Neuromodulation: Technology at the Neural Interface Received: August 21, 2013
Revised: December 26, 2013
Accepted: January 22, 2014
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12166
Spinal Cord Stimulation for Visceral Pain— A Novel Approach Ganesan Baranidharan, FRCA, FFPMRCA*; Karen H. Simpson, FRCA, FFPMRCA*; Karthikeyan Dhandapani, FRCA, FFPMRCA, DA† Background: Spinal cord stimulation and dorsal column stimulation have been used successfully in the management of visceral pain for many years. A novel technique of ventral column stimulation has been used in our institute with good outcomes since 2007. We describe a retrospective series of 26 patients with visceral neuropathic pain who were treated with neuromodulation. Methods: Patients with either dermatomal hyperalgesia or sympathetically mediated neuropathic abdominal pain who had been treated with spinal cord stimulation were assessed. An independent observer conducted a face-to-face interview with each patient to collect data including demography, electrode placement, electrode mapping, and outcomes. Results: There was significant reduction in visual analog pain scores from a median 9 at baseline to 4 at 26 months (p ≤ 0.05). Reduction in opioid consumption was very significant from a baseline median oral morphine equivalent of 160 mg to 26 mg (p < 0.001). In addition, quality of life, activities of daily living, and patient global impression of change improved. Conclusion: There is a need to further investigate the use of ventral stimulation for visceral pain syndromes. This would need multicenter trials to collect adequate numbers of patients to allow hypothesis testing to underpin recommendations for future evidence-based therapies. Keywords: Abdominal pain, spinal column stimulation, ventral column stimulation, visceral pain Conflict of Interest: Dr. Ganesan Baranidharan has received honoraria and has a consultancy agreement with the following device companies: Nevro Corp, St. Jude Medical, Spinal Modulation. He is part of Pallium Research Group, which receives funding from both pharmaceutical and device companies for support. Dr. K H Simpson has received honoraria from PharmaLink, Inc., Grunenthal GmbH, Napp Pharmaceuticals, Pfizer, and Astellas Pharma for lectures at conferences, attending advisory boards, contributing to publications, and supporting professional development, for example, attendance at meetings. She is a founding member of the Leeds Pallium Research Group, which has received research funding from medical device and pharmaceutical companies to support the research group. Dr. K Dhandapani has no conflict of interest to declare.
INTRODUCTION Chronic abdominal pain is a common complaint in primary care and in certain specialist clinics. The estimated incidence is 22.9 per 1000 persons per year. A cross-sectional survey reported this problem in 25% of the adult population (1). Most of these patients go on to develop functional gastrointestinal disorders such as irritable bowel syndrome or functional dyspepsia. An epidemiological Danish study showed a female preponderance; nearly 43% tended to have natural reduction in symptoms by 5 years (2). Disorders of internal organs such as stomach, kidney, pancreas, liver, bowel, and pelvic organs cause visceral pain. Various mechanisms are implicated, such as inflammation, distention, ischemia, that lead to pain and nausea. The pain is the result of activation of sensory afferents from the internal organs and has five important clinical characteristics (3):
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Address correspondence to: Ganesan Baranidharan, FRCA, FFPMRCA, Leeds Teaching Hospitals NHS Trust, Leeds Pain and Neuromodulation Centre, Seacroft Hospital, D Ward, Seacroft Hospital, York Road, Leeds LS14 6UH, UK. Email: [email protected] * Leeds Pain and Neuromodulation Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK; and † Anaesthesia, George Eliot Hospital, Nuneaton, UK For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1
© 2014 International Neuromodulation Society
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It may not be evoked from all visceral organs as not all are innervated by sensory receptors or possibly because of the lack of an appropriate nociceptive stimulus. It is not always linked to injury, hence the non-structural or functional properties of visceral pain.
It is referred to the body wall; this may be explained by the central convergence of visceral and somatic inputs. It is diffuse and poorly localized, a possible consequence of the relative paucity of peripheral afferent fiber terminals in the viscera compensated for by the central rostrocaudal intraspinal arborization of visceral afferents. It is often accompanied by accentuated motor and autonomic reflexes, which are considered a reaction to a warning system.
BARANIDHARAN ET AL. The management of pain in this group of patients is difficult because of the nature of the condition. They tend to have a constant background pain with acute exacerbations depending on their problem. This pattern is seen in chronic pancreatitis, irritable bowel syndrome, Crohn’s disease, and ulcerative colitis; there also may be cutaneous manifestations of neuropathic pain. Neuromodulation has been used successfully in managing visceral pain (4–9). Stimulation also is used in motility disorders of the gastrointestinal tract (10). The cases series by Khan et al. and Kapural et al. showed that dorsal column stimulation (DCS) significantly reduced pain scores and decreased opioid consumption. In our institution, we have used spinal column stimulation (SCS) to manage visceral neuropathic pain. This cases series explains our patient selection criteria and the results of our novel technique of ventral column stimulation.
METHODS In the Leeds Pain and Neuromodulation Centre, patients with visceral neuropathic pain have been managed with SCS since 1995. This study used an independent observer to retrospectively review our patients after local institute audit registration. Data collection included age, gender, demographics, duration and area of pain, diagnosis, type of pain, response to sympathetic block, referred dermal hyperalgesia, visual analog scale (VAS) changes, pre- and post-opioid and anti-neuropathic drug usage, patient global impression of change, and return to work. SCS electrode details were recorded; ventral electrode stimulation was mapped on each contact at our programming clinic to determine the best anatomical target area for ventral stimulation. The implanted pulse generator power requirements were noted. Patient Selection Our patient selection was based on finding dermatomal allodynia or hyperalgesia consistent with the area of pain (suggesting neuropathic pain) and/or a 50% or greater reduction in pain after coeliac plexus block (suggesting a sympathetically mediated pain). Most patients needed a complex multidisciplinary approach involving a pain clinician, gastroenterologist, surgeon, psychologist, specialist nurses, and occasionally, liaison psychiatrist. Kapural et al. emphasized the importance of coeliac plexus block in patient selection and placing the SCS electrode on the posterior column in his case series (9). We placed our electrodes ventrally at T9/10 for upper abdominal pain and at T10/11–T11/12 for lower abdomen pain. The programming started with a very narrow pulse width (50–182 msec), and we used frequencies from 10–50 Hz. Any increase in pulse width can stimulate the ventral fibers resulting in unwanted muscle spasms. Some patients did get paresthesia stimulation as low as 1 mA. There is a need to use a slow increase in strength of stimulation to avoid painful paresthesia. Once paresthesia is satisfactory, we increase the pulse width to check for muscle contraction or spasm. If this occurs with slight increase in pulse width, the electrodes should be moved more medially. Our patients use their SCS as required. Most of them use this constantly other than at sleep in the DCS group. The stimulation makes the acute episodes painful, and the patients need to switch the stimulator. Patients reported that it reduces the acute exacerbations.
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Ventral Electrode Placement The epidural entry was as lateral as possible with 20–30 degrees angle to the skin. The electrodes were then passed anterior with the www.neuromodulationjournal.com
Figure 1. Tuohy needle entry to the lateral epidural space with the bevel facing the nerve root and the electrode in position. This electrode can have two programs to control the entire upper abdomen as it crosses the midline.
Figure 2. Lateral view showing the electrode in the ventral epidural space.
aid of a curved tip introducer and a rotation away from the midline on electrode advancement with bevel of the Tuohy needle facing laterally. Care was taken when the electrode tip came close to the nerve root (Figs. 1 and 2). We described and analyzed the data using nonparametric measures in view of the small group size and non-normal distribution of
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Neuromodulation 2014; 17: 753–758
NEW APPROACH: VENTRAL COLUMN STIMULATION
Table 1. Characteristics of Patients Using Spinal Column Stimulation for Visceral Pain. Age
Sex
Electrode
Diagnosis
Years of pain
Pain location
Type of pain
Response to sympathetic block
Dermatomal changes
Duration FU
49 45 74 80 24 37
F F M F M F
Ventral Ventral Ventral Ventral Ventral Ventral
6 5 14 25 7 8
RUQ LLQ RUQ, LUQ diffuse RUQ, LUQ diffuse RLQ RLQ
Mixed Neuropathic Neuropathic Neuropathic Mixed Mixed
Y Y NK ND Y ND
NR Y Y Y N NR
9 26 16 50 27 24
36 53 54 50 40 75 37 56 59 58 56 46 24 24 39 63 52 30 46 60
M F F M M M F F M M M M M M M F F F M F
Ventral Ventral Dorsal Dorsal Dorsal Dorsal Dorsal Dorsal Dorsal Dorsal Dorsal Ventral Ventral Ventral Ventral Ventral Ventral Ventral Ventral Dorsal
Post cholecystectomy Crohn’s disease Pancreatitis Post gastric bypass complication IBD Adhesions (appendix, bowel obstruction) Pancreatitis Post Nissens surgery Gall bladder/IBD Other Other Pancreatitis UC operated Post Oopherectomy Pancreatitis Other Post Nissens surgery Renal calculi Renal calculi—congenital Pancreatitis Pancreatitis IBD Unknown Unknown Liver pathology Liver pathology
9 6 9 20 11 16 6 16 15 10 15 NK 16 4 9 NK
LUQ EPI RUQ, LLQ LUQ RUQ UMB LUQ, LLQ LLQ UMB RLQ EPI Renal angle Renal angle RUQ LUQ LLQ and RLQ EPI EPI RUQ RUQ
Neuropathic Neuropathic Mixed Mixed Neuropathic Neuropathic Neuropathic Neuropathic Mixed Neuropathic Nociceptive Nociceptive Neuropathic Neuropathic Neuropathic Neuropathic Neuropathic Neuropathic Neuropathic Mixed
Y Y ND NK ND NK Y ND ND ND ND NK Y Y Y Y NK Y Y NK
Y Y Y NR Y NR Y Y Y Y NR NR Y Y NR Y NR Y Y NK
25 9 53 45 69 75 20 49 30 46 101 20 19 24 NK 48 18 12 NK NK
NK NK NK
EPI, epigastric; FU, follow up; IBD, inflammatory bowel disease; LLQ, left lower quadrant; LUQ, left upper quadrant; N, no; ND, not done; NK, not known; NR, not recorded; Post, posterior; RLQ, right lower quadrant; RUQ, right upper quadrant; UC, ulcerative colitis; UMB, umbilical; Y, yes.
some values. We used Mann–Whitney U-test for analysis; we calculated the Z score for normally distributed data. Graphs were produced using standard packages.
RESULTS
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Data were available from 26 patients with severe visceral pain who had an SCS implant in our unit prior to September 2011. Four patients failed the trial and did not have an implant. One patient, even though had a successful trial with ventral stimulation, preferred to have splanchnic radio frequency as he was not keen on implanted devices. Two patients failed both ventral and DCS, and one failed DCS. There were 14 men and 12 women with a median age 50 (range 24–80) years, who had suffered abdominal pain for a median 11 (range 4–25) years. The diagnosis, type, and location of pain varied (Table 1). There was a median 26 (range 9–101) months follow-up at the time of assessment. SCS electrodes were placed ventrally from 2007 onward; initial success in getting electrodes to the ventral space varied. We have 10 patients with dorsal column electrodes and 16 with ventral placements. Five patients were explanted in total. One was secondary to infection and another one had frequent falls causing device-related complications. Three eventually did not need the stimulator (ventral electrodes) as their pain came under control after a period of stimulation, which ranged from 18 months to 5 years. There was no cor-
relation between these three patients. The diagnosis included nonalcoholic pancreatitis and postsurgical and unknown cause. All had dermatomal hyperalgesia and two responded well to sympathetic block, with this not been done on the third patient. The first ventral column SCS patient had 50 months therapy and was then explanted as her pain had settled. The visual analog scores and opioid consumption data were available for 21 patients. The preimplant VAS score was median (interquartile range (IQR)) 9 (1) and the postimplant score was median (IQR) 4 (2.5); (Z = 5.53, p ≤ 0.05). The median (IQR) morphine equivalent dose before SCS was 160 (250) mg and the median (IQR) postimplant dose was 26 (108) mg (Z = 3.5, p < 0.001). There was an overall 75% reduction in anti-neuropathic drug such as amitriptyline, gabapentin, and pregabalin consumption postimplant (N = 15). One patient required an increase in pregabalin from 150 mg to 600 mg. Nine of 15 patients totally stopped all anti-neuropathic drugs. There was a statistically significant improvement in patient global impression of change (Z = −5.2, p < 0.05). Quality of life including daily activities (Z = −3.1, p < 0.05) and mood (Z = −2.3, p < 0.05) both significantly improved. There was no significant change in sleep (Z = −1.8, p = 0.06) (Figs. 3 and 4). There was no difference in VAS scores for dorsal and ventral group. Four of the ventral patients were trialed with both and had preferred the ventral electrode. We also converted some dorsal patients to ventral electrodes on revision surgery for electrode problems. We have not compared the groups due to small group size and the above reasons. The ventral stimulation group had much
BARANIDHARAN ET AL.
Table 2. Stimulation Parameters for Dorsal and Ventral Stimulation.
Ventral (N = 11) Dorsal (N = 9)
PW
Freq
Amp
76 (100) 300 (170)
20 (25) 50 (17.5)
2 (4.7) 9.5 (5)
All values are expressed in median and interquartile ratio. Amp, amplitude in milliamperes; Freq, frequency in hertz; PW, pulse width in microseconds.
Figure 3. Visual analog scale (VAS) in 21 patients showing a significant reduction from baseline scores (p ≤ 0.05). FU, follow up; IQR, interquartile range.
Figure 4. Decrease of opioid use in 21 patients showing a significant reduction compared with the baseline (p < 0.001). FU, follow up; IQR, interquartile range.
lower current requirements compared with the dorsal group. This is explained by the cerebrospinal thickness in dorsal and ventral space. The ventral group was able to use SCS during sleep, as there was little positional effect on paresthesia. Two patients had muscle spasm with stimulation but still continued to use their SCS, as pain relief was good. The spasms settled with alterations in frequency (Table 2).
DISCUSSION
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We describe a novel approach in stimulating the ventral column for managing visceral pain. These patients all had previous multiple investigations and treatments in various different hospitals. They were all taking large doses of opioid and anti-neuropathic drugs before neuromodulation was attempted. Dorsal column electrodes are normally placed around T5/6 to get appropriate paresthesia coverage. Cerebrospinal fluid is thickest at this level (11). Energy requirements are high, as the current has to travel across a thick www.neuromodulationjournal.com
cerebrospinal fluid layer. Patients find that continuous use during the night is a problem as the stimulation intensity changes with pressure and posture. We noticed that this is a problem with dorsal electrodes. Campbell noted that “stimulation of the anterolateral quadrant contralateral to the side of pain may require less current for pain control than stimulation with electrodes over the posterior cord” (12). Our electrode placement in the ventral space achieved paresthesia only on the ipsilateral side. A contralateral placement was not tried, as we expected that paresthesia into the pain area is required to achieve pain relief. Noxious stimuli travel from peripheral nerves to dorsal root ganglia to reach the dorsal horn of spinal cord. Fibers decussate to travel up the spinothalamic tracts. Visceral nociception is modulated through lateral spinothalamic tract and postsynaptic dorsal column pathway (13). Most past studies were designed to prove the effect of stimulation in the dorsal column to provide visceral analgesia. However, the sympathetic efferent is very close to the ventral column so this also could contribute to the success of the therapy as small group of our patients had responded positively to coeliac plexus block before neuromodulation (14,15). To increase our understanding of the physiology of stimulation in our patients, we performed a blinded measurement of mesenteric blood flow with carotid flow as a control in two thin patients with and without stimulation after a 12-hour fast. Unfortunately, the results varied. Based on this, we decided that mesenteric blood flow can be affected by so many factors, and it is unsuitable for measuring sympathetic function in this situation (16). Ness carried out animal studies looking at visceral pain pathways. He showed that “visceromotor responses to colorectal distention were maintained in rats with dorsal midline lesions but absent in rats with bilateral lateral lesions. Since the visceromotor reflex is known to involve spino-bulbo-spinal circuitry, it is not known whether the lateral lesions were affecting ascending or descending pathways or both.” His study supports other evidence that visceral nociceptive information ascends in the spinal cord by both dorsal midline and lateral spinal pathways (17). We know that placing electrodes ventrally can activate normal structures that cannot be activated by DCS, for example, ventral roots, lateral corticospinal tract, and ventral spinothalamic tract (18). There also are descending pain pathways that are very difficult to stimulate using a dorsal electrode, for example, dorsal fasciculus (Lissauer’s tract). Visceral pain pathways converge to the spinal column via the dorsal root ganglion (DRG), and this could be a very good target for managing visceral neuropathic pain (19). Animal studies have shown the existence of gap junctions in the DRG that persist even after the inflammation in the colon has settled. This could explain some of the complexity in managing visceral pain (20). DRG stimulation is used to treat dermatomal neuropathic pain. Ventral electrodes are placed at T9/10 and this might affect the DRG. We performed DRG stimulation for a patient with pancreatitis and a
© 2014 International Neuromodulation Society
Neuromodulation 2014; 17: 753–758
NEW APPROACH: VENTRAL COLUMN STIMULATION We performed an N of 1 trial on four patients, where anterior electrodes were considered far superior than posterior during their trial period. It has been reported that electrodes placed anterior were superior to posterior even though both helped to relieve pain (21,22). Quality of life changes, the ability to use continuously at night along, and reduced current requirements make ventral stimulation a good alternative for those with visceral pain. Initial failure of neuromodulation was in patients with opioidseeking behaviors and lack of response to sympathetic blocks. Since then we have been strict in selecting only those patients with dermatomal hyperalgesia and/or who responded to sympathetic block. We strongly recommend multidisciplinary approach to avoid selecting unsuitable patients. However, patients taking large doses of opioids, for example, morphine equivalent of 720 mg, are not always unsuitable, as we have found very rapid dose reduction to be possible once stimulation has been established. In conclusion, our series has shown a new area within the spinal column that can be stimulated for management of visceral neuropathic pain. We also postulate that DRG stimulation might have a role in visceral neuromodulation in the future. Patient selection is paramount and future randomized studies are needed to determine the relationship between success of therapy and the parameters we have found to be important, that is, dermatomal hyperalgesia and response to sympathetic block. Figure 5. A ventral electrode seen with two dorsal root ganglion (DRG) electrodes in place. The DRG electrodes achieved same stimulation, with less movement-related increase in paresthesia.
Authorship Statement Dr. Baranidharan developed the technique, performed the cases, and wrote the manuscript. Dr. Simpson trained with the new technique, performed the manuscript, and made the appropriate revisions to the manuscript. Dr. Dhandapani independently assessed the follow-up of the patients and contributed to the manuscript.
How to Cite this Article: Baranidharan G., Simpson K.H., Dhandapani K. 2014. Spinal Cord Stimulation for Visceral Pain—A Novel Approach. Neuromodulation 2014; 17: 753–758
REFERENCES
Figure 6. Lateral view showing the ventral electrode and the DRG electrodes in position. DRG, dorsal root ganglion.
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patient with liver capsule pain. These patients had a positive ventral electrode trial, but stimulation parameters were too narrow. This led us to try DRG electrodes at T7/8 for pancreatitis and at T10/11 liver pain. This gave better stimulation without the variation in perceived paresthesia. Our ventral electrodes might be having their effect on the DRG (Figs. 5 and 6).
1. Wallander MA, Johansson S, Ruigómez A, García Rodríguez LA. Unspecified abdominal pain in primary care: the role of gastrointestinal morbidity. Int J Clin Pract 2007;61:1663–1670. doi: 10.1111/j.1742-1241.2007.01529.x 2. Kay L, Jørgensen T, Jensen KH. Epidemiology of abdominal symptoms in a random population: prevalence, incidence, and natural history. Eur J Epidemiol 1994;10:559– 566. 3. Al-Chaer ED, Traub RJ. Biological basis of visceral pain: recent developments. Pain 2002;96:221–225. 4. Khan YN, Raza SS, Khan EA. Application of spinal cord stimulation for the treatment of abdominal visceral pain syndromes: case reports. Neuromodulation 2004;8:14– 27. doi: 10.1111/j.1094–7159.2005.05216.x 5. Krames E, Mousad DG. Spinal cord stimulation reverses pain and diarrheal episodes of irritable bowel syndrome: a case report. Neuromodulation 2004;7:82–88. doi: 10.1111/j.1094–7159.2004.04011.x 6. Kim JK, Hong SH, Kim M-H, Lee J-K. Spinal cord stimulation for intractable visceral pain due to chronic pancreatitis. J Korean Neurosurg Soc 2009;46:165–167. doi: 10.3340/jkns.2009.46.2.165 7. Kapur S, Mutagi H, Raphael J. Spinal cord stimulation for relief of abdominal pain in two patients with familial Mediterranean fever. Br J Anaesth 2006;97:866–868. doi: 10.1093/bja/ael279 8. Kapural L, Narouze SN, Janicki TI, Mekhail N. Spinal cord stimulation is an effective treatment for the chronic intractable visceral pelvic pain. Pain Med 2009;7:440–443. doi: 10.1111/j.1526–4637.2006.00165.x 9. Kapural L, Nagem H, Tlucek H, Sessler DI. Spinal cord stimulation for chronic visceral abdominal pain. Pain Med 2010;11:347–355. doi: 10.1111/j.1526–4637.2009.00785.x
BARANIDHARAN ET AL. 10. Sevcencu C. A review of electrical stimulation to treat motility dysfunctions in the digestive tract: effects and stimulation patterns. Neuromodulation 2007;10:85–99. doi: 10.1111/j.1525-1403.2007.00097.x 11. Struijk JJ, Holsheimer J, Barolat G, He J, Boom HBK. Paresthesia thresholds in spinal cord stimulation: a comparison of theoretical results with clinical data. IEEE Trans Rehab Eng 1993;1:101–108. doi: 10.1109/86.242424 12. Campbell J. Examination of possible mechanisms by which stimulation of the spinal cord in man relieves pain. Appl Neurophysiol 1981;44:181–186. 13. Krames ES, Foreman R. Spinal cord stimulation modulates visceral nociception and hyperalgesia via the spinothalamic tracts and the postsynaptic dorsal column pathways: a literature review and hypothesis. Neuromodulation 2007;10:224–237. doi: 10.1111/j.1525-1403.2007.00112.x 14. Linderoth B, Foreman RD. Physiology of spinal cord stimulation: review and update. Neuromodulation 1999;2:150–164. doi: 10.1046/j.1525-1403.1999.00150.x 15. Linderoth B, Foreman RD. Mechanisms of spinal cord stimulation in painful syndromes: role of animal models. Pain Med 2007;7 (s1):S14–S26. 16. Healy DA, Neumyer MM, Atnip RG, Thiele BL. Evaluation of celiac and mesenteric vascular disease with duplex ultrasonography. J Ultrasound Med 1992;11:481–485. 17. Ness TJ. Evidence for ascending visceral nociceptive information in the dorsal midline and lateral spinal cord. Pain 2000;87:83–88. 18. Holsheimer J. Which neuronal elements are activated directly by spinal cord stimulation. Neuromodulation 2002;5:25–31. doi: 10.1046/j.1525-1403.2002._2005.x 19. Devor M. Unexplained peculiarities of the dorsal root ganglion. Pain 1999; Suppl. 6:S27–S35. 20. Huang T-Y, Belzer V, Hanani M. Gap junctions in dorsal root ganglia: possible contribution to visceral pain. Eur J Pain 2010;14:49. doi: 10.1016/j.ejpain.2009.02.005; e1–49.e11. 21. Larson SJ, Sances A, Cusick JF, Meyer GA. A comparison between anterior and posterior spin . . . Surg Neurol 1975;4(1):180–186. 22. Hoppenstein R. Electrical stimulation of the ventral and dorsal . . . Surg Neurol 1975;4(1):187–194.
COMMENT As the authors point out, chronic abdominal visceral pain is common and there are a variety of functional diagnoses associated with these symptoms. The spinal cord’s cross sectional representation of input from the viscera significantly exceeds that of somatic input. The large variety of different tracts and their functional role in the spinal cord suggest there may be many new targets for relief of pain. The notion that effective spinal cord stimulation for pain always requires a dorsal column target is obsolete. This case series is one example of these advances in our treatment options for this difficult to treat population. Larger studies are needed to confirm these results. Furthermore, with all the treatment options available, studies are also needed to clarify the position of this therapy in existing treatment paradigms. Edgar Ross, MD Boston, MA, USA
Comments not included in the Early View version of this paper.
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Neuromodulation 2014; 17: 753–758
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Revised: December 26, 2013
Accepted: January 22, 2014
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12166
Spinal Cord Stimulation for Visceral Pain— A Novel Approach Ganesan Baranidharan, FRCA, FFPMRCA*; Karen H. Simpson, FRCA, FFPMRCA*; Karthikeyan Dhandapani, FRCA, FFPMRCA, DA† Background: Spinal cord stimulation and dorsal column stimulation have been used successfully in the management of visceral pain for many years. A novel technique of ventral column stimulation has been used in our institute with good outcomes since 2007. We describe a retrospective series of 26 patients with visceral neuropathic pain who were treated with neuromodulation. Methods: Patients with either dermatomal hyperalgesia or sympathetically mediated neuropathic abdominal pain who had been treated with spinal cord stimulation were assessed. An independent observer conducted a face-to-face interview with each patient to collect data including demography, electrode placement, electrode mapping, and outcomes. Results: There was significant reduction in visual analog pain scores from a median 9 at baseline to 4 at 26 months (p ≤ 0.05). Reduction in opioid consumption was very significant from a baseline median oral morphine equivalent of 160 mg to 26 mg (p < 0.001). In addition, quality of life, activities of daily living, and patient global impression of change improved. Conclusion: There is a need to further investigate the use of ventral stimulation for visceral pain syndromes. This would need multicenter trials to collect adequate numbers of patients to allow hypothesis testing to underpin recommendations for future evidence-based therapies. Keywords: Abdominal pain, spinal column stimulation, ventral column stimulation, visceral pain Conflict of Interest: Dr. Ganesan Baranidharan has received honoraria and has a consultancy agreement with the following device companies: Nevro Corp, St. Jude Medical, Spinal Modulation. He is part of Pallium Research Group, which receives funding from both pharmaceutical and device companies for support. Dr. K H Simpson has received honoraria from PharmaLink, Inc., Grunenthal GmbH, Napp Pharmaceuticals, Pfizer, and Astellas Pharma for lectures at conferences, attending advisory boards, contributing to publications, and supporting professional development, for example, attendance at meetings. She is a founding member of the Leeds Pallium Research Group, which has received research funding from medical device and pharmaceutical companies to support the research group. Dr. K Dhandapani has no conflict of interest to declare.
INTRODUCTION Chronic abdominal pain is a common complaint in primary care and in certain specialist clinics. The estimated incidence is 22.9 per 1000 persons per year. A cross-sectional survey reported this problem in 25% of the adult population (1). Most of these patients go on to develop functional gastrointestinal disorders such as irritable bowel syndrome or functional dyspepsia. An epidemiological Danish study showed a female preponderance; nearly 43% tended to have natural reduction in symptoms by 5 years (2). Disorders of internal organs such as stomach, kidney, pancreas, liver, bowel, and pelvic organs cause visceral pain. Various mechanisms are implicated, such as inflammation, distention, ischemia, that lead to pain and nausea. The pain is the result of activation of sensory afferents from the internal organs and has five important clinical characteristics (3):
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Address correspondence to: Ganesan Baranidharan, FRCA, FFPMRCA, Leeds Teaching Hospitals NHS Trust, Leeds Pain and Neuromodulation Centre, Seacroft Hospital, D Ward, Seacroft Hospital, York Road, Leeds LS14 6UH, UK. Email: [email protected] * Leeds Pain and Neuromodulation Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK; and † Anaesthesia, George Eliot Hospital, Nuneaton, UK For more information on author guidelines, an explanation of our peer review process, and conflict of interest informed consent policies, please go to http:// www.wiley.com/bw/submit.asp?ref=1094-7159&site=1
© 2014 International Neuromodulation Society
Neuromodulation 2014; 17: 753–758
753
It may not be evoked from all visceral organs as not all are innervated by sensory receptors or possibly because of the lack of an appropriate nociceptive stimulus. It is not always linked to injury, hence the non-structural or functional properties of visceral pain.
It is referred to the body wall; this may be explained by the central convergence of visceral and somatic inputs. It is diffuse and poorly localized, a possible consequence of the relative paucity of peripheral afferent fiber terminals in the viscera compensated for by the central rostrocaudal intraspinal arborization of visceral afferents. It is often accompanied by accentuated motor and autonomic reflexes, which are considered a reaction to a warning system.
BARANIDHARAN ET AL. The management of pain in this group of patients is difficult because of the nature of the condition. They tend to have a constant background pain with acute exacerbations depending on their problem. This pattern is seen in chronic pancreatitis, irritable bowel syndrome, Crohn’s disease, and ulcerative colitis; there also may be cutaneous manifestations of neuropathic pain. Neuromodulation has been used successfully in managing visceral pain (4–9). Stimulation also is used in motility disorders of the gastrointestinal tract (10). The cases series by Khan et al. and Kapural et al. showed that dorsal column stimulation (DCS) significantly reduced pain scores and decreased opioid consumption. In our institution, we have used spinal column stimulation (SCS) to manage visceral neuropathic pain. This cases series explains our patient selection criteria and the results of our novel technique of ventral column stimulation.
METHODS In the Leeds Pain and Neuromodulation Centre, patients with visceral neuropathic pain have been managed with SCS since 1995. This study used an independent observer to retrospectively review our patients after local institute audit registration. Data collection included age, gender, demographics, duration and area of pain, diagnosis, type of pain, response to sympathetic block, referred dermal hyperalgesia, visual analog scale (VAS) changes, pre- and post-opioid and anti-neuropathic drug usage, patient global impression of change, and return to work. SCS electrode details were recorded; ventral electrode stimulation was mapped on each contact at our programming clinic to determine the best anatomical target area for ventral stimulation. The implanted pulse generator power requirements were noted. Patient Selection Our patient selection was based on finding dermatomal allodynia or hyperalgesia consistent with the area of pain (suggesting neuropathic pain) and/or a 50% or greater reduction in pain after coeliac plexus block (suggesting a sympathetically mediated pain). Most patients needed a complex multidisciplinary approach involving a pain clinician, gastroenterologist, surgeon, psychologist, specialist nurses, and occasionally, liaison psychiatrist. Kapural et al. emphasized the importance of coeliac plexus block in patient selection and placing the SCS electrode on the posterior column in his case series (9). We placed our electrodes ventrally at T9/10 for upper abdominal pain and at T10/11–T11/12 for lower abdomen pain. The programming started with a very narrow pulse width (50–182 msec), and we used frequencies from 10–50 Hz. Any increase in pulse width can stimulate the ventral fibers resulting in unwanted muscle spasms. Some patients did get paresthesia stimulation as low as 1 mA. There is a need to use a slow increase in strength of stimulation to avoid painful paresthesia. Once paresthesia is satisfactory, we increase the pulse width to check for muscle contraction or spasm. If this occurs with slight increase in pulse width, the electrodes should be moved more medially. Our patients use their SCS as required. Most of them use this constantly other than at sleep in the DCS group. The stimulation makes the acute episodes painful, and the patients need to switch the stimulator. Patients reported that it reduces the acute exacerbations.
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Ventral Electrode Placement The epidural entry was as lateral as possible with 20–30 degrees angle to the skin. The electrodes were then passed anterior with the www.neuromodulationjournal.com
Figure 1. Tuohy needle entry to the lateral epidural space with the bevel facing the nerve root and the electrode in position. This electrode can have two programs to control the entire upper abdomen as it crosses the midline.
Figure 2. Lateral view showing the electrode in the ventral epidural space.
aid of a curved tip introducer and a rotation away from the midline on electrode advancement with bevel of the Tuohy needle facing laterally. Care was taken when the electrode tip came close to the nerve root (Figs. 1 and 2). We described and analyzed the data using nonparametric measures in view of the small group size and non-normal distribution of
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NEW APPROACH: VENTRAL COLUMN STIMULATION
Table 1. Characteristics of Patients Using Spinal Column Stimulation for Visceral Pain. Age
Sex
Electrode
Diagnosis
Years of pain
Pain location
Type of pain
Response to sympathetic block
Dermatomal changes
Duration FU
49 45 74 80 24 37
F F M F M F
Ventral Ventral Ventral Ventral Ventral Ventral
6 5 14 25 7 8
RUQ LLQ RUQ, LUQ diffuse RUQ, LUQ diffuse RLQ RLQ
Mixed Neuropathic Neuropathic Neuropathic Mixed Mixed
Y Y NK ND Y ND
NR Y Y Y N NR
9 26 16 50 27 24
36 53 54 50 40 75 37 56 59 58 56 46 24 24 39 63 52 30 46 60
M F F M M M F F M M M M M M M F F F M F
Ventral Ventral Dorsal Dorsal Dorsal Dorsal Dorsal Dorsal Dorsal Dorsal Dorsal Ventral Ventral Ventral Ventral Ventral Ventral Ventral Ventral Dorsal
Post cholecystectomy Crohn’s disease Pancreatitis Post gastric bypass complication IBD Adhesions (appendix, bowel obstruction) Pancreatitis Post Nissens surgery Gall bladder/IBD Other Other Pancreatitis UC operated Post Oopherectomy Pancreatitis Other Post Nissens surgery Renal calculi Renal calculi—congenital Pancreatitis Pancreatitis IBD Unknown Unknown Liver pathology Liver pathology
9 6 9 20 11 16 6 16 15 10 15 NK 16 4 9 NK
LUQ EPI RUQ, LLQ LUQ RUQ UMB LUQ, LLQ LLQ UMB RLQ EPI Renal angle Renal angle RUQ LUQ LLQ and RLQ EPI EPI RUQ RUQ
Neuropathic Neuropathic Mixed Mixed Neuropathic Neuropathic Neuropathic Neuropathic Mixed Neuropathic Nociceptive Nociceptive Neuropathic Neuropathic Neuropathic Neuropathic Neuropathic Neuropathic Neuropathic Mixed
Y Y ND NK ND NK Y ND ND ND ND NK Y Y Y Y NK Y Y NK
Y Y Y NR Y NR Y Y Y Y NR NR Y Y NR Y NR Y Y NK
25 9 53 45 69 75 20 49 30 46 101 20 19 24 NK 48 18 12 NK NK
NK NK NK
EPI, epigastric; FU, follow up; IBD, inflammatory bowel disease; LLQ, left lower quadrant; LUQ, left upper quadrant; N, no; ND, not done; NK, not known; NR, not recorded; Post, posterior; RLQ, right lower quadrant; RUQ, right upper quadrant; UC, ulcerative colitis; UMB, umbilical; Y, yes.
some values. We used Mann–Whitney U-test for analysis; we calculated the Z score for normally distributed data. Graphs were produced using standard packages.
RESULTS
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Data were available from 26 patients with severe visceral pain who had an SCS implant in our unit prior to September 2011. Four patients failed the trial and did not have an implant. One patient, even though had a successful trial with ventral stimulation, preferred to have splanchnic radio frequency as he was not keen on implanted devices. Two patients failed both ventral and DCS, and one failed DCS. There were 14 men and 12 women with a median age 50 (range 24–80) years, who had suffered abdominal pain for a median 11 (range 4–25) years. The diagnosis, type, and location of pain varied (Table 1). There was a median 26 (range 9–101) months follow-up at the time of assessment. SCS electrodes were placed ventrally from 2007 onward; initial success in getting electrodes to the ventral space varied. We have 10 patients with dorsal column electrodes and 16 with ventral placements. Five patients were explanted in total. One was secondary to infection and another one had frequent falls causing device-related complications. Three eventually did not need the stimulator (ventral electrodes) as their pain came under control after a period of stimulation, which ranged from 18 months to 5 years. There was no cor-
relation between these three patients. The diagnosis included nonalcoholic pancreatitis and postsurgical and unknown cause. All had dermatomal hyperalgesia and two responded well to sympathetic block, with this not been done on the third patient. The first ventral column SCS patient had 50 months therapy and was then explanted as her pain had settled. The visual analog scores and opioid consumption data were available for 21 patients. The preimplant VAS score was median (interquartile range (IQR)) 9 (1) and the postimplant score was median (IQR) 4 (2.5); (Z = 5.53, p ≤ 0.05). The median (IQR) morphine equivalent dose before SCS was 160 (250) mg and the median (IQR) postimplant dose was 26 (108) mg (Z = 3.5, p < 0.001). There was an overall 75% reduction in anti-neuropathic drug such as amitriptyline, gabapentin, and pregabalin consumption postimplant (N = 15). One patient required an increase in pregabalin from 150 mg to 600 mg. Nine of 15 patients totally stopped all anti-neuropathic drugs. There was a statistically significant improvement in patient global impression of change (Z = −5.2, p < 0.05). Quality of life including daily activities (Z = −3.1, p < 0.05) and mood (Z = −2.3, p < 0.05) both significantly improved. There was no significant change in sleep (Z = −1.8, p = 0.06) (Figs. 3 and 4). There was no difference in VAS scores for dorsal and ventral group. Four of the ventral patients were trialed with both and had preferred the ventral electrode. We also converted some dorsal patients to ventral electrodes on revision surgery for electrode problems. We have not compared the groups due to small group size and the above reasons. The ventral stimulation group had much
BARANIDHARAN ET AL.
Table 2. Stimulation Parameters for Dorsal and Ventral Stimulation.
Ventral (N = 11) Dorsal (N = 9)
PW
Freq
Amp
76 (100) 300 (170)
20 (25) 50 (17.5)
2 (4.7) 9.5 (5)
All values are expressed in median and interquartile ratio. Amp, amplitude in milliamperes; Freq, frequency in hertz; PW, pulse width in microseconds.
Figure 3. Visual analog scale (VAS) in 21 patients showing a significant reduction from baseline scores (p ≤ 0.05). FU, follow up; IQR, interquartile range.
Figure 4. Decrease of opioid use in 21 patients showing a significant reduction compared with the baseline (p < 0.001). FU, follow up; IQR, interquartile range.
lower current requirements compared with the dorsal group. This is explained by the cerebrospinal thickness in dorsal and ventral space. The ventral group was able to use SCS during sleep, as there was little positional effect on paresthesia. Two patients had muscle spasm with stimulation but still continued to use their SCS, as pain relief was good. The spasms settled with alterations in frequency (Table 2).
DISCUSSION
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We describe a novel approach in stimulating the ventral column for managing visceral pain. These patients all had previous multiple investigations and treatments in various different hospitals. They were all taking large doses of opioid and anti-neuropathic drugs before neuromodulation was attempted. Dorsal column electrodes are normally placed around T5/6 to get appropriate paresthesia coverage. Cerebrospinal fluid is thickest at this level (11). Energy requirements are high, as the current has to travel across a thick www.neuromodulationjournal.com
cerebrospinal fluid layer. Patients find that continuous use during the night is a problem as the stimulation intensity changes with pressure and posture. We noticed that this is a problem with dorsal electrodes. Campbell noted that “stimulation of the anterolateral quadrant contralateral to the side of pain may require less current for pain control than stimulation with electrodes over the posterior cord” (12). Our electrode placement in the ventral space achieved paresthesia only on the ipsilateral side. A contralateral placement was not tried, as we expected that paresthesia into the pain area is required to achieve pain relief. Noxious stimuli travel from peripheral nerves to dorsal root ganglia to reach the dorsal horn of spinal cord. Fibers decussate to travel up the spinothalamic tracts. Visceral nociception is modulated through lateral spinothalamic tract and postsynaptic dorsal column pathway (13). Most past studies were designed to prove the effect of stimulation in the dorsal column to provide visceral analgesia. However, the sympathetic efferent is very close to the ventral column so this also could contribute to the success of the therapy as small group of our patients had responded positively to coeliac plexus block before neuromodulation (14,15). To increase our understanding of the physiology of stimulation in our patients, we performed a blinded measurement of mesenteric blood flow with carotid flow as a control in two thin patients with and without stimulation after a 12-hour fast. Unfortunately, the results varied. Based on this, we decided that mesenteric blood flow can be affected by so many factors, and it is unsuitable for measuring sympathetic function in this situation (16). Ness carried out animal studies looking at visceral pain pathways. He showed that “visceromotor responses to colorectal distention were maintained in rats with dorsal midline lesions but absent in rats with bilateral lateral lesions. Since the visceromotor reflex is known to involve spino-bulbo-spinal circuitry, it is not known whether the lateral lesions were affecting ascending or descending pathways or both.” His study supports other evidence that visceral nociceptive information ascends in the spinal cord by both dorsal midline and lateral spinal pathways (17). We know that placing electrodes ventrally can activate normal structures that cannot be activated by DCS, for example, ventral roots, lateral corticospinal tract, and ventral spinothalamic tract (18). There also are descending pain pathways that are very difficult to stimulate using a dorsal electrode, for example, dorsal fasciculus (Lissauer’s tract). Visceral pain pathways converge to the spinal column via the dorsal root ganglion (DRG), and this could be a very good target for managing visceral neuropathic pain (19). Animal studies have shown the existence of gap junctions in the DRG that persist even after the inflammation in the colon has settled. This could explain some of the complexity in managing visceral pain (20). DRG stimulation is used to treat dermatomal neuropathic pain. Ventral electrodes are placed at T9/10 and this might affect the DRG. We performed DRG stimulation for a patient with pancreatitis and a
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NEW APPROACH: VENTRAL COLUMN STIMULATION We performed an N of 1 trial on four patients, where anterior electrodes were considered far superior than posterior during their trial period. It has been reported that electrodes placed anterior were superior to posterior even though both helped to relieve pain (21,22). Quality of life changes, the ability to use continuously at night along, and reduced current requirements make ventral stimulation a good alternative for those with visceral pain. Initial failure of neuromodulation was in patients with opioidseeking behaviors and lack of response to sympathetic blocks. Since then we have been strict in selecting only those patients with dermatomal hyperalgesia and/or who responded to sympathetic block. We strongly recommend multidisciplinary approach to avoid selecting unsuitable patients. However, patients taking large doses of opioids, for example, morphine equivalent of 720 mg, are not always unsuitable, as we have found very rapid dose reduction to be possible once stimulation has been established. In conclusion, our series has shown a new area within the spinal column that can be stimulated for management of visceral neuropathic pain. We also postulate that DRG stimulation might have a role in visceral neuromodulation in the future. Patient selection is paramount and future randomized studies are needed to determine the relationship between success of therapy and the parameters we have found to be important, that is, dermatomal hyperalgesia and response to sympathetic block. Figure 5. A ventral electrode seen with two dorsal root ganglion (DRG) electrodes in place. The DRG electrodes achieved same stimulation, with less movement-related increase in paresthesia.
Authorship Statement Dr. Baranidharan developed the technique, performed the cases, and wrote the manuscript. Dr. Simpson trained with the new technique, performed the manuscript, and made the appropriate revisions to the manuscript. Dr. Dhandapani independently assessed the follow-up of the patients and contributed to the manuscript.
How to Cite this Article: Baranidharan G., Simpson K.H., Dhandapani K. 2014. Spinal Cord Stimulation for Visceral Pain—A Novel Approach. Neuromodulation 2014; 17: 753–758
REFERENCES
Figure 6. Lateral view showing the ventral electrode and the DRG electrodes in position. DRG, dorsal root ganglion.
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patient with liver capsule pain. These patients had a positive ventral electrode trial, but stimulation parameters were too narrow. This led us to try DRG electrodes at T7/8 for pancreatitis and at T10/11 liver pain. This gave better stimulation without the variation in perceived paresthesia. Our ventral electrodes might be having their effect on the DRG (Figs. 5 and 6).
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COMMENT As the authors point out, chronic abdominal visceral pain is common and there are a variety of functional diagnoses associated with these symptoms. The spinal cord’s cross sectional representation of input from the viscera significantly exceeds that of somatic input. The large variety of different tracts and their functional role in the spinal cord suggest there may be many new targets for relief of pain. The notion that effective spinal cord stimulation for pain always requires a dorsal column target is obsolete. This case series is one example of these advances in our treatment options for this difficult to treat population. Larger studies are needed to confirm these results. Furthermore, with all the treatment options available, studies are also needed to clarify the position of this therapy in existing treatment paradigms. Edgar Ross, MD Boston, MA, USA
Comments not included in the Early View version of this paper.
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