Acta Neurochir (Wien) (1998) 140: 12711277

Acta Neurochirurgica
> Springer-Verlag 1998 Printed in Austria

The Eect of Peripheral Glycerol on Trigeminal Neuropathic Pain Examined by Quantitative Assessment of Abnormal Pain and Sensory Perception
P. K. Eide1, T. Rabben2, P. Skjelbred3, and A. Stubhaug4
1 Department of Neurosurgery, The National Hospital, Oslo, Norway 2 Department of Pharmacology, University of Oslo, Oslo, Norway l Hospital, Oslo, Norway 3 Department of Maxillofacial Surgery, Ulleva 4 Department of Anaesthesiology, The National Hospital, Oslo, Norway

Summary
In nine patients with trigeminal neuropathic pain after nerve injury, we examined prospectively the eect of peripheral glycerol neurolysis on abnormal pain and sensory perception. In the painful facial skin area of these patients, we found increased temperature and tactile thresholds and the presence of abnormal temporal summation of pain. In seven patients, neuropathic pain was peripheral and disappeared after application of local anaesthesia at or proximal to the site of nerve injury. Neuropathic pain was central in two patients, and unresponsive to local anaesthesia applied proximal to the site of nerve injury. Six weeks after injection of glycerol proximal to the site of nerve injury, no or marginal pain relief was found in 8 patients with peripheral or central trigeminal neuropathic pain. On the other hand, in one of the patients with peripheral trigeminal neuropathic pain, glycerol was given at the site of nerve injury, and produced total pain relief for the whole observation period of 7 months. In this patient, pain relief was associated with normalisation of abnormal temporal summation of pain, which was not observed in the 8 patients with no or marginal pain relief. No further changes in temperature or tactile thresholds were found in any of the 9 patients after a single injection of absolute glycerol. Total pain relief in one of the patients probably is related to the ability of glycerol to inhibit ongoing ectopic impulse generation at the site of nerve injury. We suggest that glycerol-induced reduction of primary aerent hyperactivity may secondarily result in down-regulation of central neuronal hyperexcitability. The ecacy of application of glycerol at the site of nerve injury in patients with peripheral trigeminal neuropathic pain may warrant further investigation. However, this prospective study does not provide evidence that application of glycerol proximal to the site of nerve injury has a place in the treatment of trigeminal neuropathic pain. Keywords: Trigeminal neuropathic pain; glycerol neurolysis; quantitative somatosensory testing.

Introduction Trigeminal neuropathic pain after nerve injury is characterised by continuous dysaesthesia pain, intermittent attacks of pain, pain evoked by non-painful

stimulation (allodynia) and sensory changes in the involved skin area [7, 12]. The treatment of trigeminal neuropathic pain remains a great challenge partially due to lack of knowledge of the pathophysiological mechanisms. An important mechanism may be formation of repetitive ectopic impulses at the site of nerve injury leading to ongoing primary aerent hyperactivity [9]. Secondarily, sensitisation of central neurones may result in hyperexcitability of wide dynamic range neurones [2, 28]. Particularly in patients in whom central sensitisation depends on ongoing primary aerent input, a rational treatment would be inhibition of peripheral ectopic impulse generation. Glycerol is a neurolytic agent found endogenously, that may act as a membrane stabilising agent by inhibition of ectopic impulse generation at the site of nerve injury [6]. Peripheral glycerol injections are used extensively among maxillofacial and oral surgeons to treat trigeminal neuralgia [13, 29] and painful neuroma [22]. In patients with neuropathic pain, destructive procedures generally are regarded as contra-indicated because of short-lasting eect and risk of producing further sensory loss and dysaesthesia pain. However, in the clinical situation it may be dicult to dierentiate trigeminal neuralgia from trigeminal neuropathic pain, and a trial of peripheral or retrogasserian glycerol may be given. Our policy not to treat patients with neuropathic facial pain with peripheral or percutaneous retrogasserian glycerol rhizolysis (PRGR) mainly rests on clinical experience rather than on results of controlled studies.

1272

P. K. Eide et al. were determined by a Somedic Thermotester (Somedic AB, Stockholm, Sweden), using a modication of the Marstock method [16]. A Peltier-type thermode (3.75 or 12.5 cm 2 ) was warmed up or cooled down at a rate of 1:5  C/second, and the patients responded to each individual thermal sensation by pressing a button, that reversed the temperature of the thermode to the baseline temperature (32  C). An average of three measurements was calculated. Cut-o temperatures were 5 and 52  C. Threshold values for tactile sensation were assessed by von Frey laments (Stoelting Co., Illinois, USA) applied in an ascending and descending order of magnitude to assess both the disappearance and appearance thresholds. The force required to bend each lament, measured in grams (0.008279.4 g/mm 2 ) was converted to log 10 of force (1.656.65 log 10 ). Temporal summation of pain was evoked by repetitive pricking of the skin with a von Frey lament (279.4 g/mm 2 /6.65 units) at a rate of about 3/s. If temporal summation of pain was present, stimulation initially was not painful, and pain appeared after 5 to 15 seconds with progressive increase in intensity. Stimulation lasted for 30 seconds. To eliminate the impact of spatial summation of pain, the same spot of the skin was pricked with the von Frey lament. All the characteristics of abnormal temporal summation of pain were recorded: Pain intensity, radiation of pain and after-sensation. Change in pain intensity was measured by a visual analogue scale 100 mm (0 no pain, 100 unbearable pain), before stimulation and at the peak of pain. Radiation of pain was recorded in two directions and an area calculated. Statistical Analysis In this study each patient served as his or her own control by the comparison of sensory and pain perception in the trigger area and the contra-lateral non-painful facial skin area. The data were evaluated by non-parametric statistical analysis. Signicant dierences between paired groups were calculated by Wilcoxon signed rank test. Calculations were performed by the computer program S-Plus version 4.0 (MathSoft, Cambridge, MA). Two-tailed P values were calculated, and signicance was accepted at the 5% level.

This open prospective study was undertaken to test whether application of glycerol at or proximal to the site of trigeminal nerve injury might relieve pain in patients with peripheral trigeminal neuropathic pain. The hypothesis is that glycerol might relieve pain by inhibition of ectopic impulse generation, thereby reducing ongoing primary aerent hyperactivity. Patients and Methods
Patients All the patients included in this study were selected from a previous study of patients with trigeminal neuropathic pain after peripheral nerve injury [12]. The patients were admitted from The l University Hospital Department of Maxillofacial Surgery, Ulleva and from The Department of Oral Surgery and Oral Medicine, The Dental Faculty, University of Oslo. The diagnosis was made on the basis of the description of pain (the presence of continuous and intermittent dysaesthesia pain and allodynia), the pain history (pain that started immediately after injury of one or more trigeminal nerve branches) and the results of neurophysiological assessment (increased sensory thresholds and abnormal responsiveness to nonpainful stimulation). The study was approved by the Ethical Committee of Health Region II in Norway. Injection Procedures For the second trigeminal branch, the injection site for local anaesthesia/glycerol was the infra-orbital foramen, and for the third branch, the injection site was the mandibular foramen. Before injection of glycerol, local anaesthesia (Marcain9 5%, Astra) was given in a volume of 4 ml. In one patient (no. 3) local anaesthesia was given at the site of nerve injury (inferior alveolar nerve at the level of the mandibular foramen). In the other eight patients local anaesthesia was given proximal to the site of nerve injury since it was impossible to give glycerol directly to the site of nerve injury. Correct placement of local anaesthesia was conrmed by assessment of sensory loss in the skin. Pain relief was assessed by a visual analogue scale. After about 5 min, glycerol was given at the same site as the local anaesthetic. Absolute glycerol was given in a volume of 0.5 ml. The patients stayed in the department for 1 hour before discharge. Follow-up Procedure The intensity of continuous dysaesthesia pain was measured by a visual analogue scale 100 mm (0 no pain, 100 unbearable pain), before treatment and then after 6 weeks. Any side-eects were noted by the patient, and each patient also was contacted by telephone to detect any side-eects. Assessments of tactile and temperature thresholds and temporal summation of pain were performed one week before treatment, and then 6 weeks after treatment. Examination of Sensory and Pain Perception Somatosensory measurements were carried out within the painful facial skin area and in the contra-lateral non-painful facial skin area. The sequence of examining painful and non-painful sides was changed in random order. Threshold temperatures for sensations of warmth and heat pain

Results Patients Demographic data of the nine patients included in the study are shown in Table 1. Trigeminal neuropathic pain was caused by a peripheral nerve injury in all patients. The description of the characteristics of pain in these patients is shown in Table 2. The injection procedure was well tolerated by patients. Some subcutaneous swelling and local numbness at the injection site was noted by 3 of 9 patients. Intensity of Continuous Pain As indicated in Table 1, local anaesthesia given at or proximal to the aected trigeminal nerve, totally relieved continuous pain in 6 patients and nearly totally relieved pain in one patient (peripheral neuropathic

Trigeminal Neuropathic Pain and Peripheral Glycerol Table 1. Demographic Data of Patients with Trigeminal Neuropathic Pain after Nerve Injury Patient (no) Sex: female/male Age (years) Side of pain Trigeminal branches Duration of pain (years) Cause of pain: dental injury surgery Pain relief after marcaine injection: none partial total Pain relief 6 weeks after glycerol injection: none partial total No. 1 F 64 right 23 13 No. 2 F 59 left 23 10 No. 3 M 83 right 3 19 No. 4 F 80 right 2 20 No. 5 F 60 left 3 7 No. 6 F 62 right 2 5 No. 7 F 54 left 23 14 No. 8 F 36 right 3 2

1273

No. 9 M 32 left 3 2

Table 2. Characteristics of Pain in Patients with Trigeminal Neuropathic Pain after Nerve Injury Spontaneous continuous pain burning cutting tingling Pricking aching tightening squeezing itching cruel piercing numbness Spontaneous intermittent pain throbbing stabbing sharp stinging radiating Evoked pain. provoking factors movement touch cold heat 9/9 (100%) 7/9 (78%) 5/9 (56%) 6/9 (67%) 6/9 (67%) 9/9 (100%) 5/9 (56%) 5/9 (56%) 1/9 (11%) 6/9 (67%) 9/9 (100%) 6/9 (67%) 4/9 (44%) 4/4 (100%) 3/4 (75%) 4/4 (100%) 1/4 (25%) 4/4 (100%) 6/9 (67%) 5/6 (83%) 2/6 (33%) 3/6 (50%) 3/6 (50%)

negligible, and one patient reported total pain relief. This patient still was pain-free after an observation period of 7 months. Local anaesthesia and glycerol were given at the site of nerve injury in this patient, but were given proximal to the site of nerve injury in the other 8 patients. The intensity of continuous pain was measured by the visual analogue scale before and after treatment. Statistical analysis revealed that in the 7 patients with peripheral neuropathic pain, the intensity of continuous pain was signicantly reduced 6 weeks after glycerol treatment (P 0:03) (Wilcoxon signed rank test). On the other hand, when the whole group of 9 patients were considered, the intensity of continuous pain was not signicantly reduced (P 0:1) (Wilcoxon signed rank test) (Fig. 1). Temperature and Tactile Thresholds Temperature and tactile thresholds on the painful side and the contra-lateral non-painful skin area are shown in Table 3. The results show that before glycerol treatment thresholds for sensation of warmth, heat pain, and pressure were signicantly increased in the painful facial skin area compared to the contra-lateral non-painful skin area. The dierences in threshold values between the painful side and the contra-lateral non-painful side were not changed post-operatively. Statistical comparison of threshold-dierences before and after glycerol treatment showed no signicant changes in warmth

Data presented as numbers of patients using the various descriptions.

pain). Pain was unaected in two patients though local anaesthesia caused loss of sensation in the involved skin area (central neuropathic pain). Six weeks after treatment with glycerol, both patients with central neuropathic pain reported a slight enhancement of pain. Five of 6 patients with peripheral neuropathic pain reported that pain relief was

1274

P. K. Eide et al.

Fig. 1. Intensity of continuous dysaesthesia pain before and after peripheral injection of glycerol, measured by means of a visual analogue scale 100 mm (0 no pain, 100 unbearable pain). Pain intensity before treatment represents the average of two measurements separated by one week (Before). Pain intensity after treatment was assessed 6 weeks after glycerol treatment (After). Statistical analysis showed no signicant dierence in pain intensity before and after treatment (P 0:10) (Wilcoxon signed rank test)

ent characteristics of abnormal temporal summation of pain were unchanged after glycerol treatment (Table 4). However, in the patient that was pain-free after peripheral glycerol neurolysis, abnormal temporal summation of pain was normalised. We calculated the dierences in characteristics of abnormal temporal summation of pain between painful and non-painful sides, and compared the dierences before and after glycerol injection. Statistical analysis revealed no signicant dierences in pain intensity (P 0:8), after-sensation pain (P 1:0), and radiation of pain (P 0:2) before and after glycerol treatment (Wilcoxon signed rank test). Discussion Trigeminal Neuropathic Pain All the patients included in this study suered from trigeminal neuropathic pain after nerve injury, which corresponds to the diagnosis secondary trigeminal pain according to the International Association for the Study of Pain (IASP) [25]. Pain started immediately after a history of nerve injury in all patients, and resulted in subjective sensation of altered facial sensation and continuous and intermittent dysaesthetic pain with allodynia (i.e. pain evoked by non-painful stimulation). According to IASP, neuropathic pain is Pain initiated or caused by a primary lesion or dysfunction in the nervous system [25].

(P 0:7), heat pain (P 1:0), or tactile (P 0:3) thresholds (Wilcoxon signed rank test). Temporal Summation of Pain As presented in Table 4, all the characteristics of temporal summation of pain (change in pain intensity, radiation of pain and after-sensation) were signicantly more abnormal on the painful side than in the contra-lateral non-painful skin area. The prospective study demonstrated that the dier-

Table 3. Temperature and Tactile Thresholds Before and after Peripheral Glycerol Treatment Before treatment non-painful side Warm threshold ( C) Heat pain threshold ( C) Tactile threshold (log10 0.1 mg) 35 (34.236.2) 42.1 (37.144.9) 1.65 (1.652.44) painful side 35.7 (34.446.4)** 44.1 (38.746.7)** 2.36 (1.653.22)** After treatment non-painful side 33.7 (33.235.7) 40.4 (35.945.4) 1.65 (1.652.44) painful side 35.7 (32.938.1)** 44.0 (38.145.7) 2.36 (1.653.22)**

Median given, with range in parentheses. Statistical dierences between painful and non-painful sides: **P < 0:02; (Wilcoxon signed rank test).

Table 4. Temporal Summation of Pain Before and after Peripheral Glycerol Treatment Before treatment non-painful side Change in pain intensity (mm) After-sensation (sec) Radiation of pain (cm 2 ) 12 (019) 0 (05) 0 (00.3) painful side 50 (1390)**** 15 (390)*** 16 (364)*** After treatment non-painful side 21 (039) 3 (010) 0.5 (04) painful side 53 (18100)*** 5 (090)** 9 (0.325)*

Median given, with range in parentheses. Statistical dierences between painful and non-painful sides: *P < 0:05; **P < 0:02; ***P < 0:01; ****P < 0:005 (Wilcoxon signed rank test).

Trigeminal Neuropathic Pain and Peripheral Glycerol

1275

We have previously pointed out that the diagnosis of trigeminal neuropathic pain should not only be based on the symptoms and the pain description of the patient, but should also involve neurophysiological assessment [12]. In the painful facial skin area of the patients reported here, increased warmth thresholds reect damage of thin nonmyelinated bres whereas increased tactile thresholds reect damage of thick, myelinated bres [30]. Abnormal temporal summation of pain is an example of abnormal pain responsiveness involving central mechanisms. The underlying mechanism may be hyperexcitability of 2nd order wide dynamic range neurones [11, 12]. Peripheral and Central Neuropathic Pain This study demonstrates that application of local anaesthesia proximal to the site of nerve injury may be used to test whether neuropathic pain primarily involves peripheral or central mechanisms. The disappearance of pain after application of local anaesthesia proximal to the site of nerve injury may suggest that pathological pain is both initiated and maintained by peripheral mechanisms and depends on ongoing peripheral input. Devor [9] has demonstrated spontaneous hyperactivity of injured peripheral nerves due to generation of ectopic impulses and cross-excitations at the site of nerve injury. After peripheral damage of the trigeminal nerve, ectopic impulse generation at the site of injury may produce spontaneous hyperactivity of primary aerent neurones [4, 5]. In an animal model of trigeminal neuropathic pain, chronic constriction injury of the rat infra-orbital nerve produced a behavioural syndrome indicative of continuous dysaesthesia pain in addition to mechanical allodynia [31]. In patients with peripheral trigeminal neuropathic pain, pain relief might be produced by peripheral approaches which inhibit the pacemaker activity at the site of nerve injury. This is the putative mechanism of action of local anaesthetics and other membrane stabilising agents [14]. The theoretical rationale for other peripheral approaches including cryotherapy, alchohol neurolysis and neuroma resection, is to stop abnormal peripheral input. Glycerol is a neurolytic agent which has been used particularly to treat trigeminal neuralgia. Long-term relief of trigeminal neuralgia is obtained by application of glycerol to peripheral branches of the trigeminal nerve [13, 29] or to the gasserian ganglion in Meckel's

cave (PRGR) [18]. The mechanism of action of glycerol might be to reduce abnormal ectopic hyperactivity in damaged peripheral nerves. Burchiel found that application of glycerol to injured nerves reduced abnormal neuronal hyperactivity without aecting normal signal trac in the nerve [6]. Rappaport showed that peripheral glycerol reduced abnormal nociceptive behaviour in an animal model of peripheral neuropathic pain [27]. In two patients with continuous pain which was non-responsive to local anaesthesia applied proximal to the site of nerve injury, pain initially was caused by a peripheral nerve injury. In these patients, pain may have become independent of the peripheral mechanisms and might be maintained by hyperactivity of central neurones. A number of studies have demonstrated the presence of spontaneous hyperactivity of neurones in the central trigeminal nucleus after damage of peripheral branches of the trigeminal nerve [1, 3, 20, 24]. Anatomical studies have shown that deaerentation may produce degeneration [17] and abnormal synapse formation [21] of central trigeminal tract neurones. Fromm proposed that loss of central inhibitory mechanisms may be one mechanism leading to hyperexcitability of central wide dynamic range neurones [15]. Accordingly, though the injury primarily was peripheral, irreversible central functional and morphological changes may result in pain that is maintained by central mechanisms which are largely independent of peripheral input. The Eect of Peripheral Glycerol on Trigeminal Neuropathic Pain A single peripheral injection of glycerol was not associated with increased sensory loss in the painful skin area. We have previously shown that after a single PRGR in patients with trigeminal neuralgia, quantitative assessment of sensory thresholds did not show increased sensory loss [11]. These data gave no evidence that a single injection of glycerol produces increased nerve injury. It should be noted, however, that glycerol is a neurolytic agent. Repeated treatments would be expected to cause increased sensory loss since both morphological [19, 23] and electrophysiological studies [6, 23] have demonstrated neurotoxic actions of glycerol. Sensory loss was somewhat more severe in patients with dysaesthesia pain after repeated PRGR [11]. Pain relief after peripheral glycerol treatment was

1276

P. K. Eide et al.

assessed after 6 weeks in order to reduce the impact of actions of local anaesthesia. Only long-lasting pain relief was of clinical interest. In the group of nine patients, the intensity of continuous pain measured by the visual analogue scale was not signicantly reduced. In the seven patients with peripheral trigeminal neuropathic pain, the intensity of continuous pain measured by the visual analogue scale was signicantly reduced though these patients reported that pain relief was negligible. When considering that this was an open study, a bias eect of the procedure probably explains the reduction in pain intensity measured by the visual analogue scale [8, 26]. It is, however, unlikely that a bias eect could explain the total pain relief for 7 months in the one patient with neuropathic pain for 19 years. Abnormal temporal summation of pain, similar to that demonstrated in patients with trigeminal neuralgia [11], was demonstrated in all nine patients before treatment. We have previously argued that abnormal temporal summation of pain reects hyperexcitability of 2nd order wide dynamic range neurones induced and maintained by hyperactivity of primary aerent neurones [1012]. In the 8 patients with no or marginal pain relief, no normalisation of abnormal temporal summation of pain was found. In the one patient that was pain-free after treatment, pain relief was associated with normalisation of abnormal temporal summation of pain. Similarly, after PRGR in patients with trigeminal neuralgia, total pain relief was associated with normalisation of abnormal temporal summation of pain [11]. In these patients, glycerol was applied to the gasserian ganglion in Meckel's cave. When considering the data that glycerol may inhibit abnormal ectopic impulse generation [6, 27], our results may suggest that in peripheral trigeminal neuropathic pain, ectopic impulse generation takes place at the site of peripheral nerve injury. In trigeminal neuralgia, on the other hand, the gasserian ganglion is an important site for abnormal impulse generation. Conclusions Trigeminal neuropathic pain should be classied as peripheral or central, depending on the response to local anaesthesia. Application of glycerol proximal to the site of trigeminal nerve injury was not associated with pain relief in patients with peripheral or central trigeminal neuropathic pain. On the contrary, injection of glycerol at the site of trigeminal nerve injury

produced long-term complete pain relief in one patient. In this patient, pain relief was associated with normalisation of abnormal temporal summation of pain, indicative of down-regulation of central neuronal hyperexcitability. No change in abnormal temporal summation of pain was found in the 8 patients with no or marginal pain relief. Generally, peripheral neurolytic treatments in patients with neuropathic facial pain have been abandoned in the neurosurgical literature due to increased risk of developing sensory loss and dysaesthesia pain. This policy is supported by this prospective study. However, the observation of long-term total pain relief in one patient in whom glycerol was applied to the site of nerve injury, warrants further investigation. References
1. Anderson LS, Black RG, Abraham J, Ward AA Jr (1971) Neuronal hyperactivity in experimental trigeminal deaerentation. J Neurosurg 35: 444452 2. Bennett GJ (1994) Neuropathic pain. In: Wall PD, Melzack RM (eds) Textbook of pain. Churchill Livingstone, Edinburgh, pp 201224 3. Black RG (1974) A laboratory model for trigeminal neuralgia. Adv Neurol 4: 651659 4. Bongenhielm U, Robinson PP (1996) Spontaneous and mechanically evoked aerent activity originating from myelinated bres in ferret inferior alveolar nerve neuromas. Pain 67: 399 406 5. Burchiel KJ (1980) Abnormal impulse generation in focally demyelinated trigeminal roots. J Neurosurg 53: 674683 6. Burchiel KJ, Russell LC (1985) Glycerol neurolysis: Neurophysiological eects of topical glycerol application on rat saphenous nerve. J Neurosurg 63: 784788 7. Burchiel KJ (1993) Trigeminal neuropathic pain. Acta Neurochir [Suppl] (Wien) 58: 145149 8. Colditz GA, Miller JN, Mosteller F (1989) How study design aects outcomes in comparisons of therapy. I: Medical. Statistics in medicine 8: 441454 9. Devor M (1994) The pathophysiology of damaged peripheral nerves. In: Wall PD, Melzack RM (eds) Textbook of pain. Churchill Livingstone, Edinburgh, pp 79100 10. Eide PK, Stubhaug A, Stenehjem AE (1995) Central dysesthesia pain after traumatic spinal cord injury is dependent on Nmethyl-D-aspartate receptor activation. Neurosurgery 37: 10801087 11. Eide PK, Stubhaug A (1998) Relief of trigeminal neuralgia after percutaneous retrogasserian glycerol rhizolysis is dependent on normalization of abnormal temporal summation of pain without general impairment of sensory perception. Neurosurgery. 43: 462474 12. Eide PK, Rabben T (1998) Trigeminal neuropathic pain: Pathophysiological mechanisms examined by quantitative assessment of abnormal pain and sensory perception. Neurosurgery. (Accepted for publication) 13. Fardy MJ, Zakrzewska JM, Patton DW (1994) Peripheral surgical techniques for the management of trigeminal neuralgia alcohol and glycerol injections. Acta Neurochir (Wien) 129: 181185

Trigeminal Neuropathic Pain and Peripheral Glycerol 14. Fields HL, Rowbotham MC, Devor M (1997) Excitability blockers: Anticonvulsants and low concentration local anesthetics in the treatment of chronic pain. In: Dickenson A, Besson J-M (eds) The pharmacology of pain. Springer Berlin Heidelberg New York Tokyo, pp 93116 15. Fromm GH (1991) Pathophysiology of trigeminal neuralgia. In: Fromm GH, Sessle BJ (eds) Trigeminal neuralgia. Current concepts regarding pathogenesis and treatment. ButterworthHeinemann Boston, MA, pp 105130 16. Fruhstorfer H, Lindblom U, Schmidt WG (1976) Method for quantitative estimation of thermal thresholds in patients. J Neurol Neurosurg Psychiatry 39: 10711075 17. Gobel S, Binck JM (1977) Degenerative changes in primary trigeminal axons and in neurons in nucleus caudalis following tooth pulp extirpations in the cat. Brain Res 132: 347354 18. Haakanson S (1981) Trigeminal neuralgia treated by the injection of glycerol into the trigeminal cistern. Neurosurgery 9: 638 646 19. Hara H, Kobayashi S (1992) Glycerol injection to the rat trigeminal nerve: Histological and immunohistochemical studies. Acta Neurochir (Wien) 119: 111114 20. Hu JW, Dostrovsky JO, Lenz YE, Ball GJ, Sessle BJ (1986) Tooth pulp deaerentation is associated with functional alterations in the properties of neurons in the trigeminal spinal tract nucleus. J Neurophysiol 56: 16501668 21. Irish PS, Iliakis B, Anderson NL, Westrum LE (1996) Electron microscopic analysis of lesion-induced changes in synaptic structure and immunogold labeling of neurotransmitters within the feline trigeminal nucleus. Synapse 24: 4859 22. Kirvela O, Nieminen S (1990) Treatment of painful neuromas with neurolytic blockade. Pain 41: 161165 23. Lunsford LD, Bennett MH, Martinez AJ (1985) Experimental trigeminal glycerol injection. Electrophysiologic and morphologic eects. Arch Neurol 42: 146149 24. Macon JB (1979) Deaerentation hyperactivity in the monkey spinal trigeminal nucleus: Neuronal responses to amino acid iontophoresis. Brain Res 161: 549554 25. Merskey H, Bogduk N (1994) Classication of chronic pain. IASP Press, Seattle 26. Miller JN, Colditz GA Mosteller F (1989) How study design aects outcomes in comparisons of therapy. II: Surgical. Stat Med 8: 455466 27. Rappaport ZH, Seltzer Z, Zagzag D (1986) The eect of glycerol on autotomy. An experimental model of neuralgia pain. Pain 26: 8591 28. Sessle BJ (1991) Physiology of the trigeminal system. In: Fromm GH, Sessle BJ (eds) Trigeminal neuralgia. Current concepts regarding pathogenesis and treatment. ButterworthHeinemann, Boston, pp 71104 29. Statjcic Z (1989) Peripheral glycerol injections in the treatment of idiopathic trigeminal neuralgia. Int J Oral Maxillofac Surg 18: 255257 30. Verdugo RJ, Ochoa JL (1992) Quantitative somatosensory thermotest. A key method for functional evaluation of small calibre aerent channels. Brain 115: 893913 31. Vos BP, Strassmann AM, Maciewicz RJ (1994) Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat's infraorbital nerve. J Neurosci 14: 27082723

1277
treatment the authors have employed Quantitative sensory testing which in this case has proven to be extremely valuable. I am not ready to accept that trigeminal neuropathic pain should be classied as peripheral or central depending upon the response to a local anaesthetic. This statement is too conclusive and rm and I suggest that it should be stated somewhat less denitely, particularly in view of the much more balanced view represented by the word ``suggests'' on page 9. I would propose instead something like: ``in clinical practice it may be useful to dierentiate. . . .'' B. Meyerson This is an interesting paper addressing the abnormal sensory decits in peripheral neuropathic pain in adjunct with glycerol treatment of the peripheral nerve. It is of the ulmost importance to try to elucidate the pathophysiological mechanism in trigeminal neuropathic pain, a mechanism which is essentially unknown and could contribute to the improve in treatment. Clinically it has been well known for a long period of time that retrogasserian glycerol injections usually are of no benet in cases of neuropathic pain. Trigeminal neuralgia and trigeminal neuropathic pain seem to be opposite entities. It has been suggested that in trigeminal neuralgia localised demyelination anywhere along the trigeminal nerve or central connections could establish a site for ectopic impulse generation and hence membrane stabilizing substance as Carbamazepine is impressively eective. However in trigeminal neuropathic pain the same substance is essentially ineective. In addition it is enigmatic that sensitization of central neurones in classical trigeminal neuralgia is so uncommon inspite of longstanding symptoms often lasting up to 12 years. In this study it is evident that there was no pain relief from the application of glycerol proximal to the site of the trigeminal nerve in patients with peripheral or central trigeminal neuropathic pain nor were there any permanent changes in the sensory perception following the glycerol treatment. The absence of any measurable eect in sensory perception or not even a subtle pain relief suggests that there could have been a suboptimal application or penetration of glycerol to the nerve. The clinical sensory loss following the injection of such a large quantity as 4 ml local anaesthesic will not prove that the tip of the needle is very close to the nerve. In addition local anaesthesics are more likely to penetrate into the nerve as evidenced by the generally fast clinical eect. Glycerol readily penetrates cell membrane but requires about 25 minutes to obtain equilibrium. The presence of a perincurium most probably increases the interval to equilibrium. Additionally the nerve has to be surrounded by glycerol. It is also not unlikely that the injected local anaesthetic is not fully absorbed after ve minutes and it will therefore dilute the injected glycerol. This could be of great importance as the suggested mode of action of glycerol is that of its high hyperosmolarity. The action of the glycerol might as well have been confounded by the previous injection of local anaesthetic. The comparatively small amount of injected glycerol also has to be commented on. In retrogasserian glycerol injections the deposition of glycerol most likely is more adequate as the injection is done into a more conned space. In the present setting pronounced morphological changes are not really to be expected. Bremerich and Reisert found only subtle histomorphological changes after deposition of glycerol adjacent to the foramen ovale in rats. (Bremerich A, Reisert I (1991) Die perineurale Leitungsblockade mit Glycerin und Phenol-Glycerin. Eine histomorphologischmorphometrische Studie. Dtsch Zahn Z 46: 825827). kanson S. Ha Correspondence: Per Kristian Eide, M.D., Ph.D., Department of Neurosurgery, The National Hospital, Pilestredet 32, N-0027 Oslo, Norway.

Comments
I nd this to be a very interesting and important paper. The study is well designed and meticulosly performed. In the evaluation of the