Botox Rx for Neuropathy by Clark1968

Botulinum toxin for diabetic neuropathic pain: A randomized double-blind crossover trial R. Y. Yuan, J. J. Sheu, J. M. Yu, W. T. Chen, I. J. Tseng, H. H. Chang and C. J. Hu Neurology 2009;72;1473-1478; originally published online Feb 25, 2009; DOI: 10.1212/01.wnl.0000345968.05959.cf

This information is current as of February 25, 2010

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/cgi/content/full/72/17/1473

Neurology® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2009 by AAN Enterprises, Inc. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

Downloaded from www.neurology.org at MEMORIAL HOSPITAL on February 25, 2010

Botulinum toxin for diabetic neuropathic pain A randomized double-blind crossover trial

R.-Y. Yuan, MD J.-J. Sheu, MD J.-M. Yu, MD W.-T. Chen, MD I.-J. Tseng, RN H.-H. Chang, MBA C.-J. Hu, MD

Address correspondence and reprint requests to Dr. Chaur-Jong Hu, Department of Neurology, Taipei Medical University Hospital and Shuang Ho Hospital, 252 Wu-Hsing Street, Taipei 110, Taiwan chaurjongh@tmu.edu.tw

ABSTRACT

Background: Diabetic neuropathy is a common complication in diabetes, with patients typically experiencing diverse sensory symptoms including dysesthesias in the feet and usually accompanied by sleep disturbance. There is still no comprehensive understanding of the underlying biologic processes responsible for diabetic neuropathic pain. Thus, the current symptomatic therapy remains unsatisfactory. Recent experimental evidence suggests that botulinum toxin type A (BoNT/A) may not only inhibit the release of acetylcholine at the neuromuscular junctions, but also modulate afferent sensory fiber firing, thereby relieving neuropathic pain.

Methods: A double-blind crossover trial of intradermal BoNT/A for diabetic neuropathic pain in 18 patients was conducted to evaluate the effectiveness.

Results: We find significant reduction in visual analog scale (VAS) of pain by 0.83 ⫾ 1.11 at 1 week, 2.22 ⫾ 2.24 at 4 weeks, 2.33 ⫾ 2.56 at 8 weeks, and 2.53 ⫾ 2.48 at 12 weeks after injection in the BoNT/A group, as compared to the respective findings for a placebo group of 0.39 ⫾ 1.18, ⫺0.11 ⫾ 2.04, 0.42 ⫾ 1.62, and 0.53 ⫾ 1.57 at the same timepoints (p ⬍ 0.05). Within the BoNT/A group, 44.4% of the participants experienced a reduction of VAS ⱖ3 within 3 months after injection, whereas there was no similar response in the placebo group. At the 4-week postinjection stage, improvement in sleep quality was measured using the Chinese version of the Pittsburgh Sleep Quality Index.

Conclusions: This pilot study found that botulinum toxin type A significantly reduced diabetic neuropathic pain and transiently improved sleep quality. Further large-scaled study is warranted. Neurology® 2009;72:1473–1478 GLOSSARY BoNT/A ⫽ botulinum toxin type A; CMAP ⫽ compound motor action potential; CPSQI ⫽ the Chinese version of the Pittsburgh Sleep Quality Index; MCS ⫽ Mental Component Summary; NCV ⫽ nerve conduction velocity; NE ⫽ neurologic examination; PCS ⫽ Physical Component Summary; SAP ⫽ sensory action potential; SF-36 ⫽ Short Form–36 quality-of-life questionnaire; SONO ⫽ sonography study of feet for exclusion of peripheral artery occlusion; VAS ⫽ visual analog scale.

Neuropathic pain is one of the most common complications of diabetic neuropathy.1 More than 25% of patients with type 2 diabetes have neuropathic pain syndromes.2 The pain, usually attacking the distal extremities, results in disturbed sleep and diminished quality of life.2 Unlike nociceptive pain, which is related to tissue damage from many types of irritants, neuropathic pain arises from damage to the peripheral nervous system or CNS. Both peripheral and central sensitization processes are involved in the pathophysiology of neuropathic pain.3,4 Alterations to the sympathetic nerve terminals induced by inflammation from either neuropathy or tissue damage enhance the release of various pain substances into the peripheral nervous system.5 The resultant damage to nervous afferent C- and A-delta fibers causes ectopic discharge, with the reduction in nociceptor thresholds and the resultant accumulation of sodium channels subse-

Editorial, page 1456 e-Pub ahead of print on February 25, 2009, at www.neurology.org. From the Department of Neurology (R.-Y.Y., J.-J.S., J.-M.Y., C.-J.H.), Taipei Medical University and Hospital; The Neurologic Institute (W.-T.C.), Taipei Veterans General Hospital; College of Nursing (I.-J.T.), Taipei Medical University; Department of International Trade (H.-H.C.), Chungyu Institute of Technology, Keelung; and Department of Neurology (C.-J.H.), Taipei Medical University, Shuang-Ho Hospital, Taiwan. Disclosure: The authors report no disclosures. Copyright 2009 by25, AAN Enterprises, Inc. Downloaded from www.neurology.org at MEMORIAL HOSPITAL on © February 2010

1473

Figure 1

CONSORT flowchart: Study design and main results

quently being followed by neuroplasticity, alternation of the modulatory systems, and then central sensitization.6 Although many symptomatic therapies are available for neuropathic pain, including antidepressants, anticonvulsants, and opioids, as well as some novel strategies, many of these remain unsatisfactory.7 A small number of patients do not tolerate the adverse events. Botulinum toxin has been found to suppress both nociceptor sensitization and neuropathic pain such as trigeminal neuralgia and carpal tunnel syndrome. 8-10 In this study, we evaluate the effects of intradermal, rather than intramuscular, BoNT/A injections on pain symptoms in patients with diabetic neuropathic pain. METHODS This is a randomized double-blind crossover trial. The study design is shown in the CONSORT flowchart (figure 1).11,12 The Clinical Trial Registration number is NCT00336349 (www.clinicaltrials.gov).

Patients. A total of 20 patients with type 2 diabetes were recruited for this study. Each of these patients was required to have a minimum history of 3 years of diabetes mellitus and neuropathic pain in both feet. There were also prerequisites that the medication for neuropathic pain had not been changed within 1474

the previous 1-month period and that the symptoms were stationary. The symptoms included bilateral pedal paresthesia and stocking distribution of tingling pain, burning, sharp shooting pain, and pruritic pain, which would fit the diagnostic criteria for neuropathic pain based on the DN4 questionnaire; furthermore, nerve conduction velocity (NCV) examinations should show polyneuropathy patterns. DN4 is a clinician-administered questionnaire. It consists of both sensory descriptors by interview and signs based on bedside sensory examination. It has a high level of sensitivity and specificity in discriminating neuropathic from nociceptive and somatic pain, and can help in the correct detection of neuropathic pain.13 The patients should have four or more items positive among the 10 items of the DN4 questionnaire. The NCV examination should show either reduction of amplitude or slowing down of conduction velocity in peroneal, tibial, or sural nerve. The cutoff values of NCV examination were 40 m/sec for motor NCV and 2 mV for compound motor action potential (CMAP) and 2 ␮V for sensory action potential (SAP). The visual analog scale (VAS) of all patients at entry time was ⬎4.0. No alterations were made to the prescribed medications for neuropathic pain during the study period. The exclusion criteria included peripheral arterial occlusion disease, diagnosed based on sonography with ankle-brachial (A/B) ratios below 1.0, any infection at the injection site, and any lumbar-sacral radiculopathy based upon clinical presentation, neurologic examination, and lumbar spine x-ray films. Patients with motor deficit were excluded. The other possible confounding causes of painful neuropathy, such as alcoholism and renal function impairment, were also excluded. This study was approved by the Intra-institute Research Board at Taipei Medical University Hospital, with each of the participants providing written informed consent.

Intradermal BoNT/A injection. The patients were initially selected at random to receive either BoNT/A or normal saline injections on both feet. Twelve weeks later, each participant was crossed over to received a second injection with the other treatment, saline or BoNT/A. The injections were distributed across the dorsum of the foot, in a grid distribution pattern covering a total of 12 (3 ⫻ 4) sites (figure 2A). The distribution of these sites was such that the distance between them was approximately equal. To keep the study blind, the preparation of saline and BoNT/A was performed by an independent study nurse, who did not participate in the interview of participants. The patients were first asked to clean their feet; then 2% Xylocaine jelly was applied as a topical anesthetic for 3 minutes. After the Xylocaine jelly was removed with water, the feet were thoroughly cleansed with an antiseptic solution of 75% alcohol– beta iodine and three subsequent applications of 75% alcohol. Fifty units of BoNT/A in 1.2 mL 0.9% saline were then administered intradermally into each foot, with each injection comprising approximately 4 U BoNT/A (BOTOX), 0.10 mL, using a 5/16-inch, 30-g needle. The 0.9% saline injections were performed in an identical manner (figure 2A).

Outcome assessment. The VAS, the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI), and the Short Form–36 (SF-36) quality-of-life questionnaire were performed at 1-week, 4-week, 8-week, and 12-week intervals after the initial injection.14,15 For VAS measurement, the study nurse asked the patients to point out the current pain severity during the last day on a rule with 0.0 –10.0 scales (0.0 ⫽ no pain, 10.0 ⫽ unbear-

Neurology 72 28, 2009 Downloaded fromApril www.neurology.org at MEMORIAL HOSPITAL on February 25, 2010

Figure 2

Time frame and the main result of this trial

group. The changes in the CPSQI and SF-36 scores for paired samples between the BoNT/A and placebo groups were also tested using the Student t test.

Of the 20 patients enrolled in this study, 18 completed the full 6-month trial. The mean age of the patients was 65.6 ⫾ 9.2 years, with a mean diabetes history of 9.3 ⫾ 6.9 years; the mean DN4 items were 7.3 ⫾ 1.5, and most of the participants were taking anticonvulsants for treatment of neuropathic pain. The baseline VAS scores were 6.36 ⫾ 1.16 for all participants at the entry time, and 6.42 ⫾ 1.11 in BoNT/A group, 5.97 ⫾ 1.51 in placebo group before the treatment, p ⫽ 0.322 (tables 1 and 2). The mean motor NCV of all participants is 33.6 ⫾ 2.8 m/sec for peroneal nerve, 32.4 ⫾ 3.0 m/sec for tibial nerve, 1.2 ⫾ 0.5 mV for peroneal CMAP, 1.0 ⫾ 0.5 mV for tibial CMAP, and the mean sural SAP is 1.0 ⫾ 0.6 ␮V. One patient withdrew for personal reasons while another withdrew following a motor vehicle accident which resulted in a foot injury requiring dressing over the feet. There was one case of a mild local skin infection at the injection site one day after injection; however, the infection improved soon after oral antibiotic therapy for a period of 3 days. No other adverse events were reported.

RESULTS Patient characteristics.

(A) Injections were distributed across the dorsum of the foot, in a grid pattern, typically 2 to 3 cm apart. A volume of 1.2 mL was administered intradermally into each foot, with each injection comprising approximately 4 U BoNT/A (0.10 mL) using a 5/16-inch, 30-g needle. The 0.9% saline injections were carried out in an identical manner. The patients took BoNT/A or saline randomly at the first injection and took another kind of medication, saline or BoNT, 3 months later. (B) Changes of VAS in BoNT and placebo groups. The bar chart shows mean changes of VAS with standard error of mean (SEM). #p ⬍ 0.05 by comparison with 0, in terms of no change; *p ⬍ 0.05 by comparison of two groups. NE ⫽ neurologic examination; NCV ⫽ nerve conduction velocity examination; SONO ⫽ sonography study of feet for exclusion of peripheral artery occlusion; VAS ⫽ visual analog scale; CPSQI ⫽ the Chinese version of the Pittsburgh Sleep Quality Index; SF-36 ⫽ Short Form–36 quality-oflife questionnaire.

able pain). Changes in VAS score within 12 weeks are the primary endpoint and changes in sleep and life quality are the secondary endpoints for this study.

Statistical analysis. Reductions in VAS in the BoNT/A and placebo groups at the 1-, 4-, 8-, and 12-week stages were assessed using the Student t test to identify any significant changes following the treatment. The reductions in VAS were therefore compared between the BoNT/A and placebo groups for paired samples using the Student t test, with p ⬍ 0.05 being regarded as significant. The mean of the SD in the reduction in VAS among the placebo group was about 1.5; as a result, we defined a good response as being characterized by a reduction of VAS ⱖ3, which was approximately twice the SD value of the placebo

Reductions in VAS. The reductions in VAS in the BoNT/A group were 0.83 ⫾ 1.11 after 1 week, 2.22 ⫾ 2.24 after 4 weeks, 2.33 ⫾ 2.56 after 8 weeks, and 2.53 ⫾ 2.48 after 12 weeks. The reductions in VAS in the placebo group were 0.39 ⫾ 1.18 after 1 week, – 0.11 ⫾ 2.04 after 4 weeks, 0.42 ⫾ 1.62 after 8 weeks, and 0.53 ⫾ 1.57 after 12 weeks. As compared to the placebo group, there were significant reductions in VAS in the BoNT/A group for each of these timepoints, p ⫽ 0.014 at 4 weeks, 0.039 at 8 weeks, and 0.024 at 12 weeks. In a comparison between the two groups for each of these timepoints, the differences between the groups achieved significance at the 4-, 8-, and 12week stages. The BoNT/A treatment began to show a trend toward improving after just 1 week, with the effect ultimately lasting for 12 weeks. Within the BoNT/A treatment group, 44.4% (8/18) experienced good responses (a reduction in VAS of ⱖ3) within 3 months after the initial injection, whereas no good responses were found in the placebo group, p ⬍ 0.005 (table 2 and figure 2B). Reduction in total scores for CPSQI. The scores for

the CPSQI indicated that most of the participants were poor sleepers (CPSQI ⱖ7); however, the difference in the improvement in sleep quality between the BoNT/A treatment group and the placebo group reached significance (p ⬍ 0.05) only 4 weeks after

Neurology April 28, Downloaded from www.neurology.org at MEMORIAL HOSPITAL on72 February 25,2009 2010

1475

Table 1

Demographic information

Variables

Values, mean ⴞ SD

Total n

Items/score, mean ⴞ SD

Age, y

65.6 ⫾ 9.2

—

Gender Male

—

Female

—

9.3 ⫾ 6.9

Duration of diabetes, y Neuropathic Pain Diagnostic Questionnaire (DN4)

—

7.3 ⫾ 1.5 6.36 ⫾ 1.16

VAS baseline Medication for neuropathic pain Anticonvulsants

—

9/18

—

Antidepressants

—

1/18

—

Both

—

1/18

—

Neither

—

7/18

—

VAS ⫽ visual analog scale.

the initial injection, with scores of 1.72 ⫾ 1.82 for the BoNT/A group and ⫺0.11 ⫾ 2.78 for the placebo group, p ⫽ 0.04 (table 3). The data do not support sleep improvement with BoNT/A treatment at weeks 1, 8, and 12. They might indicate that BoNT/A improved the sleep quality at only one timepoint after injection and the effect was transient. The data do not support sleep improvement with BoNT/A treatment at week 12, the endpoint of study design. Reduction in SF-36 physical and mental component scores. A comparison was undertaken of the changes

in the scores for the physical and mental components of the SF-36 quality-of-life questionnaire between the two groups at the same timepoints; however, there were no significant differences or improvements found in these components during the period of our study (table 3). DISCUSSION This pilot study of intradermal BoNT/A injections for diabetic neuropathic pain suggests a potential role for intradermal BoNT/A as a potentially effective treatment. Although it was not the case for every patient, it was found in this doubleblind crossover study that BoNT/A did significantly improve the mean VAS of pain at the 4-week stage after the injections for a period lasting at least 12 weeks. On the other hand, the relatively modest decrease in VAS values among the saline group did not reach significance and it could be a placebo effect. Furthermore, there were no major complications arising as a result of these injections. In several preclinical models, BoNT/A effectively blocks the release of calcitonin gene-related peptide, substance P, and glutamate from afferent nerve ter1476

minals.16,17 Extracellular ATP is implicated in a considerable number of sensory processes, including pain. BoNT/A has been reported to block an ATP receptor, P2X3, which is almost exclusively expressed in the sensory neurons. Furthermore, evidence shows that this receptor plays a specific role in nociception, with the activation of P2X3 by ATP leading to a much stronger nociceptive effect in inflamed tissue.18,19 BoNT/A also effectively blocks the translocation of the pain-related transient receptor potential channel receptor (TRPV1) in peripheral nociceptor terminals.20 The VAS scores before treatment (week 0) were a little lower in the placebo group than in BoNT/A. This might be attributed to the impact of BoNT/A on a few participants who took BoNT/A therapy first and the effectiveness persisted for over 12 weeks when they took placebo therapy. Therefore, it is possible that the VAS at 1 and 4 weeks might be skewed toward showing a lesser difference between the groups. Our study design only surveys the VAS at single timepoints instead of averaged pain severity within a specific period. This made the question easier to understand for the elderly participants but this study design could lose the information of some time periods. The study design referred to the previous experience of BoNT/A, with the mean effective dosage of BoNT/A for trigeminal neuralgia being 3.17–3.31 units/cm2.9 Since the area of each dorsal foot is over 100 cm2 for most people, the dosage adopted for this trial of diabetic neuropathic pain was below 0.5 units/cm2, which is much lower than that for trigeminal neuralgia. Whether increase of dosage could enhance the efficacy of BoNT/A for diabetic neuropathic pain is uncertain. Clearly, however, the optimal dosage for diabetic neuropathic pain will require further investigation. Most of the reports on BoNT/A injections for dystonia indicate that the respective onset and effectiveness duration were about 1 week and 3 months. In the present study, the onset occurred later than 1 week after the injections, with the effectiveness possibly lasting for at least 3 months; therefore, the course of intradermal BoNT/A injections for diabetic neuropathic pain is clearly similar to, but not the same as, the course of BoNT/A injections for dystonia or trigeminal neuralgia. Thus, further comprehensive trials are clearly warranted in order to determine the onset and effectiveness duration. It is already well recognized that BoNT/A inhibits the release of the neurotransmitter-containing vesicles from the nerve ending into the synapse. In a formalin-induced pain study, the antinociceptive effect of BoNT/A was found to have an association

Neurology 72 28, 2009 Downloaded fromApril www.neurology.org at MEMORIAL HOSPITAL on February 25, 2010

Table 2

Changes in VAS in the two treatment groups BoNT/A group, mean ⴞ SD

Week 0

6.42 ⫾ 1.11

⫺0.83 ⫾ 1.11*

Placebo group, mean ⴞ SD

p Value

5.97 ⫾ 1.51

0.322

⫺0.39 ⫾ 1.18

0.309

⫺2.22 ⫾ 2.24*

⫺0.11 ⫾ 2.04

0.014†

⫺2.33 ⫾ 2.56*

⫺0.42 ⫾ 1.62

0.039†

⫺2.53 ⫾ 2.48*

⫺0.53 ⫾ 1.57

No. of patients with reduced VAS >3 within 12 wk

8/18

0/18

0.024† ⬍0.005‡

*p ⬍ 0.05 by comparison with 0, in terms of no change. †p ⬍ 0.05. ‡p ⬍ 0.005. VAS ⫽ visual analog scale; BoNT/A ⫽ botulinum toxin type A.

with the inhibition of glutamate release from the primary afferent terminals.21 Glutamate is also involved in the induction and maintenance of central sensitization of pain by exerting its postsynaptic effect via the NMDA receptors.22 Those raise the possibility of potential central effects of BoNT/A. There are deTable 3

bates that BoNT/A injection at peripheral sites results in alternation of central modulatory system then changes the pain severity over the sites without BoNT/A injection. To avoid the confusion of central effects of BoNT/A, our study design is BoNT/A or saline injection in both feet simultaneously instead of injection of BoNT/A and saline separately for comparison of each other in the mean time. This study is unable to approach the issue of central effects of BoNT/A. Botulinum toxin has been used in various types of pain therapy, including migraine, myofascial pain syndrome, plantar fasciitis, arthritis, and trigeminal neuralgia.9,23-26 These trials have succeeded in extending the field of traditional pain therapy, particularly for the unsatisfactory treatment of neuropathic pain. Since diabetic neuropathic pain is associated with sleep impairment, it may be an important factor in life and sleep quality among diabetic patients. Sleep disturbance is therefore also an issue of importance in the care of diabetic patients.27 Our results raised a

Results of the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI) and Physical and Mental Component Summaries (PCS and MCS) of the Chinese version of the Short Form-36 (SF-36) quality-of-life questionnaire Changes

Time point

BoNT/A group

Placebo group

9.67 ⫾ 3.77

9.67 ⫾ 4.17

BoNT/A group

Placebo group

—

p Value

CPSQI Baseline 1 wk

8.22 ⫾ 3.66

8.61 ⫾ 3.27

⫺1.44 ⫾ 1.64

⫺1.06 ⫾ 3.00

4 wk

7.94 ⫾ 3.52

9.78 ⫾ 3.83

⫺1.72 ⫾ 1.82

0.11 ⫾ 2.78

0.58 0.04*

8 wk

8.44 ⫾ 4.00

9.28 ⫾ 3.75

⫺1.22 ⫾ 1.07

⫺0.39 ⫾ 2.75

0.26

12 wk

8.28 ⫾ 2.71

9.06 ⫾ 3.52

⫺1.39 ⫾ 1.24

⫺0.61 ⫾ 2.28

0.32

PCS

39.05 ⫾ 18.10

33.80 ⫾ 17.09

—

MCS

60.89 ⫾ 20.43

64.39 ⫾ 17.42

—

PCS

37.93 ⫾ 17.19

36.83 ⫾ 14.77

⫺1.12 ⫾ 8.89

3.03 ⫾ 9.77

0.840

MCS

59.51 ⫾ 21.96

65.47 ⫾ 22.59

⫺1.38 ⫾ 6.24

1.09 ⫾ 12.97

0.080

SF-36 0 wk

1 wk

4 wk PCS

42.33 ⫾ 16.87

38.15 ⫾ 14.98

4.40 ⫾ 9.86

2.53 ⫾ 12.73

0.095

MCS

62.61 ⫾ 23.37

60.75 ⫾ 19.29

3.10 ⫾ 7.63

1.32 ⫾ 11.30

0.488

PCS

42.58 ⫾ 14.44

41.41 ⫾ 16.11

0.25 ⫾ 5.66

3.27 ⫾ 9.11

0.725

MCS

63.75 ⫾ 23.65

59.69 ⫾ 22.30

1.14 ⫾ 6.80

⫺1.06 ⫾ 8.89

0.256

8 wk

12 wk PCS

42.23 ⫾ 16.07

39.80 ⫾ 18.31

⫺0.35 ⫾ 4.22

⫺1.06 ⫾ 7.83

0.365

MCS

64.12 ⫾ 23.51

60.62 ⫾ 19.53

0.37 ⫾ 6.19

0.93 ⫾ 1.91

0.072

Lower CPSQI score indicates better sleep quality. Higher SF-36 score indicates better life quality. *p ⬍ 0.05. BoNT/A ⫽ botulinum toxin type A. Neurology April 28, Downloaded from www.neurology.org at MEMORIAL HOSPITAL on72 February 25,2009 2010

1477

possibility of improvement of sleep quality by BoNT/A therapy. The treatment significantly improved sleep quality only at the 4-week timepoint, although there were trends toward improvement at the other timepoints (table 3). However, the impact on sleep quality from improvement in neuropathic pain needs further investigation because the results of improvement of sleep quality did not parallel with neuropathic pain at other timepoints. In this study, BoNT/A injections failed to improve life quality surveyed by SF-36 in physical and mental domains. This result might reflect the complexity of contributory factors in life quality. Improvement of neuropathic pain induced by BoNT/A injections might be not significant enough on alteration of life quality. What diabetic patients consider in measuring their life quality needs further investigation. This trial indicates that intradermal BoNT/A injections are an effective and safe method of relieving diabetic neuropathic pain in the feet. The detailed underlying mechanisms, optimal dosage, and precise course of therapy require further evaluation. AUTHOR CONTRIBUTIONS Ing-Jy Tseng, College of Nursing, Taipei Medical University, Taipei, Taiwan, and Hsiu-Hui Chang, Department of International Trade, Chungyu Institute of Technology, Keelung, Taiwan, conducted the statistical analysis.

10.

11.

12.

13.

14.

15.

16.

17.

18.

ACKNOWLEDGMENT The authors thank Michael S. Altus, PhD, ELS, Intensive Care Communications, Inc., for editing. Allergan Asia Ltd. (Taipei, Taiwan) provided BOTOX (botulinum toxin type A).

19.

20. Received July 4, 2008. Accepted in final form December 16, 2008. REFERENCES 1. Boulton AJ. Diabetic neuropathy: classification, measurement and treatment. Curr Opin Endocrinol Diabetes Obes 2007;14:141–145. 2. Davies M, Brophy S, Williams R, Taylor A. The prevalence, severity and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care 2006;29:1518–1522. 3. Baron R. Mechanisms of disease: neuropathic pain: a clinical perspective. Nat Clin Pract Neurol 2006;2:95–106. 4. Pace MC, Mazzariello L, Passavanti MB, Sansone P, Barbarisi M, Aurilio C. Neurobiology of pain. J Cell Physiol 2006;209:8–12. 5. Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol 2001;429:23–37. 6. Aurilio C, Pota V, Pace MC, Passavanti MB, Barbarisi M. Ionic channels and neuropathic pain: Physiopathology and applications. J Cell Physiol 2008;215:8–14. 7. Cruccu G. Treatment of painful neuropathy. Curr Opin Neurol 2007;20:531–535. 8. Argoff CE. A focused review on the use of botulinum toxins for neuropathic pain. Clin J Pain 2002;18(6 suppl):S177– 181. 9. Piovesan EJ, Teive HG, Kowacs PA, Della Coletta MV, Werneck LC, Silberstein SD. An open study of botulinum A toxin treatment of trigeminal neuralgia. Neurology 2005;65:1306–1308. 1478

21.

22.

23.

24.

25.

26.

27.

Tsai CP, Liu CY, Lin KP, Wang KC. Efficacy of botulinum toxin type A in the relief of carpal tunnel syndrome: a preliminary experience. Clin Drug Invest 2006;26:511–515. Altman DG, Schulz KF, Moher D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001;134:663–694. Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001;357:1191–1194. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114:29–36. Tsai PS, Wang SY, Wang MY, et al. Psychometric evaluation of the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI) in primary insomnia and control subjects. Qual Life Res 2005;14:1943–1952. Wang SJ, Fuh JL, Lu SR, Juang KD. Quality of life differs among headache diagnoses: analysis of SF-36 survey in 901 headache patients. Pain 2001;89:285–292. Chuang YC, Yoshimura N, Huang CC, Chiang PH, Chancellor MB. Intravesical botulinum toxin A administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol 2004;172:1529–1532. Aoki KR. Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A. Neurotoxicology 2005;26:785–793. Paukert M, Osteroth R, Geisler HS, et al. Inflammatory mediators potentiate ATP-gated channels through the P2X(3) subunit. J Biol Chem 2001;276:21077–21082. Ford AP, Gever JR, Nunn PA, et al. Purinoceptors as therapeutic targets for lower urinary tract dysfunction. Br J Pharmacol 2006;147:S132–143. Morenilla-Palao C, Planells-Cases R, Garcı´a-Sanz N, Ferrer-Montiel A. Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity. J Biol Chem 2004;279:25665–25672. Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalininduced pain. Pain 2004;107:125–133. Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg 2003;97:1108–1116. Liu YC, Fuh JL, Chen RC, Lin KP, Wang SJ. Botulinum toxin type A in the prophylactic treatment of transformed migraine in Taiwanese patients: a review of 30 consecutive cases. J Chin Med Assoc 2007;70:535–540. Lew HL, Lee EH, Castaneda A, Klima R, Date E. Therapeutic use of botulinum toxin type A in treating neck and upper-back pain of myofascial origin: a pilot study. Arch Phys Med Rehabil 2008;89:75–80. Babcock MS, Foster L, Pasquina P, Jabbari B. Treatment of pain attributed to plantar fasciitis with botulinum toxin A: a short-term, randomized, placebo-controlled, doubleblind study. Am J Phys Med Rehabil 2005;84:649–654. Mahowald ML, Singh JA, Dykstra D. Long term effects of intra-articular botulinum toxin A for refractory joint pain. Neurotox Res 2006;9:179–188. Zelman DC, Brandenburg NA, Gore M. Sleep impairment in patients with painful diabetic peripheral neuropathy. Clin J Pain 2006;22:681–685.

Neurology 72 28, 2009 Downloaded fromApril www.neurology.org at MEMORIAL HOSPITAL on February 25, 2010

including high-resolution figures, can be found at: http://www.neurology.org/cgi/content/full/72/17/1473

Supplementary Material

Supplementary material can be found at: http://www.neurology.org/cgi/content/full/01.wnl.0000345968.059 59.cf/DC1

Subspecialty Collections

This article, along with others on similar topics, appears in the following collection(s): All Clinical Neurology http://www.neurology.org/cgi/collection/all_clinical_neurology Endocrine http://www.neurology.org/cgi/collection/endocrine Peripheral neuropathy http://www.neurology.org/cgi/collection/peripheral_neuropathy All Clinical trials http://www.neurology.org/cgi/collection/all_clinical_trials Neuropathic pain http://www.neurology.org/cgi/collection/neuropathic_pain

Permissions & Licensing

Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.neurology.org/misc/Permissions.shtml

Reprints

Information about ordering reprints can be found online: http://www.neurology.org/misc/reprints.shtml

Downloaded from www.neurology.org at MEMORIAL HOSPITAL on February 25, 2010