiate analgesics with alcohol or other CNS depressants, because this combination is potentially harmful and possibly lethal.33

Therapeutic doses of morphine have minimal effects on blood pressure, cardiac rate, or cardiac rhythm when patients are supine; however, morphine does produce venous and arteriolar vessel dilation, and orthostatic hypotension may result. Hypovolemic patients are more susceptible to morphine-induced cardiovascular changes (e.g., decreases in blood pressure).33 Because morphine prompts a decrease in myocardial oxygen demand in ischemic cardiac patients,33 it can be used to treat pain associated with myocardial infarction.

Morphine decreases the propulsive contractions of the GI tract33 resulting in constipation. Morphine-induced spasms of the sphincter of Oddi have also been observed.33 However, the clinical significance of such an occurrence is unclear. Urinary retention is another potential side effect of morphine; tolerance develops to this effect over time.33 Morphine-induced histamine release often manifests as pruritus, and may even exacerbate bronchospasm in patients with a history of asthma.33 Therapeutic doses of morphine are not contraindicated in head injury, but drug-induced respiratory depression can increase intracranial pressure. Thus, caution is advised in head trauma patients who are not ventilated because morphine may exaggerate this pressure33 and cloud the neurologic examination results.

Morphine is metabolized to two major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).33 M6G contributes to analgesia, whereas M3G may contribute to side effects.33 The metabolites are renally cleared and can accumulate in patients with renal impairment, contributing to greater side effects.33 Morphine also affects the hypothalamus inhibiting the release of gonadotropin-releasing hormone, thus decreasing plasma testosterone and cortisol (opioid hypogonadism).33 Male patients may present with symptoms of erectile dysfunction, decreased libido, and decreased analgesic efficacy of the opioid. Women may experience alopecia, amenorrhea, depressed mood, and decreased analgesic efficacy. Recommendations for clinical replacement of these hormones in patients using chronic opioid therapy are not well defined.42 While the clinical meaning has not clearly been elucidated, morphine and other opioids, depending on the situation being used, may either enhance or inhibit the immune system.33

Hydromorphone is more potent than morphine, but its overall pharmacologic profile parallels that of morphine. Some clinicians believe hydromorphone is associated with fewer side effects, especially pruritus, compared with other opioids. However, the research is limited and does not conclusively demonstrate this difference. Oxymorphone can be administered orally and by injection. Although extended-release and immediate-release oral products are available, making oxymorphone useful in chronic and acute pain, it offers no pharmacologic advantage over morphine. Levorphanol has an extended half-life, but its overall therapeutic effects are similar to the other agents in this class.

Codeine is a commonly used opiate in the treatment of mild-to-moderate pain. It often is combined with other analgesic products (e.g., acetaminophen). Unfortunately, it has the same propensity to produce side effects as morphine. Hydrocodone is another commonly prescribed opiate and is available for pain only in combination products with other analgesic agents (e.g., acetaminophen, ibuprofen). Its pharmacologic properties are similar to those of morphine. Oxycodone is a useful oral analgesic for moderate-to-severe pain. This is especially true when the product is used in combination with nonopioids. Although oxycodone shares basic morphine characteristics, the availability of an immediate-release and controlled-release oral dosage form also makes it very useful in chronic pain as well as acute pain.

Meperidine and Congeners (Phenylpiperidines) The prototype phenylpiperidine, meperidine, has a pharmacologic profile comparable with that of morphine; however, it is not as potent and has a shorter analgesic duration. Meperidine offers no analgesic advantage over morphine, has greater toxicity (CNS hyperirritability caused by its renally eliminated metabolite normeperidine),43 and should be limited in use. In particular, avoid long-term usage and use in patients at greatest risk for toxicity (e.g., elderly patients and those with renal dysfunction).

Fentanyl is a synthetic opioid structurally related to meperidine that is used often in anesthesiology as an adjunct to general anesthesia.43 This agent is more potent and faster acting than meperidine (Table 44-4). It can be administered parenterally, transmucosally, sublingually, intranasally, and transdermally.

Methadone and Congeners Methadone has gained considerable popularity because of its oral efficacy, extended duration of action, and low cost. Although methadone is effective in acute pain,44 it has gained particular prominence in treating cancer pain32 and has increasingly been used in the management of chronic noncancer pain.32 This despite the fact that, it has an unpredictable half-life, it can cause excessive sedation, and it is difficult to titrate. Properties unique to methadone, compared with other opioids, include the D-isomer’s ability to antagonize NMDA receptors, agonist effects at κ- and δ-opioid receptors, and blockade of serotonin and norepinephrine reuptake.36,45 These properties may prove useful in the treatment of neuropathic and chronic pain. However, few trials have thoroughly evaluated methadone’s risks versus benefits.32 Epidemiologic studies suggest a growing number of methadone-related deaths, and cardiac arrhythmias have been associated with methadone, particularly at higher doses or when used concurrently with other agents that prolong QTc intervals.32 Recommendations exist for specific echocardiogram monitoring for methadone; however, concerns exist regarding their applicability.46 The equianalgesic dose of methadone may decrease with higher doses of the previous opioid,36 complicating conversions from other opioids to methadone.

Opioid Agonist–Antagonist Derivatives Analgesic agents that stimulate the analgesic portion of opioid receptors while blocking or having no effect on the toxicity portion would be considered ideal. The agonist–antagonist derivatives were developed with this in mind. This analgesic class produces analgesia and has the potential for less respiratory depression than opioid agonists.33 These agents are considered to have a lower abuse potential than morphine, but psychotomimetic responses (e.g., hallucinations and dysphoria, as seen with pentazocine), limited analgesic effect, and a propensity to initiate withdrawal in opioid-dependent populations29,33,44 have diminished their widespread clinical use.

Opioid Antagonists The opioid antagonist naloxone binds competitively to opioid receptors but does not produce an analgesic or opioid side-effect response. Therefore, it is used most often to reverse the toxic effects of agonist- and agonist–antagonist-derived opioids. Other opioid antagonists exist, including naltrexone and methylnaltrexone. Naltrexone’s use is primarily limited to addiction medicine, while methylnaltrexone is used for opioid-induced constipation.44

Central Analgesics

Tramadol and tapentadol are the only centrally acting analgesics currently available in the United States. Tramadol binds to μ-opiate receptors and inhibits norepinephrine and serotonin reuptake. Tapentadol also binds the μ-opiate receptor, but inhibits largely norepinephrine reuptake. Tramadol is indicated for the relief of moderate to moderately severe pain, while tapentadol is indicated for moderate-to-severe acute pain and diabetic peripheral neuropathy.44

Both tramadol and tapentadol have side-effect profiles similar to that of the previously mentioned opioid analgesics (e.g., dizziness, nausea, somnolence, and constipation).47,48 Tapentadol is a schedule II controlled substance, while tramadol is not scheduled federally, although it is a schedule IV in some states.47 Tapentadol has not been systematically evaluated in patients with seizures, and it should be used with caution in seizure patients.44 Seizure risk may be elevated in patients taking tramadol.44 Tramadol may have a place in treating patients with chronic pain, especially neuropathic pain,49 while tapentadol may be useful in the management of acute pain and when using the controlled release format in chronic pain44 (e.g., diabetes-related nerve pain).50

Adjuvant Analgesics

Adjuvant analgesics represent a diverse group of pharmacologic agents with individual characteristics that make them useful in the management of pain but that typically are not classified as analgesics. Examples of adjuvant analgesics include antidepressants and anticonvulsants. Images Chronic pain that has a neuropathic component (e.g., diabetic neuropathy) often requires adjuvant analgesic therapy (Table 44-8). Anticonvulsants (e.g., gabapentin, pregabalin, which may decrease neuronal excitability), tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitor antidepressants (e.g., nortriptyline, duloxetine—which block the reuptake of serotonin and norepinephrine, thus enhancing pain inhibition), and topically applied local anesthetics (which decrease nerve stimulation) all have demonstrated efficacy in managing various chronic pain conditions.49

TABLE 44-8 Pharmacologic Management of Chronic Noncancer Pain


In the management of cancer pain, radiopharmaceuticals (e.g., strontium-89 or samarium), corticosteroids, and bisphosphonates are useful adjuvant analgesics in treating bone pain.51 Although antihistamines and amphetamines have been used as adjuvant pain medications,23 they have demonstrated only limited success.

Multimodal Therapy

Multimodal therapy is the concomitant use of different therapeutic interventions with the intent of obtaining additive therapeutic effects. Multimodal analgesia, one type of multimodal therapy, includes combining medications from different classes (e.g., combination therapy with opioids and nonopioids or adjuvant analgesics).11 This often results in analgesia superior to that produced by either agent alone.11Multimodal analgesia may also permit the use of lower doses and provide a more favorable side-effect profile.11 Multimodal therapy is useful for the management of both acute and chronic pain.

Regional Analgesia

Regional analgesia with properly administered local anesthetics can provide relief of both acute and chronic pain (Table 44-9).3,40 These agents can be positioned by injection (e.g., in joints, in the epidural or intrathecal space, along nerve roots, or in a nerve plexus) or topically. Lidocaine in the form of a patch has proven effective in treating focal neuropathic pain.49 Regional application of local anesthetics relieve pain by blocking nerve impulses.44 High plasma concentrations can cause CNS excitation and depression, including dizziness, tinnitus, drowsiness, disorientation, muscle twitching, seizures, and respiratory arrest.43 Cardiovascular effects include myocardial depression, hypotension, decreased cardiac output, heart block, bradycardia, arrhythmias, and cardiac arrest.44 Disadvantages of such methods include the need for skillful technical application, need for frequent administration, and highly specialized followup procedures.

TABLE 44-9 Injectable Local Anestheticsa


Special Considerations in Acute Pain

Images Images Images Images Images The World Health Organization (WHO) recommends a three-step ladder approach using the simplest dosage schedules and medications with the least amount of potential harm based on pain intensity ratings from mild, to moderate, to severe.23 An acute pain algorithm outlining how to use these principles is given in Figure 44-2. The importance of reassessment and titration during this process cannot be overemphasized.28,52 Empiric or preemptive analgesia to prevent pain when anticipated should be considered particularly prior to procedures.39

Special Considerations in Cancer Pain

Managing the pain of cancer encompasses both acute and chronic management techniques.Images Thus, pharmacologic treatment and psychological therapies are best combined with surgical methods, anesthetic procedures, and supportive care measures in a multidisciplinary approach to pain relief. Assessment of the factors given in Table 44-2 also applies to cancer patients. Special attention must be given to continual reassessment of the painful state, adverse effects with medications, and aberrant behaviors.Images Individualization of therapy is always required.23,29,53 Supportive care, in and outside the hospital, using programs such as hospice is one of the cancer patient’s greatest allies, not only in coping with pain but also in accepting the disease. The positive effect this has on the patient cannot be overstated. Pharmacologic management is the mainstay of therapy, and a typical progression of analgesic use in oncology patients is outlined in Figure 44-3.


FIGURE 44-3 Algorithm for pain management in oncology patients. (Data modified from the Kaiser Permanente Algorithm for Pain Management in Patients with Advanced Malignant Disease).

Special Considerations in Chronic Noncancer Pain

Images Chronic noncancer pain is complex and therapeutic management should be multidisciplinary. Evaluation objectives include establishing an accurate diagnosis, identifying iatrogenic factors, obtaining a comprehensive psychiatric and psychosocial assessment, paying special attention to family and social problems, obtaining a description of factors that alleviate or exacerbate pain, and establishing effective goals of therapy.2Images In many cases the exact etiology of pain may not always be identifiable. Images In all cases of chronic noncancer pain, an integrated systematic approach (such as that often provided by specialty pain providers), with a strong emphasis on patient–clinician relationships, is essential. Patients and clinicians must realize that maximally effective treatment may take months or even years. The pharmacologic approach to common types of chronic noncancer pain is outlined in Table 44-8. Although opioids continue to be commonly utilized in the management of chronic noncancer pain and are often effective for individual patients, limited data have been published supporting long-term use of opioids. Thus, there is some debate regarding the benefit of chronic opioid therapy for chronic pain. However, when opioids are used, appropriate patient selection is critical to ensure optimal efficacy and minimal risks or negative outcomes. Steps should be taken to identify and manage risks prior to therapy and may include screening for risk of opioid misuse/abuse, utilizing treatment agreements that outline patient and provider expectations and responsibilities, and distinctly outlining the treatment plan with patients.32“Universal precautions” for pain management have been suggested as a method to standardize the assessment and ongoing management of chronic pain with opioids and incorporate many of these principles.54

Clinical Controversy…

Some clinicians believe that daily opioid doses in chronic noncancer patients should be limited because the risk of potential abuse and adverse effects may out-weigh the benefits. In fact, some guidelines have even incorporated recommendations to limit doses to less than 120 mg of morphine or its daily equivalent. Other clinicians believe by careful screening of patients for risks of abuse, frequent monitoring, identifying targeted pain symptoms, utilizing pain treatment “agreements,” and distinctly outlining the treatment plans with patients, opioids can be titrated to effect, based on symptoms with no defined maximum dose.

Special Populations

The elderly and the young are at a higher risk for under-treatment because of inability to communicate or rate their pain. It is in these cases that parent or caregiver input becomes paramount to identify changes in behavior which might suggest pain (e.g., fussy, inconsolable, changes in eating patterns, crying out, or agitation). When patients cannot verbalize their pain (e.g., coma), monitoring behaviors (e.g., agitation) and physiologic signs and symptoms (e.g., heart rate) is appropriate.

ImagesImages In addition, those living with chronic, debilitating, and life-threatening illnesses need specialized pain control and care that is palliative in nature.55 Although care must be taken in these populations to ensure that proper individualized treatment plans follow accepted guidelines,5558 the key concepts in pain management as outlined in this chapter are the guiding tenets in maximizing pain control.


Opioid and nonopioid analgesics do not typically lend themselves to serum level monitoring with the exception of select anticonvulsants. However, little correlation is evident between serum drug concentrations of anticonvulsants and analgesic efficacy.

While there is still much to learn, recent research has illustrated genetic differences in pain transmission and response interindividually as well as between genders, ages, and ethnicity. More interesting is the pharmacogenomic variability of analgesic response to both opioid and nonopioid analgesics. Qualitative genotyping (e.g., CYP 2D6, CYP 2B6) may be useful when considering the addition of an opioid metabolized via one of these enzymes. Codeine, oxycodone, hydrocodone, and methadone, among others, are all either converted to active or inactive metabolites via one of these enzyme pathways. Given that 1% to 3% of Caucasians and up to 30% of Asians possess the allele coding for reduced activity of these enzymes (poor metabolizer), genotyping prior to initiation may be prudent for these drugs and these individuals. Individuals who possess the allele coding for increased activity of these enzymes may also have unexpected outcomes, and genotyping may be useful to identify these patients. Genotype results may further help explain cases where patients require higher doses or have greater than expected toxicity. Future research may identify specific opioid-receptor subtype expression, which may lead to early identification of opioid analgesic response.59


Images Images Consistent monitoring for effectiveness (e.g., pain relief, adequate functionality) and adverse effects (e.g., sedation) is critical in optimizing therapeutic outcomes. Numerous validated scoring tools exist (e.g., numeric rating scale, visual analog scale, etc.);3,6062 however, the tools need to be appropriate for the type of pain being evaluated, and can be inadequate if not used consistently, or used without clinical judgment. Pain management efficacy, any change in pain, and medication side effects (e.g., opioid-induced sedation or constipation) must be assessed and reassessed on a regular basis. Frequency of reassessment should be dictated by the medication’s route of administration, duration of action, various pharmacokinetic factors, or other concomitant therapies. Postoperative pain and acute exacerbation of cancer pain may need to be assessed hourly, whereas chronic noncancer pain may require only daily or less frequent assessment. Pain intensity assessment is vital in acute pain, whereas functionality becomes more of an issue in chronic pain. Quality of life must be assessed on a regular basis in all patients. Many advocate using the four “A”s (analgesia, activity, aberrant drug behavior, and adverse effects) as key assessment measures for any patient with chronic pain.63

It is important to note that often objective signs are lacking for pain evaluation. Acute pain may result in increased sympathetic tone (e.g., hypertension, tachycardia, and tachypnea); however, this response is usually diminished as acute pain progresses to chronic pain. The clinician must rely on the patient’s description of their pain.29

Images All opioids can cause constipation. The best management of constipation is prevention. Patients should be counseled on the proper intake of fluids and fiber. A stimulating laxative should be added with chronic opioid use.Images CNS depressants (e.g., alcohol, benzodiazepines) amplify CNS depression when used with opioid analgesics, and use of these combinations should be discouraged when possible. When the combinations are used, patients should be monitored closely (Tables 44-5 and 44-6).

Clinical Controversy…

Some clinicians believe that opioid risk evaluation and mitigation strategies, which consist of mandatory care-giver enrollment, prescriber training, patient medication guides, and patient prescriber agreements, as outlined by the Federal Food and Drug Administration will decrease opioid misuse and lead to better patient care. Others feel this leads to increased costs and becomes a barrier to effective pain therapy.




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