Leave a comment

6 Assessment of Pain

6 Assessment of Pain
The Massachusetts General Hospital Handbook of Pain Management

Assessment of Pain

Alyssa A. LeBel

When you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meager and unsatisfactory kind: it may be the beginning of knowledge, but you have scarcely, in your thoughts, advanced to the stage of science.
—William Thompson Lord Kelvin, 1824–1907

I. Pain history

1. Pain assessment tools

2. Pain location

3. Pain etiology
II. Physical examination

1. General physical examination

2. Specific pain evaluation

3. Neurologic examination

4. Musculoskeletal system examination

5. Assessment of psychological factors
III. Diagnostic studies
IV. Conclusion
Selected Reading

Pain is a complex multidimensional symptom determined not only by tissue injury and nociception but also by previous pain experience, personal beliefs, effect, motivation, environment, and, at times, pending litigation. There is no objective measurement of pain. Self-report is the most valid measure of the individual experience of pain. The pain history is key to the assessment of pain and includes the patient’s description of pain intensity, quality, location, timing, and duration, as well as ameliorating and exacerbating conditions.
Frequently, pain cannot be seen, defined, or felt by the examiner, and the physician must assess the pain from a combination of factors. The most important of these is the patient’s report of pain, but other factors such as personality and culture, psychological status, the potential of secondary gain, and the possibility of drug-seeking behavior also deserve consideration. Reports of pain may not correlate with the degree of disability or findings on physical examination. It is important to remember, however, that to our patients and their families, distress, suffering, and pain behaviors are often not distinguished from the pain itself.
Acute pain diagnosis and measurement require frequent and consistent assessment as part of daily clinical care to ensure rapid titration of therapy and preemptive interventions. Chronic pain is often more diagnostically challenging than acute pain, but it is no less compelling. Application of a structured history and comprehensive physical examination will define treatable problems and identify complicating factors. Somatic, visceral, or neuropathic pain, or a combination of these problems, suggests specific diagnoses and interventions. An understanding of pain pathophysiology guides rational and appropriate treatment.
The general medical history may contribute significantly, and it is always included as part of the pain assessment (see Chapter 4). The specific pain history includes three main issues—intensity, location, and pathophysiology. The following questions help define them:

What is the time course of the pain?

Where is the pain?

What is the intensity of the pain?

What factors relieve or exacerbate the pain?

What are the possible generators of the pain?
1. Pain assessment tools
Pain cannot be objectively measured, and its intensity is very difficult and often frustrating to try to pinpoint. Several tests and scales are available. Some of the more commonly used are discussed here.
Unidimensional self-report scales
In practice, self-report scales serve as very simple, useful, and valid methods for assessing and monitoring patients’ pain.
VERBAL DESCRIPTOR SCALES. The patient is asked to describe his or her pain by choosing from a list of adjectives that reflect gradations of pain intensity. The five-word scale consists of mild, discomforting, distressing, horrible, and excruciating. Disadvantages of this scale include the limited selection of descriptors and the fact that patients tend to select moderate descriptors rather than the extremes.
VERBAL NUMERIC RATING SCALES. These are the simplest and most frequently used scales. On a numeric scale (most commonly 0 to 10, with 0 being “no pain” and 10 being “the worst pain imaginable”), the patient picks a number to describe the pain. Advantages of numeric scales are their simplicity, reproducibility, easy comprehensibility, and sensitivity to small changes in pain. Children as young as 5 years who are able to count and have some concept of numbers (e.g., “8 is larger than 4”) may use this scale.
VISUAL ANALOG SCALES. These are similar to the verbal numeric rating scales, except that the patient marks on a measured line, one end of which is labeled “no pain” and the other end, “worst pain imaginable,” where the pain falls. Visual scales are more valid for research purposes, but they are less used clinically because they are more time consuming to conduct than verbal scales.
“FACES” PAIN RATING SCALE. Evaluating pain in children can be very difficult because of the child’s inability to describe pain or understand pain assessment forms. This scale depicts six sketches of facial features, each with a numeric value, 0 to 5, ranging from a happy, smiling face to a sad, teary face (Fig. 1). To extrapolate this scale to the visual analog scale, multiply the chosen value by two. This scale may also be beneficial for mentally impaired patients. Children as young as 3 years may reliably use this scale.

Figure 1. Wong-Baker’s “faces” pain rating scale. Explain to the person that each face is for someone who feels happy because he has no pain (hurt) or sad because he has some or a lot of pain. Face 0 is very happy because he doesn’t hurt at all. Face 1 hurts just a little bit. Face 2 hurts a little more. Face 3 hurts even more. Face 4 hurts a whole lot. Face 5 hurts as much as you can imagine, although you don’t have to be crying to feel this bad.

Multidimensional instruments
Multidimensional instruments provide more complex information about the patient’s pain and are especially useful for assessment of chronic pain. As they are time consuming, they are most frequently used in outpatient and research settings.
McGill Pain Questionnaire (MPQ)
The MPQ is the most frequently used multidimensional test. Descriptive words from three major dimensions of pain (sensory, affective, and evaluative) are further subdivided into 20 subclasses, each containing words that represent varying degrees of pain. Three scores are obtained, one for each dimension, as well as a total score. Studies have shown the MPQ to be a reliable instrument in clinical research.
Brief Pain Inventory (BPI)
In the BPI, patients are asked to rate the severity of their pain at its “worst,” “least,” and “average” within the past 24 hours, as well as at the time the rating is made. It also asks patients to represent the location of their pain on a schematic diagram of the body. The BPI correlates with scores of activity, sleep, and social interactions. It is cross-cultural and a useful method for clinical studies (Fig. 2).

Figure 2. Brief pain inventory (see text). Reprinted with permission from the University of Wisconsin–Madison, Department of Neurology, Pain Research Group.

Massachusetts General Hospital (MGH)
Pain Center pain assessment form
The MGH form (Fig. 3) combines many of the preceding assessment instruments and is given to all patients on initial consultations at the MGH Pain Center. It elicits information about pain intensity, its location (via a body diagram), quality of pain, therapies tried, and past and present medications. It takes 10 to 15 minutes to complete and is an extremely valuable instrument. Its disadvantages are that it is time consuming to complete and it is not applicable if there are language constraints.

Figure 3. The Massachusetts General Hospital (MGH) Pain Center’s pain assessment form.

Pain Diaries
A diary of a patient’s pain is useful in evaluating the relationship between pain and daily activity. Pain can be described using the numeric rating scale, during activities such as walking, standing, sitting, and routine chores. Blocks of time are usually hourly. Medication use, alcohol use, emotional responses, and family responses may also be helpful information to record. Pain diaries may reflect a patient’s pain more accurately than a retrospective description that may significantly over- or underestimate pain.
2. Pain location
Knowing the location and distribution of pain is extremely important for understanding the pathophysiology of the pain complaint. Body diagrams, found in some of the assessment instruments, can prove very useful. Not only can the clinician view the patient’s perception of the topographic area of pain but the patient may demonstrate psychological distress by an inability to localize the pain or by magnifying it and projecting it to other areas of the body.
Is the pain localized or referred? Localized pain is pain that is confined to its site of origin without radiation or migration. Referred pain usually arises from visceral or deep structures and radiates to other areas of the body. A classic example of referred pain is shoulder pain from phrenic nerve irritation (causes include liver metastases from pancreatic cancer) (Table 1).

Table 1. Examples of referred pain

Is pain superficial/peripheral or visceral? Superficial pain, arising from tissues rich in nociceptors, such as skin, teeth, and mucous membranes, is easily localized and limited to the affected part of the body. Visceral pain arises from internal organs, which contain relatively few nociceptors. Visceral afferent information may converge with superficial afferent input at the spinal level, referring the perception of visceral pain to a distant dermatome. Visceral pain is diffuse and often poorly localized. In addition, it often has an associated autonomic component, such as diaphoresis, capillary vasodilation, hypertension, or tachycardia.
3. Pain etiology
By taking a complete history and answering the preceding two questions, the clinician can begin to formulate the causes of the pain. The rest of the history, as well as the physical examination, can be tailored to systematically explore aspects of pain, such as symptoms and physical signs, common to the particular type of pain in question.
It is possible to describe different types of pain, and they tend to present differently (e.g., nociceptive pain is associated with tissue injury caused by trauma, surgery, inflammation or tumor; neuropathic pain is invariably associated with sensory change; radicular pain is often associated with radiculopathy). The history and physical examination help to identify these differences. Because the different types of pain tend to respond to different treatments, the identification of pain type during pain assessment is important. The types can be categorized as follows:

Nociceptive pain arises from activation of nociceptors. Nociceptors are found in all tissues except the central nervous system (CNS); the pain is clinically proportional to the degree of activation of afferent pain fibers and can be acute or chronic (e.g., somatic pain, cancer pain, postoperative pain).

Neuropathic pain is caused by nerve injury or disease, or by involvement of nerves in other disease processes such as tumor or inflammation. Neuropathic pain may occur in the periphery or in the CNS.

Sympathetically mediated pain is accompanied (at some point) by evidence of edema, changes in skin blood flow, abnormal sudomotor activity in the regional of pain, allodynia, hyperalgesia, or hyperpathia.

Deafferentation pain is chronic and results from loss of afferent input to the CNS. The pain may arise in the periphery (e.g., peripheral nerve avulsion) or in the CNS (e.g., spinal cord lesions, multiple sclerosis).

Neuralgia pain is lancinating and associated with nerve damage or irritation along the distribution of a single nerve (e.g., trigeminal) or nerves.

Radicular pain is evoked by stimulation of nociceptive afferent fibers in spinal nerves, their roots, or ganglia, or by other neuropathic mechanisms. The symptom is caused by ectopic impulse generation. It is distinct from radiculopathy, but the two often arise together.

Central pain arises from a lesion in the CNS, usually involving the spinothalamic cortical pathways (i.e., thalamic infarct). The pain is usually constant, with a burning, electrical quality, and it is exacerbated by activity or changes in the weather. Hyperesthesia and hyperpathia and/or allodynia are invariably present, and the pain is highly resistant to treatment.

Psychogenic pain is inconsistent with the likely anatomic distribution of the presumed generator, or it exists with no apparent organic pathology despite extensive evaluation.

Referred pain often originates from a visceral organ (see Table 1). It may be felt in body regions remote from the site of pathology. The mechanism may be the spinal convergence of visceral and somatic afferent fibers on spinothalamic neurons. Common manifestations are cutaneous and deep hyperalgesia, autonomic hyperactivity, tenderness, and muscular contractions.
A complete examination is required, including a general physical examination followed by a specific pain evaluation, and neurologic, musculoskeletal, and mental status assessments. It is important not to limit the examination to the painful location and surrounding tissues and structures.
1. General physical examination
This physical examination consists of the usual head-to-toe examination as described in Chapter 4. It is important to note the following points:

Appearance—obese, emaciated, histrionic, flat effect

Posture—splinting, scoliosis, kyphosis

Gait—antalgic, hemiparetic, using assistive devices

Expression—grimacing, tense, diaphoretic, anxious

Vital signs—sympathetic overactivity (tachycardia, hypertension), temperature asymmetries
It is also important to watch how a patient dresses and moves. Favoring an extremity or protecting a part of the body may not be appreciated unless the relevant movements are elicited. Some elements of the comprehensive examination may be missed if a clinician is fearful of invading the patient’s privacy.
2. Specific pain evaluation
After the general examination, the clinician evaluates the painful areas of the body. The history often directs the search for physical findings. Inspection of the skin may reveal changes in color, flushing, edema, hair loss, presence or absence of sweat, atrophy, or muscle spasm. Inspection of nails may show dystrophic changes. Nerve root injury may be manifest as goose flesh (cutis anserina) in the affected dermatome. Palpation allows mapping of the painful area and detection of any change in pain intensity within the area, as well as during the examination, and helps to define pain type and trigger points. Patient responses, both verbal and nonverbal, should be noted, as well as the appropriateness of the responses and their correlation with affect. Factors that reproduce, worsen, or decrease the pain are sought.
While conducting the physical examination, it is important to identify any changes in sensory and pain processing that may have occurred. These changes may be manifest as anesthesia, hypoesthesia, hyperesthesia, analgesia, hypoalgesia, allodynia, hyperalgesia, or hyperpathia.
3. Neurologic examination
Subtle physical findings are often found only during the neurologic examination. It is essential to conduct a comprehensive neurologic examination when first assessing a patient with pain, to identify associated, and possibly treatable, neurologic disease. The examination can be performed in 5 to 10 minutes. Later in the course of treatment, the neurologic examination can be more focused and briefer.
Mental function is assessed by evaluating the patient’s orientation to person, place, and time, short- and long-term memory, choice of words used to describe symptoms and answer questions, and educational background.
The cranial nerves should be examined, especially in patients complaining of head, neck, and shoulder pain symptoms. Table 2 lists the function of each cranial nerve.

Table 2. Neurologic examination of cranial nerves

A simple assessment of spinal nerve function should also be performed. Spinal nerve sensation is determined by the use of cotton or tissue paper for light touch, and pinprick for sharp pain and proprioception. Potentially painful peripheral neuropathies are listed in Table 3. Spinal nerve motor function is determined by deep tendon reflexes, the presence or absence of the Babinski reflex, and tests of muscle strength. Table 4 lists sensory and motor manifestations of common root syndromes.

Table 3. Painful sensory neuropathies

Table 4. Pain-induced disturbances of gait

Coordination is assessed by testing balance, rapid hand movement, finger-to-nose motion, toe-to-heel motion, gait, and Romberg’s test. Cerebellar dysfunction can often be detected during these maneuvers. Table 5 lists pain disturbances, caused by various disease processes, that can affect gait.

Table 5. Common painful root syndromes

Pain of psychogenic origin usually results in a neurologic examination whose findings are not typical of organic pathology. Abnormal pain distributions, such as glove or stocking patterns and exact hemianesthesia, are common in patients with psychogenic pain.
4. Musculoskeletal system examination
Abnormalities of the musculoskeletal system are often evident on inspection of the patient’s posture and muscular symmetry. Muscle atrophy usually indicates disuse. Flaccidity indicates extreme weakness, usually from paralysis, and abnormal movements indicate neurologic damage or impaired proprioception. Limited range of motion of a major joint can indicate pain, disc disease, or arthritis. Palpation of muscles helps in evaluating range of motion and in determining whether trigger points are present. Coordination and strength are also tested.
5. Assessment of psychological factors
Complete assessment of pain includes analysis of the psychological aspects of pain and the effects of pain on behavior and emotional stability. Such assessment is challenging, because many patients are unaware of or reluctant to present psychological issues. It is also more socially acceptable to seek medical than psychiatric care.
Initially, the use of a descriptive pain questionnaire, such as the MPQ, may provide some evidence of a patient’s affective responses to pain. For example, whereas words such as aching and tingling refer to sensory aspects of pain, words such as agonizing and dreadful suggest negative feelings and do not aid in characterizing the pain sensation. For a fuller description of psychological evaluation in pain management, see Chapter 15.
A patient’s personality greatly influences his or her response to pain and choice of coping strategies. Some patients may benefit from the use of strategies of control, such as distraction and relaxation. Patients who have an underlying anxiety disorder may be more likely to seek high doses of analgesics. Therefore, inquiry regarding a patient’s history of coping with stress is often useful.
As part of the pain history, the clinician should include questions about some of the common symptoms in patients with chronic pain: depressed mood, sleep disturbance, preoccupation with somatic symptoms, reduced activity, reduced libido, and fatigue. Standardized questionnaires, such as the Minnesota Multiphasic Personality Inventory (MMPI), may expand the assessment. On this inventory, patients with chronic pain characteristically score very high on the depression, hysteria, and hypochondriasis scales. However, the MMPI may reflect functional limitation secondary to pain as well as psychological abnormality associated with chronic pain, limiting its interpretation for some patients suspected of having psychogenic pain.
A number of psychological processes and syndromes predispose patients to chronic pain. Predisposing disorders include major depression, somatization disorder, conversion disorder, hypochondriasis, and psychogenic pain disorder. The diagnosis of somatization disorder is quite specific, although many patients with chronic pain may somatize (i.e., focus on somatic complaints). This diagnosis requires a history of physical symptoms of several years’ duration, beginning before the age of 30 years and including complaints of at least 14 specific symptoms for women and 12 for men. These symptoms are not adequately explained by physical disorder, injury, or toxic reaction.
Psychogenic pain may occur in susceptible individuals. In some patients, pain may ameliorate more unpleasant feelings, such as depression, guilt, or anxiety, and distract the patient from environmental stress factors. Features from the patient’s history that suggest a psychogenic component to chronic pain include the following:

Multiple locations of pain at different times

Pain problems dating since adolescence

Pain without obvious somatic cause (especially in the facial or perineal area)

Multiple, elective surgical procedures

Substance abuse (by patient and/or significant other)

Social or work failure
Psychogenic pain is clearly distinct from malingering. Malingerers have an obvious, identifiable environmental goal in producing symptoms, such as evading law enforcement, avoiding work, or obtaining financial compensation. Patients with psychogenic pain make illness and hospitalization their primary goals. Being a patient is their primary way of life. Such patients are unable to stop symptom production when it is no longer obviously beneficial.
The physical examination in patients with psychological factors exacerbating pain may be perplexing. Some findings may not correspond to known anatomic or physiologic information. Examples of such findings include the following:

Manual testing inconsistent with patient observation during sitting, turning, and dressing

Grasping with three fingers

Antagonist muscle contraction on attempted movement

Decreased tremor during mental arithmetic exercises

A positive Romberg’s sign with one eye closed

Vibration absent on one side of midline (skull, sternum)

Inconsistency of timed vibration when affected side is tested first

Patterned miscount of touches

Difficulty touching the good limb with the bad

A slight difference in sensation on one side of the body
Useful neurologic signs are deep tendon reflexes, motor tone and bulk, and the plantar response. Observation is critical. Pain drawings at multiple time intervals are also useful in evaluating a patient with chronic pain of unclear etiology.
The diagnosis and understanding of a patient’s pain complaint can usually be obtained after a thorough history and physical examination. Diagnostic and physiologic studies are used to support a clinician’s suspicion, as well as to assist in the diagnosis. Some of the more common studies used for pain assessment include the following.
Conventional radiography is used to diagnose bony abnormalities, such as pathologic fractures seen in bony metastases, spine pathology (including spondylolisthesis, stenosis, and osteophyte formation), and bone tumors. Some soft-tissue tumors and bowel abnormalities can also be seen. Radiographs of the painful area have usually been obtained by the referring physician.
A CT scan is most often used to define bony abnormalities, and MRI best shows soft-tissue pathology. Spinal stenosis, disc herniation or bulge, nerve root compression, and tumors in all tissues can be diagnosed, as well as some causes of central pain, such as CNS infarcts or plaques of demyelination.
Diagnostic blocks may differentiate somatic from visceral pain and confirm the anatomic location of peripheral nerve pain. They may help localize painful pathology or contribute to the diagnosis of complex regional pain syndrome (CRPS). They are also necessary precedents to neurolytic blocks for malignant pain or radiofrequency lesions. Diagnostic blocks are described in detail in Chapter 12.
Drug challenges are used to predict drug treatment utility and to help in the assessment of pain etiology. For example, brief intravenous infusions of opioids, lidocaine, and phentolamine are used to predict opioid sensitivity in nonmalignant chronic pain, to predict sensitivity to sodium channel blockade in neuropathic pain, and to assess the potential reversibility of the sympathetic component of pain in CRPS. The value of this type of testing in predicting treatment efficacy is debatable. In most reports, chronic treatment has been limited to responders, which precludes validation of the infusion as a predictive test.
Various neurophysiologic tests are used to help in the diagnosis of pain syndromes and related neurologic disease (see Chapter 7). The neurophysiologic tests most commonly used in pain clinics are categorized as quantitative sensory testing (QST), and these tests specifically evaluate patients’ responses to carefully quantified physical stimuli.
Thermography is a noninvasive way of displaying the body’s thermal patterns. A normal thermal pattern is relatively symmetric. Tissue pathology is associated with chemical and metabolic changes that may cause abnormal thermal patterns by altering vascularity, such as in CRPS. The differences in patterns of color are not specific for underlying central or peripheral pathology.
Myelography is the injection of radiopaque dye into the subarachnoid space to radiographically visualize spinal cord/column abnormalities, such as disc herniation, nerve root impingement, arachnoiditis, and spinal stenosis. Major disadvantages of this procedure are postdural-puncture headache and meningeal irritation.
Bone scanning is the use of a radioactive compound to detect bone lesions, including neoplastic, infectious, arthritic, and traumatic lesions; Paget’s disease; and the osteodystrophy of reflex sympathetic dystrophy. The radioactive compound accumulates in areas of increased bone growth or turnover. The test is very sensitive for subtle bone abnormalities that may not appear on conventional radiographs.
Small punch skin biopsy (immunolabeled to show the cutaneous sensory nerve endings) is a new tool with which to directly visualize the cutaneous endings of pain neurons. Although currently available at only a few centers, this technique is replacing sural nerve biopsy for the diagnosis of sensory neuropathies. The technique appears to be helpful for diagnosing focal painful nerve injuries. Research has shown that various painful neuropathic conditions are associated with loss of nociceptive innervation in painful skin. Skin biopsies are only minimally invasive, can be repeated, and can be performed in areas other than those innervated by the sural nerve.
Functional brain imaging , such as by positron emission tomography or functional MRI, is an investigative tool at present with provocative findings regarding the cortical and subcortical processing of pain information. Functional MRI shows pain to be a remarkably distributed system at the cortical level.
The assessment of pain can be challenging and intensive, but it is an essential component of pain management, and it allows the pain physician to devise optimal treatment for some of medicine’s most complex patients. The patient must be treated as a complete person and not just as a painful location. Believing the patient and establishing rapport are of the utmost importance. A systematic approach, grounded in a knowledge of anatomy and physiology, will assist the clinician in determining the pathophysiology of the patient’s pain complaint. Then, therapy can be formulated, promptly initiated, and easily reassessed.

Beecher HK. Measurement of subjective responses. New York: Oxford University Press, 1959.

Boivie J, Hansson P, Lindblom U. Touch, temperature and pain in health and disease: Mechanisms and assessments. Progress in pain research and management, volume 3. Seattle: IASP Press, 1994.

Carlsson AM. Assessment of chronic pain. I: Aspects of the reliability and validity of the visual analogue scale. Pain 1983;16:87–101.

Gracely RH. Evaluation of multidimensional pain scales. Pain 1992;48:297–300.

Katz J. Psychophysical correlates of phantom limb experience. J Neurol Neurosurg Psychiatry1992;55:811–821.

Lowe NK, Walder SM, McCallum RC. Confirming the theoretical structure of the McGill pain questionnaire in acute clinical pain. Pain1991;46:53–60.

McGrath PA. Pain in children: Nature, assessment and treatment. New York: Guilford Press, 1990.

Melzack R. The McGill pain questionnaire: Major properties and scoring methods. Pain 1975;1:277–299.

Melzack R, Katz J. Pain measurement in persons in pain. In: Wall PD, Melzack R, eds. Textbook of pain, 4th ed. New York: Churchill-Livingstone, 1999.

Price DD, Bush FM, Long S, et al. A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales. Pain 1994;56:217–226.

1 Comment

5 Diagnostic Imaging and Pain Management

5 Diagnostic Imaging and Pain Management
The Massachusetts General Hospital Handbook of Pain Management

Diagnostic Imaging and Pain Management

Onassis A. Caneris

I have a little shadow that goes in and out with me,
And what can be the use of him is more than I can see.
He is very, very like me from the heels up to the head;
And I see him jump before me when I jump into my bed.
—Robert Louis Stevenson, 1850–1894

I. Imaging techniques and studies

1. Plain film radiology

2. Fluoroscopy

3. Computed tomography

4. Magnetic resonance imaging

5. Myelography

6. Bone scans and nuclear medicine

7. Discography

8. Positron-emission tomography
II. Headache

1. Primary headache

2. Secondary headache
III. Craniofacial pain syndromes

1. Trigeminal neuralgia

2. Glossopharyngeal neuralgia
IV. Central pain syndromes

1. Thalamic pain syndromes

2. Spinal cord injury
V. Vertebral axis pain

1. Plain x-ray evaluation of low back pain

2. MRI and low back pain

3. Pain after lumbar surgery

4. Arachnoiditis

5. Metastatic disease of the spine

6. Infectious processes of the vertebral spine
VI. Conclusion
Selected Reading

In recent years, there have been tremendous advances in understanding the pathophysiology and mechanisms of pain; concomitantly, there have been enormous advances in diagnostic imaging. Diagnostic imaging is an essential tool for the pain practitioner, who uses it to understand, diagnose, and treat pain. Although plain x-rays remain the mainstay of diagnostic imaging, advanced modalities including computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine studies have proved extremely valuable diagnostic tools for patients with pain. Over the past decade, the use of new technologies has resulted in a 50% increase in healthcare costs. It becomes increasingly important for the pain physician to have a clear understanding of imaging studies and to optimize the use of diagnostic imaging. Consultation with a radiologist or imaging specialist often aids in choosing the most cost-effective test for establishing a diagnosis and in understanding the underlying pathology.
1. Plain film radiology
Plain x-rays (static x-rays) generate two-dimensional (2D) images that primarily display skeletal tissue, but in addition soft tissue anatomy is either seen or inferred. Contemporary x-ray technology generally produces high-quality images with minimal radiation exposure. X-rays are produced as electrons from a cathode are accelerated by electrical current toward an anode target. The x-ray beam is differentially absorbed as it passes through a portion of the patient and then goes on to expose film. Radiopaque contrast materials given orally, locally, intravenously, and intrathecally may be used to aid the study. Most contrast materials used with plain x-rays are iodine-based. Plain x-rays remain the first-line examination for many conditions.
2. Fluoroscopy
The principles of fluoroscopy are the same as those of plain x-rays. The primary difference is that the transmitted radiation is viewed on a fluorescent screen rather than on a static film, and the patient can be imaged in real time. The image is generally amplified by an image intensifier. Fluoroscopy can be used both in diagnostic studies and in assisting with therapeutic treatment.
3. Computed tomography
The prototype CT scanner was developed in the 1960s. Firstgeneration scanners took days to collect data and then hours to reconstruct the images. In the early 1970s, CT scanning for imaging the brain became available. Today’s fourth-generation scanners have significantly improved quality, and the imaging time is significantly shortened. In CT imaging, the x-ray tube produces a beam of energy that passes through a single section of the patient. This beam is then detected by a circular array of detectors on the opposite side. Both the detector and the x-ray source rotate around an axis of the patient and produce exposures at small intervals of rotation. Subsequently, computer reconstruction results in a display of the targeted area. The resolution can be as small as 0.5 mm. Intravenous contrast can be used to enhance the imaging of vascular structures as well as normal tissues.
CT scanning offers the advantage of three-dimensional (3D) images, but they are generally in standard cross-sectional or axial planes. Quantitative CT scanning is particularly useful in measuring bone density for the assessment of osteoporosis. 3D CT also allows postreconstruction images to be rotated at various angles. CT displays soft tissues fairly well and is used for soft tissue imaging if MRI (which provides superior soft tissue contrast) is not available, or if the patient cannot tolerate MRI because of claustrophobia or because it is a more lengthy process.
4. Magnetic resonance imaging
As early as the 1940s and 1950s, nuclear magnetic resonance (NMR) was used to image chemical compounds by exposing them to strong magnetic fields. By the mid 1980s, clinical NMR had become common, and the name was changed to magnetic resonance imaging because of public anxiety engendered by the word nuclear
A significant difference between MRI scanning and CT and x-rays is that MRI uses no ionizing radiation. In MRI, signals are obtained by subjecting the tissues to strong magnetic fields, which influence hydrogen ions in the tissues to align in a certain direction. Tiny radiofrequency signals are emitted as the hydrogen ions “relax” when the magnetic field is removed. The image represents the intensities of the electromagnetic signals emitted from the hydrogen nuclei in the patient. A tissue such as fat, which is rich in hydrogen ions, gives a bright signal, whereas bone gives a void, or essentially no signal. Abnormal tissue generally has more free water and displays different MR characteristics.
The MR signal is a complex function of the concentration of deflected normal hydrogen ions, buildup and relaxation times of the magnetic field (T1 and T2 respectively), flow or motion within the sample, and the MR sequence protocol. Three types of MR sequences are used: spin echo, gradient echo, and inversion recovery. MRI is easily able to provide multiplanar images. Its advantage over CT is its superior contrast of soft tissues, especially neural tissue. The addition of gadolinium as a contrast material aids in defining tumors and inflammatory processes.
5. Myelography
Injection of radiocontrast material into the intrathecal space, followed by imaging using conventional x-ray techniques or CT, provides diagnostic information about potential structural abnormalities affecting the spinal nerves. When noninvasive imaging with either MRI or CT does not provide adequate information, myelography, which was once the gold standard for assessing the spine, remains an option for diagnosing structural spine disease. It is also useful for imaging patients who have had spinal instrumentation, which tends to produce extensive artifact on CT.
Postmyelogram CT imaging is sometimes useful for detecting subtle spinal nerve impingement caused by far-posterior lateral intervertebral disc herniation that has been missed by MRI. Its disadvantages are that it is invasive and, unlike MRI, it utilizes ionizing radiation.
6. Bone scans and nuclear medicine
The field of nuclear medicine followed the discovery of radioactivity in 1896. There are three types of radioactive emissions: positive particles (alpha particles); negative particles (beta particles); and high-penetration gamma radiation. The scintillation events are detected by a scintillation camera and mapped in 2D space. Nuclear medicine uses the tracer principle, which essentially tags certain physiologic substances in the body and measures its distribution and flow or its presence in a target system. A radiopharmaceutical agent is injected into the patient and the radioactive decay is detected by a detection device, for example, a gamma counter.
Bone scans are commonly used to evaluate complaints of skeletal pain. Radiopharmaceuticals labeled with technetium-99m localize areas of increased bone turnover and blood flow that represent increased rates of osteoblastic activity. Bone scans are more sensitive than x-rays in detecting skeletal pathology. One third of patients with pain and known malignant disease with normal x-rays have metastatic lesions on bone scans. The specificity of bone scans is not high, which can sometimes be a problem.
7. Discography
Discography involves injecting the nucleus pulposus of an intervertebral disc with contrast material under fluoroscopic guidance. This can provide objective structural and anatomic information regarding the intervertebral disc. In addition, it can provide subjective information as to whether a particular disc is the source of a patient’s axial lumbar pain.
8. Positron-emission tomography
In positron-emission tomography (PET), positron emissions are detected with a circular array of detectors. The number of decays is displayed to produce an image of specific metabolic processes. PET is an excellent tool for quantification of various metabolic and physiologic changes and processes, making it a functional imaging device. The collection of literature about PET scanning and functional neuroimaging of pain processes is increasing.
Headache is a frequent presentation in both the primary care physician’s office and the pain clinic. The pain specialist must become familiar with the indications for imaging in the assessment of patients with headache. The vast majority of patients who complain of headache and have normal neurologic examinations have a normal CT imaging study.
In a large prospective study of 195 headache patients with normal neurologic examinations, only a minority (9%) had abnormal CT scans (seven had tumor, five had hydrocephalus, three had arteriovenous malformations, two had hemorrhages, and one had cerebral infarction). In a retrospective study of 505 patients with headache without regard to neurologic examination, 35 patients (7%) had abnormal imaging studies. In a study of 350 patients who complained of headache and were prospectively studied with contrast scans, seven patients (2%) had positive scans. Positive pathology included metastasis, sinusitis with epidural abscess, meningiomas, and subdural hemorrhage. In all patients with positive scans, abnormal neurologic exams were present.
An overview of the available data suggests that of 100,000 patients who complain of headache as a sole symptom and have a normal neurologic examination, less than one has a tumor or other significant pathology on cranial imaging studies. It becomes evident that a careful history and neurologic examination are crucial for deciding whether a patient is at risk and whether to order a diagnostic test. Imaging studies ordered without good clinical indication are usually unhelpful and certainly expensive.
1. Primary headache
In patients who present with a history characteristic of primary headache without additional neurologic symptoms and with normal neurologic examinations, it is exceedingly rare to find imaging abnormalities. In a study of 435 patients with symptoms characteristic of classic migraine, contrast-enhanced CT scans were reviewed; one patient was found to have a choroid plexus tumor and no other abnormalities were found. The patient continued to have classic migraines after neurosurgical removal of this tumor, and it was most likely an incidental finding. In a study of 90 patients with “chronic headaches” lasting more than 1 week, CT scanning of all patients found no significant abnormalities. Patients were followed clinically and developed no significant problems.
2. Secondary headache
Several other clinical scenarios warrant discussion. In patients without history of headaches, presenting with the “worst headache of my life,” acute subarachnoid hemorrhage needs to be considered. In such cases, emergent noncontrast CT scanning is the imaging evaluation of choice. Noncontrast CT scanning is extremely sensitive for identifying the presence of acute blood. Additionally, in patients who complain of new headache and fever, lumbar puncture may be indicated. A noncontrast CT scan to exclude a space occupying lesion, which would be a contraindication for lumbar puncture, is indicated before proceeding.
Noncontrast CT scanning is also indicated in acute trauma, because it best identifies acute hemorrhage and lesions of the bone. Contrast CT scanning is indicated when there is clinical suspicion of vascular lesions, neoplastic lesions, or inflammatory conditions. Plain x-rays are not helpful in evaluating headache. In the nonacute setting, MRI scanning has a high degree of sensitivity for intracranial pathology. Diagnostic criteria and imaging for secondary headache are discussed in Chapter 28.
Of patients with newly diagnosed brain tumors, 40% present with a chief complaint of headache. Obstructing the flow of cerebrospinal fluid (CSF), thus increasing intracranial pressure, can produce headaches. Not infrequently, larger parenchymal tumors may initially not produce headache. In patients presenting with headache and focal or lateralizing neurologic symptoms, MRI with contrast material would be the imaging study of choice.
Carotid artery dissection
Symptoms of carotid artery dissection include new-onset unilateral headache with associated anterior cervical pain. Fluctuating hemispheric neurologic deficits as well as Horner’s syndrome may also be present. Carotid dissections are most common in association with trauma; fibromuscular dysplasia may also predispose to carotid dissection. The most common location for dissection is several centimeters above the carotid bifurcation.
Arterial angiography is usually most effective in making the diagnosis, but MRI and magnetic resonance angiography (MRA) may also be helpful, particularly in subsequent follow-up examinations. MRI scanning demonstrates high signal intensity, which usually represents a clot or low arterial flow.
Cerebrovenous and sinus occlusive disease
The most common presenting symptom with either venous or sinus occlusive disease is headache; more than 75% of these patients generally complain of headache. Occlusive disease frequently results in increased intracranial pressure. Cerebral ischemia may also result. Cavernous sinus thrombosis produces severe retroorbital or periorbital pain with proptosis and ophthalmoparesis. Traditional contrast angiography is in most circumstances the imaging study of choice, but traditional angiography is being replaced by MRA and MRI.
Both CT and MRI are appropriate in the evaluation of hydrocephalus. Aqueductal stenosis is seen on imaging studies represented by dilatation of the lateral ventricles and the third ventricle, with a normal appearance of the fourth ventricle; MRI is the imaging study of choice.
In pseudotumor cerebri, imaging studies tend to be normal. Diagnosis is made by examination of the CSF with careful manometry and identification of increased intracranial pressure.
Low Pressure Headache
Postural headaches can be seen as a result of diminished intracranial pressure. These headaches are most commonly seen after lumbar puncture, but they can also be seen after trauma or can occur “spontaneously.” CT and MRI tend to be normal. Isotope cysternography may demonstrate the site of dural leakage of CSF.
Chiari Malformation
Patients with Chiari malformations very frequently present with headache as a primary symptom. Additional neurologic complaints are often associated. MRI is the modality of choice for imaging Chiari malformations. Three types are identified. In type 1, the cerebellar tonsils are displaced caudally into the cervical spinal canal. In type 2, there is additional caudal displacement of the lower cerebellum as well as the brainstem; anatomic abnormalities are seen in the fourth ventricle, and there is associated meningomyelocele. In type 3, either encephalocele or spina bifida is also present.
1. Trigeminal neuralgia
Severe unilateral paroxysmal lancinating pain in the distribution of the trigeminal nerve is characteristic of trigeminal neuralgia. Trigeminal neuralgia is idiopathic. Imaging studies are generally negative. In patients with trigeminal neuropathy and trigeminal neuropathic pain in which atypical features exist, it is important to evaluate for other diagnostic possibilities. MRI is the imaging modality of choice. Occasionally, vascular malformations, aneurysms, and tumors cause trigeminal neuropathy. Multiple sclerosis is sometimes associated with neuropathic facial pain, in which case lesions of increased T2-weighted signal intensity on MRI may be seen in the trigeminal brainstem dorsal root entry zones.
2. Glossopharyngeal neuralgia
The characteristic pain of glossopharyngeal neuralgia is similar to that of trigeminal neuralgia, but it is located unilaterally in the posterior tongue throughout the tonsillar area and sometimes at the auricular area. It also is most frequently idiopathic. In isolated glossopharyngeal neuralgia, imaging studies are rarely positive.In patients with evidence of associated pathology, particularly at the brainstem, MRI with contrast medium is the imaging study of choice.
Central neuropathic pain can result after there has been injury to the primary somatosensory nervous system. Constant burning neuropathic pain is typically seen. Infarction, trauma, and radiation are frequent causes.
1. Thalamic pain syndromes
Injury to the thalamus, specifically the ventral posterolateral nucleus of the thalamus, results in constant burning pain in the contralateral hemi-corpus, including the face, arm, trunk, and leg, although variations in the distribution of pain do exist. This most frequently results from thalamic infarction but can also be the result of hemorrhage, trauma, or space-occupying lesions, including tumor, infection, and abscess. Imaging reveals signal abnormalities in the thalamus contralateral to the pain. A “pseudo-thalamic pain syndrome” can result after injury to the thalamocortical white matter tract. Clinical presentation is the same, but MRI reveals abnormalities in the thalamocortical radiations. In exceptional cases, the MR image is normal but pathology be delineated using functional imaging studies.
2. Spinal cord injury
Injury to the spinal cord at any level can result in a central pain syndrome. Damage to the spinothalamic tract frequently results in central neuropathic pain. Significant central neuropathic pain accompanies spinal cord injury in 25% of patients. Underlying pathology may be trauma, space-occupying lesions including neoplasms, demyelinating process including multiple sclerosis, and syringomyelia. MRI is the imaging modality of choice. In multiple sclerosis, lesions of increased T2-weighted signal intensity are seen in the white matter tracts of the spinal cord. In syringomyelia, MRI reveals a central cavity that shows high signal intensity on T2- weighted images and diminished signal on T1-weighted images.
Low back pain is an extremely common presentation to both the primary care physician and the pain clinic. Underlying pathologic processes affecting the lumbar spine include disc degeneration, degrees of intervertebral disc herniation, osteoarthrosis of the facet joints, fracture of a vertebra, dislocation of a vertebra, spondylolisthesis, and osteoporosis. Degenerative changes causing low back pain may be difficult to distinguish from other common causes, including pain of muscular origin and pain of additional soft tissue origin. Less common alternative causes include intradural and extradural neoplasms, infections, and congenital abnormalities of the spine. The history and physical examination are the basis of the evaluation, but imaging studies may be needed to make a definitive diagnosis.
The primary rationale for radiographic imaging of low back pain is to exclude or define serious pathology. The majority of low back pain originates from soft tissues, and imaging studies are often not helpful. In older patients, imaging studies frequently reveal abnormalities that may or may not be responsible for the patient’s pain syndrome. Plain x-rays can be helpful in diagnosing spondylolysis (pars interarticularis defects, usually at L5 or sometimes L4), ankylosing spondylitis, fractures, and occasionally degenerative disc disease. When neurologic signs or symptoms are present, including those of sciatica, MRI is the imaging modality of choice. MRI without contrast material can detect herniation of lumbar discs with compression of nerve roots causing radicular symptoms.
In patients with a previous history of lumbar surgery, it is imperative to also obtain a contrast-enhanced study, which helps differentiate recurrence of disc herniation from epidural scar tissue; the latter is detected by T1-weighted signal enhancement after administration of contrast. In patients with a clinical complaint of lumbar claudication and suspected spinal stenosis, both CT and MRI are appropriate. CT offers the advantage of superior imaging of bony hypertrophic changes of the lumbar spine.
1. Plain x-ray evaluation of low back pain
Plain x-ray provides an adequate assessment of the configuration and alignment of the lumbar vertebral spine with a high degree of accuracy. There have been a number of natural history and comparative studies evaluating the usefulness of plain x-rays in evaluating low back pain. In a large retrospective study reviewing 1,000 lumbar spine radiographs from patients who complained of low back pain, more than one half of the radiographs were normal. In another study of 780 patients, only 2.4% had unique diagnostic findings on plain radiographs.
Most episodes of low back pain resolve within 7 weeks of onset. It is generally felt that the risks and cost of taking radiographs for all patients at a first presentation of low back pain do not justify the possible small associated benefit. General recommendations for radiographs in patients with low back pain are as follows:

For patients with a first episode of low back pain, present for less than 7 weeks, who have not been treated or who are improving with treatment, no radiographs of the lumbar spine are indicated unless an atypical clinical finding or special psychological or social circumstances exist. Atypical history includes age over 65, history suggesting a high risk for osteoporosis, symptoms of persistent sensory deficit, pain worsening despite treatment, intense pain at rest, fever, chills, unexplained weight loss, and recurrent back pain with no radiographs within the past 2 years. Atypical physical findings include significant motor deficit and unexplained deformity.

For patients with recurrent low back pain, radiographs are not indicated if a previous radiographic study had been done within 2 years.

Patients with a history of a brief, self-limited previous episode of low back pain do not require radiographs within the first 7 weeks of a current episode if they are improving.
In general, anteroposterior and lateral views are the only views that should be done initially. In patients with chronic pain or additional history and physical findings that suggest stenosis or instability, flexion and extension films may be indicated.
2. MRI and low back pain
MRI has a very high sensitivity for detecting pathology of the lumbar spine. A poor correlation exists between the severity of pain symptoms and the extent of morphologic changes seen on MRI studies: a significant percentage of normal individuals without lumbar pain have degenerative changes on MRI (as many as 50% to 60%) and even disc herniation (as many as 20%). Careful attention must be paid to correlating clinical symptoms with radiographic findings; otherwise, imaging findings may be used inappropriately to justify unneeded intervention or treatment.
Age-related morphologic changes occur in the lumbar spine throughout life. There is a decrease in water and glycosaminoglycans in the intervertebral disc, and there is also an increase in collagen. On MRI, this is seen as loss of signal intensity on T2- weighted images, a reduction in the height of vertebral bodies, a reduction in the height of the intervertebral discs, and a reduction in the caliber of the spinal canal. The onset of degenerative processes of the lumbosacral spine seem to be consistently marked by tears of the annulus fibrosis, as well as by MRI and histologic changes of the vertebral bone marrow adjacent to the intervertebral spaces. Facet degeneration rarely occurs in the absence of disc degeneration, and it seems likely that facet osteoarthropathy results from the added stress of increased loading after disc space narrowing has occurred. Multiple studies have found an association between degenerated disc and facet osteoarthritis using imaging criteria.
In patients with radicular symptoms, the clinical evaluation can usually predict the spinal nerve involved. The actual spinal pathology, however, cannot be predicted with clinical evaluation alone, and MRI examination can be of great assistance. A spinal nerve can be compressed by a disc at either the traversing segment by central disc herniation or at the exiting segment by a lateral disc herniation. In these circumstances, imaging is beneficial for defining the site of pathology. Symptomatic patients may have neuroimaging abnormalities at more than one spinal level.
3. Pain after lumbar surgery
In patients who have had previous back surgery and now complain of recurrent radicular pain, the differential diagnosis includes the following:

Incorrect original diagnosis or concomitant disease

Spinal nerve or dorsal root ganglion pathology, including axonal injury or persistent neurapraxic injury

Retained or recurrent intervertebral disc fragment

Epidural fibrosis

Central sensitization

Complex regional pain syndrome
Postoperative fibrosis is a natural consequence of surgical procedures. Numerous reports suggest that fibrosis and adhesions cause compression or tethering of the spinal nerves and their roots, which in turn causes recurrent radicular pain and physical impairment. The literature repeatedly suggests that fibrosis is the major cause of recurrent symptoms when no alternative bony or disc pathology can be found. It has also been suggested that fibrosis may be causal in as much as 25% of all patients with failed back surgery syndrome.
Recurrent radicular pain is defined as pain in a patient who had a successful outcome from the primary surgery at 1 month postoperatively but has had recurrence of radicular pain within 6 months postoperatively. A significant association between the size of the peridural scar and incidence of pain has been demonstrated in this group of patients.
In patients who have had lumbar surgery and present with recurrent radicular pain, it is essential to obtain an MRI scan without and with contrast. This assists in differentiating between a recurrent or retained disc fragment and epidural scarring.
The criteria used to identify epidural fibrosis by MRI include the following:

Epidural scar is isointense to hypointense relative to the intervertebral disc on T1-weighted images on an MRI scan.

Peridural scar tends to form in a curvilinear pattern surrounding the dural tube, with homogenous intensity.

Traction of the dural tube toward the side of the soft tissue is more characteristic of scar.

Scar tissue is seen to consistently enhance immediately after the injection of contrast material, regardless of its location.
The criteria used to identify recurrent herniated disc by MRI include the following:

Recurrent herniated disc material is isointense to the intervertebral disc on T1-weighted images. There tends to be a more variable appearance on T2-weighted images.

Recurrent herniations tend to have a polypoid configuration with a smooth outer margin.

Recurrent disc material does not enhance within the first 10 to 20 minutes after administration of contrast material.
4. Arachnoiditis
Arachnoiditis, which is distinct from epidural scar formation, involves inflammatory and scar tissue within the dura surrounding the spinal nerves. The MRI characteristics of arachnoiditis show three different possible patterns. The first is centrally clumped spinal nerve roots in the thecal sac seen on T1-weighted images; the second is peripheral adhesions of roots to the thecal sac; the third is an increased soft tissue signal within the thecal sac below the conus. Arachnoiditis typically presents as polyradicular lower extremity pain.
5. Metastatic disease of the spine
Severe back pain is a common presentation of metastatic disease of the lumbar spine. The most common tumors that metastasize to bone and thus the lumbar spine are lung, prostate, and breast. Multiple myeloma and breast cancer typically are osteolytic, whereas prostate tends to cause osteosclerotic changes. Bone scans are very sensitive for detecting metastatic involvement of the lumbar spine. The correlation between the severity of bone scan and the intensity of pain is generally poor.
When spinal cord compression resulting from epidural metastatic disease is suspected, MRI is the imaging modality of choice and contrast enhancement is recommended. Back pain is a common presentation of spinal cord compression. When significant reduction of vertebral body height is seen, concomitant epidural involvement is common. Disruption of the pedicle on imaging suggests metastatic disease and, when seen on a plain radiograph, warrants thorough investigation.
6. Infectious processes of the vertebral spine
Plain x-rays can be utilized to assess osteomyelitis. Characteristic changes include loss of end-plate definition, associated soft tissue swelling, destruction of vertebral bodies, and loss of intervertebral disc height. MRI detects involvement of the disc space. Occasionally, MRI is negative and radionucleotide imaging studies can be helpful in establishing the diagnosis. The characteristics of osteomyelitis as seen on MRI include decreased signal intensity, a loss of delineation and demarcation of the vertebral end plate on T1- weighted images; and increased signal intensity in the intervertebral disc on T2-weighted images.
Imaging studies are indispensable tools for the pain physician, who must use them not only as appropriate diagnostic tools but also in a cost-effective manner. Consultation with the department of radiology may be helpful when a diagnosis is uncertain.

Atlas SW, ed. Magnetic resonance imaging of the brain and spine. New York: Raven Press, 1996.

Modic MT, Masaryk TJ, Ross JS, eds. Magnetic resonance imaging of the spine. Chicago: Year Book Medical, 1989.

Osborn AG. Diagnostic neuroradiology. St Louis: Mosby. 1994.


4 The History and Clinical Examination

4 The History and Clinical Examination
The Massachusetts General Hospital Handbook of Pain Management

The History and Clinical Examination

Jan Slezak and Asteghik Hacobian

To each his suff’rings: all are men,
Condemn’d alike to groan,
The tender for another’s pain,
Th’ unfeeling for his own.
—Thomas Gray, 1716–1771

I. Patient interview

1. Pain history

2. Medical history

3. Drug history

4. Social history
II. Patient examination

1. General examination

2. Systems examination
III. Inconsistencies in the history and physical examination
IV. Conclusion
Selected Reading

The key to accurate diagnosis is a comprehensive history and detailed physical examination. Combined with a review of the patient’s previous records and diagnostic studies, these lead to a diagnosis and appropriate treatment. In pain medicine, a majority of patients have seen multiple providers, have had various diagnostic tests and unsuccessful treatments, and are finally referred to the pain clinic as a last resort. With advances in research and better education of primary care providers, this trend is beginning to change, and more patients are being referred to pain management specialists earlier, with better outcomes as a result.
1. Pain history
Development and timing
The pain history should reveal the location of the pain, the time of its onset, its intensity, its character, associated symptoms, and factors aggravating and relieving the pain.
It is important to know when and how the pain started. The pain onset should be described and recorded (e.g., sudden, gradual, rapid). If the pain started gradually, patients find identifying an exact time of onset difficult. In the case of a clear inciting event, the date and circumstances of onset of pain may point to the event. The condition of the patient at the onset of pain should be noted if possible. In cases of motor vehicle accidents or work-related injuries, the state of the patient before and at the time of the impact should be clearly understood and documented.
The time of the onset of the pain can be very important. If that interval is short, as in acute pain, the treatment should focus on the underlying cause. In chronic pain, the underlying cause has usually resolved and the treatment should focus on chronic pain management.
Various methods are used to measure the intensity of pain, fully described in Chapter 6. Because the complaint of pain is purely subjective, it can be compared only to the sufferer’s own pain over a period of time; it cannot be compared to another person’s report of pain. Of the numerous scales for reporting the so-called level of pain, the most common is the visual analog scale (VAS) of pain intensity, in which patients are instructed to place a marker on a 100-mm continuous line between “no pain” and “worst imaginable pain.” The mark is measured using a standard ruler and recorded as a numeric value between 0 and 100.
An alternative method of reporting the intensity of pain is the numeric rating scale. The patient directly assigns a number between 0 (no pain) and 10 (the worst pain imaginable). Another commonly used method is a verbal categorical scale, with intensity ranging from no pain through mild, moderate, and severe to the worst possible pain.
The patient’s description of the character of pain is quite helpful in distinguishing between different types of pain. For example, burning or “electric shocks” often describe neuropathic pain, whereas cramping usually represents nociceptive visceral pain (spasm, stenosis, or obstruction). Pain described as throbbing or pounding suggests vascular involvement.
The pattern of pain-spread from the onset should also be noted. Some types of pain change location or spread further out from the original area of insult or injury. The direction of the spread also provides important clues to the diagnosis and ultimately to the treatment of the condition. For example, a complex regional pain syndrome can start in a limited area, such as a distal extremity, and then spread proximally, in some instances even to the contralateral side.
Associated symptoms
The examiner should ask about the presence of associated symptoms, including numbness, weakness, bowel and or bladder dysfunction, edema, cold sensation, or loss of use of an extremity because of pain.
Aggravating and relieving factors
Aggravating factors should be elicited, because they sometimes explain the pathophysiologic mechanisms of pain. Various stimuli can exacerbate pain. Exacerbating mechanical factors, such as different positions or activities (sitting, standing, walking, bending, and lifting) may help differentiate one cause of pain from another. Biochemical changes (e.g., glucose and electrolyte levels, hormonal imbalance), psychological factors (e.g., depression, stress, and other emotional problems), and environmental triggers (e.g., dietary influences, weather changes including barometric pressure changes) may surface as important diagnostic clues.
Relieving factors are also important. Certain positions will alleviate pain better than others (e.g., in most cases of neurogenic claudication, sitting is a relieving factor, whereas standing or walking worsens the pain). Pharmacologic therapies and “nerve blocks” affording relief to the patient help the clinician determine the diagnosis and select the appropriate treatment.
Previous treatment
All previously attempted treatment modalities should be listed at the interview. Knowing the history of the degree of pain relief, the duration of treatment, the dosages of prior medications, and adverse reactions helps to avoid repeating procedures or using pharmacologic management that has not helped in the past. The list should include all treatment modalities including physical therapy, occupational therapy, chiropractic manipulation, acupuncture, psychological help, and visits to other pain clinics.
2. Medical history
Review of systems
A complete review of all systems is an integral part of a comprehensive evaluation for chronic and acute pain. Some systems could be directly or indirectly related to the patient’s presenting symptoms and some are important in the management or treatment of the painful condition. Examples are the patient with a history of bleeding problems who may not be a suitable candidate for certain injection therapies, and someone with impaired renal or hepatic function who may need adjustments in medication dosage.
Past medical history
All medical problems that the patient has had in the past should be reviewed, including conditions that were resolved. Previous trauma and any psychological or behavioral issues in the past or present should be recorded.
Past surgical history
A list of all operations and complications should be made, preferably in chronological order. As some painful chronic conditions are sequelae of surgical procedures, this information is important for diagnosis and management.
3. Drug history
Current medications
The practitioner must prescribe and intervene based on the knowledge of which medications the patient is taking, because complications, interactions, and side effects need to be taken into account. A list should be made of all medications currently being used by the patient, including pain medications. It should also include nonprescription and alternative medications (e.g., acetaminophen, aspirin, ibuprofen, and vitamins).
Allergies, both to medications and to nonmedications (latex, food, environmental), should be noted. The nature of a specific allergic reaction to each medication or agent should be clearly documented.
4. Social history
General social history
Understanding the patient’s social structure, support systems, and motivation is essential in analyzing psychosocial factors. Whether a patient is married, has children, and has a job makes a difference. Level of education, job satisfaction, and general attitude towards life are extremely important. Smoking, alcohol consumption, and history of drug or alcohol abuse are important in evaluating and designing treatment strategies. Lifestyle questions about how much time is taken for vacation or is spent in front of television, favorite recreations and hobbies, adequate exercise, and regular sleep, give the practitioner a more comprehensive overview of the patient.
Family history
A complete family history, including health status of the patient’s parents, siblings, and offspring, offers important clues for understanding a patient’s biologic and genetic profile. The existence of any unusual diseases in the family should be noted. A history of chronic pain and disability in family members (including the spouse) should be ascertained. Even clues that have no direct genetic or biologic basis may help by revealing coping mechanisms and codependent behavior.
Occupational history
The patient’s highest level of education completed and degrees obtained should be identified. The specifics of the present job and as well as of previous employment should be noted. The amount of time spent on each job, reasons for leaving, any previous history of litigation, job satisfaction, whether the patient works full time or part time are important in establishing the occupational framework. Whether the patient has undergone disability evaluations, functional capacity assessment, or vocational rehabilitation is also relevant.
The clinical examination is a fundamental and valuable diagnostic tool. Over the past few decades, advances in medicine and technology and a better understanding of the pathophysiology of pain have dramatically improved the evaluation process. The lack of a specific diagnosis in a majority of patients presenting to the pain clinic underscores the need for detail-oriented examinations.
The consequences of improper coding and inadequate documentation to support charges billed to Medicare for evaluation and management services include various sanctions. Complying with regulations by appropriate documentation not only will result in higher reimbursement but also will provide protection against fraud and abuse. The number of levels of evaluation and management services that can be coded depends on the complexity of the examination, which in turn reflects the nature of the presenting problem and the clinical judgment of the provider. Types of examinations include either general multisystem (10 organ systems: musculoskeletal, nervous, cardiovascular, respiratory, ear/nose/mouth/throat, eyes, genitourinary, hematologic/lymphatic/ immune, psychiatric, and integumentary) or single-organ-system examinations. In pain medicine, the most commonly examined systems are the musculoskeletal and nervous systems.
If interventional pain management is part of a diagnostic or therapeutic plan, the evaluation should reveal whether the patient has risk factors for the procedure being considered. Coagulopathy, untreated infection, or preexisting neurologic dysfunction should be documented prior to placement of a needle or catheter or implantation of a device. Extra caution is needed when administering medications such as (a) local anesthetics to a patient with seizure disorder, (b) neuraxial anesthetics to a patient who may tolerate vasodilatation poorly, or (c) glucocorticoids to a diabetic patient. Preanesthetic evaluation should assess ability to tolerate sedation or the anesthesia itself if indicated for a procedure.
The following sections outline a physical examination that incorporates the musculoskeletal and neurologic assessment relevant to pain practice. The examination starts with the evaluation of single systems and commonly proceeds from head to toe.
1. General examination
(i) Constitutional Factors
Height, weight, and vital signs (blood pressure, heart rate, respiratory rate, body temperature) should be measured and recorded. Appearance, development, deformities, nutrition, and grooming are noted. Scan the room for presence of assistive devices brought by the patient. Patients who smoke or drink heavily may carry an odor. Observing the patient who is unaware of being watched may reveal discrepancies that were not seen during the evaluation.
(ii) Pain behavior
Note facial expression, color, and grimacing. Speech patterns suggest emotional factors as well as intoxication with alcohol or prescription or nonprescription drugs. Some patients attempt to convince the practitioner how much pain they are suffering by augmenting their verbal presentation with grunting, moaning, twitching, grabbing the painful area, exaggerating the antalgic gait or posture, or tightening muscle groups. This, unfortunately, makes the objective examination more difficult.
(iii) Skin
Evaluate for color, temperature, rash, and soft-tissue edema. Trophic changes of skin, nails, and hair are frequently seen in advanced stages of complex regional pain syndrome.
2. Systems examination
(i) Cardiovascular System
A systolic murmur with propagation suggests aortic stenosis, and the patient may not tolerate the hypovolemia and tachycardia that accompany rapid vasodilatation (e.g., after administration of neuraxial local anesthetics or sympathetic or celiac plexus blockade). The patient with irregular rhythm may have atrial fibrillation and be anticoagulated. Feel the pulsation of arteries (diabetes, complex regional pain syndrome, thoracic outlet syndrome), venous filling, presence of varicosities, and capillary return.
(ii) Lungs
Examination of lungs may reveal abnormal breath sounds such as crackles, which may be a sign of congestive heart failure and low cardiac reserve. Rhonchi and wheezes are signs of chronic obstructive pulmonary disease. Caution in performing blocks around the chest cavity is advised, as there is an increased risk of causing pneumothorax.
(iii) Musculoskeletal system
The musculoskeletal system examination includes inspection of gait and posture. Deformities and deviation from symmetry are observed. After taking the history, the examiner usually has an idea from which body part the symptoms originate. If this is not the case, a brief survey of structures in the relevant region might be necessary. Positive tests then warrant further and more rigorous evaluation of the affected segment.
Palpation of soft tissues, bony structures, and stationary or moving joints may reveal temperature differences, presence of edema, fluid collections, gaps, crepitus, clicks, or tenderness. Functional comparison of the left and right sides, checking for normal curvature of the spine, and provocation of usual symptoms with maneuvers can help identify the mechanisms and location of the pathologic process.
Examination of range of motion may demonstrate hyper- or hypomobility of the joint. Testing active movement will determine range, muscle strength and willingness of the patient to cooperate. Passive movements, on the other hand, when performed properly, test for pain, range, and end-feel. Most difficulties arise when examining patients in constant pain, as they tend to respond to most maneuvers positively, therefore making the specificity of tests low.
For the patient with back pain, the suggested sequence of examinations is testing of range of motion of cervical, thoracic, and lumbosacral spine; sacroiliac and hip joints; and the straight leg raising test (see Chapter 27).
Specific tests:
Straight leg raising test
The straight leg raising (or Lasegue’s Sign) test determines the mobility of the dura and dural sleeves from L4 to S2. The sensitivity of this test to diagnose lumbar disc herniation ranges between .6 and .97, with a specificity of .1 to .6. Tension on the sciatic nerve begins with 15 to 30 degrees of elevation in the supine position. This puts traction on the nerve roots from L4 to S2 and on the dura. The end of the range is normally restricted by hamstring muscle tension at 60 to 120 degrees. More than 60 degrees of elevation causes movement in the sacroiliac joint and therefore may be painful in sacroiliac joint disorders.
Basic sacroiliac tests
Sacroiliac tests are performed to determine when pain occurs in the buttock.

Push the ilia outward and downward in the supine position with the examiner’s arms crossed. If gluteal pain results, the test is repeated with patient’s forearm placed under the lumbar spine to stabilize the lumbar joints.

Forcibly compress the ilia to the midline with the patient lying on the painless side. This stretches posterior sacroiliac ligaments.

Exert forward pressure on the center of the sacrum with the patient prone.

Patrick’s or “FABER’S” test—Flex, abduct, and externally rotate femur while holding down contralateral anterior superior iliac spine. Stretches anterior sacroiliac ligament and reveals pain caused by ligamentous strain.

Force lateral rotation of the hip joint with knee held in 90 degrees of flexion and the patient in the supine position.
Spinal flexibility
Spinal flexion, extension, and rotation and lateral bending may be limited or painful, leading to a diagnosis of zygapophyseal joint, discogenic, muscular, or ligamentous pain.
Adson’s test
Adson’s test has been advocated for diagnosis of thoracic outlet syndrome. The examiner evaluates the change of radial artery pulsation in a standing patient with arms resting at the side. Ipsilateral head rotation during inspiration may cause vascular compression by the anterior scalene muscle. During the modified Adson’s test, the patient’s head is rotated to the contralateral side. Pulse change suggests compression by the middle scalene muscle. Both tests are regarded by some as unreliable, as the findings may be found positive in about 50% of the normal population.
Tinel test
The Tinel test involves percussion of the carpal tunnel. When it is positive, it gives rise to distal paresthesias. It can be performed at other locations (e.g., the cubital or tarsal tunnel), where it might be suggestive of nerve entrapment. Phalen’s test is positive for carpal tunnel syndrome when a passive flexion in the wrist for 1 minute, followed by sudden extension, results in sensation of paresthesias.
(iv) Neurologic examination
Table 1 summarizes the localization of cervical and lumbar radicular nerves.

Table 1. Cervical and lumbar radicular localization

Evaluation of the motor system starts with observation of muscle bulk and tone and the presence of spasm. Muscle strength is tested in upper and lower extremities. Weakness might be caused by the patient’s unwillingness to cooperate or trying to prevent pain provocation, or by poor effort, reflex neural inhibition in the painful limb, or an organic lesion. Further information is obtained by examination of deep tendon reflexes, clonus, and pathologic reflexes such as the Babinski. Evaluation of coordination and fine motor skills may reveal associated dysfunctions.
The integrity of cranial nerve function is tested by examination of visual fields, pupil and eye movement, facial sensation, facial symmetry and strength, hearing (using tuning fork, whisper voice, or finger-rub), spontaneous and reflex palate movement, and tongue protrusion.
Sensation is tested to light touch (A-b fibers), pinprick (A-D fibers), hot and cold stimuli (A-D and C fibers). Tactile sensation can be evaluated quantitatively with von Frey filaments. The sharp end of a broken sterile wooden Q-tip is a convenient and safe tool for testing sensation to pinprick. The following are often observed in neuropathic pain conditions:
Hyperesthesia–increased sensitivity to stimulation, excluding the special senses
Dysesthesia–an unpleasant abnormal sensation, either spontaneous or evoked
Allodynia–pain caused by a stimulus that normally does not provoke pain
Hyperalgesia–an increased response to a stimulus that is normally painful
Hyperpathia–a painful syndrome characterized by an abnormally painful reaction to stimulus (especially a repetitive one), as well as increased threshold
Summation–a repetitive pinprick stimulus applied at intervals of more than 3 seconds, with a gradually increasing sensation of pain with each stimulus
(v) Mental status examination
The mental status examination is a part of the neuropsychiatric assessment. Examine level of consciousness, orientation, speech, mood, affect, attitude, and thought content. The Mini-Mental Status Exam (MMSE) of Folstein is a useful guide for documenting level of mental function. There are five areas of mental status tested: orientation, registration, attention and calculation, recall, and language. Each correct answer is given one point. A maximum score on the Folstein is 30. A score of less than 23 is abnormal and suggests cognitive impairment.
Inconsistencies in the history and physical examination, vague description of symptoms, and evidence of intense suffering, together with inappropriate pain behavior, may suggest symptom exaggeration, malingering for compensation, and other gains or psychogenic pain. The frequently cited Waddell nonorganic signs may raise suspicion in patients with lower back pain. It may be warranted to proceed with the SF-36 or another instrument designed to identify underlying problems or issues. The Waddell nonorganic signs are grouped into five categories:


Widespread superficial sensitivity to light touch over lumbar spine

Bone tenderness over a large lumbar area


Axial loading, during which light pressure is applied to the skull in the upright position

Simulated rotation of lumbar spine with the shoulders and pelvis remaining in the same plane


Greater than 40 degrees difference in sitting versus supine straight leg raising

Regional disturbance

Motor: generalized giving way or cogwheeling resistance in manual muscle testing of lower extremities

Sensory: nondermatomal loss of sensation to pinprick in lower extremities


Disproportionate pain response to testing (pain behavior with assisted movement using cane or walker, rigid or slow movement, rubbing or grasping the affected area for more than 3 seconds, grimacing, sighing with shoulders rising and falling)
The history and physical examinations are the foundations for pain evaluation and treatment and essential elements of good pain management. They need to be tailored to the individual patient, the complexity of the pain problem, and the medical condition of the patient. The standard history and physical examinations outlined here can be applied to most patients presenting in the pain clinic.

Benzon H, ed. Essentials of pain medicine and regional anesthesia. Philadelphia: Churchill-Livingstone, 1999.

Kanner R, ed. Pain management secrets. Philadelphia: Hanley & Belfus, 1997.

Ombregt L, ed. A system of orthopaedic medicine. London: WB Saunders, 1997.

Raj P, ed. Pain medicine: A comprehensive review. St. Louis: Mosby Year Book, 1996.

Tollison D, ed. Handbook of pain management. Baltimore: Williams & Wilkins, 1994.

Leave a comment

3 The Placebo Effect

3 The Placebo Effect
The Massachusetts General Hospital Handbook of Pain Management

The Placebo Effect

Brian W. Dubois and Paul J. Christo

Impatient at being kept awake by pain, I availed myself of the stoical means of concentration upon some indifferent object of thought, such as for instance the name of “Cicero” with its multifarious associations; in this way I found it possible to divert my attention, so that the pain was soon dulled.
—Immanuel Kant, 1724–1804

I. Placebos and the natural course of illness
II. Active agents
III. Placebo characteristics

1. Placebo response rate

2. Placebos and procedures

3. Placebo sag in chronic pain

4. The active placebo

5. The nocebo
IV. Placebo mechanisms

1. Cognitive theory

2. Conditioning theory

3. Endogenous opioids
V. Conclusion
Selected Reading

The word placebo was originally used to describe something that was pleasing, for example, a medical treatment that was used more to please the patient than to treat the medical condition. In present day medical terminology, a placebo is a drug or therapy that simulates medical treatment but has no specific action on the condition being treated. A placebo often provides a real therapeutic benefit even though it does not have a specific therapeutic action. It is well known that receiving medical treatment, in and of itself, often produces a “nonspecific” therapeutic benefit. It is unclear, however, how such a benefit arises and whether it occurs because patients expect relief from medical treatment or because their anxiety is reduced. Placebos have been administered deliberately (for example, in an attempt to satisfy patients who wish to pursue medical therapy), and they have been administered unintentionally, as in the use of therapies whose efficacy was later refuted. In one form or another, placebos have been used since the dawn of medical therapy.
Henry K. Beecher, the first chairman of anesthesia at the Massachusetts General Hospital, made some classic observations about pain plasticity, which have led to the present-day concept that pain and pain perception can be altered by a variety of central nervous system (CNS) factors. He first observed that after battle, soldiers experienced less pain and requested less morphine than did civilians hospitalized after surgery. He surmised that this effect was caused by lower levels of anxiety in the soldiers, who were relieved to be off the battlefield, in sharp contrast to the civilian patients whose concerns about surgery and hospitalization filled them with heightened anxiety. He had observed that a patient’s state of mind could alter pain perception, and he studied other possible ways that a subject could conjure up feelings that would suppress pain.
In 1955, he published a classic study, “The Powerful Placebo,” in which he analyzed the findings of 15 drug trials involving placebos in a thousand patients with various ailments. In the study, he noted a consistent therapeutic response to placebos for a variety of medical conditions. He surmised that patients’ expectations of benefit were sufficient to achieve therapeutic benefit. As a result, Beecher advocated the use of placebos, blinding, and controls in medical studies. He had not only altered the standard for medical studies, he had also introduced psychosomatic medicine into modern medicine.
Since the publication of Beecher’s classic study, placebos have been commonly used in studies in an attempt to separate out the “nonspecific” therapeutic benefits of medical treatment from true treatment efficacy. Many clinical and preclinical studies are conducted against a placebo-group baseline. The following are typical study designs involving placebos:

The double-blinded, placebo-controlled study , comparing a drug (or therapy) with a placebo when neither the patient nor the investigator knows what the patient is receiving.

The single-blinded study , comparing a drug (or therapy) with a placebo when the patient is blinded to what he is receiving but the investigator knows.

The open-label study , when both the patient and the investigator know what the patient is receiving.

The crossover study , when the patient sequentially receives both the placebo and the drug (or therapy), usually in a blinded fashion.
Many diseases are characterized by periods of acute exacerbation followed by periods of remission or resolution. Common complaints such as backaches, headaches, muscle strains, earaches, and coughs usually improve spontaneously. The natural course of untreated illness must be appreciated to understand the true benefit of treatments.
The placebo effect, or the nonspecific therapeutic benefit derived from a placebo treatment, must be distinguished from the recovery or remission that occur during the natural course of disease. Most placebo-controlled studies do not include an untreated group, and consequently they cannot measure the magnitude of the true placebo effect in the study. By directly comparing the placebotreated group with the untreated group, the placebo effect can be quantified for a given study.
Since most placebo-controlled studies do not include an untreated group, the reported placebo effect probably overestimates the true placebo effect. In fact, a published search by Ernst and Resch of clinical trials containing both an untreated group and a placebo group from the Medline literature (from 1986 to 1994) yielded only 12 reports, of which six dealt with pain relief. In the pain trials, the authors noted that placebo treatments were more effective in alleviating pain than no treatment. The untreated group, however, did improve, and this improvement, the authors note, must be appreciated to quantify the true placebo effect.
Active drugs or therapies have an efficacy greater than that shown by a placebo. The difference in efficacy between an active drug and a placebo defines the specific therapeutic benefit of the active drug. The greater the difference between the active drug and the placebo, the greater the specific therapeutic benefit of the active drug. The overall therapeutic effect of an active drug is therefore composed of two components: (a) the specific therapeutic benefit and (b) the nonspecific (placebo) effects of treatment. As Beecher put it, “The power attributed to morphine is presumably its drug effect plus a placebo effect.” Any factor of treatment that potentially increases the nonspecific (placebo) component of therapy increases the overall perceived therapeutic effect of the active drug.
1. The Placebo response rate
Beecher and others have examined the benefit of placebos in treating minor ailments such as headaches, nausea, anxiety, angina, backaches, and coughs. Beecher found that the number of patients given a placebo who had a response, defined as “a 50% or more relief of pain,” varied widely, ranging from 15% to 53%. (The myth that the placebo response rate is approximately 30% originates from the gross averaging of these numbers.) Other investigators have also observed a wide range of placebo response rates, and some report response rates that are much higher than the 15% to 53%. High reported placebo response rates might overestimate the true placebo response if the remitting nature of the ailment is not appreciated.
The placebo response is very much influenced by patient perception and expectations. In fact, patients often feel better simply because medical treatment has been initiated. An impressive medical setting instills patient confidence and expectation of good medical treatment. The placebo response can be further augmented by a good physician–patient interaction. Physician expectations, and patients’ perceptions of them, have also been shown to influence the placebo effect. For example, Gracely and colleagues, in a controlled double-blinded study of postoperative dental pain, showed that patients were influenced by subconscious signals received from their physicians. In the study, a first group of patients received a placebo, an opioid antagonist, or an opioid (an expected pain reliever), while a second group of patients received just the placebo or the opioid antagonist. Patients receiving the placebo in the second group had more pain than those receiving the placebo in the first group. It was argued that the clinicians’ knowledge of the range of treatment alternatives (no opioid in the second group) was unconsciously communicated and perceived by the patients.
The placebo response has not been linked to any particular personality trait or personality type. As yet, there is no reliable way to predict who will respond to a placebo. Beecher, in his early studies, for example, could not find any response-rate difference that was based on sex or intelligence. In a recent study in a depressed patient population, Wilcox and colleagues looked at age, sex, marital status, education, duration of illness, and severity of illness to predict placebo response rates. No significant prediction of placebo response could be made on the basis of sex, age, education, or duration of illness. They did, however, find a slightly increased placebo response rate when the depression was less severe and when the patient was married.
2. Placebos and procedures
The placebo response is also seen with nondrug therapies, including medical devices and invasive procedures. For example, Hashish and colleagues have shown that ultrasound therapy reduces pain and swelling after dental surgery, but that it is no more effective than mock ultrasound therapy. A powerful placebo response to ligation of the internal mammary arteries for the treatment of angina became apparent after the treatment was widely popularized. The procedure was thought to improve coronary blood flow, and it was associated with a dramatic improvement in anginal symptoms and exercise tolerance in multiple non-placebocontrolled trials. Subsequent double-blinded studies using sham skin incisions with no ligation showed a similarly dramatic (70%) response in anginal symptoms and exercise tolerance. The ligation procedure has since been abandoned.
3. Placebo sag in chronic pain
Placebo sag is a decrease in the placebo response rate seen in patients who have experienced a number of treatment failures. Positive treatment experiences tend to augment the placebo response, whereas negative treatment experiences tend to cause an “extinction of the placebo response.” Placebo sag has been described in patients with chronic pain, who frequently feel that previous pain therapies have failed them. Treatment of their pain becomes even more difficult, because not only are they less likely to respond to placebo but also they are less likely to respond to active medications (all of which have a placebo or nonspecific therapeutic treatment component to them).
4. The active placebo
During double-blinded placebo-controlled studies, patients (and evaluators) can sometimes differentiate placebos from active drugs on the basis of side effects. This is particularly true with psychiatric and pain treatments, when drugs have significant neurologic and cognitive effects. To enhance blindability in placebo-controlled trials, some investigators have proposed using active placebos. An active placebo is a drug that simulates medical treatment (through side effects) but has no specific action on the condition being treated. For example, certain antidepressants have significant anticholinergic properties. An active placebo for an antidepressant trial could be a substance with anticholinergic properties that does not have specific antidepressant properties.
5. The nocebo
Another observation made by Beecher was that “toxic” side effects may result from placebo drug administration, including “nausea, drowsiness, headache, fatigue, and dry mouth.” These “noxious” side effects have subsequently been termed nocebo effects. Other investigators have noted these effects and have even described allergic-type reactions after placebo administration. Such side effects are augmented by heightened patient expectations of possible negative effects. Moreover, when patients expect little therapeutic benefit from therapy, they are at an increased risk of side effects. For example, it is reported that young healthy volunteers who feel they have little to gain from a treatment tend to experience more side effects.
Many investigators feel that the placebo effect is caused by a reduction in patient anxiety and its consequent reduction in pain perception. Beecher, in fact, observed that placebos “are most effective when stress, anxiety, or pain is the greatest,” and he noted the importance of a patient’s “perception” and “reaction” to pain.
1. Cognitive theory
The cognitive theory states that the expectations of patients play an important role in the placebo response. Clinically, it seems clear that patients who expect a good response from treatment look for signs of a good response and try to dismiss any negative effects. Investigators have shown that patients’ expectations of a drug’s effects will alter their perception of those effects. For example, when patients were blindly given a psychostimulant, investigators showed that the stimulatory effects could be either exaggerated or diminished depending on whether the patient was told that the drug was a stimulant or a sedative.
2. Conditioning theory
The conditioning theory states that learning through association is important in the placebo response. Further, this theory proposes that the placebo response is a conditioned response that can be elicited by stimuli that, through prior conditioning, produce a reduction in symptoms. Evidence of this exists in both animals and humans. Ivan Pavlov, who described classical conditioning, demonstrated a conditioned placebo response in dogs. He reported that dogs, which previously received morphine when placed in an experimental chamber, displayed morphine-like effects when again placed in the experimental chamber. Since then, a number of investigators have published studies demonstrating conditioned responses to placebos in animals.
In humans, a learned placebo response to the analgesic effects of propoxyphene for the treatment of pain was demonstrated by Laska and Sunshine. In their study, patients were given the analgesic at different strengths. The patients who received the higher strength received greater analgesia. All patients were then given a placebo. The patients who had received the higher-strength analgesic thought the placebo was much more effective than the patients who had received the lower-strength analgesic. Here, the previous analgesic experience predicted the efficacy of the placebo.
3. Endogenous opioids
Endogenous opioids may be responsible for placebo analgesia, because naloxone, an opioid antagonist, has been shown to reverse placebo analgesia. Levine and colleagues, for example, examined the effects of naloxone on placebo analgesia in postoperative dental pain. They termed patients whose pain responded to placebo “placebo responders,” and those patients whose pain worsened after placebo administration, “placebo nonresponders.” When naloxone was given after placebo to patients in both groups, the placebo responders had a much greater increase in pain than the placebo nonresponders. This suggested that placebo-induced analgesia in the placebo-responder group was mediated by the release of endogenous opioids.
Ter Riet and colleagues recently reviewed the literature and found studies supporting naloxone reversibility of placebo-induced analgesia in both postoperative and experimentally induced pain. Another study that supports the role of endogenous opioids in the placebo response was conducted by Lipman and colleagues. These investigators measured endogenous opioid “peak B” fraction endorphin levels in cerebrospinal fluid after placebo administration in chronic pain patients. After placebo administration, they found that peak-B endorphin levels were significantly higher in placebo responders than in placebo nonresponders.
Because the placebo effect is a real therapeutic benefit, it is clear that the use of placebos to differentiate “real” pain and illness from “imagined” pain or illness is incorrect and inappropriate. The benefit of the placebo response, as well as a patient’s trust, can easily be lost if placebos are used inappropriately. Even during the conduct of a trial, patients should be informed that they might receive a placebo. Although the placebo effect may be a confounding factor when determining new drug efficacy, it is of considerable benefit to the practicing clinician, and this should not be sacrificed. The effect is not simply a response to a dummy drug or procedure but is a response that can be triggered by many factors, such as the smell of a doctor’s office, the sight of a needle, or the soothing words of a caregiver. By working to build good patient relationships, the placebo effect can be maximized. Maximizing the nonspecific (placebo) component of treatment increases the perceived therapeutic effect of both active and inactive treatments.

Beecher HK. The powerful placebo. JAMA 1955;159:1602–1606.

Ernst E, Resch KL. Concept of true and perceived placebo effects. Br Med J 1995;311:551–553.

Gracely RH, Duloner R, Wolskee PT, et al. Placebo and naloxone can alter post-surgical pain by separate mechanisms. Nature 1983;306:264–265.

Hashish I, Hai HK, Harvey W, et al. Reduction of postoperative pain and swelling by ultrasound treatment: A placebo effect. Pain 1988;33:303–311.

Heeg MF, Deutsch KF, Deutsch E. The placebo effect. Eur J Nucl Med 1997;24:1433–1440.

Laska E, Sunshine A. Anticipation of analgesia: A placebo effect. Headache 1973;13:1–11.

Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet 1978;2:654–657.

Lipmann JJ, Miller BE, Mays KS, et al. Peak B endorphin concentration in cerebrospinal fluid: Reduced in chronic pain patients and increased during the placebo effect. Psychopharmacology 1990;102:112–116.

Margo CE. The placebo effect. Surv Ophthalmol 1999;44:31–43.

Pavlov I. Conditioned reflexes. London: Oxford Press, 1927.

ter Riet G, de Craen AJM, deBoer A, Kessels AGH. Is placebo analgesia mediated by endogenous opioids? A systematic review. Pain 1998;76:273–275.

Turner JA, Deyo RA, Loeser JD, et al. The importance of placebo effects in pain treatment and research. JAMA 1994;271:1609–1614.

Wilcox CS, Cohn JB, Linden RD, et a. Predictors of placebo response: A retrospective study. Psychopharmacol Bull 1992;28: 157–162.

1 Comment

2 Pain Mechanisms and Their Importance in Clinical Practice and Research

2 Pain Mechanisms and Their Importance in Clinical Practice and Research
The Massachusetts General Hospital Handbook of Pain Management

Pain Mechanisms and Their Importance in Clinical Practice and Research

Isabelle Decosterd and Clifford J. Woolf

After great pain, a formal feeling comes
The Nerves sit ceremonious, like Tombs
The stiff Heart questions was it He, that bore,
And Yesterday, or Centuries before?
— Emily Dickinson, 1830–1886

I. Fundamental pain mechanisms

1. Response to acute painful stimuli

2. Peripheral sensitization

3. Central sensitization

4. Disinhibition

5. Structural reorganization

6. Overview
II. Toward a new conceptual approach for the understanding of pain
III. Implications for therapeutic approaches
IV. Implications for evaluation of efficacy of new therapies
V. Conclusion
Selected Reading

It has become increasingly clear from animal models and from preclinical and clinical studies that multiple mechanisms operating at different sites and with different temporal profiles induce chronic pain syndromes. The identification of these mechanisms may provide the best lead to effective pain treatment, especially in the case of novel treatments. Whereas primary disease factors initiate pain mechanisms, it is the pain mechanisms, not the disease factors, that produce chronic pain. Identifying the causes of diseases is important, but it is also essential to differentiate them from pain mechanisms. Because a particular disease may activate several different pain mechanisms, a disease-based classification is useful primarily for disease-modifying therapy, but less for pain therapy. Similarly, symptoms are not equivalent to mechanisms, although they may reflect them. The same symptom may be produced by different mechanisms and a single mechanism may elicit different symptoms.
In this chapter, we propose a new way of analyzing pain, based on the current understanding of pain mechanisms, and we show the implications of this for assessing pain in individual patients and for evaluating new forms of diagnosis and therapy.
1. Response to acute painful stimuli
Acute pain is initiated by a subset of highly specialized primary neurons, the high-threshold nociceptors, innervating peripheral tissues (skin, muscle, bone, viscera). The peripheral terminals of these sensory neurons are adapted so as to be activated only by intense or potentially damaging peripheral noxious stimuli. These receptors are functionally distinct from the low-threshold sensory fibers, which are normally activated only in response to nondamaging low-intensity innocuous stimuli. Nociceptor transduction mechanisms involve activation of any of the following:

Temperature-sensitive receptor ion-channel sensors [such as vanilloid (capsaicin) receptor subtype 1 (VR1) and vanilloidreceptor–like protein 1 (VRL1)]

Channels (yet to be identified) sensitive to intense mechanical deformation or stretch of the membrane

Chemosensitive receptors [such as VR1, dorsal root acidsensing ionic channel (DRASIC) and ATP-gated ion channel type 3 (P2X3)] activated by protons, purines, amines, peptides or growth factors, and cytokines released from damaged tissue or inflammatory cells
2. Peripheral sensitization
The sensitivity of the peripheral terminal is not fixed, and its activation either by repeated peripheral stimulation or by changes in the chemical milieu of the terminal increases the excitability of the terminal and decreases the threshold for initiation of an action potential in the primary sensory neuron. This phenomenon is referred to as peripheral sensitization. Peripheral sensitization reflects changes in the channel kinetics caused both by transduction in ion channels themselves (autosensitization, resulting from prior activation) and by an increase in excitability of the terminal membrane (heterosensitization, initiated by sensitizing stimuli such as inflammatory mediators that do not activate the usual pain transducers).
Autosensitization of vanilloid receptors (VR1, VRL1), for instance, may represent both (a) conformational changes of the receptor secondary to the external heat stimuli and (b) the entry of calcium through the transducer itself, leading to activation of protein kinase C, which phosphorylates VR1. Heterosensitization is driven by sensitizing agents such as prostaglandin E2, histamine, bradykinin, serotonin, and neurotrophic factors that can activate intracellular kinases. Intracellular kinases have the ability to phosphorylate and change the activity state of voltage-gated sodium channels such as SNS (the sensory-neuron–specific sodium channel PN3/Nav1.8).
3. Central sensitization
In addition to changes in the sensitivity of the nociceptor peripheral terminal, post-injury pain hypersensitivity is also an expression of modulation of nociceptive synaptic transmission in the dorsal horn of the spinal cord. This is called central sensitization. Input from nociceptors to the spinal cord evokes an immediate sensation of pain that lasts for the duration of the noxious stimulus and also induces an activity-dependent functional plasticity in the dorsal horn that outlasts the stimulus. The increased excitability is triggered by peripheral nociceptor input, releasing excitatory amino acids and neurotransmitters that act on spinal cord postsynaptic receptors to produce inward currents, as well as activating signal transduction cascades in the neuron.
These processes result in activation of both serine/threonine kinases and tyrosine kinases, which, by phosphorylating membrane proteins, particularly the receptors for N-methyl-D-aspartate glutamate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate, increase membrane excitability by changing ion channel properties. This boost in excitability recruits existing subthreshold inputs to the dorsal horn neurons, thereby amplifying responses to noxious and non-noxious stimuli. The changes may be restricted to the activated synapse or spread to the adjacent synapse, and they are responsible for pain produced by low-threshold afferent inputs and the spread of pain hypersensitivity to regions beyond the tissue injury (secondary hyperalgesia).
Central sensitization is a major contributor to inflammatory and neuropathic pain, producing a largely NMDA-dependent, brush- or pinprick-evoked secondary hyperalgesia and a tactile allodynia. In inflammation, this activity-dependent central plasticity is driven by input from sensitized afferents innervating the inflamed tissue. After nerve injury, central sensitization can be driven by the ectopic activity in the injured fibers resulting from changes in the expression, distribution, or activity of ion channels. These central functional changes are contributed to by changes or switches in the phenotype of sensory neurons. Up to 30 molecules, mainly neuromodulators [such as galanin, vasoactive intestinal peptide (VIP), cholecystokinin (CCK), neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), and nitric oxide synthase (NOS)] that alter synaptic drive and modify the response to basal stimulation, are regulated after nerve injury. In addition to the change in gene expression of the level of neuromodulators, novel expression also occurs, so that subpopulations of dorsal root ganglion (DRG) cells that do not normally express a neuromodulator, such as substance P or BDNF, begin to do so.
For example, substance P, which is normally expressed only in nociceptors, begins to be expressed in low-threshold sensory neurons after both inflammation and nerve injury. This means that although central sensitization is normally evoked only by nociceptor input, input from A fibers can also produce this phenomenon after nerve injury or inflammation. One example of this is the development of a progressive tactile pain hypersensitivity with the repeated touch of inflamed skin.
4. Disinhibition
In addition to the activity-dependent increase in membrane excitability triggered by peripheral input, a decrease in phasic and tonic inhibition can also produce changes in dorsal horn excitability. This disinhibition may result from a down-regulation of inhibitory transmitters or their receptors, and from a disruption of descending inhibitory pathways. Furthermore, nerve injury, by virtue of injury discharge and ectopic activity, may lead to cell death in the superficial lamina of the dorsal horn, where inhibitory interneurons are concentrated.
5. Structural reorganization
After nerve injury, another anatomic change occurs: the structural reorganization of central connections. This involves the sprouting or growth of the central terminals of low-threshold mechanoreceptors from their normal termination site in the deep dorsal horn into lamina II (See Chapter 1, figure 2), the site of termination of nociceptor C-fiber terminals. The sprouted low threshold A fibers make synaptic contact in lamina II with neurons that normally receive nociceptor input, and this new pattern of synaptic input provides an anatomic substrate for tactile pain hypersensitivity.
6. Overview
A complex system of mechanistic changes occurs then, following the activation of the somatosensory pathways by both peripheral inflammatory and nerve lesions. An increase in the gain of the nociceptive system, in the periphery and in the central nervous system, is caused by activity-dependent plasticity, and it manifests as a widely distributed but transient pain hypersensitivity. With time, the changes evolve so that a number of different mechanisms that induce pain hypersensitivity are recruited. Three different forms (activation, modulation, and modification) of neural plasticity that produce pain hypersensitivity are summarized in Figure 1. Activation is directly linked to the noxious stimuli and it involves transduction and transmission of the signal. Modulation involves the peripheral and central sensitization processes. Modification of the system includes gene regulation, altered connectivity, and cell death. Persistent pain states may be associated with mechanisms that involve changes that are irreversible, such as cell death.

Figure 1. The three forms of neural plasticity that can produce pain hypersensitivity are summarized, highlighting the molecular and cellular changes implicated in pain mechanisms. (Modified from Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:1765–1769, with permission.)

The current clinical evaluation of pain uses an etiologic or disease-based approach. This approach, however, should be modified to incorporate a mechanism-based diagnosis of pain. Identifying the causative disease is essential, particularly when disease modifying treatment is required, but in the vast majority of patients with persistent pain, the disease or pathology cannot be treated, and the injury is not reversible. In these cases, it is helpful to consider pain as the disease, and to attempt to identify mechanisms responsible for the pain rather than to categorize the patient primarily on the basis of underlying disease.
Given that mechanisms that produce pain in normal and pathologic conditions are being identified with increasing frequency in the laboratory, it is appropriate to begin to assess how such mechanisms fit into the overall schema of pain production. The notion of basal pain sensitivity, a term that represents the current status of an individual’s pain sensitivity, is fundamental. Basal pain sensitivity represents the pain experienced either spontaneously (i.e., in the absence of any identifiable stimulus) or evoked directly by, and within a short period of, a defined stimulus. In normal situations, there is no spontaneous or background pain, and pain is elicited only by intense or noxious stimuli. The amplitude of the pain, beyond a clear threshold level, is determined by the intensity of the stimulus, and the localization and timing of the sensation reflects the site and duration of the stimulus. This constitutes a state of pain normosensitivity. Normosensitivity is distinct from:

Pain hypersensitivity, in which pain may arise spontaneously, apparently in the absence of any peripheral stimulus

Hyperalgesia, in which the response to noxious stimuli is exaggerated

Hyperpathia, in which the pain may persist, radiate, or become excessively amplified

Allodynia, in which normally innocuous stimuli may produce pain
Normosensitivity is also distinct from those situations in which pain sensitivity is reduced, pain hyposensitivity, where suprathreshold noxious stimuli fail to elicit any pain response.
The aim of a mechanism-based approach is to first evaluate basal pain sensitivity by eliciting key aspects of the nature of the patient’s symptoms. Figure 2 shows how basal pain sensitivity can be qualitatively assessed by selectively eliciting the nature of symptoms. This can be accomplished using a relatively brief, semidirected interview (together with simple sensory testing to evoke symptoms) designed specifically to establish whether the patient’s basal pain sensitivity is normal, above normal, or below normal, and the extent to which the pain is spontaneous or evoked. The goal of the assessment is to characterize the clusters of symptoms, their onset and evolution, and to identify when possible the mechanisms responsible for the symptoms. Careful questioning, rather than the usual global assessments, will produce a new sort of clinical pain record based on the nature of the reported pain, to supplement the standard history (Chapter 4) and physical examination. Of course, this new approach needs to be validated, but its simplicity is likely to be its strength, increasing its usefulness beyond tertiary referral centers. The approach may be adopted in the future to aid treatment selection, especially when treatment efficacy is closely correlated with pain mechanisms (see Section IV).

Figure 2. Canvas for an interview-based qualitative assessment of pain. (Modified from Woolf CJ, Decosterd I. Implications for recent advances in the understanding of pain pathophysiology for the assessment of pain in patients. Pain 1999;6:S141–S147, with permission.)

The conventional assessment of pain syndromes includes the causative disease, the anatomic referral pattern of the pain, and a quantitative evaluation [such as the visual analog scale (VAS)]. This approach groups patients into categories based on their disease syndromes, such as neuropathic pain, headache, osteoarthritic pain, or cancer pain. Contemporary preclinical basic science has successfully elucidated the molecular mechanisms of action of current analgesics (opiates, nonsteroidal anti-inflammatory drugs, and sodium channel blockers) and their effects on pain mechanisms. Yet there is an extremely poor correlation between the efficacy of analgesics and pain syndromes. The increasingly popular measure of the number needed to treat (NNT) is an efficacy index representing the number of patients who need to be treated with a certain drug to obtain one patient with a defined degree of pain relief. The NNT, which has been studied in different pain categories, is a good example of the lack of specificity and predictive value of the current pain classifications. The NNT measure of efficacy does not reveal any consistent differences across different pain conditions for distinct drug classes observed. The goal of a mechanism-based assessment of pain is to provide a classification in which the categorization of patients into mechanism-based subpopulations will aid the rational treatment of pain. Dividing pain into components that reflect some of the major pain mechanisms may help identify how and why certain treatments work, thus revealing useful correlations between pain mechanisms and treatments.
A major problem in clinical studies of pain is that the high intraand interpatient variability in pain scoring using global outcome measures makes it very difficult to evaluate the efficacy of novel analgesics. The usual explanations for this variability are the complexity of pain mechanisms, changes in the primary disease, and psychological factors. Another approach is therefore called for, one that provides new clinical outcome measures that enable an evaluation of whether new analgesics have an action on particular pain mechanisms.
If a new therapy is given to patients selected only on the basis of a particular disease (e.g., diabetic neuropathy), and the clinical outcome measure is a simple global pain measure (e.g., a VAS score of pain at rest), it is simply not possible to assess whether the treatment acts on a particular mechanism (e.g., central sensitization) and reduces a particular symptom (e.g., tactile or cold allodynia). Because the degree of central sensitization may differ considerably in this cohort of patients, any treatment that acts only on central sensitization will produce highly varied responses across the population. Once drugs are available that act specifically on novel pharmacologic targets such as the receptors and ion channels of DRG-specific VR1, P2X3, DRASIC, and SNS/SNS2 (SNS2 is sensory neuron-specific voltage-gated sodium channel NaN/Nav1.9), patients will need to be selected on the basis of a reasonable assessment that their pain involves one of these targets. For example, since VR1 is involved in encoding heat pain, a VR1 antagonist would not be expected to have any effect on a patient with tactile allodynia. Selection of patients on the basis of categories, instead of on the basis of mechanisms, is likely to result in a cohort of patients whose pain mechanisms are quite different. Only a limited number of these patients can be expected to respond to a mechanism-specific drug treatment. Patients who do not respond to the treatment produce a false-negative result by diluting the benefit in a subgroup with the targeted mechanism.
In the last decade, neurobiology research has enormously increased our knowledge of the fundamental mechanisms responsible for producing chronic pain. On the other hand, changes in clinical pain management have been slow. The challenge now is to bridge the large gap between basic research and clinical practice by utilizing new inputs from basic science in the classification, assessment, diagnosis, and treatment of pain.
McCleskey EW, Gold MS. Ion channels of nociception. Annu Rev Physiol 1999;61:835–856.
Mogil JS, Yu L, Basbaum AI. Pain genes? Natural variation and transgenic mutants. Annu Rev Neurosci 2000;23:777–811.
Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999;83:389–400.
Woolf CJ, Bennett GJ, Doherty M, et al. Towards a mechanism-based classification of pain? Pain 1998;77:227–229.
Woolf CJ, Decosterd I. Implications for recent advances in the understanding of pain pathophysiology for the assessment of pain in patients. Pain 1999;6:S141–S147.
Woolf CJ, Mannion RJ. Neuropathic pain: Aetiology, symptoms, mechanisms, and management. Lancet 1999;353:1959–1964.
Woolf CJ, Max MB. Mechanism-based pain diagnosis: Issues for analgesic drug development. Anesthesiology 2001 (in press).
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:1765–1769.
Yaksh TL. Spinal systems and pain processing: Development of novel analgesic drugs with mechanistically defined models. Trends Pharmacol Sci 1999;20:329–337.


1 Neural Basis of Pain

1 Neural Basis of Pain
The Massachusetts General Hospital Handbook of Pain Management

Neural Basis of Pain

Gary J. Brenner

Severe pain is world destroying.
—Elaine Scarry from The Body in Pain

I. Nociceptors

1. Definitions

2. Primary afferent fibers

3. Dorsal horn synapses and biochemical mediators

4. Peripheral sensitization
II. Ascending nociceptive pathways

1. Topographical arrangement of the dorsal horn (Rexed laminae)

2. Dorsal horn projection neurons

3. Spinothalamic tract

4. Spinohypothalamic tract

5. Cranial nerves

6. Central sensitization
III. Supraspinal systems: integration and higher processing

1. Thalamus

2. Hypothalamus

3. Limbic system

4. Cerebral cortex

5. Cingulate cortex
IV. Pain modulation

1. Descending systems

2. “On” and “off” cells: a component of descending analgesia

3. Projections to the dorsal horn
V. Conclusion
Selected Reading

One of the most important functions of the nervous system is to provide information about potential bodily injury. Pain is defined by the International Association for Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.” The body’s perception of pain is termed nociception. The pain system may be grossly divided into the following components:

Nociceptors are the specialized receptors in the peripheral nervous system that detect noxious stimuli. Primary nociceptive afferent fibers, normally Adelta (Ad) and C fibers, transmit information regarding noxious stimuli to the dorsal horn of the spinal cord.

Ascending nociceptive tracts, for example the spinothalamic and spinohypothalamic tracts, convey nociceptive stimuli from the dorsal horn of the spinal cord to higher centers in the central nervous system (CNS).

Higher centers in the CNS are involved in pain discrimination, including affective components of pain, memory components of pain, and motor control related to the immediate aversive response to painful stimuli.

Descending systems allow higher centers of the CNS to modify nociceptive information at multiple levels.
1. Definitions
Although it is somewhat confusing, the term nociceptor is used to refer to the free nerve terminals of primary afferent fibers that respond to painful, potentially injurious stimuli, as well as to the entire apparatus (sensory neuron including free terminals) capable of transducing and transmitting information regarding noxious stimuli. In this chapter, the term nociceptor will be used to refer to the entire nociceptive primary afferent.
Free nerve terminals contain receptors capable of transducing chemical, mechanical, and thermal signals. Recently, for example, a membrane receptor that responds to heat has been discovered, and, interestingly, this receptor is also stimulated by capsaicin, the molecule responsible for the “hot” sensation associated with hot peppers. Nociceptive terminals innervate a wide variety of tissues and are present in both somatic and visceral structures including the cornea, tooth pulp, muscles, joints, the respiratory system, the cardiovascular system, the digestive system, the urogenital system, and the meninges, as well as the skin.
Nociceptors may be divided according to three criteria: degree of myelination, type(s) of stimulation that evokes a response, and response characteristics. Using the criterion of degree of myelination (which is related to conduction velocity), nociceptors can be divided into two classes: Ad fibers are thinly myelinated and conduct at a velocity of 2 to 30 meters per second. C fibers are unmyelinated and conduct at less than 2 m/sec (Table 1).

Table 1. Classification of fibers in peripheral nerves

Ad and C nociceptors can be further divided according to the stimuli that they sense. They may respond to mechanical, chemical, or thermal (heat and cold) stimuli, or to a combination of these (polymodal). For example, C-fiber mechano-heat receptors respond to noxious mechanical stimuli and intermediate heat stimuli (41° to 49°C), have a slow conduction velocity, and constitute the majority of nociceptive afferent fibers. Ad-fiber mechano-heat receptors can be divided into two subtypes. Type I receptors have a high heat threshold (>53°C) and conduct at relatively fast velocities (30 to 55 m/sec). These receptors detect pain sensation during high-intensity heat responses. Type II receptors have a lower heat threshold and conduct at a slower velocity (15 m/sec). Some receptors respond to both warmth and thermal pain. There are also both C and Ad fibers that are mechanically insensitive but respond to heat, cold, and a variety of chemicals, such as bradykinin, hydrogen ions, serotonin, histamine, arachidonic acid, and prostacyclin.
2. Primary afferent fibers
The neural impulses originating from the free endings of nociceptors are transmitted via primary afferent nerves to the spinal cord, or via cranial nerves to the brainstem if they come from the head or neck. Most primary afferent fibers innervating tissues below the level of the head have cell bodies located in the dorsal root ganglion (DRG) of spinal nerves. Primary afferent fibers of cranial nerves V, VII, IX, and X (the sensory cranial nerves) have cell bodies in their respective sensory ganglia.
The majority of nociceptors are C fibers, and 80% to 90% of C fibers respond to nociceptive input. The differences in conduction velocities and response characteristics of Ad and C fibers may explain the typical subjective pain experience associated with a noxious stimulus: a first pain (called epicritic pain) that is rapid, well localized, and pricking in character (Ad), followed by a second pain (called protopathic pain) that is burning and diffuse (C). Visceral afferent nociceptive fibers (Ad and C) travel with sympathetic and parasympathetic fibers; their cell bodies are also found in the DRG. Muscle is also innervated by both Ad and C fibers and, interestingly, muscle pain appears to be limited in quality to that of a cramp.
3. Dorsal horn synapses and biochemical mediators
Primary afferent nociceptors enter the spinal cord via Lissauer’s tract and synapse on neurons in the dorsal horn (Fig. 1). Lissauer’s tract is a bundle of predominately (80%) primary afferent fibers, consisting mainly of Ad and C fibers that penetrate the spinal cord en route to the dorsal horn. After entering the spinal cord, Ad and C fibers run up or down one or two segments before synapsing with second-order neurons in the dorsal horn.

Figure 1. Diagrammatic cross section of the spinal cord.

The dorsal horn synapse is an important site of further processing and integration of the incoming nociceptive information. The dorsal horn may be a point at which nociceptive information is conducted to higher centers, or it may be a point at which nociceptive information is inhibited by descending systems. The responsiveness of dorsal horn neurons may change in response to prior noxious afferent input, particularly repetitive input (central sensitization).
Biochemical mediators
Numerous neurotransmitters and other biochemical mediators are released in the dorsal horn. These substances are derived from three main sources:

Primary afferent fibers


Descending fiber systems
The neurochemistry of the dorsal horn is complicated and there are qualitative differences between the pharmacology of acute pain and that of the facilitated pain states associated with chronic noxious stimulation. Some of the neurochemical mediators can be categorized as excitatory or inhibitory, although many serve complex and mixed functions. For example, the endogenous opioid dynorphin may be inhibitory or excitatory depending on the state of the nervous system. The following are examples of excitatory and inhibitory substances active in the dorsal horn.
Excitatory neuromediators:

Excitatory amino acids—glutamate and aspartate

Neuropeptides—substance P (SP) and calcitonin gene-related peptide (CGRP)

Growth factor—brain-derived neurotrophic factor (BDNF)
Inhibitory neuromediators:

Endogenous opioids, such as enkephalin and b-endorphin

Gamma-aminobutyric acid (GABA)

Cells of the dorsal horn possess specific receptors for the substances just listed, as well as receptors for a multitude of other neurochemicals (some probably undiscovered). Of particular note is one of the glutamate receptors, the N-methyl-D-aspartate (NMDA) receptor, which is widely distributed in the dorsal horn. Extensive experimental data now implicate the NMDA receptor in the generation and maintenance of facilitated pain states.
4. Peripheral sensitization
Prolonged noxious stimulation can sensitize nociceptors. Sensitization refers to a decreased threshold as well as to an increased response to suprathreshold stimulation. It is observed following direct nerve injury and inflammation, and it is the result of a complex set of transcriptional and post-translational changes in the primary nociceptive afferents. Sensitization of the entire nociceptive pathway can arise secondary to changes in the CNS (central sensitization) or the periphery (peripheral sensitization). Once sensitization is established, it may be impossible to separate central contributions from peripheral contributions to the process of sensitization. The related topics of hyperalgesia, allodynia, inflammation, and nerve injury are briefly discussed next.
Tissue damage results in activation of nociceptors, and if the damage is prolonged and intense it can generate a state in which there is a lowered threshold to painful stimuli. This state is known as hyperalgesia. In areas of hyperalgesia it is also possible to observe an increased response to noxious stimuli. There are alterations in both the subjective and the neurophysiologic responses to stimuli. The subjective response is characterized by a lowered pain threshold and an increase in pain response, while nociceptors demonstrate a corresponding decreased threshold and increased response. Primary hyperalgesia is hyperalgesia at the site of injury, and secondary hyperalgesia refers to hyperalgesia in the surrounding skin. Neural changes producing hyperalgesia can also occur in the CNS (central sensitization).
In addition to the development of a lowered threshold for noxious stimuli following tissue damage (hyperalgesia), it is possible to observe a post-injury state in which normally innocuous stimuli are perceived as painful. This phenomenon is termed allodynia. For example, very light touch in the area of a burn or associated with post-herpetic neuralgia can generate excruciating pain. Like hyperalgesia, allodynia is most likely caused by plastic changes in both primary sensory fibers and spinal cord neurons.
Inflammation, the characteristic reaction to injury, results in rubor, calor, dolor, tumor, and functio laesa (i.e., redness, heat, pain, swelling, and loss of function). During an inflammatory response, activation of nociceptive pathways can lead to sensitization resulting clinically in spontaneous and increased stimulation-induced pain (i.e., hyperalgesia and allodynia). Release of prostaglandins, cytokines, growth factors, and other mediators by inflammatory cells can directly stimulate nociceptors. The precise nature of this interaction between the immune and nervous systems and the manner in which this can lead to pathologic pain states, however, remains to be clarified. The critical observation is that inflammation is an important cause of both acute and chronic alterations in pain processing and sensation.
Nerve injury
Direct neural trauma can also lead to pathologic pain states characterized by spontaneous pain (i.e., pain occurring in the absence of any stimulus), hyperalgesia, and allodynia. Such neuropathic pain can arise following injury to peripheral or central elements of the pain system. A clinical example of this is complex regional pain syndrome type I (CRPS-I), formerly called reflex sympathetic dystrophy (RSD), in which an apparently minor injury can lead to sensitization of pain processing in a region including but not limited to that involved in the injury.
1. Topographical arrangement of the dorsal horn (rexed laminae)
The gray matter of the spinal cord can be divided into 10 laminae (the Rexed laminae I through X) on the basis of the histologic organization of the numerous types of cell bodies and dendrites. The dorsal horn is composed of laminae I through VI (Fig. 2). The majority of nociceptive input converges on lamina I (the marginal zone), lamina II (the substantia gelatinosa), and lamina V in the dorsal horn. However, some primary visceral and somatic nociceptive afferent fibers synapse in other laminae. Cutaneous mechanoreceptor Ad afferent fibers synapse in laminae I, II, and V; visceral mechanoreceptor Ad fibers synapse in laminae I and V; cutaneous nociceptor C fibers synapse in laminae I and II; and visceral nociceptive C fibers synapse in many laminae including I, II, IV, V, and X. The ascending spinal pathways involved with nociceptive transmission arise mainly from laminae I, II, and V (Fig. 3). These pathways include the spinothalamic tract, the spinohypothalamic tract, the spinoreticular tract, and the spinopontoamygdala tract.

Figure 2. Rexed laminae I through X of the spinal cord.

Figure 3. Ascending pain pathways. (Reproduced with permission from Bonica JJ, ed. The Management of Pain, vol. 1. Philadelphia: Lea and Febiger, 1990:29.)

2. Dorsal horn projection neurons
The second-order neurons in the pain pathway are the dorsal horn projection neurons (or their equivalent in cranial pathways). Their cell bodies are in the spinal cord (or in cranial nerve nuclei in the head and neck), and they are classified according to their response characteristics. High-threshold [HT; also called nociceptivespecific (NS)] cells respond exclusively to noxious stimuli; these cells receive input only from nociceptors (i.e., Ad and C fibers). Their receptive fields are small and organized somatotopically, being most abundant in lamina I.
Other cells, called wide dynamic range (WDR) cells, respond to a range of stimuli from innocuous to noxious. They integrate information from A-beta (Ab; transmitters of information about nonnoxious stimuli), Ad , and C fibers. These cells have larger receptive fields, are the most prevalent cells in the dorsal horn, and are found in all laminae, with a concentration in lamina V. The convergence of sensory information onto a single dorsal horn neuron is critical for the coding of stimulus intensity in terms of output frequency by these second-order neurons.
3. Spinothalamic tract
The spinothalamic tract (STT) (Fig. 3) is the most important of the ascending pathways for the transmission of nociceptive stimuli. It is located in the anterolateral quadrant of the spinal cord. The cell bodies of STT neurons reside in the dorsal horn; most of their axons cross at the midline in the ventral white commissure of the spinal cord and ascend in the opposite anterolateral quadrant, although some do remain ipsilateral. Neurons from more distal regions of the body (e.g., the sacral region) are found more laterally, and neurons from more proximal regions (e.g., the cervical region) are found more medially within the spinothalamic tract as it ascends. STT neurons segregate into medial and lateral projections to the thalamus (see Limbic System, later).
Neurons that project to the lateral thalamus arise from laminae I, II, and V, and from there they synapse with fibers that project to the somatosensory cortex. The fibers are thought to be involved in sensory and discriminative aspects of pain.
Neurons that project to the medial thalamus originate from the deeper laminae VI and IX. The neurons send collateral projections to the reticular formation of the brainstem and midbrain, the periaqueductal gray matter (PAG), and the hypothalamus, or directly to other areas of the basal forebrain and somatosensory cortex. They are thought to be involved with autonomic reflex responses, state of arousal, and emotional aspects of pain.
4. Spinohypothalamic tract
Nociceptive and non-nociceptive information from neurons within the dorsal horn is conveyed directly to diencephalic structures, such as the hypothalamus, by a recently discovered pathway—the spinohypothalamic tract. This pathway projects to the region of the brain (the hypothalamus) that is involved in autonomic functions such as sleep, appetite, temperature regulation, and stress response. In fact, the majority (60%) of SHT neurons project to the contralateral medial or lateral hypothalamus and, therefore, are presumed to have a significant role in autonomic and neuroendocrine responses to painful stimuli. Thus, the SHT appears to form the anatomic substrate that coordinates reflex autonomic reactions to painful stimuli. Some of its connections (e.g., to the suprachiasmatic nucleus, which partly controls the sleep/wake pattern) may account for behaviors such as difficulty in sleeping with painful conditions, particularly chronic pain. The majority of SHT neurons respond preferentially to mechanical nociceptive stimulation, and a smaller number respond to noxious thermal stimulation. The fibers of the SHT cross midline in the supraoptic decussation. The spinoreticular tract (SRT) and the spinopontoamygdala tract are also probably involved with state of arousal and emotional aspects of pain.
5. Cranial nerves
The transmission of pain in the head and neck has many of the same characteristics as the nociceptive system, which has firstorder synapses in the dorsal horn of the spinal cord. The face and oral cavity are richly innervated with nociceptors. The primary nociceptive afferent fibers for the head originate mainly from cranial nerve V but also from cranial nerves VII, IX, and X, and from the upper cervical spinal nerves. The primary afferent fibers of the cranial nerves project mainly to nuclei of the trigeminal system, whereas the upper cervical nerves project to second-order neurons in the dorsal horn of the spinal cord. From there, projections continue to the supraspinal systems.
Trigeminal System
The trigeminal system (V) receives afferent input from the three divisions of the trigeminal nerve (ophthalmic, maxillary, and mandibular), which serve the entire face as well as the dura and the vessels from a large portion of the anterior two thirds of the brain. The trigeminal has three sensory nuclei, all of which receive projections from cells that have cell bodies located within the trigeminal ganglion, a structure similar to the DRG. The three nuclei are the mesencephalic, the main sensory, and the spinal trigeminal. The latter is further divided into the subnucleus oralis, the subnucleus interpolaris, and the subnucleus caudalis. The sub-nucleus caudalis (also known as the medullary dorsal horn) extends caudally from the medulla to the level of the upper cervical segments of the spinal cord (C3 to C4).
The trigeminal nuclei give rise to several ascending pathways. The axons of cell bodies in the main sensory nucleus and the subnucleus oralis project either ipsilaterally, forming the dorsal trigeminothalamic tract, or contralaterally, in the ventral trigeminothalamic tract. Both tracts terminate in the thalamus. The subnucleus caudalis contributes as well to the trigeminothalamic tracts, but it also has direct projections to the thalamus, the reticular formation, and the hypothalamus.
Glossopharyngeal nerve
The glossopharyngeal nerve (IX) conveys impulses associated with tactile sense, thermal sense, and pain from the mucous membranes of the posterior third of the tongue, tonsil, posterior pharyngeal wall, and eustachian tubes.
Vagus nerve
The vagus nerve (X) conveys impulses associated with tactile sense from the posterior auricular skin and external auditory meatus, and those associated with visceral sensation from the pharynx, larynx, trachea, esophagus, and thoracic and abdominal viscera, via the spinal trigeminal tract and the fasciculus solitarius (the sensory tract of VII, IX, and X).
6. Central Sensitization
Just as prolonged noxious stimulation of nociceptors can result in altered pain states (peripheral sensitization), so repetitive stimulation of second-order (and higher-order) neurons can alter pain processing (central sensitization). Hyperalgesia and allodynia are manifestations of central as well as peripheral sensitization (see Peripheral Sensitization, earlier). The ability of the neural tissue to change in response to various incoming stimuli is a key function of the nervous system, and it is termed neural plasticity. Presumably, this function has some evolutionary or protective advantage, although in clinical pain practice, a disadvantage is often seen—the development of chronic pain. Both short-term and long-term plastic changes occur in the dorsal horn. Wind-up is an increase in the ratio of outgoing to incoming action potentials of a dorsal horn neuron with each successive nociceptive stimulus. It occurs in response to repetitive C-fiber stimulation, and it is reversed as soon as the stimulation ceases. This is an example of a short-term plastic change. Central sensitization (including windup) is associated with NMDA receptor activation. In the case of long-term sensitization, various mechanisms produce the changes and there may be associated new gene expression (e.g., C-fos).
Integration of pain in higher centers is complex and poorly understood. At a basic level, the integration and processing of painful stimuli may fall into the following broad categories:
Discriminative component: This somatotopically specific component involves the primary (SI) and secondary (SII) sensory cortex. The level of integration allows the brain to define the location of the painful stimulus. Integration of somatic pain, as opposed to visceral pain, takes place at this level. The primary and secondary cortices receive input predominantly from the ventrobasal complex of the thalamus, which is also somatotopically organized.
Affective component: The integration of the affective component of pain is very complex and involves various limbic structures. In particular, the cingulate cortex is involved in the affective components of pain (it receives input from the parafascicular thalamic nuclei and projects to various limbic regions). The amygdala is also involved in the integration of noxious stimuli.
Memory components of pain: Recent evidence has demonstrated that painful stimuli activate CNS regions such as the anterior insula.
Motor control and pain: The supplemental motor area is thought to be involved in the integration of the motor response to pain.
1. Thalamus
The thalamus is a complex structure that acts as the relaying center for incoming nociceptive stimuli, and it has two important divisions that receive nociceptive input. First is the lateral division, formed by the ventrobasal complex in which nociceptive specific input from NS and WDR neurons synapses. It is somatotopically organized and projects to the somatosensory cortex. Second is the medial division, which consists of the posterior nucleus and the centrolateral nucleus. It is thought that these nuclei project to limbic structures involved in the affective component of pain, because there is no nociceptive-specific information conveyed by them to higher cortical regions.
The medial and intralaminar nuclei receive input from many ascending tracts, in particular the STT, and the reticular formation. There is little evidence of somatotopic organization of these nuclei. The ventrobasal thalamus is organized somatotopically and can be further subdivided into (a) the ventral posterior lateral nucleus, which receives input mainly from the STT but also from the dorsal column system and the somatosensory cortex, to which it projects, and (b) the ventral posterior medial nucleus, which receives input from the face via the trigeminothalamic tract and projects to the somatosensory cortical regions of the face. Input to the posterior thalamus comes mainly from the STT, the spinocortical tract, and the dorsal column nuclei. The receptive fields are large and bilateral and lack somatotopic organization. The posterior nuclei project to the somatosensory cortex and appear to have a role in the sensory experience of pain. The STT also sends projections to the centrolateral nucleus, which is involved in motor activity (e.g., the cerebellar and cerebral cortex).
2. Hypothalamus
The hypothalamus receives innocuous and noxious stimuli from all over the body, including deep tissues such as the viscera (see Spinohypothalamic Tract, earlier). The hypothalamic neurons are not somatotopically organized and therefore do not provide discriminatory aspects and localization of pain. Some hypothalamic nuclei send projections to the pituitary gland via the hypophyseal stalk, the brainstem, and the spinal cord. The gland regulates both the autonomic nervous system and neuroendocrine response to stress, including pain.
3. Limbic system
The limbic system consists of subcortical regions of the telencephalon, mesencephalon, and diencephalon. It receives input from the STT, the thalamus, and the reticular formation, and it projects to various parts of the cerebral cortex, particularly the frontal and temporal cortex. It is involved in the motivational and emotional aspects of pain, including mood and experience.
4. Cerebral cortex
The somatosensory cortex and the cingulate cortex are involved in pain. The somatosensory cortex is the most important area for nociception. It is located posterior to the central sulcus of the brain, and it receives input from the various nuclei of the thalamus, particularly the ventral posterior lateral and medial nuclei and the posterior thalamus. The somatosensory cortex is cytoarchitecturally organized and therefore has an important role in the discriminatory aspect and localization of pain. Efferent fibers from the somatosensory cortex travel back to the thalamus and contribute to the descending nociceptive system.
5. Cingulate cortex
The cingulate cortex is a component of the limbic system. The limbic system receives sensory and cortical impulses and activates visceral and somatic effectors; it contributes to the physiologic expression of behavior and emotion. The limbic system includes the subcallosal, cingulate, and parahippocampal gyri and hippocampal formation as well as the following subcortical nuclei: the amygdala, the septal nuclei, the hypothalamus, the anterior thalamic nuclei, and the nuclei in the basal ganglia. Recent work has demonstrated that the cingulate gyrus is activated in humans by painful stimuli. Cingulate cortex lesions have been used in an attempt to alleviate pain and suffering.
Figure 4 and Figure 5 illustrate pathways involved in the modulation of nociceptive information. The evidence for descending controls came from two basic observations. The first observation, in the late 1960s, was that neurons in the dorsal horn of decerebrate animals are more responsive to painful stimuli with spinal cord blockade. The second observation, in the late 1980s, was that electrical stimulation of the PAG profoundly relieved pain in animals. So great was the stimulation-produced analgesia that surgery could be performed on these animals without apparent pain. Furthermore, the animals behaved normally in every other way and there was no observed effect on other sensory modalities. These studies were pivotal in demonstrating an anatomic basis for the “natural equivalent” of stimulation-produced analgesia. Furthermore, subsequent studies demonstrated that small concentrations of morphine, when injected into regions such as the PAG, produced significant analgesia. Interestingly, both stress-induced analgesia and stimulation-induced analgesia can be reversed by opioid antagonists. A number of brain centers are involved in the intrinsic modulation of noxious stimuli. These include the somatosensory cortex, the hypothalamus (paraventricular nucleus, lateral hypothalamus), the midbrain PAG, areas in the pons including the lateral tegmental area, and the raphe magnus. Electrical stimulation of these regions in humans (in some cases) and in animals produces analgesia.

Figure 4. Descending pain pathways. 5-HT, serotonin; NE, noradrenergic input; ALF, anterolateral fasciculus; STT, spinothalamic tract; SRT, spinoreticular tract; SMT, spinomesencephalic tract. (Reproduced with permission from Bonica JJ, ed. The Management of Pain, vol. 1. Philadelphia: Lea and Febiger, 1990:108.)

Figure 5. Cross section of the spinal cord showing the location of the ascending pain pathways (e.g., the spinothalamic tract). The descending pain pathways are in the dorsolateral funiculus (not shown) of the spinal cord.

Fibers from these central structures descend directly or indirectly (e.g., PAG to raphe magnus) via the dorsolateral funiculus to the spinal cord and send projections to laminae I and V. Activation of the descending analgesic system has a direct effect on the integration and passage of nociceptive information at the level of the dorsal horn. Blockade of the dorsolateral funiculus (with cold or sectioning) increases the response of nociceptive second-order neurons following activation by painful stimuli.
1. Descending systems
The descending system appears to have three major functionally interrelated components: the opioid, the noradrenergic, and the serotonergic systems.
Opioid system
The opioid system is involved in descending analgesia. Opioid precursors (pro-opiomelanocortin, proenkephalin, and prodynorphin) and their respective peptides (beta-endorphin, met- and leuenkephalin, and dynorphin) are present in the amygdala, the hypothalamus, the PAG, the raphe magnus, and the dorsal horn. With the recent advent of opioid receptor cloning, knowledge is steadily increasing about the action sites of the various opioids (i.e., on mu, delta, and kappa receptors).
Noradrenergic System
Noradrenergic neurons project from the locus caeruleus and other noradrenergic cell groups in the medulla and pons. These projections are found in the dorsolateral funiculus. Stimulation of these areas produces analgesia, as does the administration (direct or intrathecal) of an alpha-2-receptor agonist such as clonidine.
Serotonergic System
Many neurons in the raphe magnus are known to contain serotonin [5-hydroxytryptamine (5-HT)], and they send projections to the spinal cord via the dorsolateral funiculus. Pharmacologic blockade, or lesioning, of the raphe magnus can reduce the effects of morphine, and administration of 5-HT to the spinal cord produces analgesia.
2. “On” and “off” cells: a component of descending analgesia
Nociceptive cells in the dorsal horn can be activated or inhibited following stimulation of the PAG. Therefore, it is reasonable to posit the existence of brain centers that provide both excitatory and inhibitory descending output. The raphe magnus, and other brain regions known to be involved in descending modulation (e.g., the PAG), appears to generate such output. Several types of neurons involved in the control of nociceptive information reside in the raphe magnus: in particular, there are neurons named “on” cells and “off” cells based on apparent function.
“On” cells are active prior to a nocifensive withdrawal reflex (e.g., tailflick). These cells are stimulated by nociceptive input; they are excited by stimulation and are inhibited by morphine. “On” cells facilitate nociceptive transmission in the dorsal horn. “Off” cells shut off prior to a nocifensive withdrawal reflex. These cells are inhibited by noxious stimuli, whereas they are excited by electrical stimulation and by morphine. It has been postulated that opioids act to inhibit inhibitory interneurons (GABAergic) that act on “off” cells and that, in this way, they produce a net excitatory effect on these cells. “Off” cells inhibit nociceptive transmission in the dorsal horn.
3. Projections to the dorsal horn
The nerve fibers that originate in nuclei that are involved in pain modulation terminate in the dorsal horn predominately in laminae I and II but also in other laminae, including IV, V, VI, and X. Thus there is a circuitry of projecting neurons acting directly or indirectly via interneurons on afferent fibers as well as projecting neurons such as the spinothalamic tract neurons.
The neuroanatomy and neurochemistry of the pain system is extremely complex. Neuroanatomic techniques have taught us a great deal about the “connectivity” of the system. Newer techniques have enabled the study of individual cells and specific cell populations in an attempt to elucidate roles in both ascending and descending systems. Sophisticated imaging—for example, functional magnetic resonance imaging and positron emission tomography—have allowed investigation of in vivo brain activity in the presence of acute and chronic pain. Thus, the nociceptive system continues to be investigated using reductionistic and holistic approaches to better understand its resting and pathologic states.

Fields HL. Pain. New York: McGraw-Hill, 1999.

Kruger L, ed. Pain and touch. San Diego: Academic Press, 1996.

Scarry E. The body in pain: The making and unmaking of the world. Oxford: Oxford University Press, 1985.

Simone DA. Peripheral mechanisms of pain perception. In: Abram SE, ed. The atlas of anesthesia: Pain management. Philadelphia: Churchill-Livingstone, 1998:1.1–1.11.

Waldman SD, Winnie AP, eds. Part I. Anatomy and physiology of pain: Clinical correlates. In: Interventional pain management, 4th ed. Philadelphia: WB Saunders, 1996:1–72.

Wall PD, Melzack R, eds. Textbook of pain, 4th ed. Philadelphia: Churchill-Livingstone, 1999.


Anesthesia for the Pregnant Patient

Anesthesia for the Pregnant Patient

Eveline A. M. Faure, MD
Department of Anesthesia and Critical Care (emeritius)
University of Chicago

“She is the highest nature can achieve and by her mold all beauty tests itself”
Dante Alighieri, Vita Nuova

Physiologic Changes


Analgesic and Anesthetic Techniques


Other Resources
Society for Obstetric Anesthesia and Perinatology (SOAP)

A. Physiologic changes of pregnancy

1. Cardiovascular adaptation
a. Blood volume increases by 40% at term; plasma volume increases more than red cell volume, resulting in lower hemoglobin

b. Cardiac output rises during the second trimester to meet the increased oxygen consumption to a 20% increase at term. CO exceeds 50% during labor and remains elevated until the third postpartum day.

c. Heart rate increases and peripheral vascular resistance and diastolic blood pressure (BP) decrease. Central venous pressure is unchanged.

d. The growing uterus receives 20% of the cardiac output; uterine enlargement causes compression of the inferior vena cava and the aorta, resulting in maternal hypotension and fetal distress

Figure 1. Changes in blood volume, plasma volume, red cell volume, and cardiac output during pregnancy and in the puerperium. The curves were constructed from various resports in the literature and illustrate trends in percent change rather than absolute values.

Figure 2. Changes in maternal heart rate, stroke volume, and cardiac output during pregancy with the gravida in the supine position and in the lateral position. These curves are based on data derived from several studies, including Ueland, K., et al.: Am. J. Obstet. Gynecol. 104:856, 1969.
e. Clinical implications: to avoid aortocaval compression, parturients should never be allowed to rest in the supine position. Sympathetic blockade due to spinal or epidural anesthesia interferes with the compensatory vasoconstrictor reflex, resulting in profound hypotension in spite of adequate intravascular volume expansion

Figure 3. Changes in arterial blood pressure, venous pressure, and total peripheral resistance during pregnancy.
f. Definition of hypotension in obstetrics: systolic BP below 100 mm Hg or 20% from preanesthetic level (30% in hypertensive patients)
g. Clinical implications: engorgement of the epidural vasculature makes puncture of an epidural vein more likely. The decrease in epidural space by the engorged vessels leads to decreased drug requirement: pregnant patients need only two-thirds of the amount of local anesthetics used in nonpregnant patients

Figure 4. Diagram of the caval venous system and its connections with the vertebral and azygous systems. Commonest sites of compression of the inferior vena cava (IVC) are: (a) suprahepatic in lordotic position; (b) uterus at term; and (c) pressure at pelvic brim in exaggerated lordosis and term pregnancy. (Courtesy of Bromage, P.R., Epidural Analgesia: Philadelphia, W.B. Saunders, 1978.)

Figure 6. Pulmonary volumes and capacities in the nonpregant state and in the gravida at term. (Courtesy of Bonica, J.J.: Principles and Practice of Obstetric Analgesia and Anesthesia, Philadelphia, F.A. Davis Company, 1967.)
2. Respiratory adaptation
a. Upper airway: capillary engorgement of the respiratory tract leads to edema and increased friability of the mucous membranes with increased tendency to severe hemorrhage during insertion of nasogastric or endotracheal tubes. Preeclamptic patients may have vocal cord edema requiring small-diameter endotracheal tubes
b. Mechanics of respiration: the expanding uterus displaces the diaphragm cephalad, decreasing functional residual capacity (FRC). Vital capacity (VC) and inspiratory capacity remain unchanged, because of an increase in anteroposterior thoracic diameter. Tidal volume increases by 40% and respiratory rate by 15% resulting in a raise in alveolar ventilation by 70%. The elevated progesterone level has been assumed to stimulate the rise in alveolar ventilation
c. Maternal blood gas: increase in alveolar ventilation produces respiratory alkalosis with compensatory renal excretion of bicarbonate and correction of pH. Oxygenation is improved, O2 saturation is close to 100%
d. Clinical implications: due to the decreased FRC, parturients are more susceptible to hypoxia and hypercarbia during apnea while pushing and after induction of general anesthesia. The supine and lithotomy position assumed during birth aggravates the onset of hypoxia. Severe hyperventilation during pain leads to hypocarbia, causing uterine artery vasoconstriction. The decreased FRC implies that preoxygenation and induction of anesthesia with inhalation agents occur more rapidly, as does emergence. Administration of supplemental 100% oxygen is mandatory during fetal distress and prior to induction of general anesthesia

Figure 7. Changes in the outline of the heart, lungs, and thoracic cage that occur in pregnancy. The gradual migration of the uterus cephalad causes the diaphragm to move upward and thus encroach on the lungs, and causes the heart to be displaced laterally and anteriorally, but this is counterbalanced by an increase in the anterior-posterior and transvers diameters of the chest wall. (From Bonica, J. J.: Principles and Practice of Obstetric Analgesia and Anesthesia, Philadelphia, F.A. Davis Company, 1967, as modified from and courtesy of Klaften, E. and Palugvav, H. Arch.Gvnaek. 78:1, 1959.)

3. Gastrointestinal changes
a. Elevated progesterone levels decrease gastric mobility and food absorption, and lower esophageal sphincter tension at term
b. Placental secretion of gastrin results in higher gastric acidity and gastric volume
c. The enlarged uterus increases intragastric pressure and the gastroesophageal angle flattens
d. Clinical implications: these gastrointestinal changes result in an increased danger of vomiting and aspiration of gastric contents in the parturient. Regardless of the number of hours after last food intake, all parturients are considered to have a full stomach! In addition to the unpredictability of last meal prior to onset of labor, pain, anxiety, and narcotic pain medication totally block gastric emptying. It is therefore recommended that no solid food be given to parturients and that liquids be restricted to a small amount of ice chips
e. Medical control of the full stomach: although histamine2-blocking agents (cimetidine, ranitidine) have been used in elective cesarean section patients with success, the time required to change gastric acidity is unpredictable and too long to be effective in labor patients. Metoclopramide increases gastric motility and lower esophageal sphincter tone, and has central antiemetic effects. Oral clear liquid antacids (Bicitra) .3 M sodium citrate, 30 mL, is sufficient to buffer gastric acidity acutely. It may ameliorate pulmonary irritation from gastric acid, if aspiration occurs
f. Prevention of aspiration of gastric contents: whenever possible, regional anesthesia is chosen over general anesthesia. Clear oral liquid antacid, 30 mL, is administered 10 minutes prior to induction. Preoxygenate with 100% oxygen for 3 minutes; induce anesthesia with a fast-acting IV agent, followed by a muscle relaxant, with cricoid pressure and intubation, inflating the cuff immediately. If difficult intubation is anticipated, awake intubation with topical spray and mild sedation is indicated

4. Renal function
a. Renal plasma flow increases to 80% above normal by the middle of the second trimester and decreases slightly at term
b. Glomerular filtration rate (GFR) rises to 50% above prepregnant levels by the sixteenth gestational week and remains high until delivery, leading to an increase in creatine clearance
c. Glycosuria is due to the increased load of glucose presented by the increased GFR
d. Progesterone causes dilation of the renal calyces, causing an increased incidence of urinary tract infections

5. Liver function: hepatic blood flow is unchanged, but liver function test may be slightly abnormal; plasma cholinesterase is slightly decreased

6. Hematological changes
a. The increased plasma volume exceeds the increase in red cell mass, leading to a decrease in blood viscosity and “dilutional anemia”
b. Coagulation factors I, VII, X, and XII are increased and render pregnancy a “hypercoagulable state” as a protection to the parturient against bleeding at the time of delivery

B. Pain pathways

1. First stage of labor: pain from uterine contraction and cervical dilation is transmitted via efferent nerve fibers arising from the uterus together with the sympathetic chain and enters the spinal cord at the tenth thoracic level through the First lumbar segment

2. In the late first and early second stages of labor, noxious stimulation of other pelvic structures that are innervated by lower lumbar and sacral sensory fibers leads to additional pain

3. During delivery, perineal distention by the fetal presenting part, stretching and tearing of the perineum result in transmission of pain signals from the three sacral segments: S2-S4

4. During cesarean section, painful stimuli arise from the abdominal peritoneum, uterus, bladder, ureters, and rectum. Therefore, nerve fibers arising from the second thoracic level to the fourth sacral level need to be blocked

Figure 8. Peripheral parturition pain pathways. The uterus, including the cervix, is supplied by sensory (pain) fibers that pass from the uterus to the spinal cord by accompanying sympathetic nerves in the sequence summariezed in the text. The primary pathways (shown as thick lines in the inset) enter the 11th and 12th spinal segments while the secondary auxiliary pathways enter at T10 and L1. The pathways from the perineum pass to the sacral spinal cord via the pudendal nerves. (Modified from and courtesy of Bonica, J.J.: Principles and Practice of Obstetric Analgesia and Anesthesia, Philadelphia, F.A. Davis Company, 1967.)

A. Local anesthetic agents used in obstetrical anesthesia

1. Esters
a. Procaine (Novocain), chloroprocaine (Nesacaine)
Rapid onset
Low toxicity
Fast metabolism: T_ in plasma of pregnant women is 23 seconds
Disadvantage: possible allergy to the nitrogen in para-position
b. Tetracaine (Pontocaine)
Advantage: long-acting
Disadvantages: patchy sensory block, high toxicity

2. Amides:
a. lidocaine (Xylocaine), bupivacaine (Marcaine)
Good sensory block at low concentrations with minimal motor block
Longer duration
Rare allergy
Metabolized in the liver
Bupivacaine is highly cardiotoxic if injected inadvertently into a vein. The toxic dose is 1 mg/kg IV
Tachyphylaxis may occur after repeated doses of plain lidocaine

3. Toxicity of local anesthetic agents
a. Central nervous system: moderately elevated blood levels cause drowsiness, slurred speech, “feeling drunk,” ringing in ears. Major toxicity reactions are seizures and coma
b. Cardiovascular: irregular heart rhythm, A-V block, ventricular fibrillation leading to a fall in cardiac output and cardiovascular collapse with cardiac arrest
c. Prevention: before each therapeutic epidural dose of local anesthetic, a small test dose of 3 mL has to be administered, the patient has to be observed and questioned about any strange sensations, and blood pressure and oxygen saturation monitored. The person administering epidural anesthesia has to be trained in CPR. Appropriate resuscitation equipment must be available and functioning
d. Treatment: minor symptoms can be treated with the administration of oxygen and reassurance of the patient. In case of seizure, sodium pentothal 50 mg or diazepam 10 mg IV has to be given to interrupt the seizure. The airway has to be protected by endotracheal intubation facilitated by succinylcholine 40 mg IV, and the lungs have to be ventilated with 100% oxygen to assure oxygenation and ventilation. Cardiovascular support with vasopressors, fluid therapy including cardiac massage may be necessary. Emergency cesarean delivery of the baby may be necessary, if persistent fetal bradycardia is present

Table 1

Recommended Maximum Doses of Local Anesthetics
Used in Epidural Anesthesia for Obstetrics
Without Epinephrine
With Epinephrine

B. Sedatives and hypnotics

1.a. Barbiturates: pentothal and methohexital are used as induction agents for general anesthesia because of the rapid onset. All barbiturates are depressant to mother and baby, dependent on dosage and individual duration, and not used for sedation

b. Benzodiazepines: diazepam (Valium) and midazolam (Versed) are anxiolytics and anticonvulsants, and may be used in small doses (5 mg and 2 mg IV). In larger doses, both cause neonatal hypotonia, hypothermia, delayed feeding, increased jaundice, and kernicterus

c. Hydroxyzine (Vistaril) and promethazine (Phenergan) are depressant to mother and baby and have not been useful in obstetrics

d. Propofol (Deprivan) has been introduced as an induction agent for general anesthesia in doses 2-2.5 mg/kg. While maternal cardiovascular status is unchanged, neonatal irritability is noted. In smaller doses, 1-2 mg/kg, maternal awareness is possible

e. Ketamine, 1 mg/kg, produces dissociative analgesia, amnesia, and sedation, while maintaining maternal BP, and does not depress the fetus. It is contraindicated in patients with preeclampsia or hypertension and may cause a hypertensive crisis when combined with ergonovine or vasopressors

f. Scopolamine, an anticholinergic and amnestic agent, is no longer used because of its deleterious effects

C. Opioids and opioid agonist/antagonist

1. Opioids
a. Morphine, meperidine (Demerol), fentanyl, and sufentanil are the most effective systemic analgesics. No narcotic currently available can produce effective analgesia during labor without producing respiratory depression in mother and neonate when given intravenously or intramuscularly. Other side effects include nausea and vomiting, orthostatic hypotension, delayed gastric motility, somnolence, and uncooperativeness in the mother. Epidural or subarachnoid administration of opioids alone or in combination with local anesthetics is now frequently used because the amount of local anesthetic needed for efficient analgesia is greatly reduced when combined with opioids. Systemic effects are minimal and the duration of analgesia is markedly prolonged. The more lipid-soluble the opioid, the greater the spread into the nervous tissue and the more rapid the clearance from the cerebrospinal fluid (meperidine, fentanyl, and sufentanil). Morphine is relatively non-lipid soluble and slowly penetrates the dura and nerve tissue, resulting in slow onset and long duration. Epidural morphine, 4-5 mg (onset 30-45 minutes), provides analgesia up to 24 hours postoperatively. Epidural fentanyl, 100-200 mcg, has a quick onset (5-10 min) with brief (60-140 min) satisfactory analgesia. Epidural sufentanil 10-20 mcg results in 1 hour of pain relief. Subarachnoid morphine in doses as small as 0.25 mg can provide safe analgesia for the first and second stages of labor. The slow onset can be overcome by adding 25 mcg of fentanyl. Subarachnoid meperidine 10-20 mg produces analgesia lasting approximately 2 hours. Sufentanil, 10 mcg, provides analgesia for 1-2 hours. Side effects of spinal opioids include pruritus, nausea and vomiting, and rarely, delayed respiratory depression

2. Opioid agonist/antagonist
a. Butorphanol (Stadol) and nalbuphine (Nubain): when used alone, these drugs have poor analgesic properties and may produce maternal somnolence
b. When used in addition to opioids, epidural butorphanol 4 mg with epidural morphine greatly reduces the incidence of pruritus

D. Inhalational agents

1. Nitrous oxide
a. Maternal effects: low blood solubility of nitrous oxide renders uptake and recovery very rapid. Although its analgesic effects are good, its low potency does not provide complete analgesia for delivery. Nitrous oxide administered in analgesic concentrations (50-75%) does not cause maternal cardiovascular or respiratory depression and does not affect uterine contractility
b. Neonatal effects: respiratory depression and fetal acidosis occur after long administration, especially if maternal analgesia is incomplete and maternal catecholamines are elevated

2. Halogenated agents: halothane, enflurane, isoflurane
a. Maternal effects: in anesthetic concentrations, all halogenated agents cause cardiovascular and respiratory depression. Uterine activity decreases in a dose-related fashion. In low concentrations, 0.4-0.8%, these agents are used to prevent maternal awareness during general anesthesia for cesarean section. When uterine relaxation is needed (entrapment of the second twin, the fetal head, retained placenta), rapid uterine relaxation is provided by hyperventilation of the mother under general, endotracheal anesthesia with high concentrations of these agents. Intravenous oxytocin is needed to reverse uterine relaxation after washout of the inhalational agent. Danger: maternal hyperventilation with high concentrations of a halogenated agent may result in cardiovascular collapse from cardiac depression
b. Fetal effects: low concentrations over a short period of time cause neonatal sedation. Higher concentrations and prolonged administration result in neonatal apnea and hypotension

A. Psychological preparation: Lamaze, natural childbirth classes, and self-hypnosis training are useful in decreasing the anxiety associated with labor and delivery and may reduce the amount of analgesia needed

B. Intravenous or intramuscular narcotics provide incomplete analgesia and interfere with the mother’s ability to concentrate and cooperate

C. Paracervical block

1. Injection of small amounts of local anesthetic into the cervix provides temporary pain relief. It is indicated in parturients with a history of short labor. Pudendal block may be needed for delivery

2. Complications
a. Short duration
b. May lead to high fetal and uterine drug levels leading to fetal bradycardia and uterine vasoconstriction

D. Pudendal block, perineal infiltration

1. Pain from uterine contraction is not blocked

2. Possible intravascular injection and maternal overdose

Figure 9. Regional anesthetic techniques used for obstetric analgesia- anesthesia. Lumbar sympathetic block is rarely used but is highly effective in relieving pain of the first stage and may be prefereable to paracervical block, especially in high risk pregnancies. (Modified from and courtesy of Bonica, J.J.: An atlas on mechanisms and pathways of pain in labor. What’s New, 217:16, 1960.)

Regional anesthesia: epidural analgesia, segmental lumbar, and caudal

Labor and delivery
Maternal effects: segmental analgesia to the 10th thoracic dermatome causes little or no change in maternal cardiovascular status or uterine blood flow with adequate, acute hydration, and prevention of aortocaval compression
Fetal effects: small amounts of local anesthetics do not effect the baby
Course of labor: uterine contractility may improve with pain relief, due to a decrease in maternal norepinephrine
Contraindication for regional anesthesia
Patient refusal
Bleeding diathesis
Active neurological disease
Infection at the site of injection
Inability to communicate

Table 2. Drugs used for Epidural Anesthesia for Labor and Delivery

A. Initial block
1. Bupivacaine: 0.25%, 10 mL
2. Sufentanil: 10-15 mcg, saline 10 mL
3. Bupivacaine: 0.125, plus
a. Fentanyl: 1 mcg/mL, or
b. Sufentanil: 10-15 in saline 10 mL
B. Subsequent block
1. Intermittent as above
2. Continuous infusion rate 10-12 mL/hr
a. Bupivacaine 0.0625 plus fentanyl 1-2 mcg/mL, or
b. Bupivacaine 0.0625 plus sufentanil 0.1-0.2 mcg/mL
C. If perineal analgesia is needed for delivery, administer 10-15 mL of lidocaine 1-2% or chloroprocaine 3%

Cesarean section: higher sensory and sympathetic block to T2 results in peripheral vasodilation, capillary engorgement, decreased venous return and is associated with an incidence of hypotension of 30-50% even if prehydrated with 20 mL/kg and left lateral tilt is maintained. Administration of oxygen by face mask is mandatory
Drug options
Lidocaine 2%, 20-25 m/L, with or without epinephrine, 1:200,000, and fentanyl 50 mcg
Bupivacaine 0.5%, 20-25 m/L with fentanyl 50 mcg, or
Chloroprocaine 3%, 20-30 m/L
Treatment of hypotension: increase lateral tilt, increase IV fluids, administer ephedrine 5 mg IV in increments as soon as first fall in blood pressure is noted. Ephedrine is the vasopressor of choice because it does not cause uterine vasoconstriction in clinical doses

Figure 10. Influence of vasopressors on uterine blood flow and mean arterial pressure (MABP). Note that ephedrine does not influence uterine blood flow even with doses that increas maternal MABP as much as 50%. On the other hand, other vasopressors decrease uterine blood flow, and the greater the increase in MABP (and presumably the greater the dose of the vasopressor) the greater the decrease in uterine blood flow. (Courtesy of Bromage, P.R.: Epidural Analgesia, Philadelphia, W.B.Saunders Co., 1978; developed from data by Ralston, D., Shnider, S., and deLorimier, A.: Anesthesiology 40:354, 1974.)

Spinal anesthesia for labor and delivery

Opioids are indicated in early labor
Short onset
No cardiovascular effects
No motor block
Side effects
Reversal of side effects may be achieved with naloxone (Narcan) 0.04 mg IV or nalbuphine (Nubain) 5 mg IV and 5 mg IM
Opioids do not provide sufficient analgesia for delivery–pudendal block is required

Local anesthetics: tetracaine 4-5 mg or lidocaine 30-40 mg are sufficient for delivery. Advantages include fast onset of complete anesthesia for operative delivery; small amount of drug does not affect the baby, provided no hypotension ensues

Spinal anesthesia for cesarean section
Short onset
The use of small amounts of drugs

Drug options
Tetracaine 10-12 mg in 10% dextrose
Bupivacaine 10-15 mg (7.5% in 8.5% dextrose)
Lidocaine 75-100 mg (5% in 7.5 % dextrose)
Disadvantage: sudden onset of hypotension in 50-80% of cases, even with adequate intravenous preload with 20 mL/kg crystalloid and adequate left lateral tilt. Prophylactic intramuscular ephedrine is of limited value
Complications of regional anesthesia
Intravascular injection of epidural dose local anesthetics results in maternal seizure with fetal distress
Maternal hypotension and, if untreated, fetal acidosis
Total spinal with respiratory and cardiovascular collapse
Postdural puncture headache

General anesthesia for cesarean section

Indications: rapid induction of anesthesia for emergency cesarean section (fetal distress, bleeding placenta previa, placental abruption, uterine rupture, delivery of the second entrapped twin)
Technique: preoxygenation, three deep breaths of 100% oxygen, 4 mg/kg of thiopental IV or 1 mg/kg of ketamine IV and 1.5 mg/kg succinylcholine IV while an assistant applies cricoid pressure. After 40-60 sec, the trachea is intubated and the endotracheal tube sealed by inflating the cuff. The patient’s lungs are ventilated with nitrous oxide (5 L/min) plus oxygen (5 L/min) plus either halothane 0.5%, isoflurane 0.75%, or enflurane 1%. Muscle relaxants are used as necessary. After the umbilical cord has been clamped, deepen anesthesia with nitrous oxide and narcotic. The inhalational agent may be discontinued. The patient is extubated awake

Contraindications: patient refusal

Aspiration of gastric contents is the leading cause of maternal morbidity and mortality due to anesthesia
Inability to intubate and/or ventilate the patient: obstetrical patients are 10x more at risk than nonpregnant patients due to changed anatomy (short neck, large breasts, laryngeal edema, morbid obesity, emergency)
Severe hypertension due to light anesthesia and tracheal stimulus leads to a decrease in uterine perfusion, fetal distress, and may aggravate pre-existing hypertension (preeclampsia)
Maternal awareness and recall during anesthesia
Uterine relaxation and increased blood loss

Figure 11. The effects of pain-induced stress on maternal arterial blood pressure, noradrenalin blood level, and uterine blood flow. The stress was induced by aplication of an electric current on the skin of a ewe at term. Note that the increase in arterial pressure is very transient but the decay in norephinephrine level is more protracted and is reflected by a mirror-image decrease in uterine blood flow. (Courtesy of Shnider, S.M., et al.: Anesthesiology 50:30, 1979.)

Neonatal outcome in general anesthesia vs regional anesthesia: if conducted without complications, there is no difference in neonatal outcome as measured in Apgar scores or newborn acid-base status between these anesthetic techniques

General anesthesia: induction to delivery time has to be kept under 10 minutes and uterine to delivery time shorter than 3 minutes

Regional anesthesia: induction to delivery time is not important, but uterine incision to delivery time has to be kept under 3 minutes for the baby to be vigorous at birth

Zador G, Willeck-Lund G, Nillson BA. Acid-base changes associated with labor. Acta Obstet Gynecol Scand [Suppl] 1974;34:41-49.

Abboud TK, Nagappala S, Murakawa K, David S, Haroutunian S, Zakarian M, et al. Comparison of the effects of general and regional anesthesia for cesarean section on neonatal neurologic and adaptive capacity scores. Anesth Analg 1985;64:996-1000.

Attia RR, Ebeid AM, Fisher JE, et al. Maternal, fetal, and placental gastrin concentrations. Anaesthesia 1982;37:18-21.

Bader AM, Datta S, Arthur GR, Benvenuti E, Courtney M, Hauch M. Maternal and fetal catecholamines and uterine incision-to-delivery interval during elective cesarean section. Obstet Gynecol 1990;75:600-603.

Brizgys RV, Dailey PA, Shnider SM, Kotelko DM, Levinson G. The incidence and neonatal effects of maternal hypotension during epidural anesthesia for cesarean section. Anesthesiology 1987;64:782-786.

Celleno D, Capogna G, Tomassetti M, Costantino P, DiFeo G, Nisini R. Neurobehavioral effects of propofol on the neonate following elective caesarean section. Br J Anaesth 1989;62:649-654.

Davison JM. Overview: kidney function in pregnant women. Am J Kidney Dis 1987;9:248-252.

Eckstein KL, Marx GF. Aortocaval compression: incidence and prevention. Anesthesiology 1965;40:381-384.

Gilroy RJ, Mangura BT, Lavietes MH. Rib cage and abdominal volume displacements during breathing in pregnancy. Am Rev Respir Dis 1988;137:668-672.

Glassenberg R. General anesthesia and maternal mortality. Sem Perinatol 1991;15(5):386-396.

Gutsche, BB. Prophylactic ephedrine preceding spinal analgesia for cesarean section. Anesthesiology 1976;45:462-465.

James CF, Gibbs CP, Banner TE. Postpartum perioperative risk of pulmonary aspiration. Abstracts of scientific papers, Society for Obstetric Anesthesia and Perinatology. Vancouver: May, 1983.

Jones CM, Creiss FC. The effect of labor on maternal and fetal circulating catecholamines. Am J Obstet Gynecol 1982;194:149-153.

Lind LJ, Smith AM, McIver DK, et al. Lower esophageal sphincter pressures in pregnancy. Can Med Assoc J 1968;98:571-574.

Maltau JM, Eielsen OV, Stotcke KT. Effect of stress during labor on the concentration of cortisol and estriol in maternal plasma. Am J Obstet Gynecol 1979;134:681-684.

Marx GF, Luykx WM, Cohen S. Fetal-neonatal status following caesarean section for fetal distress. Br J Anaesth 1984;56:1009-1013.

Moore DC. Spinal anesthesia: bupivacaine compared with tetracaine. Anesth Analg 1980;59:743-750.

Moya F, Morishima HO, Shnider SM, et al. Influence of maternal hyperventilation on the newborn infant. Am J Obstet Gynecol 1965;90:76-84.

O’Sullivan GM, Sutton AJ, Thompson SA, et al. Noninvasive measurement of gastric emptying in obstetric patients. Anesth Analg 1987;66:505-511.

O’Brien WF, Saba HI, Knuppel RA, et al. Alterations in platelet concentration and aggregation in normal pregnancy. Am J Obstet Gynecol 1986;155:486-490.

Palahniuic RJ, Shnider SM, Eger EI. Pregnancy decreases the requirement for inhaled anesthetic agents. Anesthesiology 1974;41:82-87.

Pernoll ML, Metcalf J, Schlenlser TL. Oxygen consumption at rest and during exercise in pregnancy. Respir Physiol 1975;22:285-292.

Prowse CM, Gaenster EA. Respiratory and acid-base changes during pregnancy. Anesthesiology 1965;26:381-384.

Ralston DH, Shnider SM, deLorimier AA. Effects of equipotent ephedrine, metaraminol, mephentermine, and methoxamine on uterine blood flow in the pregnant ewe. Anesthesiology 1974;40:354-370.

Russell GN, Smith CL, Snowdon SL, et al. Preoxygenation and the parturient patient. Anaesthesia 1987;42:346-351.

Ueland K. Maternal cardiovascular hemodynamics. VII. Intrapartum blood volume changes. Am J Obstet Gynecol 1976;126:671-676.

Wittels B, Glosten B, Faure EA, Moawad A, et al. Opioid antagonist adjuncts to epidural morphine for postcesarean analgesia: maternal outcomes. Anesth Anal 1993;77:925-932.