The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”.1 Pain remains the most common symptom for which a patient seeks out medical care. 

A simple classification of pain includes somatic, visceral, and neuropathic. Somatic and visceral pain are elicited by injury to tissue and ceases with healing of the tissue.  Neuropathic pain results from injury to the nerve and often persists long after healing. It is commonly described as a burning or stabbing pain that may occur in paroxysmal episodes known as lancinating or “lightning”.

Pain syndromes can become complex and defy simple pathophysiological explanations. Patients describe extreme burning, dysesthetic pain sensations involving large areas of the body with little relation to any demonstrated soft tissue or nerve injury. Autonomic dysfunction is manifest by temperature and color changes, edema, and trophic changes.  Formerly known as reflex sympathetic dystrophy and causalgia, these pain syndromes are now labeled Complex Regional Pain Syndrome Type I (CRPS- I), or if there is a documented nerve injury, Type II (CRPS-II).12  

Nerve Injury and Pain

Pain sensations normally derive from activity generated in nociceptors, terminals of certain sensory nerves. When nociceptors are stimulated they respond by increasing their rate of activity which the nervous system interprets as pain. Injury may induce a nerve to become spontaneously active.  If an injured nociceptor develops ongoing spontaneous activity the patient suffers “neuropathic pain”.  For example, injury to the C7, C8 roots, lower trunk of brachial plexus or the ulnar nerve can lead to burning pain in the 4th and 5th fingers of the hand  (dermatomes subserved by these nerves).  This can account for certain phantom pains.

A few fibers can become ectopically excitable such that stimulation along the course of the nerve elicits a response.  In theses circumstances, palpation of the nerve can result in a nerve discharge thus the patient describes pain even with gentle prodding of the nerve.

Influence of the Nerve Injury Milieu

After some soft tissue injuries, a nerve may become entrapped in the fibrotic reaction which occurs in response to injury.  This can lead to compression or tethering of the nerve resulting in pressure and traction forces on the nerve. As a consequence, movement of the extremity results in excessive traction on the nerve  resulting in local tenderness.

Neuromas

When a nerve is severed the axons in the proximal end remain in continuity with their cell body (located in the dorsal root ganglion or anterior spinal cord).  In the distal nerve, the axons have been disconnected from their cell body and die.  The axons in the proximal nerve will send out sprouts in an attempt to re-innervate the distal portion of the nerve and re-establish connection with the end terminals. 

A neuroma is a densely packed cluster of regenerative sprouts which forms when the continuity of the nerve is interrupted and regeneration is blocked by fibrous scar tissue or the distal part of the nerve is removed from the region by trauma. As described above, the milieu the neuroma finds itself in may greatly influence the degree of resulting pain.  Excessive scar formation, external pressure from prosthesis, and chronic inflammation from poor wound healing can all lead to chronic pain. 

Surgical management of neuromas involves division of the nerve proximal to the neuroma.  The proximal end is then turned  and  protected by deeply seating it in muscle or bone.  Although a new neuroma will form, it will hopefully not be subject to repeated motion at a joint or to mechanical pressure.

Palliative Measures for Pain Control

Techniques for management of pain have been traditionally separated into treatment of acute pain, cancer pain and chronic nonmalignant (non-cancer) pain. It was initially thought that certain medications were appropriate for only certain types of pain, however, this has become less clear.  For example, use of opioids to manage chronic non-malignant pain was frowned upon because of potential for addiction and lack of efficacy in pain relief.  This class of drug has more recently been demonstrated to be highly beneficial for neuropathic pain and nonmalignant pain syndromes including chronic back pain.

 The goal of therapy is to bring pain symptoms into an acceptable range for the patient. This is best attempted by a trial of each drug, titrating the dose up until symptoms are controlled or unacceptable side effects arise.  While complete remission is unlikely, by using a combination of medications it is often possible to bring symptoms within a tolerable range of pain.  A typical end point is a drop of 50% of the pain.

Physical Therapy

Patients who suffer from chronic pain often benefit from various forms of physical therapy. Pain in a limb can lead to disuse of the extremity with subsequent adhesive capsulitis in the joints.  Contractures of ligament and tendons occurs further limiting range of motion.  Pain secondary to the musculo-skeletal issues can then complicate the picture.  An aggressive therapy program will maintain both active and passive range of motion as well as general muscle conditioning.  Mobilization of the affected limb has long been considered a corner stone in the management of reflex sympathetic dystrophy.2

Antidepressants

Neuropathic pain is a common example of chronic non-malignant pain which has been favorably responsive to medications such as antidepressants and anticonvulsants.  These drugs may be used as a first line therapeutic regime and often lower the necessary dose of a primary analgesic. Tricyclic antidepressants have been studied in various  pain syndromes and have been shown to be beneficial in a number of conditions including neuropathic pain and peripheral neuropathy.5  While depression is likely to play a role in the perception of pain, the efficacy of these drugs has been established at doses too small and at a time interval too short to be attributable to alterations of mood.  By taking the medication at night, patients benefit from a good night sleep, something often lacking in these patients.  Regardless of the Tricyclic antidepressant of choice, it is important to remember that the analgesic properties may take a week or more to have an affect on symptoms.

Anticonvulsants

Pain that is paroxysmal and lancinating might be generated by ectopically excitable sites on the injured nerve.  This situation has been likened to epilepsy in the brain, but occurring in the peripheral nervous system. The use of an anticonvulsant may suppress foci of activity and thus eliminate the pain. Gabapentin (Neurontin) has been shown to possess anxiolytic and antinociceptive properties in addition to its effectiveness as an anticonvulsant.  Gabapentin also has a favorable safety profile relative to other anticonvulsants and is becoming the anticonvulsant of choice for treatment of neuropathic pain.11;13

Opioids

An opioid is any member of the group of analgesics which shares the properties of morphine.  Opioids produce analgesia through their activities at opioid receptors in the central and peripheral nervous system.  Opioid analgesics differ principally in potency and duration of action.

The use of opioids for the management of nonmalignant pain has been going through a revolution.10  It has become clear that many types of pain previously not thought to be opioid sensitive, including various forms of neuropathic pain, are in fact opioid sensitive.  The dosage should be titrated up until pain relief is achieved or unacceptable side effects occur.  When used for chronic treatment, a slow release opioid such as Methadone or MS-Contin is utilized.  These allow a more sustained drug level avoiding the peaks and valleys in blood level associated with short acting drugs. 

Multiple studies have been published in the last decade that have demonstrated usefulness of spinal administration of opioids for malignant and non malignant etiologies of pain.14  Implantable morphine pumps for spinal administration allow more direct application of the analgesic pharmacopoeia, providing greater potency and efficacy.  These pumps, however, should only be used in patients in whom oral administration of opioids has failed either due to unacceptable side affects or lack of efficacy.

The stigma of drug addiction to opioid medication has hampered the use of a very effective pain management drug.  It needs to be stressed that although physical dependence to opioids is routine, psychological addiction is uncommon.  In general, when opioids are given to control pain, psychological dependence does not result. The development of tolerance is a complex clinical issue and should not be confused with abuse.9 

Electrical Stimulation Modalities

Transcutaneous electrical nerve stimulation (TENS) attempts to control pain through stimulation of peripheral nerves.  TENS devices stimulate peripheral nerves with electrical pulses of varying amplitudes and frequencies. It is thought that TENS activates the descending inhibitory pain fibers to induce analgesia or blocks the primary afferent (Gait Control Theory 6). TENS is most effective in patients suffering from musculoskeletal pain, phantom limb pain, and headache.7  TENS units are frequently employed by physiotherapists taking advantage of the pain relief to allow further mobilization of the affected limb.

Spinal cord stimulation (SCS) delivers electrical stimulation to the dorsal columns of the spinal cord by way of electrodes placed in the epidural space. When the electrode is properly placed, the patient feels paresthesia or “buzzing” sensations in the same distribution as the pain often accompanied by reports of decreased pain.  Presently, failed back syndrome is the most common indication for its use8, but neuropathic pain is also known to respond. A more recent advance has been the application of the electrode directly to the injured peripheral nerve with thus far, a fairly good ability to control neuropathic pain.4 

Dorsal Root Entry Zone Lesion

Avulsions of the brachial or lumbar plexus occurs when the nerves of the plexus are sufficiently stretched such that the spinal roots are torn free from the spinal cord.  Avulsion is severely traumatic to the dorsal horn of the spinal cord resulting in a local gliotic scar.  It has been postulated that the scar induces an epileptic focus in the dorsal horn.  If the WDR cells discharge secondary to activity in the scar, severe disabling pain in the affected dermatome occurs.  This accounts for certain forms of phantom pain.

When oral medications fail to control the pain of avulsion, consideration is given to surgical intervention.  The dorsal root entry zone (DREZ) procedure involves use of a radio-frequency electrode to create a series of lesions in the dorsal horn region of  the spinal cord.  The effectiveness of this operation for pain secondary to avulsion injury has been  impressive.3

Summary

Pain is a complex phenomenon influenced by subjective and emotional factors. When a nerve is injured, neuropathic pain may result. This form of pain is often out of proportion to the injury and spreads in a distribution greater than that of the affected nerve.

Neuropathic pain is generally responsive to opioids but anticonvulsants such as Gabapentin and anti-depressants including Amitriptyline,  have been shown to be beneficial. When these therapies fail, electrical stimulation modalities such as TENS or spinal cord stimulation may be of benefit.  In patients with pain secondary to scar foci or entrapment, neurolysis may be indicated. In the specific case of brachial plexus avulsion, the DREZ operation has been shown to relieve pain.

Reference List 
1.  Textbook of Pain, ed Third. New York : Churchill Livingstone, 1994,
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4.  Laryea JA, Schon LC, Belzberg AJ: Peripheral Nerve Stimulators for Pain Control. Seminars in Neurosurgery 12:125-130, 2001
5.  Max MB, Lynch SA, Muir J, et al: Effects of Desipramine, Amitriptyline and Fluoxetine on pain in diabetic neuropathy. N.Engl.J.Med. 326(19):1250-1256, 1992
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8.  North RB, Kidd DH, Lee MS, et al: Spinal cord stimulation versus reoperation for the failed back surgery syndrome:  A prospective, randomized study design. Stereotact.Funct.Neurosurg. 62:267-272, 1995
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10.  Portenoy RK: Opioid therapy for chronic nonmalignant pain: a review of the critical issues. J Pain Symptom Manage 11:203-217, 1996
11.  Rosner H, Rubin L, Kestenbaum A: Gabapentin adjunctive therapy in neuropathic pain states. Clin J Pain 12:56-58, 1996
12.  Stanton-Hicks M, Jänig W, Hassenbusch S, et al: Reflex sympathetic dystrophy:  Changing concepts and taxonomy. Pain 63:127-133, 1995
13.  Wetzel CH, Connelly JF: Use of gabapentin in pain management. Ann Pharmacother 31:1082-1083, 1997
14.  Winkelmüller M, Winkelmüller W: Long-term effects of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology. J.Neurosurg. 85:458-467, 1996

Alan J. Belzberg, B.Sc., M.D., FRCSC is an Associate Professor of Neurosurgery at Johns Hopkins Hospital and directs the peripheral nerve program. He has lectured around the world and gained an international reputation as an outstanding  physician and surgeon treating pediatric and adult patients with nerve injury. He has an NIH funded laboratory that examines nerve regeneration and neuroma formation and has published numerous scientific articles in peer reviewed journals. With all of the accolades he has earned as a physician/scientist, his most coveted remains “best bedside personality,” something that has attracted patients from some 21 different countries.