Case Reports in Medicine

Volume 2012 (2012), Article ID 471835, 3 pages

doi:10.1155/2012/471835

Case Report

Central Neuropathic Pain in a Patient with Multiple Sclerosis Treated Successfully with Topical Amitriptyline

David J. Kopsky,¹ Remko Liebregts,² and Jan M. Keppel Hesselink³

¹Clinical Operations, Institute for Neuropathic Pain, Vespuccistraat 64-III, 1056 SN Amsterdam, The Netherlands

²Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Postbus 9101, 6500 HP Nijmegen, The Netherlands

³Research and Development, Institute for Neuropathic Pain, Spoorlaan 2a, 3735 MV Bosch en Duin, The Netherlands

Received 4 June 2012; Accepted 26 June 2012

Academic Editor: Mamede de Carvalho

Copyright © 2012 David J. Kopsky et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Central neuropathic pain in patients with multiple sclerosis (MS) is a common debilitating symptom, which is mostly treated with tricyclic antidepressants or antiepileptics. Unfortunately, the use of these drugs is often limited due to adverse events. We investigated the analgesic effect of topical amitriptyline 5% and 10% cream in a patient with central neuropathic pain due to MS. The analgesic effect of topical amitriptyline cream on neuropathic pain was dose related. To evaluate whether this analgesic effect is due to the active compound or placebo, we conducted a double-blind placebo-controlled n-of-1 study with amitriptyline 5% cream and placebo. The instruction was to alternate the creams every week following the pattern ABAB, with an escape possibility of amitriptyline 10% cream. The result was a complete pain reduction after application of cream B, while most of the time cream A did not reduce the pain. The patient could correctly unblind both creams, determining B as active. She noted that in the week of using the active cream no allodynia was present, with a carryover effect of one day.

1. Introduction

Central neuropathic pain in patients with multiple sclerosis (MS) is a common debilitating symptom, which is mostly treated with tricyclic antidepressants or antiepileptics [1]. Unfortunately, the use of these oral drugs may be limited due to accompanying adverse events, such as drowsiness, constipation, and/or urinary retention. Caution is advised with the use of these drugs, because constipation and urinary retention are common problems in MS patients [2, 3]. Topical antidepressants might reduce these dose-limiting adverse events, while still offering adequate analgesia [4, 5].

We describe here a double blind placebo controlled n-of-1 study in a patient with MS suffering from severe central neuropathic pain, which was effectively treated with topical amitriptyline cream without any lasting dose-limiting adverse events.

2. Case Report

A 62-year old woman with 14 years of primary progressive MS has been wheelchair-bound for eight years and suffered from severe neuropathic pain in the upper arms and in the left foot. The pain was characterized by pricking, tingling, numbness, and sometimes electric shocks. The average pain score, 8 on the 11-point numerical rating scale (NRS), was reduced to 6 after the usage of oral pregabalin 450 mg daily. On previously prescribed oral amitriptyline 40 mg daily she experienced intolerable adverse events, such as continuous drowsiness and tiredness. Her other complaints, such as urine retention, constipation, and spasms were successfully treated with solifenacin, polyethylene glycol, and baclofen, respectively. In May 2010, while on pregabalin treatment, the patient developed a severe burning pain in her left foot, scoring 9 on NRS. The patient also experienced electric shocks and could not bear the contact with bed sheets (allodynia).

We prescribed topical amitriptyline 5% cream to apply 3 mL once daily to the painful foot. Thirty minutes after application the patient did not experience allodynia anymore. However, when the initial pain score was higher than 5 on NRS, the burning pain was only partially reduced. Therefore, we prescribed amitriptyline 10% cream, which relieved the burning pain completely (from 9 to 0 on the NRS) already 10 minutes after each application. The relief lasted the entire day. The patient reported tiredness, as the only adverse event of the topical amitriptyline 10% cream, but even this symptom disappeared in two weeks.

In order to determine whether pain alleviation was due to topical or to systemic effect, we suggested distant application. After application to the nonpainful foot, analgesia could also be observed in the painful foot, although 15 minutes later. Due to her physical impairments the patient was not able to apply the topical amitriptyline to her painful foot. Therefore, we advised her to apply topical amitriptyline cream to her inner forearms, which turned out to have the same effect as direct application to the nonpainful foot. Also the pricking and tingling neuropathic pain in her upper arms and her left leg responded to the topical amitriptyline 5% cream, though only partially. Then however, direct application of amitriptyline 5% cream, once a day on her upper arms and her left foots reduced this pricking and tingling pain from 8 to 0 on NRS during the second day.

To further inquire into the magnitude of the placebo response, we designed a double blind placebo controlled crossover n-of-1 study, comparing topical placebo cream to amitriptyline 5%. The compounding pharmacist blinded the two creams in two separate tubes, and named the creams A and B, respectively. Successful treatment was defined based on the following criteria:

(1) relevant clinical pain reduction measured on NRS,(2) successfully unblinding the treatment, (3) no or minimal need to use escape medication.

The instruction was to apply once daily 3 mL cream to the arm from one tube during one week, with an escape possibility of amitriptyline 10%, and to alternate the tubes every week following the pattern ABAB. The result was that the pain disappeared after application of cream B, while most of the time cream A did not reduce the pain. The patient could correctly unblind both creams, determining B as active. She noted that in the week of using the active cream no allodynia was present, with a carryover effect of one day. She did not need to use the escape medication in the week of using the active cream, though she used frequently escape medication in the placebo weeks, especially when the pain scores were above 4 on NRS. As a matter of fact, the patient could correctly identify the active cream as 5%, based on her previous experiences with both 5% and 10% creams. Furthermore, the patient did not experience any adverse events.

3. Discussion

To our knowledge this is the first report of treating central neuropathic pain due to MS with topical amitriptyline cream. This double blind placebo controlled n-of-1 experiment demonstrates that most of the pain reduction could be attributed to the active compound. The use of amitriptyline 5% and amitriptyline 10% cream as escape medication was chosen, because of the profound pain reducing effect in former observations [6, 7]. The fact that the burning pain disappeared after distant application suggests a systemic effect. Despite that pregabalin 450 mg daily reduced the pricking and tingling pain, severe burning pain with allodynia developed. In contrast, a complete reduction of this burning neuropathic pain with allodynia was achieved after adding topical amitriptyline. This observation might suggest that distinct characteristics of the central neuropathic pain respond differently to different types of analgesics, supported by sparse research [8, 9]. Systematic clinical examination and research will clarify this issue in the future.

Also a local analgesic effect might play a role, because the already existing neuropathic pain in arms and left leg (mainly pricking and tingling) vanished completely only after local application. Due to the refractory and chronic character of this pain, placebo effect is less likely to contribute considerably in the positive effect. The reduction of ectopic pulses from nociceptors could be the explanation of the complete disappearance after topical amitriptyline [10]. Degeneration of some spinothalamic tract neurons can trigger pathological activity in neighboring intact afferents through the release of inflammatory mediators and neurotrophic factors. In addition, also the loss of intraspinal and descending inhibitory pathways elicits neuronal hyperexcitability [11]. Moreover, the degeneration of myelinated efferent fibers could induce spontaneous activity in uninjured C-fiber afferents [12]. To clarify which part of the analgesic response can be attributed to either systemic or local effect, in future studies serum levels of amitriptyline should be measured.

Due to controlled release characteristics of the amitriptyline cream, persistent peak-dose adverse events were absent.

Only a few case reports are available on topical analgesics in central neuropathic pain, describing the use of lidocaine 5% patches; menthol cream, and the combination cream of capsaicin 0.075%, lidocaine 3%, and isosorbide dinitrate 0.4% [13–16]. In peripheral neuropathic pain topical amitriptyline, sometimes combined with ketamine, is evaluated with mixed results, probably due to the insufficient concentration and/or a suboptimal vehicle [17, 18].

Our paper suggests a systemic as well as a local analgesic effect of topical amitriptyline cream. More research is urgently needed for this interesting therapeutic option in the treatment of central neuropathic pain.

References

C. Solaro and M. Messmer Uccelli, “Pharmacological management of pain in patients with multiple sclerosis,” Drugs, vol. 70, no. 10, pp. 1245–1254, 2010.

A. Manack, S. P. Motsko, C. Haag-Molkenteller et al., “Epidemiology and healthcare utilization of neurogenic bladder patients in a US claims database,” Neurourology and Urodynamics, vol. 30, no. 3, pp. 395–401, 2011.

C. Norton and S. Chelvanayagam, “Bowel problems and coping strategies in people with multiple sclerosis,” British Journal of Nursing, vol. 19, no. 4, pp. 220–226, 2010.

D. Strumper and M. E. Durieux, “Antidepressant as long-acting local anesthetics,” Regional Anesthesia and Pain Medicine, vol. 29, no. 3, pp. 277–285, 2004.

P. Gerner, G. Kao, V. Srinivasa, S. Narang, and G. K. Wang, “Topical amitriptyline in healthy volunteers,” Regional Anesthesia and Pain Medicine, vol. 28, no. 4, pp. 289–293, 2003.

D. J. Kopsky and J. M. Keppel Hesselink, “High doses of topical amitriptyline in neuropathic pain: two cases and literature review,” Pain Practice, vol. 12, no. 2, pp. 148–153, 2012.

R. Liebregts, D. J. Kopsky, and J. M. Keppel Hesselink, “Topical amitriptyline in post-traumatic neuropathic pain.,” J Pain Symptom Manage, vol. 41, pp. 6–7, 2011.

I. Decosterd, A. Allchorne, and C. J. Woolf, “Differential analgesic sensitivity of two distinct neuropathic pain models,” Anesthesia and Analgesia, vol. 99, no. 2, pp. 457–463, 2004.

M. J. Field, S. McCleary, J. Hughes, and L. Singh, “Gabapentin and pregabalin, but not morphine and amitriptyline, block both static and dynamic components of mechanical allodynia induced by streptozocin in the rat,” Pain, vol. 80, no. 1-2, pp. 391–398, 1999.

O. A. de Leon-Casasola, “Multimodal approaches to the management of neuropathic pain: the role of topical analgesia,” Journal of Pain and Symptom Management, vol. 33, no. 3, pp. 356–364, 2007.

G. Wasner, B. B. Lee, S. Engel, and E. McLachlan, “Residual spinothalamic tract pathways predict development of central pain after spinal cord injury,” Brain, vol. 131, no. 9, pp. 2387–2400, 2008.

G. Wu, M. Ringkamp, B. B. Murinson et al., “Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents,” Journal of Neuroscience, vol. 22, no. 17, pp. 7746–7753, 2002.

G. Wasner, D. Naleschinski, and R. Baron, “A role for peripheral afferents in the pathophysiology and treatment of at-level neuropathic pain in spinal cord injury? A case report,” Pain, vol. 131, no. 1-2, pp. 219–225, 2007.

G. H. Hans, D. N. Robert, and K. N. Van Maldeghem, “Treatment of an acute severe central neuropathic pain syndrome by topical application of lidocaine 5% patch: a case report,” Spinal Cord, vol. 46, no. 4, pp. 311–313, 2008.

G. Wasner, D. Naleschinski, A. Binder, J. Schattschneider, E. M. Mclachlan, and R. Baron, “The effect of menthol on cold allodynia in patients with neuropathic pain,” Pain Medicine, vol. 9, no. 3, pp. 354–358, 2008.

D. J. Kopsky, G. J. Amelink, and J. M. Keppel Hesselink, “Intractable neuropathic pain in spinal intramedullary cavernoma treated successfully with a novel combination cream,” Pain Medicine (United States), vol. 13, no. 5, pp. 729–730, 2012.

D. Everton, D. Bhagwat, and M. Damask, “A multicenter, double-blind, randomized, placebo controlled study of the efficacy/safety of two doses of amitriptyline/ketamine topical cream in treating post-herpetic neuralgia (PHN),” The Journal of Pain, vol. 8, no. 4, supplement, p. S47, 2007.

K. Y. Ho, B. K. Huh, W. D. White, C. C. Yeh, and E. J. Miller, “Topical amitriptyline versus lidocaine in the treatment of neuropathic pain,” Clinical Journal of Pain, vol. 24, no. 1, pp. 51–55, 2008.