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Pain responses to perineuromal injection of normal saline, gallamine, and lidocaine in humans
321
Pain, 36 (1989) 321-325 Elsevier PA1 01365
Pain responses to perineuromal injection of normal saline, gafiamine, and lidocaine in humans Charles Chabal, Department
Louis Jacobson,
Lisa C. Russell
* and Kim J. Burchiel
*
of Anesthesiology. and * Department of Neurological Surgery, University of Washington School of Medicine, Veterans Administration Medicat Center, 1660 South Columbian Way, Seattle, WA 98108 (U.S.A.)
(Received 24 May 1988, revision received and accepted 30 September 1988)
Rat neuromas have shown an increase of spontaneously active fibers to systemically administered potassium channel S--Y btocking agents such as tetraethylatnmonium chloride (TEA) and gallamine. Neuroma formation and spontaneous activity have been associated with autotomy in rats and pain in humans. To evaluate the chemo~siti~ty of human neurons to potassium channel blocking agents, 9 subjects with neuroma pain underwent perineuromal injection in a singleblinded fashion of normal saline, gallamine, and lidocaine. Sodium chloride had no effect on control pain levels, while gallamine significantly increased and lidocaine significantly decreased pain from control levels. Three of 4 patients with accompanying phantom limb pain noted an increase in pain after the injection of gallamine. The data suggest that peripheral input plays a modulating but not solitary role in both neuroma and phantom limb pain. Agents which increase potassium channel permeability or decrease sodium influx would be predicted to decreased perceived pain. Key words
Perineuromal injection; Saline; Gallamine; Lidocaine; Neuroma pain, Phantom limb pain
Introdwction
Chronic pain and dysesthesias have been associated with nerve ligation and subsequent neuroma formation in humans [17,27]. Laboratory studies using microfilament recording techniques have shown abnormal spontaneous activity originating from experimental neuromas in rats [11,34,35]. These spontaneously active fibers show excitatory changes to hypoxia [16], mechanical stimulation [2,4,21], systematically administered alpha-adrenergic agonists [16,21,34], and to sympathetic chain s~ulation [2,4,9,16,21]. Recently, similar excitatory changes have been demon-
Correspondence to: Charles Chabal, M.D., Anesthesiology Service, 112A, Veterans Administration Medical Center, 1660 South Col~bian Way, Seattle, WA 98108, U.S.A.
strated after intravenous administration of the non-depol~~g neuromuscular blocker, gallamine and the potassium channel blocker, tetraethylammonium chloride (TEA) [S]. Gallamine, like TEA, is a potent potassium chmel blocking agent and the excitatory changes observed may be co~ensurate with its potassium channel blocking property [5,25,26]. The neurophysiological evidence in animals of neuromal chemosensitivity has been demonstrated and has been postulated to contribute to the sensation of pain. However, corroborative studies in humans are lacking. In addition, extrapolating neurophysiologic data from animals to human sensations and feelings may not be valid. The following study was undertaken to evaluate the effects of a perineuromal injection of gallamine on the perception of pain in humans. From the animal data it was h~othes~~ that gallamine should
0304-3959/89/$03.50 0 1989 Elsevier Science Publishers B.V. (Biomedical Division)
322
markedly increase pain and this effect could be antagonized by local anesthetic injection.
TABLE
I
DEMOGRAPHICS
OF SUBJECTS
Subject
Age (years)
Location neuroma
1
39
2
38
3
66
Saphenous nerve 4th metacarpal Left AKA
4 5
48 50
6
46
Methods
After obtaining permission from the Human Subjects Review Committee, 9 subjects were studied at least 1 year after peripheral nerve ligation. All operative sites were well healed and all subjects complained of paresthesias and pain at or distal to the operative site with pain increased by pressure or tapping on the site. In addition, 4 of 9 subjects also complained of phantom pain concurrent with their neuroma pain. Prior to examination, subjects were asked to rate their pain as to its usual intensity and its present intensity on a visual analogue scale with 0 as no pain and 10 corresponding to unbearable pain. At the surgical site the point at which one finger could most aggravate symptoms was marked and a 25 g, 5/8 in. needle inserted. Attempts were made to insert the needle near the neuroma but not to penetrate through the neuroma to minimize mechanical injury from the needle. After a 10 min rest period 0.5 ml of normal saline was injected through the needle and a pain assessment done. After another 10 min, 5 mg of gallamine (0.25 ml) mixed with 0.25 ml of normal saline was injected through the same needle and another pain assessment done. Finally 1 ml of 1% lidocaine was injected and a final pain assessment performed. All subjects were blinded to the order of injection and they were informed that any injection could increase, decrease or not change their pain levels. As a control, in 5 subjects gallamine was injected subcutaneously into corresponding normal tissue on the contralateral side of the subject’s neuroma, and a pain assessment taken. Data analysis was done using the Wilcoxon’s rank sum test. A P < 1% was considered statistically significant.
Results
Subject demographics are shown in Table I. Usual, present, and post-injection pain levels for each agent are displayed in Table II. Normal
42
9
61
Type of pain Neuroma
Left AKA Occipital nerve Right BKA
36
x
of
Saphenous nerve Amputed humerus AKA
_- Duration (years) 10
Neuroma + phantom Neuroma + phantom Neuroma Neuroma
5 7 2
Neuroma + phantom Neuroma
7 5
Neuroma + phantom Neuroma
1.5 6
3
saline did not change pain from baseline levels, gallamine si~fi~ntly increased reported pain, and lidocaine significantly decreased pain from baseline. In 6 of 9 subjects the gallamine injection was terminated prematurely and switched to local
TABLE
II
REPORTED PAIN LEVELS FROM NEUROMA IN SUBJECTS AT CONTROL LEVEL AND AFTER INJECTION OF NORMAL SALINE, GALLAMINE, AND 1% LIDOCAINE. SCALE 0 (NO PAIN) TO 10 (UNBEARABLE PAIN) Subject
Usual pain level
Present pain level
Post saline
Post gallamine
Post lidocaine
1 2 3 4 5 6 I 8 9
6 4 8 8 9 5 8 5 5
6 4 5 5 5 5 8 5 5
I 4 5 4 5 5 8 5 5
10 7 10 6 8 10 10 8 8
0 1 0 3 2 3 3 1 4
x
6.44
5.33
5.33
8.55 *
1.88 *
* Difference between post-injection pain level and pre-injection pain level significant at the 1% level.
323 TABLE
III
REPORTED PAIN LEVELS FROM PHANTOM LIMB IN SUBJECTS AT CONTROL LEVEL AND AFTER INJECTION OF NORMAL SALINE, GALLAMINE, AND LIDOCAINE. SCALE 0 (NO PAIN) TO 10 (UNBEARABLE PAIN) Subject
Present pain level
Post saline
Post gallamine
Post lidocaine
2 3 6 8
4 4 5 5
4 4 5 5
7 9 9 10
1 1 3 1
anesthetic secondary to excruciating pain. In the 4 subjects with phantom and stump pain 3 of 4 noted that in addition to an increase in stump pain, their phantom pain also increased (Table III). In the 5 subjects who also received control injections, gallamine did not produce pain at the site of injection or in the contralateral neuroma site.
Discussion Following peripheral axotomy abnormal spontaneous activity may develop in the regenerating neurites at the end bulb neuroma and in the cells of the dorsal root ganglion [4,15,31,33,34]. In the rat neuroma model, many of these spontaneously active fibers show conduction velocities in the C and A6 fiber range [8,10,21]. These fibers show exquisite sensitivity to topical or systemic alpha agonists such as epinephrine or phenylephrine in that small quantities of these agents will increase the number of spontaneously active fibers [7] or greatly increase the firing rate of fibers that are already spontaneously active [16,21,33,34]. This excitatory effect of alpha agonists can be blocked by alpha receptor antagonists and is unaffected by beta receptor stimulation or blockade [21]. In addition to the excitatory changes seen with alpha agonist activity, neuromas display increased spontaneous activity to hypoxia, ischemia, and sympathetic chain stimulation [9,6,21,33]. Recently, spontaneously active fibers originating in neuromas have been shown to possess sensitivity
to systemic potassium channel blocking agents such as gallamine [5]. The effect, which is similar to that seen with alpha agonists, is one of markedly increased activity in spontaneously active fibers. This response to potassium channel blockers is not seen in normal neural tissue. The development of neuromas and increased spontaneous activity has been correlated with autotomy in rats [32,33,35], however, one may not project subjective human sensations and perceptions to animal behavior. Numerous nerve injuries have been associated with pain in humans. These include states associated with nerve ligation and possible neuroma formation such as stump and phantom limb pain [6,12,13,23,24], and with conditions causing partial nerve injury, such as diabetic [1,28-301 and metabolic neuropathies and causalgia [3,17,20]. With neuromas, pain is often felt to be secondary to abnormal spontaneous activity or mechanosensitivity of the regenerated nerve endings. Clinical experience of using treatments that attempt to decrease neurochemical stimulation by sympathectomy or drugs that deplete or block catecholamines have reported inconsistent results when used to treat neuroma or phantom limb pain [13,14,17]. Therefore, the exact role of neuromal chemosensitivity in the genesis or propagation of neuroma pain remains unclear. In microelectrode recordings from transected nerves in 2 patients with both phantom limb and stump pain a baseline level of abnormal activity was recorded that increased with mechanical stimulation of the neuroma [19]. Increases in both phantom limb and sharp localized pain (stump pain) paralleled the increased neural activity to mechanical stimulation. Local anesthetic infiltration of the neuromas was able to block the sharp increase in both pain and neural activity with tapping, but did not abolish background phantom pain or baseline neural activity. The remaining neural activity after neuroma blockade with local anesthetic may have been generated in the dorsal root ganglion which has been described in rats with ligated peripheral nerves [4,31]. The continued persistence of phantom limb pain at lower levels is not surprising with the clinical experience of dorsal rhizotomies and even cord transections failing to relieve pain in some patients [18].
324
In the present study we have demonstrated that perineuromal gallamine was able to cause an immediate increase in the subjects’ pain reports of both local neuromal and in some, phantom limb pain. The increase was so dramatic that the injection was often terminated prematurely and local anesthetic immediately injected. Since control injections had no effect on reported pain and because the amount of gallamine used was so small and effects so immediate it is likely that the action of gallamine was at the neuroma and not more central locations. Mechanical distortion of the neuroma by local muscle paralysis secondary to the gallamine is unlikely since these neuromas were terminal structures after amputation and surrounded primarily by fibrous tissue. This study has correlated neurophysiological changes associated with the systemic administration of potassium channel blocking agents in rats to the perception of pain and discomfort in humans. While no microelectrode recordings were made it is likely that the increased pain associated with perineuromal gallamine in our subjects was due to similar increases in spontaneous activity that have been demonstrated in animals. This theory is supported by the ability to immediately reduce reported pain by local anesthetic infiltration. The failure of saline to increase pain tends to contradict a purely mechanical phenomenon. Although a randomized order of injection would have been optimal, humanitarian considerations mandated that local anesthetic injection always follow gallamine. In summary, this study has shown neuroma chemosensitivity to potassium channel blocking agents in humans that has been demonstrated previously with neurophysiological recordings in rats. In 3 of 4 subjects who also had phantom limb pain, discomfort was also increased after gallamine. The ability of local anesthetic injection to decrease but not abolish either the increases in neuroma or phantom limb pain is consistent with previous observations and supports the concept of a peripheral lesion separately contributing to the sensation of pain or modulating more central changes associated with that lesion. These data suggest that agents, which either increase potassium conductance or inhibit the influx of sodium
ions, may decrease spontaneous neuroma and would be predicted not abolish associated pain.
activity in the to decrease if
References 1 Ballin, R.H.M. and Thomas, P.K., Hypertrophic changes in diabetic neuropathy, Acta Neuropathol., 11 (1968) 93-102. 2 Blumberg, H. and Janig, W., Discharge pattern of afferent fibers from a neuroma, Pain, 20 (1984) 335-353. 3 Bonica, J.J., Causalgia and other reflex sympathetic dystrophies. In: J.J. Bonica et al. (Ed.), Advances in Pain Research and Therapy, Vol. 13, Raven Press, New York, 1970, pp. 141-166. 4 Burchiel, K.B., Effects of electrical and mechanical stimulation on two foci of spontaneous activity which develop in primary afferent neurons after peripheral axotomy. Pain, 18 (1984) 249-265. 5 Burchiel, K.B. and Russell. L.C., Effects of potassium channel-blocking agents on spontaneous discharge from neuromas in rats, J. Neurosurg., 63 (1985) 246-249. H. and Steinbach, T., 6 Carlen, D.L., Wall, P.D., Nadvoma, Phantom limbs and related phenomena in recent traumatic amputations, Neurology, 28 (1978) 211-217. 7 Chabal, C., Russell, L.C. and Burchiel, K.B., Unpublished observation. J.W., Properties of primary 8 DeSantis, M. and Duckworth, afferent neurons from muscle which are spontaneously active after a lesion of their peripheral processes, Exp. Neurol., 75 (1982) 261-274. of myelinated affer9 Devor, M. and J&rig, W., Activation ents ending in a neuroma by stimulation of the sympathetic supply in the rat, Neurosci. Lett., 24 (1981) 43-47. 10 Devor, M. and Wall, P.D., Type of sensory fiber sprouting to form a neuroma, Nature, 262 (1976) 705-708. R. and Devor, M., Ongoing activity in 11 Govrin-Lippman, severed nerves: source and variation with time, Brain Res.. 159 (1978) 406-410. P., 12 Jensen, T.S., Krebs, B., Nielsen, J. and Rasmussen, Immediate and long-term phantom limb pain in amputees: incidence, clinical characteristics and relationship to preamputation limb pain, Pain, 21 (1985) 267-278. P., 13 Jensen, T.S., Krebs, B., Nielsen, J. and Rasmussen, Phantom limb, phantom pain and stump pain in amputees during the first six months following limb amputation, Pain, 17 (1983) 243-256. of results obtained by sym14 Kallio, K.E., Permanency pathetic surgery in the treatment of phantom pain, Acta Orthop. Stand., 19 (1950) 391-397. 15 Kirk, E., Impulses in dorsal spinal nerve rootlets in cats and rats arising from dorsal root ganglia isolated from periphery, J. Comp. Neural., 155 (1974) 165-176. E.M. and Devor, M., &topic adrenergic sensi16 Korenman, tivity in damaged peripheral nerve axons in the rat, Exp. Neurol., 72 (1981) 63-81.
325 17 Loh, L. and Nathan, D.W., Painful peripheral states and sympathetic blocks, J. Neurol. Neurosurg. Psychiat., 41 (1978) 664-671. 18 Melzack, R. and Loeser, J.D., Phantom body pain in paraplegics: evidence for a central, ‘pattern generating mechanism’ for pain, Pain, 4 (1978) 195-210. 19 Nystrom, B. and Hagbarth, K.E., Microelectrode recordings from transected nerves in amputees with phantom limb pain, Neurosci. Lett., 27 (1981) 211-216. 20 Roberts, W.J., A hypothesis on the physiological basis for causalgia and related pains, Pain, 24 (1986) 297-311. 21 Scadding, J.W., Development of ongoing activity, mechanosensitivity, and adrenaline sensitivity in severed peripheral nerve axons, Exp. Neurol., 73 (1981) 345-364. 22 Scadding, J.W., Peripheral neuropatbies. In: P.D. Wall and R. Melzack (Eds.), Textbook of Pain, Churchill Livingstone, New York, 1984, pp. 413-425. 23 Sherman, R.A., Sherman, C.J. and Gall, N.G., A survey of current phantom limb pain treatment in the United States, Pain, 8 (1980) 85-99. 24 Sherman, R.A., Sherman, C.J. and Parker, L., Chronic phantom and stump pain among American veterans: results of a survey, Pain, 18 (1984) 83-94. 25 Smith, K.J. and Schauf, C.L., Effects of gallamine and triethiodide on member currents in amphibian and mammalian peripheral nerve, J. Pharmacol. Exp. Ther., 217 (1981) 719-726. 26 Smith, K.J. and Schauf, C.L., Gallamine triethiodide (Flaxedil): tetraethylammonium and pancuronium like effects in myelinated nerve fibers, Science, 212 (1981) 1170-1172.
27 Sunderland, S., Pain mechanisms in causalgia, J. Neurol., Neurosurg. Psychiat., 39 (1976) 471-480. 28 Thomas, P.K., Morphological basis for alterations in nerve conduction in peripheral neuropathy, Proc. Roy. Sot. Med., 64 (1971) 295-298. 29 Thomas, P.K. and Eliasson, S.G., Diabetic neuropathy. In: P.J. Dyck, P.K. Thomas and E.H. Lambert (Eds.), Peripheral Neuropathy, Saunders, Philadelphia, PA, 1975, pp. 956-981. 30 Thomas, P.K. and Lascelles, R.G., The pathology of diabetic neuropathy, Quart. J. Med., 35 (1966) 489-509. 31 Wall, P.D. and Devor, M., Sensory afferent impulses originate from dorsal root ganglia as well as from the periphery in normal and nerve injured rats, Pain, 17 (1983) 321-339. 32 Wall, P.D., Devor, M., Inbal, R., Scadding, J.W., Schonfeld, D., Seltzer, Z. and Tomkiewicz, M.M., Autotomy following peripheral nerve lesions: experimental anesthesia dolorosa, Pain, 7 (1979) 103-113. 33 Wall, P. and Gutnick, M., Ongoing activity in peripheral nerves: the physiology and pharmacology of impulses originating from a neuroma, Exp. Neurol., 43 (1974) 580-593. 34 Wall, P. and Gutnick, M., Properties of afferent nerve impulses originating from a neuroma, Nature, 248 (1974) 740-743. 35 Wall, P.D., Scadding, J.W. and Tomkiewicz, M.M., The production and prevention of experimental anesthesia dolorosa, Pain, 6 (1979) 175-182.
Pain, 36 (1989) 321-325 Elsevier PA1 01365
Pain responses to perineuromal injection of normal saline, gafiamine, and lidocaine in humans Charles Chabal, Department
Louis Jacobson,
Lisa C. Russell
* and Kim J. Burchiel
*
of Anesthesiology. and * Department of Neurological Surgery, University of Washington School of Medicine, Veterans Administration Medicat Center, 1660 South Columbian Way, Seattle, WA 98108 (U.S.A.)
(Received 24 May 1988, revision received and accepted 30 September 1988)
Rat neuromas have shown an increase of spontaneously active fibers to systemically administered potassium channel S--Y btocking agents such as tetraethylatnmonium chloride (TEA) and gallamine. Neuroma formation and spontaneous activity have been associated with autotomy in rats and pain in humans. To evaluate the chemo~siti~ty of human neurons to potassium channel blocking agents, 9 subjects with neuroma pain underwent perineuromal injection in a singleblinded fashion of normal saline, gallamine, and lidocaine. Sodium chloride had no effect on control pain levels, while gallamine significantly increased and lidocaine significantly decreased pain from control levels. Three of 4 patients with accompanying phantom limb pain noted an increase in pain after the injection of gallamine. The data suggest that peripheral input plays a modulating but not solitary role in both neuroma and phantom limb pain. Agents which increase potassium channel permeability or decrease sodium influx would be predicted to decreased perceived pain. Key words
Perineuromal injection; Saline; Gallamine; Lidocaine; Neuroma pain, Phantom limb pain
Introdwction
Chronic pain and dysesthesias have been associated with nerve ligation and subsequent neuroma formation in humans [17,27]. Laboratory studies using microfilament recording techniques have shown abnormal spontaneous activity originating from experimental neuromas in rats [11,34,35]. These spontaneously active fibers show excitatory changes to hypoxia [16], mechanical stimulation [2,4,21], systematically administered alpha-adrenergic agonists [16,21,34], and to sympathetic chain s~ulation [2,4,9,16,21]. Recently, similar excitatory changes have been demon-
Correspondence to: Charles Chabal, M.D., Anesthesiology Service, 112A, Veterans Administration Medical Center, 1660 South Col~bian Way, Seattle, WA 98108, U.S.A.
strated after intravenous administration of the non-depol~~g neuromuscular blocker, gallamine and the potassium channel blocker, tetraethylammonium chloride (TEA) [S]. Gallamine, like TEA, is a potent potassium chmel blocking agent and the excitatory changes observed may be co~ensurate with its potassium channel blocking property [5,25,26]. The neurophysiological evidence in animals of neuromal chemosensitivity has been demonstrated and has been postulated to contribute to the sensation of pain. However, corroborative studies in humans are lacking. In addition, extrapolating neurophysiologic data from animals to human sensations and feelings may not be valid. The following study was undertaken to evaluate the effects of a perineuromal injection of gallamine on the perception of pain in humans. From the animal data it was h~othes~~ that gallamine should
0304-3959/89/$03.50 0 1989 Elsevier Science Publishers B.V. (Biomedical Division)
322
markedly increase pain and this effect could be antagonized by local anesthetic injection.
TABLE
I
DEMOGRAPHICS
OF SUBJECTS
Subject
Age (years)
Location neuroma
1
39
2
38
3
66
Saphenous nerve 4th metacarpal Left AKA
4 5
48 50
6
46
Methods
After obtaining permission from the Human Subjects Review Committee, 9 subjects were studied at least 1 year after peripheral nerve ligation. All operative sites were well healed and all subjects complained of paresthesias and pain at or distal to the operative site with pain increased by pressure or tapping on the site. In addition, 4 of 9 subjects also complained of phantom pain concurrent with their neuroma pain. Prior to examination, subjects were asked to rate their pain as to its usual intensity and its present intensity on a visual analogue scale with 0 as no pain and 10 corresponding to unbearable pain. At the surgical site the point at which one finger could most aggravate symptoms was marked and a 25 g, 5/8 in. needle inserted. Attempts were made to insert the needle near the neuroma but not to penetrate through the neuroma to minimize mechanical injury from the needle. After a 10 min rest period 0.5 ml of normal saline was injected through the needle and a pain assessment done. After another 10 min, 5 mg of gallamine (0.25 ml) mixed with 0.25 ml of normal saline was injected through the same needle and another pain assessment done. Finally 1 ml of 1% lidocaine was injected and a final pain assessment performed. All subjects were blinded to the order of injection and they were informed that any injection could increase, decrease or not change their pain levels. As a control, in 5 subjects gallamine was injected subcutaneously into corresponding normal tissue on the contralateral side of the subject’s neuroma, and a pain assessment taken. Data analysis was done using the Wilcoxon’s rank sum test. A P < 1% was considered statistically significant.
Results
Subject demographics are shown in Table I. Usual, present, and post-injection pain levels for each agent are displayed in Table II. Normal
42
9
61
Type of pain Neuroma
Left AKA Occipital nerve Right BKA
36
x
of
Saphenous nerve Amputed humerus AKA
_- Duration (years) 10
Neuroma + phantom Neuroma + phantom Neuroma Neuroma
5 7 2
Neuroma + phantom Neuroma
7 5
Neuroma + phantom Neuroma
1.5 6
3
saline did not change pain from baseline levels, gallamine si~fi~ntly increased reported pain, and lidocaine significantly decreased pain from baseline. In 6 of 9 subjects the gallamine injection was terminated prematurely and switched to local
TABLE
II
REPORTED PAIN LEVELS FROM NEUROMA IN SUBJECTS AT CONTROL LEVEL AND AFTER INJECTION OF NORMAL SALINE, GALLAMINE, AND 1% LIDOCAINE. SCALE 0 (NO PAIN) TO 10 (UNBEARABLE PAIN) Subject
Usual pain level
Present pain level
Post saline
Post gallamine
Post lidocaine
1 2 3 4 5 6 I 8 9
6 4 8 8 9 5 8 5 5
6 4 5 5 5 5 8 5 5
I 4 5 4 5 5 8 5 5
10 7 10 6 8 10 10 8 8
0 1 0 3 2 3 3 1 4
x
6.44
5.33
5.33
8.55 *
1.88 *
* Difference between post-injection pain level and pre-injection pain level significant at the 1% level.
323 TABLE
III
REPORTED PAIN LEVELS FROM PHANTOM LIMB IN SUBJECTS AT CONTROL LEVEL AND AFTER INJECTION OF NORMAL SALINE, GALLAMINE, AND LIDOCAINE. SCALE 0 (NO PAIN) TO 10 (UNBEARABLE PAIN) Subject
Present pain level
Post saline
Post gallamine
Post lidocaine
2 3 6 8
4 4 5 5
4 4 5 5
7 9 9 10
1 1 3 1
anesthetic secondary to excruciating pain. In the 4 subjects with phantom and stump pain 3 of 4 noted that in addition to an increase in stump pain, their phantom pain also increased (Table III). In the 5 subjects who also received control injections, gallamine did not produce pain at the site of injection or in the contralateral neuroma site.
Discussion Following peripheral axotomy abnormal spontaneous activity may develop in the regenerating neurites at the end bulb neuroma and in the cells of the dorsal root ganglion [4,15,31,33,34]. In the rat neuroma model, many of these spontaneously active fibers show conduction velocities in the C and A6 fiber range [8,10,21]. These fibers show exquisite sensitivity to topical or systemic alpha agonists such as epinephrine or phenylephrine in that small quantities of these agents will increase the number of spontaneously active fibers [7] or greatly increase the firing rate of fibers that are already spontaneously active [16,21,33,34]. This excitatory effect of alpha agonists can be blocked by alpha receptor antagonists and is unaffected by beta receptor stimulation or blockade [21]. In addition to the excitatory changes seen with alpha agonist activity, neuromas display increased spontaneous activity to hypoxia, ischemia, and sympathetic chain stimulation [9,6,21,33]. Recently, spontaneously active fibers originating in neuromas have been shown to possess sensitivity
to systemic potassium channel blocking agents such as gallamine [5]. The effect, which is similar to that seen with alpha agonists, is one of markedly increased activity in spontaneously active fibers. This response to potassium channel blockers is not seen in normal neural tissue. The development of neuromas and increased spontaneous activity has been correlated with autotomy in rats [32,33,35], however, one may not project subjective human sensations and perceptions to animal behavior. Numerous nerve injuries have been associated with pain in humans. These include states associated with nerve ligation and possible neuroma formation such as stump and phantom limb pain [6,12,13,23,24], and with conditions causing partial nerve injury, such as diabetic [1,28-301 and metabolic neuropathies and causalgia [3,17,20]. With neuromas, pain is often felt to be secondary to abnormal spontaneous activity or mechanosensitivity of the regenerated nerve endings. Clinical experience of using treatments that attempt to decrease neurochemical stimulation by sympathectomy or drugs that deplete or block catecholamines have reported inconsistent results when used to treat neuroma or phantom limb pain [13,14,17]. Therefore, the exact role of neuromal chemosensitivity in the genesis or propagation of neuroma pain remains unclear. In microelectrode recordings from transected nerves in 2 patients with both phantom limb and stump pain a baseline level of abnormal activity was recorded that increased with mechanical stimulation of the neuroma [19]. Increases in both phantom limb and sharp localized pain (stump pain) paralleled the increased neural activity to mechanical stimulation. Local anesthetic infiltration of the neuromas was able to block the sharp increase in both pain and neural activity with tapping, but did not abolish background phantom pain or baseline neural activity. The remaining neural activity after neuroma blockade with local anesthetic may have been generated in the dorsal root ganglion which has been described in rats with ligated peripheral nerves [4,31]. The continued persistence of phantom limb pain at lower levels is not surprising with the clinical experience of dorsal rhizotomies and even cord transections failing to relieve pain in some patients [18].
324
In the present study we have demonstrated that perineuromal gallamine was able to cause an immediate increase in the subjects’ pain reports of both local neuromal and in some, phantom limb pain. The increase was so dramatic that the injection was often terminated prematurely and local anesthetic immediately injected. Since control injections had no effect on reported pain and because the amount of gallamine used was so small and effects so immediate it is likely that the action of gallamine was at the neuroma and not more central locations. Mechanical distortion of the neuroma by local muscle paralysis secondary to the gallamine is unlikely since these neuromas were terminal structures after amputation and surrounded primarily by fibrous tissue. This study has correlated neurophysiological changes associated with the systemic administration of potassium channel blocking agents in rats to the perception of pain and discomfort in humans. While no microelectrode recordings were made it is likely that the increased pain associated with perineuromal gallamine in our subjects was due to similar increases in spontaneous activity that have been demonstrated in animals. This theory is supported by the ability to immediately reduce reported pain by local anesthetic infiltration. The failure of saline to increase pain tends to contradict a purely mechanical phenomenon. Although a randomized order of injection would have been optimal, humanitarian considerations mandated that local anesthetic injection always follow gallamine. In summary, this study has shown neuroma chemosensitivity to potassium channel blocking agents in humans that has been demonstrated previously with neurophysiological recordings in rats. In 3 of 4 subjects who also had phantom limb pain, discomfort was also increased after gallamine. The ability of local anesthetic injection to decrease but not abolish either the increases in neuroma or phantom limb pain is consistent with previous observations and supports the concept of a peripheral lesion separately contributing to the sensation of pain or modulating more central changes associated with that lesion. These data suggest that agents, which either increase potassium conductance or inhibit the influx of sodium
ions, may decrease spontaneous neuroma and would be predicted not abolish associated pain.
activity in the to decrease if
References 1 Ballin, R.H.M. and Thomas, P.K., Hypertrophic changes in diabetic neuropathy, Acta Neuropathol., 11 (1968) 93-102. 2 Blumberg, H. and Janig, W., Discharge pattern of afferent fibers from a neuroma, Pain, 20 (1984) 335-353. 3 Bonica, J.J., Causalgia and other reflex sympathetic dystrophies. In: J.J. Bonica et al. (Ed.), Advances in Pain Research and Therapy, Vol. 13, Raven Press, New York, 1970, pp. 141-166. 4 Burchiel, K.B., Effects of electrical and mechanical stimulation on two foci of spontaneous activity which develop in primary afferent neurons after peripheral axotomy. Pain, 18 (1984) 249-265. 5 Burchiel, K.B. and Russell. L.C., Effects of potassium channel-blocking agents on spontaneous discharge from neuromas in rats, J. Neurosurg., 63 (1985) 246-249. H. and Steinbach, T., 6 Carlen, D.L., Wall, P.D., Nadvoma, Phantom limbs and related phenomena in recent traumatic amputations, Neurology, 28 (1978) 211-217. 7 Chabal, C., Russell, L.C. and Burchiel, K.B., Unpublished observation. J.W., Properties of primary 8 DeSantis, M. and Duckworth, afferent neurons from muscle which are spontaneously active after a lesion of their peripheral processes, Exp. Neurol., 75 (1982) 261-274. of myelinated affer9 Devor, M. and J&rig, W., Activation ents ending in a neuroma by stimulation of the sympathetic supply in the rat, Neurosci. Lett., 24 (1981) 43-47. 10 Devor, M. and Wall, P.D., Type of sensory fiber sprouting to form a neuroma, Nature, 262 (1976) 705-708. R. and Devor, M., Ongoing activity in 11 Govrin-Lippman, severed nerves: source and variation with time, Brain Res.. 159 (1978) 406-410. P., 12 Jensen, T.S., Krebs, B., Nielsen, J. and Rasmussen, Immediate and long-term phantom limb pain in amputees: incidence, clinical characteristics and relationship to preamputation limb pain, Pain, 21 (1985) 267-278. P., 13 Jensen, T.S., Krebs, B., Nielsen, J. and Rasmussen, Phantom limb, phantom pain and stump pain in amputees during the first six months following limb amputation, Pain, 17 (1983) 243-256. of results obtained by sym14 Kallio, K.E., Permanency pathetic surgery in the treatment of phantom pain, Acta Orthop. Stand., 19 (1950) 391-397. 15 Kirk, E., Impulses in dorsal spinal nerve rootlets in cats and rats arising from dorsal root ganglia isolated from periphery, J. Comp. Neural., 155 (1974) 165-176. E.M. and Devor, M., &topic adrenergic sensi16 Korenman, tivity in damaged peripheral nerve axons in the rat, Exp. Neurol., 72 (1981) 63-81.
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