93Pain: Pathophysiology and Management CHAPTER 13

largely preserving the individual’s ability to recognize noxious stimuli

as painful.

■ PAIN MODULATION

The pain produced by injuries of similar magnitude is remarkably variable in different situations and in different individuals. For example,

athletes have been known to sustain serious fractures with only minor

pain, and Beecher’s classic World War II survey revealed that many

soldiers in battle were unbothered by injuries that would have produced

agonizing pain in civilian patients. Furthermore, even the suggestion

that a treatment will relieve pain can have a significant analgesic effect

(the placebo effect). On the other hand, many patients find even minor

injuries such as venipuncture frightening and unbearable, and the

expectation of pain can induce pain even without a noxious stimulus.

The suggestion that pain will worsen following administration of an

inert substance can increase its perceived intensity (the nocebo effect).

The powerful effect of expectation and other psychological variables on the perceived intensity of pain is explained by brain circuits

that modulate the activity of the pain-transmission pathways. One of

these circuits has links to the hypothalamus, midbrain, and medulla,

and it selectively controls spinal pain-transmission neurons through a

descending pathway (Fig. 13-4).

Human brain-imaging studies have implicated this pain-modulating

circuit in the pain-relieving effect of attention, suggestion, and opioid

analgesic medications (Fig. 13-5). Furthermore, each of the component structures of the pathway contains opioid receptors and is

sensitive to the direct application of opioid drugs. In animals, lesions

of this descending modulatory system reduce the analgesic effect of

Anterolateral

tract axon

Skin

Viscus

FIGURE 13-3 The convergence-projection hypothesis of referred pain. According

to this hypothesis, visceral afferent nociceptors converge on the same painprojection neurons as the afferents from the somatic structures in which the pain

is perceived. The brain has no way of knowing the actual source of input and

mistakenly “projects” the sensation to the somatic structure.

Spinal

cord

Medulla

Midbrain

Spinothalamic

tract

Hypothalamus

A B

SS

Thalamus

C

F

Injury

FIGURE 13-4 Pain-transmission and 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 paintransmission cells via cells in the medulla.

FIGURE 13-5 Functional magnetic resonance imaging (fMRI) demonstrates

placebo-enhanced brain activity in anatomic regions correlating with the

opioidergic descending pain control system. Top panel: Frontal fMRI image shows

placebo-enhanced brain activity in the dorsal lateral prefrontal cortex (DLPFC).

Bottom panel: Sagittal fMRI images show placebo-enhanced responses in the

rostral anterior cingulate cortex (rACC), the rostral ventral medullae (RVM), the

periaqueductal gray (PAG) area, and the hypothalamus. The placebo-enhanced

activity in all areas was reduced by naloxone, demonstrating the link between the

descending opioidergic system and the placebo analgesic response. (F Eippert

et al: Activation of the opioidergic descending pain control system underlies placebo

analgesia. Neuron 63(4):533-543, 2009.)

94PART 2 Cardinal Manifestations and Presentation of Diseases

systemically administered opioids such as morphine. Along with the

opioid receptor, the component nuclei of this pain-modulating circuit

contain endogenous opioid peptides such as the enkephalins and

β-endorphin.

The most reliable way to activate this endogenous opioid-mediated

modulating system is by suggestion of pain relief or by intense emotion

directed away from the pain-causing injury (e.g., during severe threat

or an athletic competition). In fact, pain-relieving endogenous opioids

are released following surgical procedures and in patients given a placebo for pain relief.

Pain-modulating circuits can enhance as well as suppress pain.

Both pain-inhibiting and pain-facilitating neurons in the medulla

project to and control spinal pain-transmission neurons. Because paintransmission neurons can be activated by modulatory neurons, it is

theoretically possible to generate a pain signal with no peripheral noxious stimulus. In fact, human functional imaging studies have demonstrated increased activity in this circuit during migraine headaches. A

central circuit that facilitates pain could account for the finding that

pain can be induced by suggestion or enhanced by expectation and

provides a framework for understanding how psychological factors can

contribute to chronic pain.

■ NEUROPATHIC PAIN

Lesions of the peripheral or central nociceptive pathways typically

result in a loss or impairment of pain sensation. Paradoxically, damage

to or dysfunction of these pathways can also produce pain. For example, damage to peripheral nerves, as occurs in diabetic neuropathy, or

to primary afferents, as in herpes zoster infection, can result in pain

that is referred to the body region innervated by the damaged nerves.

Pain may also be produced by damage to the central nervous system

(CNS), for example, in some patients following trauma or vascular

injury to the spinal cord, brainstem, or thalamic areas that contain

central nociceptive pathways. Such pains are termed neuropathic and

are often severe and resistant to standard treatments for pain.

Neuropathic pain typically has an unusual burning, tingling, or electric shock-like quality and may occur spontaneously, without any stimulus, or be triggered by very light touch. These features are rare in other

types of pain. On examination, a sensory deficit is characteristically

co-extensive with the area of the patient’s pain. Hyperpathia, a greatly

exaggerated pain response to innocuous or mild nociceptive stimuli,

especially when applied repeatedly, is also characteristic of neuropathic

pain; patients often complain that the very lightest moving stimulus

evokes exquisite pain (allodynia). In this regard, it is of clinical interest

that a topical preparation of 5% lidocaine in patch form is effective for

patients with postherpetic neuralgia who have prominent allodynia.

A variety of mechanisms contribute to neuropathic pain. As with

sensitized primary afferent nociceptors, damaged primary afferents,

including nociceptors, become highly sensitive to mechanical stimulation and may generate impulses in the absence of stimulation.

Increased sensitivity and spontaneous activity are due, in part, to an

increased density of sodium channels in the damaged nerve fiber.

Damaged primary afferents may also develop sensitivity to norepinephrine. Interestingly, spinal cord pain-transmission neurons cut off

from their normal input may also become spontaneously active. Thus,

both central and peripheral nervous system hyperactivity contribute to

neuropathic pain.

Sympathetically Maintained Pain Patients with peripheral

nerve injury occasionally develop spontaneous pain in or beyond the

region innervated by the nerve. This pain is often described as having

a burning quality. The pain typically begins after a delay of hours to

days or even weeks and is accompanied by swelling of the extremity, periarticular bone loss, and arthritic changes in the distal joints.

Early in the course of the condition, the pain may be relieved by a

local anesthetic block of the sympathetic innervation to the affected

extremity. Damaged primary afferent nociceptors acquire adrenergic

sensitivity and can be activated by stimulation of the sympathetic outflow. This constellation of spontaneous pain and signs of sympathetic

dysfunction following injury has been termed complex regional pain

syndrome (CRPS). When this occurs after an identifiable nerve injury,

it is termed CRPS type II (also known as posttraumatic neuralgia or,

if severe, causalgia). When a similar clinical picture appears without

obvious nerve injury, it is termed CRPS type I (also known as reflex

sympathetic dystrophy). CRPS can be produced by a variety of injuries,

including fractures of bone, soft tissue trauma, myocardial infarction,

and stroke. CRPS type I typically resolves with symptomatic treatment;

however, when it persists, detailed examination often reveals evidence

of peripheral nerve injury. Although the pathophysiology of CRPS

is poorly understood, the pain and the signs of inflammation, when

acute, can be rapidly relieved by blocking the sympathetic nervous

system. This implies that sympathetic activity can activate undamaged nociceptors when inflammation is present. Signs of sympathetic

hyperactivity should be sought in patients with posttraumatic pain and

inflammation and no other obvious explanation.

TREATMENT

Acute Pain

The ideal treatment for any pain is to remove the cause; thus, while

treatment can be initiated immediately, efforts to establish the

underlying etiology should always proceed as treatment begins.

Sometimes, treating the underlying condition does not immediately

relieve pain. Furthermore, some conditions are so painful that rapid

and effective analgesia is essential (e.g., the postoperative state,

burns, trauma, cancer, or sickle cell crisis). Analgesic medications

are a first line of treatment in these cases, and all practitioners

should be familiar with their use.

ASPIRIN, ACETAMINOPHEN, AND NONSTEROIDAL

ANTI-INFLAMMATORY AGENTS (NSAIDS)

These drugs are considered together because they are used for

similar problems and may have a similar mechanism of action

(Table 13-1). All these compounds inhibit cyclooxygenase (COX),

and except for acetaminophen, all have anti-inflammatory actions,

especially at higher dosages. They are particularly effective for mild

to moderate headache and for pain of musculoskeletal origin.

Because they are effective for these common types of pain and

are available without prescription, COX inhibitors are by far the

most commonly used analgesics. They are absorbed well from the

gastrointestinal tract and, with occasional use, have only minimal side effects. With chronic use, gastric irritation is a common

side effect of aspirin and NSAIDs and is the problem that most

frequently limits the dose that can be given. Gastric irritation is

most severe with aspirin, which may cause erosion and ulceration

of the gastric mucosa leading to bleeding or perforation. Because

aspirin irreversibly acetylates platelet COX and thereby interferes

with coagulation of the blood, gastrointestinal bleeding is a particular risk. Older age and history of gastrointestinal disease increase

the risks of aspirin and NSAIDs. In addition to the well-known

gastrointestinal toxicity of NSAIDs, nephrotoxicity is a significant

problem for patients using these drugs on a chronic basis. Patients

at risk for renal insufficiency, particularly those with significant

contraction of their intravascular volume as occurs with chronic

diuretic use or acute hypovolemia, should avoid NSAIDs. NSAIDs

can also increase blood pressure in some individuals. Long-term

treatment with NSAIDs requires regular blood pressure monitoring

and treatment if necessary. Although toxic to the liver when taken

in high doses, acetaminophen rarely produces gastric irritation and

does not interfere with platelet function.

The introduction of parenteral forms of NSAIDs, ketorolac and

diclofenac, extends the usefulness of this class of compounds in

the management of acute severe pain. Both agents are sufficiently

potent and rapid in onset to supplant opioids as first-line treatment

for many patients with acute severe headache and musculoskeletal

pain.

There are two major classes of COX: COX-1 is constitutively

expressed, and COX-2 is induced in the inflammatory state.

95Pain: Pathophysiology and Management CHAPTER 13

GENERIC NAME PO DOSE, mg INTERVAL COMMENTS

Anticonvulsants and Antiarrythmicsa

Carbamazepine 200–300 q6h Rare aplastic anemia, GI irritation, hepatoitoxicity

Oxcarbamazepine 300 bid Similar to carbamazepine

Gabapentinb 600–1200 q8h Dizziness, GI irritation; useful in trigeminal neuralgia

Pregabalin 150–600 bid Similar to gabapentin; dry mouth, edema

a

Antidepressants, anticonvulsants, and antiarrhythmics have not been approved by the U.S. Food and Drug Administration (FDA) for the treatment of pain. b

Gabapentin in

doses up to 1800 mg/d is FDA approved for postherpetic neuralgia.

Abbreviations: 5-HT, serotonin; NE, norepinephrine; NSAID, nonsteroidal anti-inflammatory agent.

GENERIC NAME

UPTAKE BLOCKADE SEDATIVE

POTENCY

ANTICHOLINERGIC

POTENCY

ORTHOSTATIC

HYPOTENSION

CARDIAC

ARRHYTHMIA

AVERAGE DOSE,

mg/d

RANGE,

5-HT NE mg/d

Antidepressantsa

Doxepin ++ + High Moderate Moderate Less 200 75–400

Amitriptyline ++++ ++ High Highest Moderate Yes 150 25–300

Imipramine ++++ ++ Moderate Moderate High Yes 200 75–400

Nortriptyline +++ ++ Moderate Moderate Low Yes 100 40–150

Desipramine +++ ++++ Low Low Low Yes 150 50–300

Venlafaxine +++ ++ Low None None No 150 75–400

Duloxetine +++ +++ Low None None No 40 30–60

TABLE 13-1 Drugs for Relief of Pain

GENERIC NAME DOSE, mg INTERVAL COMMENTS

Nonnarcotic Analgesics: Usual Doses and Intervals

Acetylsalicylic acid 650 PO q4h Enteric-coated preparations available

Acetaminophen 650 PO q4h Side effects uncommon

Ibuprofen 400 PO q4–6h Available without prescription

Naproxen 250–500 PO q12h Naproxen is the common NSAID that poses the least cardiovascular risk,

but it has a somewhat higher incidence of gastrointestinal bleeding

Fenoprofen 200 PO q4–6h Contraindicated in renal disease

Indomethacin 25–50 PO q8h Gastrointestinal side effects common

Ketorolac 15–60 IM/IV q4–6h Available for parenteral use

Celecoxib 100–200 PO q12–24h Useful for arthritis

Valdecoxib 10–20 PO q12–24h Removed from U.S. market in 2005

GENERIC NAME PARENTERAL DOSE, mg PO DOSE, mg COMMENTS

Narcotic Analgesics: Usual Doses and Intervals

Codeine 30–60 q4h 30–60 q4h Nausea common

Oxycodone — 5–10 q4–6h Usually available with acetaminophen or aspirin

Oxycodone extended-release — 10-40 q12h Oral extended-release tablet; high potential for misuse

Morphine 5 q4h 30 q4h

Morphine sustained release — 15–60 bid to tid Oral slow-release preparation

Hydromorphone 1–2 q4h 2–4 q4h Shorter acting than morphine sulfate

Levorphanol 2 q6–8h 4 q6–8h Longer acting than morphine sulfate; absorbed well PO

Methadone 5–10 q6–8h 5–20 q6–8h Due to long half-life, respiratory depression and sedation may persist after

analgesic effect subsides; therapy should not be initiated with >40 mg/d,

and dose escalation should be made no more frequently than every 3 days

Meperidine 50–100 q3–4h 300 q4h Poorly absorbed PO; normeperidine is a toxic metabolite; routine use of

this agent is not recommended

Butorphanol — 1–2 q4h Intranasal spray

Fentanyl 25–100 μg/h — 72-h transdermal patch

Buprenorphine 5–20 μg/h 7-day transdermal patch

Buprenorphine 0.3 q6–8h Parenteral administration

Tramadol — 50–100 q4–6h Mixed opioid/adrenergic action

COX-2-selective drugs have similar analgesic potency and produce less gastric irritation than the nonselective COX inhibitors.

The use of COX-2-selective drugs does not appear to lower the

risk of nephrotoxicity compared to nonselective NSAIDs. On the

other hand, COX-2-selective drugs offer a significant benefit in

the management of acute postoperative pain because they do not

affect blood coagulation. Nonselective COX inhibitors (especially

aspirin) are usually contraindicated postoperatively because they

impair platelet-mediated blood clotting and are thus associated

with increased bleeding at the operative site. COX-2 inhibitors,

including celecoxib (Celebrex), are associated with increased cardiovascular risk, including cardiovascular death, myocardial infarction, stroke, heart failure, or a thromboembolic event. It appears

that this is a class effect of NSAIDs, excluding aspirin. These drugs

96PART 2 Cardinal Manifestations and Presentation of Diseases

are contraindicated in patients in the immediate period after coronary artery bypass surgery and should be used with caution in

elderly patients and those with a history of or significant risk factors

for cardiovascular disease.

OPIOID ANALGESICS

Opioids are the most potent pain-relieving drugs currently available. Of all analgesics, they have the broadest range of efficacy

and provide the most reliable and effective treatment for rapid

pain relief. Although side effects are common, most are reversible:

nausea, vomiting, pruritus, sedation, and constipation are the most

frequent and bothersome side effects. Respiratory depression is

uncommon at standard analgesic doses but can be life-threatening.

Opioid-related side effects can be reversed rapidly with the narcotic antagonist naloxone. Many physicians, nurses, and patients

have a certain trepidation about using opioids that is based on a

fear of initiating addiction in their patients. In fact, there is a very

small chance of patients becoming addicted to narcotics as a result

of their appropriate medical use. For chronic pain, particularly

chronic noncancer pain, the risk of addiction in patients taking

opioids on a chronic basis remains small, but the risk does appear to

increase with dose escalation. The physician should not hesitate to

use opioid analgesics in patients with acute severe pain. Table 13-1

lists the most commonly used opioid analgesics.

Opioids produce analgesia by actions in the CNS. They activate pain-inhibitory neurons and directly inhibit pain-transmission

neurons. Most of the commercially available opioid analgesics

act at the same opioid receptor (μ-receptor), differing mainly in

potency, speed of onset, duration of action, and optimal route

of administration. Some side effects are due to accumulation of

nonopioid metabolites that are unique to individual drugs. One

striking example of this is normeperidine, a metabolite of meperidine. At higher doses of meperidine, typically >1 g/d, accumulation

of normeperidine can produce hyperexcitability and seizures that

are not reversible with naloxone. Normeperidine accumulation is

increased in patients with renal failure.

The most rapid pain relief is obtained by intravenous administration of opioids; relief with oral administration is significantly

slower. Because of the potential for respiratory depression, patients

with any form of respiratory compromise must be kept under close

observation following opioid administration; an oxygen-saturation

monitor may be useful, but only in a setting where the monitor is

under constant surveillance. Opioid-induced respiratory depression is primarily manifest as a reduction in respiratory rate and

is typically accompanied by sedation. A fall in oxygen saturation

represents a critical level of respiratory depression and the need

for immediate intervention to prevent life-threatening hypoxemia.

Newer monitoring devices that incorporate capnography or pharyngeal air flow can detect apnea at the point of onset and should

be used in hospitalized patients. Ventilatory assistance should be

maintained until the opioid-induced respiratory depression has

resolved. The opioid antagonist naloxone should be readily available whenever opioids are used at high doses or in patients with

compromised pulmonary function. Opioid effects are dose-related,

and there is great variability among patients in the doses that relieve

pain and produce side effects. Synergistic respiratory depression is

common when opioids are administered with other CNS depressants. Co-administration of benzodiazepines is particularly likely to

produce respiratory depression and should be avoided, especially in

outpatient pain management. Because of this variability in patient

response, initiation of therapy requires titration to optimal dose and

interval. The most important principle is to provide adequate pain

relief. This requires determining whether the drug has adequately

relieved the pain and timely reassessment to determine the optimal

interval for dosing. The most common error made by physicians in

managing severe pain with opioids is to prescribe an inadequate dose.

Because many patients are reluctant to complain, this practice leads to

needless suffering. In the absence of sedation at the expected time of

peak effect, a physician should not hesitate to repeat the initial dose

to achieve satisfactory pain relief.

A now standard approach to the problem of achieving adequate

pain relief is the use of patient-controlled analgesia (PCA). PCA

uses a microprocessor-controlled infusion device that can deliver

a baseline continuous dose of an opioid drug as well as preprogrammed additional doses whenever the patient pushes a button.

The patient can then titrate the dose to the optimal level. This

approach is used most extensively for the management of postoperative pain, but there is no reason why it should not be used for any

hospitalized patient with persistent severe pain. PCA is also used for

short-term home care of patients with intractable pain, such as that

caused by metastatic cancer.

It is important to understand that the PCA device delivers small,

repeated doses to maintain pain relief; in patients with severe pain,

the pain must first be brought under control with a loading dose

before transitioning to the PCA device. The bolus dose of the drug

(typically 1 mg of morphine, 0.2 mg of hydromorphone, or 10 μg

of fentanyl) can then be delivered repeatedly as needed. To prevent

overdosing, PCA devices are programmed with a lockout period

after each demand dose is delivered (typically starting at 10 min)

and a limit on the total dose delivered per hour. Although some

have advocated the use of a simultaneous continuous or basal

infusion of the PCA drug, this may increase the risk of respiratory

depression and has not been shown to increase the overall efficacy

of the technique.

The availability of new routes of administration has extended the

usefulness of opioid analgesics. Most important is the availability

of spinal administration. Opioids can be infused through a spinal

catheter placed either intrathecally or epidurally. By applying opioids directly to the spinal or epidural space adjacent to the spinal

cord, regional analgesia can be obtained using relatively low total

doses. Indeed, the dose required to produce effective analgesia

when using morphine intrathecally (0.1–0.3 mg) is a fraction of that

required to produce similar analgesia when administered intravenously (5–10 mg). In this way, side effects such as sedation, nausea,

and respiratory depression can be minimized. This approach has

been used extensively during labor and delivery and for postoperative pain relief following surgical procedures. Continuous intrathecal delivery via implanted spinal drug-delivery systems is now

commonly used, particularly for the treatment of cancer-related

pain that would require sedating doses for adequate pain control if

given systemically. Opioids can also be given intranasally (butorphanol), rectally, and transdermally (fentanyl and buprenorphine), or

through the oral mucosa (fentanyl), thus avoiding the discomfort

of frequent injections in patients who cannot be given oral medication. The fentanyl and buprenorphine transdermal patches have

the advantage of providing fairly steady plasma levels, which may

improve patient comfort.

Recent additions to the armamentarium for treating opioidinduced side effects are the peripherally acting opioid antagonists

alvimopan (Entereg) and methylnaltrexone (Rellistor). Alvimopan

is available as an orally administered agent that is restricted to the

intestinal lumen by limited absorption; methylnaltrexone is available in a subcutaneously administered form that has virtually no

penetration into the CNS. Both agents act by binding to peripheral

μ-receptors, thereby inhibiting or reversing the effects of opioids

at these peripheral sites. The action of both agents is restricted to

receptor sites outside of the CNS; thus, these drugs can reverse the

adverse effects of opioid analgesics that are mediated through their

peripheral receptors without reversing their CNS-mediated analgesic effects. Alvimopan has proven effective in lowering the duration

of persistent ileus following abdominal surgery in patients receiving

opioid analgesics for postoperative pain control. Methylnaltrexone

has proven effective for relief of opioid-induced constipation in

patients taking opioid analgesics on a chronic basis.

97Pain: Pathophysiology and Management CHAPTER 13

Opioid and COX Inhibitor Combinations When used in combination, opioids and COX inhibitors have additive effects. Because a

lower dose of each can be used to achieve the same degree of pain

relief and their side effects are nonadditive, such combinations are

used to lower the severity of dose-related side effects. However,

fixed-ratio combinations of an opioid with acetaminophen carry

an important risk. Dose escalation as a result of increased severity

of pain or decreased opioid effect as a result of tolerance may lead

to ingestion of levels of acetaminophen that are toxic to the liver.

Although acetaminophen-related hepatotoxicity is uncommon, it

remains a significant cause for liver failure. Thus, many practitioners have moved away from the use of opioid-acetaminophen combination analgesics to avoid the risk of excessive acetaminophen

exposure as the dose of the analgesic is escalated.

CHRONIC PAIN

Managing patients with chronic pain is intellectually and emotionally

challenging. Sensitization of the nervous system can occur without an

obvious precipitating cause, e.g., fibromyalgia, or chronic headache. In

many patients, chronic pain becomes a distinct disease unto itself. The

pain-generating mechanism is often difficult or impossible to determine with certainty; such patients are demanding of the physician’s

time and often appear emotionally distraught. The traditional medical

approach of seeking an obscure organic pathology is often unhelpful.

On the other hand, psychological evaluation and behaviorally based

treatment paradigms are frequently helpful, particularly in the setting

of a multidisciplinary pain-management center. Unfortunately, this

approach, while effective, remains largely underused in current medical practice.

There are several factors that can cause, perpetuate, or exacerbate

chronic pain. First, of course, the patient may simply have a disease that

is characteristically painful for which there is presently no cure. Arthritis,

cancer, chronic daily headaches, fibromyalgia, and diabetic neuropathy

are examples of this. Second, there may be secondary perpetuating

factors that are initiated by disease and persist after that disease has

resolved. Examples include damaged sensory nerves, sympathetic

efferent activity, and painful reflex muscle contraction (spasm). Finally,

a variety of psychological conditions can exacerbate or even cause pain.

There are certain areas to which special attention should be paid in

a patient’s medical history. Because depression is the most common

emotional disturbance in patients with chronic pain, patients should be

questioned about their mood, appetite, sleep patterns, and daily activity. A simple standardized questionnaire, such as the Beck Depression

Inventory, can be a useful screening device. It is important to remember that major depression is a common, treatable, and potentially fatal

illness.

Other clues that a significant emotional disturbance is contributing

to a patient’s chronic pain complaint include pain that occurs in multiple, unrelated sites; a pattern of recurrent, but separate, pain problems

beginning in childhood or adolescence; pain beginning at a time of

emotional trauma, such as the loss of a parent or spouse; a history of

physical or sexual abuse; and past or present substance abuse.

On examination, special attention should be paid to whether the

patient guards the painful area and whether certain movements or postures are avoided because of pain. Discovering a mechanical component to the pain can be useful both diagnostically and therapeutically.

Painful areas should be examined for deep tenderness, noting whether

this is localized to muscle, ligamentous structures, or joints. Chronic

myofascial pain is very common, and in these patients, deep palpation

may reveal highly localized trigger points that are firm bands or knots

in muscle. Relief of the pain following injection of local anesthetic into

these trigger points supports the diagnosis. A neuropathic component

to the pain is indicated by evidence of nerve damage, such as sensory

impairment, exquisitely sensitive skin (allodynia), weakness, and muscle atrophy, or loss of deep tendon reflexes. Evidence suggesting sympathetic nervous system involvement includes the presence of diffuse

swelling, changes in skin color and temperature, and hypersensitive

skin and joint tenderness compared with the normal side. Relief of

the pain with a sympathetic block supports the diagnosis, but once the

condition becomes chronic, the response to sympathetic blockade is

of variable magnitude and duration; the role for repeated sympathetic

blocks in the overall management of CRPS is unclear.

A guiding principle in evaluating patients with chronic pain is to

assess both emotional and somatic causal and perpetuating factors

before initiating therapy. Addressing these issues together, rather than

waiting to address emotional issues after somatic causes of pain have

been ruled out, improves compliance in part because it assures patients

that a psychological evaluation does not mean that the physician is

questioning the validity of their complaint. Even when a somatic cause

for a patient’s pain can be found, it is still wise to look for other factors.

For example, a cancer patient with painful bony metastases may have

additional pain due to nerve damage and may also be depressed. Optimal therapy requires that each of these factors be assessed and treated.

TREATMENT

Chronic Pain

Once the evaluation process has been completed and the likely

causative and exacerbating factors identified, an explicit treatment

plan should be developed. An important part of this process is to

identify specific and realistic functional goals for therapy, such as

getting a good night’s sleep, being able to go shopping, or returning to work. A multidisciplinary approach that uses medications,

counseling, physical therapy, nerve blocks, and even surgery may

be required to improve the patient’s quality of life. There are also

some newer, minimally invasive procedures that can be helpful for

some patients with intractable pain. These include image-guided

interventions such as epidural injection of glucocorticoids for acute

radicular pain and radiofrequency treatment of the facet joints for

chronic facet-related back and neck pain. For patients with severe

and persistent pain that is unresponsive to more conservative

treatment, placement of electrodes on peripheral nerves or within

the spinal canal on nerve roots or in the space overlying the dorsal

columns of the spinal cord (spinal cord stimulation) or implantation of intrathecal drug-delivery systems has shown significant

benefit. The criteria for predicting which patients will respond to

these procedures continue to evolve. They are generally reserved for

patients who have not responded to conventional pharmacologic

approaches. Referral to a multidisciplinary pain clinic for a full

evaluation should precede any invasive procedure. Such referrals

are clearly not necessary for all chronic pain patients. For some,

pharmacologic management alone can provide adequate relief.

ANTIDEPRESSANT MEDICATIONS

The tricyclic antidepressants (TCAs), particularly nortriptyline and

desipramine (Table 13-1), are useful for the management of chronic

pain. Although developed for the treatment of depression, the TCAs

have a spectrum of dose-related biologic activities that include

analgesia in a variety of chronic clinical conditions. Although the

mechanism is unknown, the analgesic effect of TCAs has a more

rapid onset and occurs at a lower dose than is typically required

for the treatment of depression. Furthermore, patients with chronic

pain who are not depressed obtain pain relief with antidepressants.

There is evidence that TCAs potentiate opioid analgesia, so they

may be useful adjuncts for the treatment of severe persistent pain

such as occurs with malignant tumors. Table 13-2 lists some of the

painful conditions that respond to TCAs. TCAs are of particular

value in the management of neuropathic pain such as occurs in

diabetic neuropathy and postherpetic neuralgia, for which there are

few other therapeutic options.

The TCAs that have been shown to relieve pain have significant

side effects (Table 13-1; Chap. 452). Some of these side effects,

98PART 2 Cardinal Manifestations and Presentation of Diseases

such as orthostatic hypotension, drowsiness, cardiac conduction

delay, memory impairment, constipation, and urinary retention, are

particularly problematic in elderly patients, and several are additive

to the side effects of opioid analgesics. The selective serotonin

reuptake inhibitors such as fluoxetine (Prozac) have fewer and less

serious side effects than TCAs, but they are much less effective for

relieving pain. It is of interest that venlafaxine (Effexor) and duloxetine (Cymbalta), which are nontricyclic antidepressants that block

both serotonin and norepinephrine reuptake, appear to retain most

of the pain-relieving effect of TCAs with a side effect profile more

like that of the selective serotonin reuptake inhibitors. These drugs

may be particularly useful in patients who cannot tolerate the side

effects of TCAs.

ANTICONVULSANTS AND ANTIARRHYTHMICS

These drugs are useful primarily for patients with neuropathic

pain. Phenytoin (Dilantin) and carbamazepine (Tegretol) were first

shown to relieve the pain of trigeminal neuralgia (Chap. 441). This

pain has a characteristic brief, shooting, electric shock-like quality.

In fact, anticonvulsants seem to be particularly helpful for pains that

have such a lancinating quality. Newer anticonvulsants, the calcium

channel alpha-2-delta subunit ligands gabapentin (Neurontin) and

pregabalin (Lyrica), are effective for a broad range of neuropathic

pains. Furthermore, because of their favorable side effect profile,

these newer anticonvulsants are often used as first-line agents.

CANNABINOIDS

These agents are widely used for their analgesic properties, although

published evidence suggests that any effects are likely to be modest,

with small increases in pain threshold reported and variable reductions in clinical pain intensity. Cannabis more consistently reduces

the unpleasantness of the pain experience and, in cancer-related

pain, can lessen the nausea and vomiting associated with chemotherapy use. Marijuana and related compounds are discussed in

Chap. 455.

CHRONIC OPIOID MEDICATION

The long-term use of opioids is accepted for patients with pain

due to malignant disease. Although opioid use for chronic pain

of nonmalignant origin is controversial, it is clear that, for many

patients, opioids are the only option that produces meaningful pain

relief. This is understandable because opioids are the most potent

and have the broadest range of efficacy of any analgesic medications. Although addiction is rare in patients who first use opioids

for pain relief, some degree of tolerance and physical dependence

is likely with long-term use. Furthermore, studies suggest that

long-term opioid therapy may worsen pain in some individuals,

termed opioid-induced hyperalgesia. Therefore, before embarking

on opioid therapy, other options should be explored, and the limitations and risks of opioids should be explained to the patient. It is

also important to point out that some opioid analgesic medications

have mixed agonist-antagonist properties (e.g., butorphanol and

buprenorphine). From a practical standpoint, this means that they

may worsen pain by inducing an abstinence syndrome in patients

who are actively being treated with other opioids and are physically

dependent.

With long-term outpatient use of orally administered opioids,

it may be desirable to use long-acting compounds such as levorphanol, methadone, extended-release morphine or oxycodone, or

transdermal fentanyl (Table 13-1). The pharmacokinetic profiles

of these drug preparations enable the maintenance of sustained

analgesic blood levels, potentially minimizing side effects such

as sedation that are associated with high peak plasma levels, and

reducing the likelihood of rebound pain associated with a rapid fall

in plasma opioid concentration. Extended-release opioid formulations are approved primarily for patients who are already taking

other opioids and should not be used as first-line opioids for pain.

Although long-acting opioid preparations may provide superior

pain relief in patients with a continuous pattern of ongoing pain,

others suffer from intermittent severe episodic pain and experience

superior pain control and fewer side effects with the periodic use of

short-acting opioid analgesics. Constipation is a virtually universal

side effect of opioid use and should be treated expectantly. As noted

earlier in the discussion of acute pain treatment, a recent advance

for patients is the development of peripherally acting opioid antagonists that can reverse the constipation associated with opioid use

without interfering with analgesia.

Soon after the introduction of an extended-release oxycodone

formulation (OxyContin) in the late 1990s, a dramatic rise in

emergency department visits and deaths associated with oxycodone

ingestion appeared. This appears to be due primarily to individuals

using a prescription opioid nonmedically. Drug-induced deaths

have rapidly risen and are now the second leading cause of death

in Americans, just behind motor vehicle fatalities. In 2011, the

Office of National Drug Control Policy established a multifaceted

approach to address prescription drug abuse, including prescription drug monitoring programs (PDMPs) that allow practitioners

to determine if patients are receiving prescriptions from multiple

providers and use of law enforcement to eliminate improper prescribing practices. In 2016, the Centers for Disease Control and

Prevention (CDC) released the CDC Guideline for Prescribing

Opioids for Chronic Pain, with recommendations for primary care

clinicians who are prescribing opioids for chronic noncancer pain.

A modified approach to opioid prescribing was published in 2019

by the Health and Human Services Task Force on chronic pain best

medical practices. These guidelines address (1) when to initiate

or continue opioids for chronic pain; (2) opioid selection, dosage,

duration, follow-up, and discontinuation; and (3) assessing risk and

addressing harms of opioid use. The recent increase in scrutiny

leaves many practitioners hesitant to prescribe opioid analgesics,

other than for brief periods to control pain associated with illness

or injury. For now, the choice to begin chronic opioid therapy

for a given patient is left to the individual practitioner. Pragmatic

guidelines for properly selecting and monitoring patients receiving

chronic opioid therapy are shown in Table 13-3; a checklist for

primary care clinicians prescribing opioids for noncancer pain is

shown in Table 13-4.

TREATMENT OF NEUROPATHIC PAIN

It is important to individualize treatment for patients with neuropathic pain. Several general principles should guide therapy: the

first is to move quickly to provide relief, and the second is to minimize drug side effects. For example, in patients with postherpetic

neuralgia and significant cutaneous hypersensitivity, topical lidocaine (Lidoderm patches) can provide immediate relief without side

effects. The anticonvulsants gabapentin or pregabalin (see above) or

antidepressants (nortriptyline, desipramine, duloxetine, or venlafaxine) can be used as first-line drugs for patients with neuropathic

pain. Systemically administered antiarrhythmic drugs such as lidocaine and mexiletine are less likely to be effective. Although intravenous infusion of lidocaine can provide analgesia for patients with

different types of neuropathic pain, the relief is usually transient,

TABLE 13-2 Painful Conditions That Respond to Tricyclic

Antidepressants

Postherpetic neuralgiaa

Diabetic neuropathya

Fibromyalgiaa

Tension headachea

Migraine headachea

Rheumatoid arthritisa,b

Chronic low back painb

Cancer

Central poststroke pain

a

Controlled trials demonstrate analgesia. b

Controlled studies indicate benefit but not

analgesia.