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Sharon M. Weinstein MD

Associate Professor of Anesthesiology, Neurology and Oncology

University of Utah

Director, Pain Medicine and Palliative Care

Huntsman Cancer Institute





Be able to:


1.      Define pain

2.      Identify the four neurophysiologic processes of pain

3.      Name the two broad classes of clinical pain states

4.      Be familiar with peripheral and central mechanisms of neuropathic pain

5.      Understand the difference between nociceptive nerve pain and neuropathic pain

6.      Be familiar with pain terminology

7.      Understand the fundamentals of pain patient evaluation




Pain is the most common reason people seek medial attention. Pain is often poorly treated, leading to needless, preventable suffering and disability. Pain may be associated with an acute or chronic condition. Chronic pain is a major public health problem in the United States, costing our society billions of dollars annually. Untreated pain can result in suicide. The benefits of adequate pain control include facilitation of diagnostic evaluation and medical treatment, improved functional status, prevention of suicide and better quality of life.

Strategies for pain relief include reducing transduction of painful peripheral stimuli, changing transmission within the central nervous system, or altering perception itself at the higher cortical level. A rational combination of pharmacologic and nonpharmacologic methods will relieve pain in the majority of patients with pain. Pharmacotherapy may be complex, combining medications of different classes to affect transduction, transmission, and/or modulation of pain signals. Physical and psychological interventions are used alone or in conjunction with medications. The pain generator should be identified when considering ablative (destructive) procedures. It is relatively contraindicated to perform neuroablation for a central pain generator.

Analgesic interventions must be integrated into the overall medical treatment plan. Pain treatment may be simply a part of routine care delivery, or provided by pain specialists with a team approach. Physician pain specialists may be neurologists, physiatrists, anesthesiologists, psychiatrists, or have other backgrounds. Pain management teams include the physician, nurse, pharmacist, social worker, psychologist, physical therapist, occupational therapist, and others. In the setting of terminal illness, spiritual care providers help relieve patient and family suffering. Americans frequently use complementary and alternative approaches such as massage therapy, acupuncture, and herbal formulations.

            With ongoing collaboration between basic science and clinical investigators, we are on the threshold of a number of significant breakthroughs in management. Physicians may look forward to a continuing expansion of our therapeutic armamentarium to relieve pain. Goals of pain treatment must be frequently reviewed and integrated into the overall management plan. Communication between professional staff, the patient and family is essential. For patients with chronic conditions, the goals of pain relief should be coupled with goals of functional restoration. The goal of pain management for patients with incurable, life-limiting disease is to provide symptom palliation, allowing the patient and family the best quality of life regardless of prognosis.



            Pain is defined as "an unpleasant sensory and emotional experience associated with tissue damage, or described in terms of such damage".  Pain is the result of transduction, transmission, modulation and perception of painful (nociceptive) impulses. In humans, parallel neural pathways transmit nociceptive stimuli from the periphery, through the spinal cord, to multiple areas of the brain. Nociceptive messages are localized, interpreted, and the affective component assigned at the supraspinal level. An endogenous opioid system exists throughout the nervous system, with opioid receptors of several subtypes. Modulation of nociceptive input by opioid and nonopioid mechanisms occurs in the periphery, the dorsal horn of the spinal cord, the brain stem, and probably in higher centers.

            Pain is best understood as a dynamic state of the nervous system. Clinical pain states may be divided into two broad classes: those associated with ongoing tissue damage (nociceptive) and those resulting from neural dysfunction in the absence of tissue damage (non-nociceptive = neuropathic). Pain may also arise from inflammation of the nerves, termed nociceptive nerve pain.


Nociceptive Pain

Nociceptive pain (inflammatory pain) refers to pain in response to activation of peripheral nociceptors by either mechanical pressure, high or low temperature or chemical mediators.

On actual tissue damage by trauma, surgery, infection or tumor, a local inflammatory reaction takes place. The inflammatory process includes the release and production of a number of chemical mediators and neuropeptides leading to sensitization, repeated and sustained depolarization of peripheral nociceptors (unmyelinayed C-fibers and thinly myelinated A-delta fibers). Any pain that is triggered by an acute damaging effect event or by ongoing tissue damage can be characterized as nociceptive pain. This pain originates from somatic structures like skin, periosteum, joints or muscles and may be referred to as somatic pain when nociception arises from somatic tissues. Nociceptive pain can also originate from visceral organs and is then designated as visceral pain. It is believed that visceral nociceptors are the free nerve endings of thin unmyelinated afferents travelling with sympathetic fibers.

Referred pain may originate from stimulation of primary afferent nociceptors in sites other than the skin such as the viscera, bony structures, ligaments and joints. Referred pain may follow a nerve root distribution (radicular referred) or may be perceived in an unrelated site (non-radicular referred). Thus, pain may be local at the site of pathology, or referred in a radicular or nonradicular pattern.


Neuropathic Pain

            The specific mechanisms for many pain states have not been fully elucidated, although several mechanisms of neuropathic pain have been identified. Structural as well as functional changes occur in the nervous system following repeated noxious stimuli, persistent tissue damaging stimuli or direct neural injury. When peripheral neurons are injured, healing results in a tangle of nerve endings referred to as a neuroma, which is highly sensitive to algesic mediators and mechanical stimuli. After peripheral nerve injury, sensitization of central neurons takes place with alteration in their firing characteristics. Synaptic patterns may be modified with formation of new receptive fields. Depletion of central inhibitory neurotransmitters occurs, along with a loss of opioid receptor binding sites in the dorsal horn neurons.  Chronic pain may be attributable to pathologic functioning of a damaged nervous system at any level.

            The primary nociceptive afferents of damaged peripheral nerve have lowered thresholds and increased expression of voltage-sensitive sodium channels. This may lead to chronic ectopic spontaneous electric impulse discharge and pacemaker activity from regenerating fibers. The mechanisms of neuropathic pain include totally or partially deafferented dorsal horn cells which become disinhibited and hyperexcitable, producing an increased spontaneous firing rate. Following deafferentation, noradrenergic perivascular axons may sprout around dorsal root ganglion sensory neurons and lead to hyperexcitability of primary sensory neurons. The hyperexcitability includes prolonged or enhanced susceptibility for incoming nociceptive afferent impulses. Local changes at the level of the damaged nerve may result in enhanced excitability of peripheral nerves by changes in morphology, local chemistry and inducing nerve growth factor.  Spontaneous ectopic discharge and hypersensitization from a nerve stump, pacemaker activity originating from a neuroma together with disinhibition at the level of second order sensory neurons in the dorsal horn, all contribute to the pain after deafferentation.


Nociceptive Nerve Pain

The presence of nervi nervorum in the nerve root sheath and epi- and perineurium has been shown by a number of investigators . The axons of the peripheral nerves are enclosed by the epi- and perineurium, which contain the myelinated and unmyelinated fibers. If a nerve trunk is compressed or infiltrated, this will be accompanied by local inflammation and edema, and the free nerve endings in the surrounding connective tissue of the nerve trunk become activated. The inflammatory process may change or sensitize the axonal membranes of sensory fibers that now may become susceptible to non-painful stimuli. Spinal nerve roots that show signs of inflammation are very sensitive to mechanical manipulation. Another factor that is probably important in causing nociceptive nerve pain is compression of a nerve root at the level of the dorsal ganglion, which is located in the intervertebral foramen. Mechanical compression at that site leads to a heavy barrage of action potentials with severe accompanying pain.

The concept of nociceptive nerve pain implies that the pain may be felt along the anatomical course of a particular nerve with or without spontaneous positive sensory phenomena like paresthesias or dysesthesias, and signs of diminished sensation in response to external stimuli like hypoalgesia. If the inflammatory process persists, degeneration or infiltration of sensory fibers in the nerve may lead to permanent nerve injury that will remain even after the inflammatory response has waned. Thus, a nociceptive nerve pain may progress with development of signs and symptoms of permanent damage to the nerve, and become a neuropathic pain. See TABLE 2.



            The pathophysiologic classification of pain forms the basis for selection of specific analgesic interventions. In the case of neuropathic pain, one may classify the pain state according to the site of injury. It is more clinically relevant to localize a neuropathic pain generator as being in the peripheral or central nervous system.

            Syndromic classifications have been elaborated for certain disease states, i.e. cancer. Cancer pain syndromes vary by tumor type and are related to patterns of tumor growth and metastasis. Pain may be directly related to antineoplastic therapy. It may be indirectly related or unrelated to either the neoplasm or its treatment (see TABLE 3).



 Patients usually suffer with pain due to more than one pathophysiologic mechanism. For example, see TABLE 4).


Patient Evaluation

As a symptom, pain gives clues regarding an injury or disease process. A thorough patient assessment is essential to the proper evaluation and management of pain. Assessment includes history taking, physical examination, and review of clinical information. At the conclusion of the patient assessment, the clinician should be able to make a pain diagnosis (identifying the pathophysiologic process underlying the complaint) on which to formulate the treatment plan.


History Taking

        Complete medical history

        Pain history

Characterize the pain complaints - the PQRST mnemonic

P = provocative, palliative factors

Q = quality, word descriptors

R = region, radiation, referral

S = severity (use intensity rating scales)

T = temporal features (onset, duration, variation)

        Efficacy and side effects of previous analgesic interventions

        Psychosocial history, including alcohol and drug use


There are no objective means to verify the experience of pain - one begins by believing a patient's complaint. Expressions of pain are highly variable, depending on age, gender, cultural background, social milieu and other factors. Often patients must be encouraged to verbalize their pain, and most need to learn means of reporting pain intensity. They may be reluctant to relate the true degree of pain intensity and minimize their report; conversely they may have developed elaborate behavioral expressions of pain over time. The report of pain intensity does not correlate well with the seriousness of the pathologic process, and there may or may not be evidence of gross pathology on examination. Note that unrelieved pain may preclude the patient's complete cooperation due to concomitant anxiety or lack of attention. Family caregivers may be helpful in supplementing the history given by the patient, especially in the pediatric population and the very ill.

Certain characteristics suggestive of neuropathic pain should be elicited. Typically patients describe burning or lancinating components of pain. Some patients offer strange complaints, such as painful numbness, itching, or crawling sensations. Radicular pain is usually associated with segmental findings on examination. Nonradicular referred pain may be associated with vague paraesthesias and tenderness at the painful site.

Although pain cannot be truly quantified, in clinical practice various pain intensity rating scales are used to establish a baseline against which the efficacy of analgesic interventions may be judged. Standardized pain assessment tools are available for adults and children. Certain tools record the impact of pain on mood, appetite, sleep, physical activities and social function. When patients are unable to communicate, behavioral observations may substitute for the self-report of pain intensity.


Physical Examination

        General examination include the painful area and mechanical evaluation

        Neurological examination  - identify neurologic abnormalities


            After taking a careful history, the examiner should have a sense of priority for certain parts of the complete physical examination. Examiners are cautioned not to assume that a patient is voluntarily misrepresenting physical symptoms. The physiologic signs of acute pain - elevated blood pressure and pulse rate - are not reliable in subacute or chronic pain.

            Physical examination will confirm or exclude structural abnormality, mechanical functional problems, and neural dysfunction. Patterns of pain referral should be kept in mind. The physical examination is directed to palpable masses. Areas of tenderness may be due to tumor infiltration, or be referred from the viscera to cutaneous or musculoskeletal sites. In the soft tissues one may palpate muscle spasms or discrete trigger points which when stimulated refer pain to another site.  A careful mechanical evaluation including active and passive joint motion, weight bearing, and gait may also reproduce the pain complaint. Sitting or standing may cause gravitational traction on tumors infiltrating nerve plexi. This can cause pain to be referred into the extremities that may be mistaken for pain due to direct involvement of skeletal tissues. A detailed neurological examination should be performed, especially if tumor involvement of the nervous system or neuropathic pain is suspected. Pain in an area of reduced sensation, allodynia, and hyperpathia or summation of painful stimuli indicate neural dysfunction. The diagnosis of Complex Regional Pain Syndrome, (causalgia, reflex sympathetic dystrophy, or sympathetically-maintained pain) is suggested when signs of marked sympathetic nervous dysfunction accompany diffuse burning or deep aching pain after injury to nerve or other tissue.

            When examining the pediatric patient in pain, patience and gentleness are especially required. The younger the patient, the less able she or he is to report pain, especially the subtle aspects. Younger patients are generally less cooperative for examination of the painful part and for maneuvers. Much of the examination of preverbal children is based on observation, supplanted by activities simulating play. Children may demonstrate more distractibility than adults, but will resist further attempts at examination if they are caught by surprise. One may obtain a more complete examination by enlisting the help of the parent or caretaker. Cooperative older children and adolescents may be examined as adults.

            Examination of the non-communicative patient poses a challenge. One relies more on nonverbal expressions and much less on cooperation for specific tests and maneuvers. Nonverbal expressions of pain include groaning, grimacing, agitation, muscle rigidity, body stillness and behavioral withdrawal. If the examiner has previously evaluated the patient in a cognitively intact state, the exam may be focused accordingly. If not, perform as much of the physical examination as possible, taking care not to provoke acute pain.


Review of Clinical Information

        Disease status

        Laboratory tests

        Diagnostic imaging

        Primary treatment plan


It is strongly recommended that an examining physician make clinicoradiographic correlation. Correct interpretation of symptomatic and asymptomatic lesions on diagnostic imaging studies requires thorough knowledge of the patient's clinical presentation.    



The Pain Diagnosis

In order to select therapeutic interventions, an understanding of the pathophysiology of the pain complaint is necessary. Patients often experience mixed pain syndromes. Treatments should be directed at the specific pathophysiology(ies) underlying the pain.





Altered Sensation (Negative)

            anaesthesia                                           absence of sensation

            analgesia                                               absence of pain to normally painful stimuli

            hypoaesthesia                                       diminished sensation

            hypoalgesia                                           diminished pain to normally painful stimuli


Altered Sensation (Positive)

            hyperaestheisa                                      increased sensitivity to stimuli

            hyperalgesia                                          increased sensitivity to painful stimuli

hyperpathia                                           increased pain threshold and increased response to repetitive painful stimuli


Abnormal Sensation

            allodynia                                               pain in response to normally nonpainful stimuli

            anaesthesia dolorosa                             pain in an anaesthetic area

            dysaesthesia                                         unpleasant sensation, spontaneous or provoked

            paraesthesia                                          abnormal sensation, spontaneous or provoked


Other Terms

            breakthrough pain                                 occurring during analgesic interval

            central pain                                           due to a central nervous system lesion

CRPS                                                  Complex Regional Pain Syndrome (reflex sympathetic dystrophy or causalgia)

            deafferentation pain                               due to nerve injury with loss of normal sensory input

            incident pain                                         provoked by a particular factor such as movement

myofascial pain                                     localized muscle tender (trigger) point which when stimulated refers pain in a characteristic nondermatomal pattern

            neuralgia                                               pain referred in a nerve distribution

            neuritis                                                  inflammation of a nerve

            neuropathic pain                                   due to neural dysfunction

            nociceptive pain                                    due to tissue injury or inflammation

            pain threshold                                       the least stimulus producing pain

            pain tolerance                                       the greatest level of pain a subject can tolerate

            sensory threshold                                  the least stimulus a subject can recognize



Reference:  Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. Second edition. IASP Task Force on Taxonomy. IASP Press, Seattle, Washington, 1994






Symptomatic trigeminal neuropathy

   Sjgren`s disease, SLE, Mixed                                       

   Connective Tissue Disease

   Other systemic disorders

   Metastatic cancer

Infraorbital or mental neuropathy

   Bone metastasis at foramen ovale or

    in mandibular bone

   Perineurial tumor extension

   Leptomeningeal cancer

Symptomatic glossopharyngeal    neuropathy 




   Herniated disc

   Vertebral metastasis

   Acute herpes zoster

   Guillain- Barre syndrome

   Perineurial tumor extension

   Leptomeningeal cancer

   Lyme disease



   Lymph node metastasis  

   Diabetic amyotrophy

   Idiopathic plexus neuritis

   Psoas hematoma

   Retroperitoneal abscess

   Pancoast tumor




   Leprosy neuritis

   Nerve compression syndromes*

The pain in peripheral nerve compression

syndromes may be different from compression pain

of nerve roots or plexus, due to differences in

surrounding connective tissue or nervi nervorum distribution




Acute procedure-related pain


Acute and chronic pain associated with direct tumor involvement

Due to invasion of bone

Due to invasion of nerves

Due to invasion of viscera

Due to invasion of blood vessels

Due to invasion of mucous membranes


Chronic pain associated with cancer therapy

Post-operative pain syndromes

Post-chemotherapy pain syndromes

Post-radiation pain syndromes


Pain unrelated to the cancer or its treatment



Adapted from Portenoy RK: Cancer pain: Epidemiology and syndromes. Cancer 63:2298-2307, 1989




Loss of any body part is commonly followed by psychological adjustment that may include a grief reaction. Nonpainful and painful phantom sensations (referred to the missing part), pain in the scar region (a stump after limb amputation), and involuntary motor activity are known to occur after surgery. Painful phantoms of limb, digit, eye, nose, teeth, tongue, breast, bladder, anus, and genital organs have been reported. Phantom pains may be described as intense versions of normal exteroceptive sensations.  Limb amputees often describe their pain as burning, tingling, "pins and needles", cramping, shocking and shooting.  Some patients offer bizarre descriptors. Visceral phantoms may be accompanied by functional urges, e.g. to void or defecate.

Different studies have noted that phantom pains can mimic preamputation pain, suggesting pain memory.  There are some data to support a positive predictive value of pre-operative pain for post-operative pain, although post-amputation phenomena are quite variable.

Gradual reduction in the frequency and duration of painful episodes is the most common course, occurring over several weeks to two years. Although the majority of patients note the onset of phantom pain immediately after amputation, late appearing phantom pain has been reported. New phantom pain in a cancer patient should be promptly investigated as potentially indicative of recurrent tumor.

Following amputation, wound pain is expected to resolve as tissue healing takes place.  Recurrent or prolonged stump pain is usually attributable to local pathology, such as tumor, circulatory disturbance, infection, poor wound healing, or an ill-fitting prosthesis.

There are few reports on the course of post-amputation pain in malignant disease. In a retrospective survey of M. D. Anderson Cancer Center limb amputees, 91% reported painful phantoms after surgery. In a prospective survey we found that stump pain intensity was maximal immediately following surgery and steadily declined within weeks to months. All patients reported phantom pain. Nonpainful phantom sensations did not correlate with post-amputation pains, and there was no correlation between stump and phantom pain intensity. In another study of seventeen cancer patients who underwent forequarter amputation, none of the seven survivors were experiencing pain requiring the use of analgesics after an average of 69 months follow-up. Larger surveys of post-mastectomy breast cancer patients reveal that at least 10% experience phantom breast pain beyond the first year.

Health care professionals and family members may overlook phantom pain in children. There are many factors that affect incidence of phantom limb pain in children including underreporting of pain and variability in the pain experience due to age or cognitive level.  A verbal child can describe feelings in a limb no longer present and distinguish stump from phantom pain.  Recent reviews of congenital and childhood amputees confirm that phantom pain affects the majority. These data underscore the need to carefully assess patients for post-amputation pain regardless of age.






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                                              Last updated:  10/05/2002                                                          © 2000-2002 John Rose, MD  University of Utah School of Medicine