Chronic pain is pain that persists beyond the ordinary time that an insult or injury needs to heal or as pain that persists beyond a stated time interval.

This time interval is often indicated as three months, though some have identified the window as six months.

 


Several factors cause, perpetuate, or exacerbate chronic pain.

First, 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.

 

Clinical Perspective:

Managing patients with chronic pain is intellectually and emotionally challenging.

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 within the spinal canal 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.

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  • 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 usually 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.1

  • 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 organic factors before initiating therapy. Addressing these issues together, rather than waiting to address emotional issues after organic 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 an organic 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 looked for and treated.

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  • Treatment plan including specific and realistic goals for therapy, e.g., getting a good night’s sleep, being able to go shopping, or returning to work. 1

  • A multidisciplinary approach that utilizes medications, counseling, physical therapy, nerve blocks, and even surgery may be required to improve quality of life.

  • Psychological evaluation is key; behaviorally based treatment paradigms are frequently helpful.

  • Some pts may require referral to a pain clinic; for others, pharmacologic management alone can provide significant help.

  • Tricyclic antidepressants are useful in management of chronic pain from many causes, including headache, diabetic neuropathy, postherpetic neuralgia, chronic low back pain, cancer, and central post-stroke pain.

  • Anticonvulsants or antiarrhythmics benefit pts with neuropathic pain (e.g., diabetic neuropathy, trigeminal neuralgia).

  • The long-term use of opioids is accepted for pain due to malignant disease, but is controversial for chronic pain of nonmalignant origin.

 

 

CDC Guideline

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, relatively 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 within the spinal canal 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 18-1), 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 18-2 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 18-1; Chap. 466). Some of these side effects, 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. 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, 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.

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, animal studies suggest that long-term opioid therapy may worsen pain in some individuals. 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 physically dependent on other opioid analgesics.

With long-term outpatient use of orally administered opioids, it is desirable to use long-acting compounds such as levorphanol, methadone, sustained-release morphine, or transdermal fentanyl (Table 18-1). 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. 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 above 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 a controlled-release oxycodone formulation (OxyContin) in the late 1990s, a dramatic rise in emergency department visits and deaths associated with oxycodone ingestion appeared, focusing public attention on misuse of prescription pain medications. The magnitude of prescription opioid abuse has grown over the last decade, leading the Centers for Disease Control and Prevention to classify prescription opioid analgesic abuse as an epidemic. This appears to be due in large part to individuals using a prescription drug nonmedically, most often an opioid analgesic. 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 that allow practitioners to determine if patients are receiving prescriptions from multiple providers and use of law enforcement to eliminate improper prescribing practices. This increased 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 18-3.

Question 1 of 1

A 72-year-old woman has stage IV ovarian cancer with diffuse peritoneal studding. She is developing increasing pain in her abdomen and is admitted to the hospital for pain control. She previously was treated with oxycodone 10 mg orally every 6 hours as needed. Upon admission, she is initiated on morphine intravenously via patient-controlled analgesia. During the first 48 hours of her hospitalization, she received an average daily dose of morphine of 90 mg and reports adequate pain control unless she is walking. What is the most appropriate opioid regimen for transitioning this patient to oral pain medication?

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Sustained-Release Morphine Immediate-Release Morphine
A. None 15 mg every 4 hours as needed
B. 45 mg twice daily 5 mg every 4 hours as needed
C. 45 mg twice daily 15 mg every 4 hours as needed
D. 90 mg twice daily 15 mg every 4 hours as needed
E. 90 mg three time daily 15 mg every 4 hours as needed
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The correct answer is C. You answered C.

The answer is C.(Chap. 10) A primary goal of palliative care medicine is to control pain in patients who are terminally ill. Surveys have found that 36%–90% of individuals with advanced cancer have substantial pain, and an individualized treatment plan is necessary for each patient. For individuals with continuous pain, opioid analgesics should be administered on a scheduled basis around the clock at an interval based on the half-life of the medication chosen. Extended- release preparations are frequently used due to their longer half-lives. However, it is inappropriate to start immediately with an extended-release preparation. In this scenario, the patient was treated with a continuous intravenous infusion via patient-controlled analgesia for 48 hours to determine her baseline opioid needs. The average daily dose of morphine required was 90 mg. This total dose should be administered in divided doses two or three times daily (either 45 mg twice daily or 30 mg three times daily). In addition, an immediate-release preparation should be available for administration for breakthrough pain. The recommended dose of the immediate release preparation is 20% of the baseline dose. In this case, the dose would be 18 mg and could be given as either 15 or 20 mg four times daily as needed.

33% of users answered correctly.

 

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. 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, typically lasting just hours after the cessation of the infusion. The oral lidocaine congener mexiletine is poorly tolerated, producing frequent gastrointestinal adverse effects. There is no consensus on which class of drug should be used as a first-line treatment for any chronically painful condition. However, because relatively high doses of anticonvulsants are required for pain relief, sedation is very common. Sedation is also a problem with TCAs but is much less of a problem with serotonin/norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine and duloxetine). Thus, in the elderly or in patients whose daily activities require high-level mental activity, these drugs should be considered the first line. In contrast, opioid medications should be used as a second- or third-line drug class. Although highly effective for many painful conditions, opioids are sedating, and their effect tends to lessen over time, leading to dose escalation and, occasionally, a worsening of pain due to physical dependence. Drugs of different classes can be used in combination to optimize pain control. Repeated injections of botulinum toxin is an emerging approach to focal neuropathic pain based on recent studies.

It is worth emphasizing that many patients, especially those with chronic pain, seek medical attention primarily because they are suffering and because only physicians can provide the medications required for pain relief. A primary responsibility of all physicians is to minimize the physical and emotional discomfort of their patients. Familiarity with pain mechanisms and analgesic medications is an important step toward accomplishing this aim.

Painful Conditions that Respond to Tricyclic Antidepressants

Postherpetic neuralgiaa
Diabetic neuropathya
Tension headachea
Migraine headachea
Rheumatoid arthritisa,b
Chronic low back painb
Cancer
Central poststroke pain

aControlled trials demonstrate analgesia.

bControlled studies indicate benefit but not analgesia.

 

Guidelines for Selecting and Monitoring Patients Receiving Chronic Opioid Therapy (COT) for the Treatment of Chronic, Noncancer Pain

Patient Selection

  • Conduct a history, physical examination, and appropriate testing, including an assessment of risk of substance abuse, misuse, or addiction.

  • Consider a trial of COT if pain is moderate or severe, pain is having an adverse impact on function or quality of life, and potential therapeutic benefits outweigh potential harms.

  • A benefit-to-harm evaluation, including a history, physical examination, and appropriate diagnostic testing, should be performed and documented before and on an ongoing basis during COT.
Informed Consent and Use of Management Plans

  • Informed consent should be obtained. A continuing discussion with the patient regarding COT should include goals, expectations, potential risks, and alternatives to COT.

  • Consider using a written COT management plan to document patient and clinician responsibilities and expectations and assist in patient education.
Initiation and Titration

  • Initial treatment with opioids should be considered as a therapeutic trial to determine whether COT is appropriate.

  • Opioid selection, initial dosing, and titration should be individualized according to the patient’s health status, previous exposure to opioids, attainment of therapeutic goals, and predicted or observed harms.
Monitoring

  • Reassess patients on COT periodically and as warranted by changing circumstances. Monitoring should include documentation of pain intensity and level of functioning, assessments of progress toward achieving therapeutic goals, presence of adverse events, and adherence to prescribed therapies.

  • In patients on COT who are at high risk or who have engaged in aberrant drug-related behaviors, clinicians should periodically obtain urine drug screens or other information to confirm adherence to the COT plan of care.

  • In patients on COT not at high risk and not known to have engaged in aberrant drug-related behaviors, clinicians should consider periodically obtaining urine drug screens or other information to confirm adherence to the COT plan of care.

Source: Adapted with permission from R Chou et al: J Pain 10:113, 2009.

 

Multiple mechanisms promote or facilitate persistent or chronic pain. These include peripheral sensitization, central sensitization, ectopic excitability, structural reorganization/phenotypic switch of neurons, primary sensory degeneration, and disinhibition. Peripheral and central sensitization are the major causes of pain hypersensitivity after injury.

Peripheral sensitization — Tissue inflammation may result in changes in the chemical environment of the peripheral terminal of nociceptors. Damaged cells may release intracellular contents and synthesize substances including cytokines, chemokines, bradykinin, histamine, prostaglandins, and growth factors. Released cellular ions create a more acidic environment.

Inflammatory cells are recruited to the site of damage, in part due to the attractant properties of proinflammatory mediators such as leukotriene B4 [LTB4] [32]. Some of these proinflammatory mediators directly activate the nociceptor terminal and produce pain (nociceptor activators); others sensitize the terminal so that it becomes hypersensitive to subsequent stimuli (nociceptor sensitizers) [12].

●The release of adenosine triphosphatase by injured cells, for example, causes immediate activation and results in immediate detection of tissue damage [28].

 

●Transient receptor potential V1 (TRPV1) channels expressed by nociceptors may produce pain some time after injury [33]. These channels are calcium-permeable nonselective cation channels gated by heat, low pH, or chemical mediators (“endovanilloids”). Activation of mitogen-activated protein kinase (MAPK) signaling in TRPV1 may contribute to hyperresponsiveness of peripheral nociceptors (peripheral sensitization). In addition to producing inflammation and inducing synthesis of several nociceptor sensitizers, IL-1beta also rapidly and directly activates nociceptors to generate action potentials and induce pain hypersensitivity [34].

 

Central sensitization — Central sensitization amplifies the synaptic transfer from the nociceptor terminal to dorsal horn neurons [12]. Initial sensitization to synaptic transfer is activity-dependent, triggered by nociceptor input into the spinal cord. Later transcriptional changes in the molecular machinery of the dorsal cell sustain the sensitization beyond the initiating stimulus (ie, transcription-dependent) [35,36]. Thus, previously subthreshold synaptic inputs to nociceptive neurons now generate an augmented action potential output.

The glutamate-activated N-methyl-D-aspartic acid (NMDA) receptor is integral to this central sensitization process [12,37]. During central sensitization, the NMDA receptor is phosphorylated, which increases its distribution in the synaptic membrane and its responsiveness to glutamate. Increased responsiveness to glutamate occurs by removal of a normal voltage-dependent magnesium ion block of the NMDA channel, increasing the time the channel is open. The increase in excitability of the dorsal horn cell means that it can be activated by normally subthreshold inputs, with increased response to suprathreshold inputs [37].

Neuroimmune interaction resulting from the action of chemical signals produced by inflammatory cells on nerve fibers may contribute to peripheral and central sensitization. Transcription-dependent central sensitization has been studied in the context of peripheral inflammation where changes in brain derived neurotrophic factor (BDNF), substance P, neurokinin 1 (NK1), dynorphin and cyclooxygenase 2 (Cox 2) are well described [38-40].

Neuron-glial interactions may also contribute to nociceptive processes [41]. The macrophage-like glial cells, quiescent in the normal spinal cord, are rapidly activated after nerve injury. These cells are a likely source of cytokines and chemokines that then act on neurons and their supporting glia to alter patterns of gene transcription.

Ectopic excitability — Increased excitability of injured and neighboring uninjured sensory neurons can generate pacemaker-like ectopic action potential discharges, resulting in sensory inflow independent of a peripheral stimulus [42,43]. These changes may manifest at the site of the injury, at a neuroma, or in the dorsal root ganglion [44]. These ectopic signals arise due to multiple factors including upregulation of voltage gated sodium channels, channel subunits, or signal receptors in myelinated neurons; or downregulation of potassium channels [45,46].

Structural reorganization/phenotypic switch — Nerve injury may result in an altered profile of sensory neurons. The central terminals of nociceptor sensory neurons terminate in the most superficial laminae of the dorsal horn in the spinal cord. In contrast, low threshold sensory fibers activated by touch, pressure, vibration, and normal ranges of movement of joints terminate in the deep laminae of the dorsal horn.

Experiments in rodents have shown that physical rearrangement of this circuitry may occur after peripheral nerve injury, with new growth of the central terminals of the low-threshold afferents seen in the zone normally occupied exclusively by nociceptor terminals [47]. Additionally, after peripheral nerve injury, the neuromodulators brain-derived neurotrophic factor (BDNF) and substance P, normally expressed only in C-fibers, may begin to be expressed in large-diameter A fiber neurons [48,49].

Primary sensory degeneration — Loss of neurons (normally a source of growth factors) and the resulting imbalance of sensory inflow may contribute to the abnormal sensations [12]. This paradoxical increase in pain perception with neurite dropout is not well understood. Conceivably, this may be related to changes in neurotrophic factors, compensatory local changes in the surrounding neurons or dorsal root ganglion/dorsal horn of the spinal cord, changes in related glia, and/or changes in cortical interpretation of afferent input.

Disinhibition — A reduction in inhibition can have an effect similar to increased excitability. Pharmacologically blocking GABA or glycine-mediated inhibition produces a pattern of pain hypersensitivity similar to that of neuropathic pain, with prominent tactile allodynia [50]. GABA blockade recruits previously absent ABeta fiber inputs to lamina II cells, effectively uncovering a previously silent synaptic pathway [51].

Partial nerve injury also reduces inhibition in the superficial dorsal horn, with selective loss of GABAergic inhibitory synaptic currents due to apoptosis in GABAergic inhibitory interneurons [52]. One week after nerve injury that produces hypersensitivity to pain, neurons begin to undergo apoptosis in the dorsal horn. The apoptosis may be due to excessive glutamate release or failure of glutamate uptake, or result from cell death-inducing signals, such as release of tumor necrosis factor-alpha from activated microglia.

Clinical implication of mechanism of pain — When pain symptoms fail to respond to traditional treatment, conventional approaches may be supplemented by a mechanism-based approach in efforts to individually tailor targeted therapy [53,54]. A mechanism-based approach accounts for the observation that patients with one disease (eg, diabetic neuropathy) may have different symptoms due to different mechanisms [55]. Data regarding the determination of the precise pain mechanism in a given patient, and the effectiveness of therapy targeted to the mechanism, are preliminary, but current knowledge provides a framework for future investigation [56].

 

Maladaptive or chronic pain represents pathologic operation of the nervous system.

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