Pain, 25 (1986) 165-170 Elsevier
165
PA1 00870
Iontophoresis of Vincristine versus Saline in Post-Herpetic Neuralgia. A Controlled Trial Paul R. Layman *. Eri Argyras ** and Christopher J. Glynn *** *Nuffield Department of Anaesthetics, John Radcliffe Hospital, Oxford (U.K.), ** Oxfvrd Regional Pain Relief Unit, Abmgdon (U.K.). and Department of Anaesthetics, University of Athens, Athens (Greece). and *** Oxford Regional Pain Relief Unit, A hingdon, and .~uf~eld Department ofAnaesthetics. Radcliffe Infirmary, Oxford ( U.K.) (Received
9 July 1985. revised received 30 September
1985, accepted
1 October
198.5)
Twenty patients with post-herpetic neuralgia (median duration 28.5 months) were randomly allocated to receive transdermal iontophoresis of either vincristine or saline. Although significant improvement in pain by word score and visual analogue scale (P = 0.05) was reported by 6 out of 10 of the vincristine group, none of the patients considered themselves ‘cured.’ There was no significant change in the saline group. No adverse haematological or neurological side effects were seen. but skin irritation and painless electrical burns were common in both groups. The dramatic relief of pain in patients with post-herpetic neuralgia of 3 months or less reported elsewhere was not seen in our group who had pain of a longer duration. This present trial does not confirm the value of vincristine iontophoresis in the treatment of post-herpetic neuralgia of over 6 months duration.
Introduction
The Periwinkle or vinca alkaloids, vincristine and vinblastine, have been shown in vitro to block axon transport in peripheral nerves at a concentration that will allow nerve conduction to continue [4,8]. Such a highly selective block has not hitherto
Correspondence Derby. U.K.
0304-3959/86/$03.50
to: Dr. P.R. Layman,
Department
0 1986 Elsevier Science Publishers
of Anaesthetics,
Derbyshire
B.V. (Biomedical
Division)
Royal
Infirmary.
been possible with the local anaesthetics which block both axon transport and conduction [lo]. Vincristine and ~,~~blast~ne were first used in the treatment of j~~tra~t~~bi~ pain by Csilfik et al. who reported dramatic relief of pain in post-herpetic neuralgia. trigeminal neuralgia. cancer pain. causalgia and other conditions. In order to provide a non-invasive therapy that was safe and acceptable, he used the technique 01 iontophoresis to drive the ionised drug into the skin in the area of pain f2.3.9). An unpublished study in Northampton showed improvement in 13 nut of 20 patients with post-herpetic neuralgia or ~lgodystrophy treated by a similar technique using vincristine. Confirmation of these encouraging findings was sought with a placebo controlled study. Post-herpetic neuralgia was chosen as the study group. as it is an easily defined diagnosis and is a condition that is sometimes unresponsive to other treatments.
Method
Approval of the Central Oxford Regional Ethicaf Committee infornled written consent of the patients was obtained.
for the study,
and
Twenty patients with post-herpetic neuralgia, which was unr~spo~si~~e to other therapies including transcutaneous electrical stimulation. subcutaneous infiltration of iignocaine and hydrocortisone, antidepressants, non-steroidal and opiate analgesics. were randomly allocated to either vincristine or saline treatment (see Table I). Atf those patients that had local anaesthetic blocks obtained total relief of pain for the duration of local anaesthesia. Six men and 14 women were studied with a mean age of 70 years (range 52-83). The median duration of pain prior to treatment was 28.5 months (range 3-96). The site of pain was in the lower cervical, thoracic or lumbar dermatomes. Patients with pain in the facial area were excluded from the study. The vin~ristine solution had a slight odour which could be recognised by the investigators. The trial was therefore single blind. None of the patients commented on the smell. Clinid exuminution The area of altered sensation (h~peraesthesja, numbness or pain) was mapped out prior to the start of the trial and reassessed at the end of the 4 week treatment and at the 6 week follow-up visit. It was not feasible to test motor power in the dermatomes affected. Measurements of haemaglobin, platelets, white cell count and liver function tests were performed before and after the 4 week treatment.
The vincristine was administered saline and 5% dimethyl sulphoxide.
as a 0.01% solution (2 mg in 20 ml) in 0.9% The contro1 solution was sterile 0.9% sodium
167
TABLE
I
PATIENT
DETAILS
I = infiltration of local anaesthetic 0 = opiate: N = non-steroidal analgesic; transcutaneous nerve stimulation; C = cryotherapy; E = epidural local anaesthetic antidepressant; S = anticonvulsant. Patient
1 2 3 4 5 6 7 8 9
Age
Sex
Vincristine(V) of conrrol if)
Duration fmonthsl
Area
76 52 80
M M F
V V
36 22
C v
33 33 17 84 24 96 30
T6 Ll T6 T5 T3 TlO c4 T12 T5
17 M -73 F
and and
steroid; steroid:
T = D =
Previous therapy
Pain at end of treatment
Pain at fOllOW-Up
HP H. P HP H H, P P HP HP H, I?
T. C. 0 E, N, 0 N
Improved Improved Unchanged Unchanged Improved Unchanged Improved Unchanged Withdrew unchanged Improved Improved Unchanged Unchanged Improved Withdrew unchanged Improved Unchanged Improved Unchanged Improved
Improved Improved Unchanged Unchanged Unnhanged Unchanged Unchanged Unchanged
Hyperaesthesia (H) or pain (PI
D D D. 0, N, I* E T. I, D. N
82 71 78 17
F M F F
V C V C c
10 I1 12 13 14 15
83 75 62 74 78 81
F F M F F F
V V C C V C
61 60 8 35 3 7
T4 CS T6 T8 T2 Tl
H. P P HP HP HP H. P
N. E T E‘ D, T N. D. I I:., N I>. N
16 I7 18 19 20
10 l-2 71 74
F 34 F F
v c v c
21 60
F
C
26
HP H H,P HP H. P
E, T, N, D I, N. c, T N, i, E, D T, I. D
81
T6 Tll T8 TS T9
8 5
S. N 7‘. D, N. E
N, I, D
Improved lmprased Unchanged Unchanged Died
Improved Unchanged Improved Unchanged Unchanged
I~~to~~~res~s of the sofution was performed 3 times weekly for 4 weeks. The area of byperaesthesia or pain, if larger than the electrode. was divided into 2 or 3 areas for treatment on consecutive occasions. Two metal electrodes, one active and one indifferent, were used for the iontophoresis. A lint pad under the active electrode (anode) was soaked with the test solution and applied to the treatment area. The indifferent electrode (cathode) was applied to the arm or leg and consisted of the metal plate and a 16-layer pad of lint soaked in tap water. The current appfied to these electrodes from a battery operated unit was adjusted to the maximum tolerated by each patient for a period of 60 min and varied from 15 to 30 mA. The current density varied from 0.15 to 0.25 mA . cme2.
chloride,
Analgesic Before complete from ‘no
measurement each treatment and at the 6 weeks foilow-up the patients were asked to a visuai analogue score of the severity of pain on a 10 cm scale ranging pain’ to ‘worst possible pain,’ plus a simple word score of ‘improved,
worse or unchanged.’
16X
Results
Two patients in the control group withdrew before the end of the course. and one patient who responded well to vincristine showing a 70%, improvement on the visual analogue score died of her long-standing cardiac failure before follow-up. After 4 weeks of treatment. 9 out of 10 patients treated with vincristine reported ‘improved’ on the word score. but only 8 out of 10 showed an improvement on the visual analogue score (mean of 59%). range 9988 positive scores only). The scores were significantly improved from baseline by Wilcoxon matched pairs signed rank test. using both positive and negative scores (P = 0.05). In contrast. 1 out of 10 patients in the control group reported ‘improved.’ with an 80% difference in her visual analogue score. At the 6 week follow-up visit, six of the vincristine group (60%) maintained some improvement in their pain on the word score and seven showed significant improvement on the visual analogue score (mean of 27%. range 7760. P = 0.05). No patient in the control group showed any improvement. However, none of the treated patients considered themselves cured. because they still had residual pain. The two methods of analgesia measurement correlated reasonably well, but some patients had difficulty understanding the visual analogue scale. Side effect5 There was no neurological deterioration detected in either group. nor were there any significant changes in haemoglobin. white cell count, platelet count or liver function tests. Most patients were prescribed a mild steroid cream to reduce irritation from both the ‘treatment’ and ‘indifferent’ areas. Despite careful placement of electrodes, several burns were seen, consisting of small 1 cm areas usually at the site of the indifferent electrode. Surprisingly. they were painless and healed over 2-3 weeks.
Discussion
Pain associated with an attack of herpes zoster is normally a self-limiting condition [l.ll]. In the unfortunate group of patients where it becomes persistent, the vast range of therapies used at one time or another for post-herpetic neuralgia demonstrates the difficulty in controlling this type of pain [5,6,12,13]. Iontophoresis of vinca alkaloids produced dramatic improvement in the 11 cases of post-herpetic neuralgia reported by Csillik et al., most of them reporting 100% relief of pain [3]. Nine of those. however, had post-herpetic neuralgia for 3 months or less before the start of treatment. Many treatments have been successful in this early period (up to 6 months) but have not been successful in patients with pain of greater than 6 months duration. The patients treated here with vincristine had a median duration of pain of 28.5 months and are therefore a substantially different patient population. In addition Csillik’s patients were treated for up to 8 weeks, compared with 4 weeks in the present study. Other differences included his occa-
169
sional use of vinblastine as an alternative to vincristine, and daily treatments compared to our thrice weekly schedule, although the apparently long duration of action of the drug on axonal transport, demonstrated by both Csillik and Fitzgerald, should make this unimportant [4,9]. The skin irritation seen in our patients would have made a daily schedule impossible. In this controlled study the placebo effect may account for the initial good response, but the vincristine group had a small (mean of 27%) but significant improvement in pain maintained at follow-up. None of the patients, however, were free of residual pain. In contrast, the control group showed no significant improvement by either analgesia measurement method at follow-up. Either the placebo reactors are all in the vincristine group or there is a real effect but it is small and poorly maintained. There were no placebo reactors in the control group at the 6 week follow-up. This observation, plus the fact that local anaesthetic block relieved their pain for the usual duration of local anaesthesia, indicates that this group of patients with long-standing post-herpetic neuralgia has pain of a physical rather than a psychological nature. Iontophoresis is an attempt to introduce an ionised drug to the nerve terminals in a safe and acceptable way. The actual mass of drug absorbed is likely to be very variable compared to the standard injection of a known quantity and may be responsible for the different therapeutic effect in our group, compared to Csillik’s group, It will depend on the magnitude of current, the duration and frequency of application, the area over which it is applied, the concentration and the physico-chemical characteristics of the drug. In addition, the skin may be more or less permeable depending on scarring, pigmentation or age of the patient. The side effects of skin irritation and thermal injury, plus the length of treatment, mitigate against the routine use of vincristine iontophoresis in intractable post-herpetic neuralgia. The lack of neurological and haematological side effects in this group is important, however, as vincristine is noted for its neurotoxicity during systemic use. If vincristine iontophoresis is used in patients with post-herpetic neuralgia of 3 months or less it may be effective. The studies of Csillik are of patients in pain where the abnormality is believed to be in the peripheral nerve. It seems probable that when pain becomes long standing (perhaps after 3 months), there are neurophysiological changes centrally in the spinal cord or elsewhere. Procedures directed solely against peripheral nerves are then unlikely to relieve the pain [7]. Our trial in post-herpetic neuralgia of over 6 months duration (where there may be central changes) showed a small and poorly maintained improvement, but interestingly as in Csillik’s trial, we found no neurological deterioration in the treated area. The marginal improvement seen in the vincristine group could be important considering the otherwise intractable nature of postherpetic neuralgia. Variations in the technique to increase the mass of drug and duration of application may prove useful. Other axon transport blocking drugs with less potential for serious side effects need to be considered as alternatives to vincristine. Finally, the presence of dimethyl sulphoxide in the treatment solution could be a significant factor producing neurotoxic or counter-irritative properties of its own. These aspects need further investigation.
‘The work of Csillik and Fitzgerald has opened up a wider perspective in the r-olc of axon transport in the aetiology and treatment of chronic pain. but the results of this present trial do not confirm the value of vincristine iontophore~t~ in the treatment of post-herpetic neuralgia of over 6 months duration.
Acknowledgements
We wish to thank Lilley industries for supplying the vincristine, R.D.G. Electromedical for the iontophores~s machines, and Miss P. Hammans for secretarial assistance.
References 1 Burgeon. C.F.. Burgoon. J.S. and Baldridge. C.D.. The natural history of herpes roster. J. Amer. med. ‘Ass.. 164 (1957)265-269. 2 C’sillik, B. and Knythar-Cstllik, E.. Regenerative synaptoneogenesis in the mammahan spinal cord: dynamics of synaptochemical restoration in the Rolando substance after transganglionic degenerative atrophy. J. neural Transm.. 52 (1981) 303.-317. 3 Csiilik. B., Knyihar-Csilhk, E. and Szuca. A., Treatment of chronic pain syndromes with iontophoresis of vinca alkaloids to the skin of patients, Neurosci. Lett.. 31 (1982) 87-90. 4 Fitzgerald, M.. Woolf. C‘J.. Gibson. S.J. and Mallaburn. P.S.. Pllterations in the structure function and chemistry of C Fibres followmg local application of ~inblast~ne to the sciatic nerve of the rat. .I. Nemo&, 4 (1984) 430-441. 5 Forrest. J.B.. The response to epidurai steroid injections in chronic dorsal root pain. Canad. anaesth. Sot. J.. 27 (1980) 40-46. 6 Friedman, A.H., Nashold, B.S. and Ovelnren-Levitt. J.. Dorsal root entry zone lesmns for the treatment of post-herpetic neuralgta, J. Neurosurg.. 60 (1984) 32581262. 7 Hitchcock. E.R. and Scharz. J.R.. Stereotaxic trigemtnal tractotomy for post-herpetic facial pain, J. Neurosurg.. 37 (1972) 412-417 8 Jackson. P. and Diamond, J.. Colchicine block of cholinesterase transport in rabbit sensory nerves without interference with the long-term viability of the axons. Brain Res., 130 (1977) 5799584. 9 Knyihar-Csillik. E., Szucs, A. and Csillik. B.. lontophoretically applied micro-tubule inhibitors induce transganglionic degenerative atrophy of primary central nociceptive terminals and abolish chronic aut~~chthonous pain. Acta neural. stand., 66 (1982)401.-412. 10 Lavoie, P.A., Block of fast axonaf transport in vitro by the local anaesthetics dtbucaine and etidocaine. .I. Pharmacol. exp. Ther.. 223 (1982) 251-256. 11 Riopelle. J.M.. Naraghi, M. and Grush. K.P.. Chronic neuralgia incidence foflowmg locai anaesthetic therapy for herpes zoster. Arch. Dermatol., 120 (I 984) 7477750. 12 Watson, P.C., Evans, R.J., Reed, K.. Menksey, H., Goldsmtth, L. and Walsh. J.. Amttriptyline versus placebo in post-herpetic neuralgia, Neurology (NY), 32 (1982) 671-673. 13 Woodforde, J.M.. Dwyer. B., McEwrn. B.W.. De Wtlde. F.W., Bleasel. K.. C‘onnelley. T.J. and Ho. C.Y.. Treatment of post-herpetic neuralgia. Med. J. Amt.. 2 (1965) x69-972