Neuromodulation: Technology at the Neural Interface Received: February 13, 2015
Revised: April 6, 2015
Accepted: April 22, 2015
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12316
Effects of Spinal Cord Stimulation on Pain Thresholds and Sensory Perceptions in Chronic Pain Patients Shihab U. Ahmed, MBBS, MPH; Yi Zhang, MD, PhD, MS; Lucy Chen, MD; Kristin St. Hillary, BS, RN; Abigail Cohen, BS; Trang Vo, BS; Mary Houghton, BS; Jianren Mao, MD, PhD Objective: Spinal cord stimulation (SCS) has been in clinical use for nearly four decades. In earliest observations, researchers found a significant increase in pain threshold during SCS therapy without changes associated with touch, position, and vibration sensation. Subsequent studies yielded diverse results regarding how SCS impacts pain and other sensory thresholds. This pilot study uses quantitative sensory testing (QST) to objectively quantify the impact of SCS on warm sensation, heat pain threshold, and heat pain tolerance. Materials and Methods: Nineteen subjects with an indwelling SCS device for chronic pain were subjected to QST with heat stimuli. QST was performed on an area of pain covered with SCS-induced paresthesia and an area without pain and without paresthesia, while the SCS was turned off and on. The temperature at which the patient detected warm sensation, heat pain, and maximal tolerable heat pain was used to define the thresholds. Results: We found that all three parameters, the detection of warm sensation, heat pain threshold, and heat pain tolerance, were increased during the period when SCS was on compared with when it was off. This increase was observed in both painful and non-painful sites. Conclusion: The observed pain relief during SCS therapy seems to be related to its impact on increased sensory threshold as detected in this study. The increased sensory threshold on areas without pain and without the presence of SCS coverage may indicate a central (spinal and/or supra-spinal) influence from SCS. Keywords: Pain, quantitative sensory testing (QST), spinal cord stimulation (SCS) Conflict of Interest: The authors report no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this study.
INTRODUCTION
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Address correspondence to: Shihab U. Ahmed, MBBS, MPH, MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 101 Merrimac Street, Suite 610, Boston, MA 02114, USA. Email: sahmed@ partners.org MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 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 Sources of financial support: None.
© 2015 International Neuromodulation Society
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Gate control theory, described by Melzack and Wall, suggests that when large afferent fibers in the dorsal column are stimulated, pain signals carried by the small fibers are blocked at the spinal cord (1). This was a seminal event in pain research and generated enormous enthusiasm for the treatment of difficult pain conditions through stimulation of large fibers at the spinal level. Spinal cord stimulation (SCS) therapy for refractory pain evolved into a direct clinical application based on this theory. Soon thereafter, Shealy et al. reported the implantation of an electrode to the thoracic dorsal column to relieve refractory pain of a cancer patient, which he describes as providing almost complete resolution of pain without involving sensory or motor systems (2). The earliest observation by Shealy and his colleagues found a significant increase in the pain threshold (50 to 250%) during SCS therapy (3). They also found no change on touch, position, and vibration sensations during the SCS. However, subsequent research studies had conflicting findings on how SCS impacts pain and other sensory thresholds. Indeed, we found only seven studies involving human trials that explored the impact of SCS on sensory and pain thresholds even as it has been used in clinical practice for more than
four decades (Table 1) (3–9). Possible reasons for these conflicting findings could be related to variations in placement of the lead (intrathecal vs. epidural) and/or sensory measurement techniques. Further, the scientific basis of how SCS reduces clinical pain remains unaddressed. Until very recently, the common belief was that the “buzzing” sensation (paresthesia) from the electrical stimulation (SCS) was associated with pain relief (10). Questions arose regarding whether pain relief was due to the change of perception (distraction
AHMED ET AL.
Table 1. The Impact of SCS on Sensory and Pain Thresholds During Its Uses for Pain Control. Study
Findings
Shealy et al., 1970 (six patients); [SCS lead placed in intrathecal space]
Pain threshold increased 50–250% from baseline with SCS but with no significant alteration of light touch, position sense, vibration, motor functions, bowel, bladder control, and sexual function (3). No change of subjective ability to perceive pain, touch, proprioception, or vibration, and no impairment of motor function (4). Patients (11/17) showed decreased perception of pain, touch, and joint rotation along with hyperreflexia. Somatosensory-evoked potential was also reduced. All changes returned to a control level one hour after the cessation of SCS (5). Immediate abolishing of spontaneous pain. SCS increased the touch and vibration thresholds but no change in pinch-induced cutaneous pain (6). Increased perception and pain threshold by electrical stimulation only from chronic SCS (at least several weeks), not immediately after SCS (7). Decreased spontaneous clinical pain and increased cutaneous heat pain threshold (8). No effect on warm and cold thresholds and no effect on heat, cold, and pressure pain thresholds (9).
Nashhold and Friedman, 1972 (30 patients); [SCS lead placed in intrathecal space] Larson et al., 1974 (18 cancer patients); [SCS lead placed in intrathecal space]
Lindblom and Meyerson, 1975 (ten patients); [SCS lead placed in intrathecal space] Doerr et al., 1978, (eight patients); [SCS lead placed in intrathecal space] Marchand et al., 1991 (eight patients); [SCS lead placed in epidural space] Kemler et al., 2001 (54 CRPS patients); [SCS lead placed in epidural space]
Here we highlight the location of lead placement, number of subjects, indications, and findings related to sensory and pain thresholds. CRPS, complex regional pain syndrome; SCS, spinal cord stimulation.
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of the mind from pain sensations) on the patient’s part or if there are changes in the processing of pain signals (e.g., change in pain thresholds). Since the publication of the first report on SCS therapy, there has been much advancement in nearly all aspects of SCS therapy. For example, leads now contain 8, 16, and 32 electrodes. The pulse generator technology also improved significantly. We have now rechargeable indwelling pulse generator (IPG). More recently, we have seen the introduction of IPG capable of generating highfrequency stimulation that does not create stimulation-induced paresthesia. Also, the earlier practice of intrathecal electrode placement has been replaced by the epidural implantation of the SCS leads. Clinically, there have been many studies demonstrating the efficacy of SCS therapy for various chronic pain conditions (11–14). However, complications from this procedure remain high, with an average of 35% (15). It is estimated that in 2008, more than 35,000 SCS cases were performed worldwide (16). With newer indications, the number is expected to rise. The estimated initial cost ranges from $21,595 to $57,800, depending on the payer (16). Although success of this mode of therapy has been reported, the associated complications and significant procedural cost strongly indicate prudence in selecting patients with the most potential benefit for this mode of therapy. An additional challenge in this regard is our limited understanding as to how SCS reduces pain. Our hypothesis is that at least one mechanism of action of SCS for clinical pain relief is due to selective modulation of the sensory response to noxious stimulation (e.g., heat). The goal of our study is to collect preliminary data on the impact of SCS on pain and sensory thresholds using a quantitative sensory testing (QST) method (17). We hope that the data from this pilot study will provide the impetus for a larger study to better understand the mechanisms of SCS therapy and thus improve patient selection and patient care. In this pilot study, we used QST to objectively quantify the impact of SCS on warm sensation (WS), heat pain threshold (HPth), and heat pain tolerance (HPto) over the painful area covered by the SCSrelated paresthesia and compare our results with findings of a nonpainful area with the same subject (no SCS-related paresthesia). www.neuromodulationjournal.com
PATIENTS AND METHODS Patients who were currently treated with SCS (for a minimum of four weeks) for chronic pain at the MGH Center Pain Medicine were invited to participate in our institutional review board (IRB)approved protocol. We included subjects aged 18 years or older and those who had an SCS device implanted for at least one month for pain control. The one month requirement was to ensure that the subject is familiar with the therapy and has recovered from the surgical implantation of the SCS device. We excluded patients who have a neurological disease or a condition causing sensory deficit to the painful area, subjects who had recent therapy that may influence QST results such as a neuroablative procedure within two months, and subjects who are unable to travel to the study center. Subjects were contacted via phone and a phone-screen was performed using an IRB-approved checklist that included our inclusion and exclusion criteria. The etiology and location of their pain for the SCS therapy initiation are listed in Table 2. Once a subject was deemed eligible for the study, and if he or she indicated willingness to participate, they were asked to withhold the SCS and their opioid medications for four hours prior to their appointment time. Figure 1 describes the flow of the subject’s visit. On the day of the visit, the study physician (SUA) explained the study and obtained the informed consent. After the subject signed the consent, we performed 1) a brief medical history, including medication use; 2) pain history including intensity, location, character, duration and, if known, the etiology; 3) identified the primary pain site; 4) performed a sensory examination (e.g., alcohol swab, cotton swab, pinprick, and vibration); and 5) recorded the routine vital signs (blood pressure, pulse, pulse oximetry). The painful area of the limb was outlined and marked for the placement of the QST probe. A nonpainful area on the opposite side without the presence of SCSinduced paresthesia was also identified and marked for the placement of the QST probe. We collected two sets of data: the first set while the SCS was off and the second set with the SCS on. After the completion of the first set of QST data, the patient was asked to
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Neuromodulation 2015; 18: 355–360
QUANTITATIVE SENSORY TESTING AND SCS THERAPY
Table 2. The Causes and Locations of Pain for Which SCS Therapy Was Initiated. Subject
Primary pain complaint
How the pain started
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Lower back and leg Left ankle bone and base of tibia Back and leg (mostly right side) Low back and left lower extremity Left lower extremity and right toes Ball of foot Left leg Left foot Back and right leg Left arm and hand Lower back Lower back and left leg Right knee, right ankle, and left leg Lower back and right hip Left lower back, left leg, and left foot Lower back and leg Lower back and leg Lower back and left leg Bilateral distal lower extremity
Injury sustained while in navy Left tibial surgery for sarcoma removal Osteoarthritis in both knees, knee replacement, fracture of right femur Injury sustained from a fall CRPS after foot surgery After foot surgeries CRPS from soccer injury and ankle stabilization surgery (following the injury) CRPS after foot surgery Unknown cause Degenerative condition at cervical spine After a work-related injury After an epidural abscess Injury sustained from a fall on ice After an MVA Pulled back multiple times over the years Unknown cause Injury sustained from a fall FBSS FBSS
CRPS, complex regional pain syndrome; FBSS, failed back surgery syndrome; MVA, motor vehicle accident; SCS, spinal cord stimulation.
Consent History and Physical
QST with SCS Off
Painful area with SCS-paresthesia coverage
Non-painful area on the opposite side, no paresthesia
QST with SCS On
Painful area with SCS-paresthesia coverage
Non-painful area on the opposite side, no paresthesia
Figure 1. Flow diagram of the subject’s visit. QST, quantitative sensory testing; SCS, spinal cord stimulation.
turn the SCS therapy on and we waited for 20 min before initiating the second set of QST (with SCS therapy on). QST QST is a method to assess the psychophysical response to a set of calibrated stimulation (17). In this study, heat stimulation was used in all QST sessions following a protocol detailed in our previous publication (18).
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To Detect HPto A contact thermode was placed at the designated body site. The temperature at the thermode-skin interface rose at 1°C/sec from a baseline of 32°C to a cutoff temperature of 52°C. Subjects were asked to stop stimulation by pressing a computer mouse button when pain was no longer tolerable (i.e., just beyond pain threshold). The stimulation was fully escapable and the subject was able to withdraw from the stimulation at any time. This same test was repeated three times with a three-min interval and the average threshold temperature from the three tests was used as the pain tolerance temperature (in degree Celsius). Statistical Analysis We used paired t-test and Fisher’s exact test in order to compare continuous and categorical outcomes between the study sites. We compared the WS, HPth, and HPto at the two QST sites with the SCS on and off for each subject. We consider 1.2°C in mean temperature to be an important difference between the painful and non-painful sites (18). The statistical package STATA Version 12 (StataCorp LP, College Station, TX, USA) was used for data analysis.
RESULTS Nineteen patients participated and completed the study. Their average age was 53 years (range 29–65 years) and they had, on average, chronic pain for 12 years (range 1.2–42 years). All nineteen
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To Detect WS A contact thermode was placed at a designated body part (e.g., forearm). The subjects were instructed to stop stimulation by pressing a computer mouse button when they first perceived WS as temperature ascended from the neutral temperature (32°C). This same test was repeated three times with a three-min interval and the average WS temperature from the three tests was used as the WS temperature (in degree Celsius).
To Detect HPth A contact thermode was placed at a designated body part. The temperature at the thermode-skin interface rose at 1°C/sec from a baseline of 32°C to a cutoff temperature of 52°C. Subjects were asked to stop stimulation by pressing a computer mouse button when pain was first detected. This same test was repeated three times with a three-min interval and the average threshold temperature from the three tests was used as the pain threshold temperature (in degree Celsius).
AHMED ET AL.
Warm Sensaon Threshold Pain Site
Heat Pain Tolerance Pain Site 51.5
*
* 51
40 39.5 39
On
38.5
Off
38 37.5
Temperature (Celcius)
Temperature (Celcius)
41 40.5
50.5 50
On
49.5
Off
49
37
48.5
36.5
48
Figure 4. Heat pain tolerance thresholds over the painful area while the SCS was off vs. on. SCS, spinal cord stimulation. *p < 0.05.
Heat Pain Threshold Pain Site
Warm Sensaon Threshold Non-Pain Site
49 48.5 48 47.5 47 46.5 46 45.5 45 44.5 44
42
*
*
41
On Off
Temperature (Celcius)
Temperature (Celcius)
Figure 2. Warm sensation thresholds over the painful area while the SCS was off vs. on. SCS, spinal cord stimulation. *p < 0.05.
40 39
On
38
Off
37 36 35
Figure 3. Heat pain thresholds over the painful area while the SCS was off vs. on. SCS, spinal cord stimulation. *p < 0.05.
Figure 5. Warm sensation thresholds over the non-painful area while the SCS was off vs. on. SCS, spinal cord stimulation. *p < 0.05.
subjects were white and 17 self-identified as non-Hispanic. Ten subjects were on disability. Subjects documented both their worst and least mean Visual Analog Scale pain score (0 = no pain and 10 = worst pain imaginable) over the preceding 24 hours as 7.39 ± 2.20 and 3.68 ± 1.95 respectively. They reported their average percent of pain relief while on SCS therapy as 57.78 ± 19.57. We measured the impact of SCS on WS, HPth, and HPto over the painful area covered by SCS-induced paresthesia and compared the same parameters on a non-painful area on the opposite side, without the presence of SCS-induced paresthesia, in each subject. We found that WS, HPth, and HPto were higher on both painful (38.67 vs. 39.87, p = 0.036; 46.52 vs. 47.59, p = 0.009; 50.12 vs. 50.71, p = 0.036) and non-painful areas (38.18 vs. 40.00, p = 0.041; 45.81 vs. 47.75, p = 0.009; 50.18 vs. 50.63, p = 0.052) when the SCS was on compared with when it was off. There were no side-effects or complications related to the uses of QST in this study.
Heat Pain Threshold Non-Pain Site
DISCUSSION
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Our preliminary data demonstrate an increase in all three QST parameters (WS, HPth, and HPto) on both the painful and the nonpainful areas after the SCS was on for 20 min (Figures 2–7). In support of our hypothesis, we found an increased threshold to noxious stimulation (HPth and HPto) while the SCS was turned on, which coincided with patients’ reported percent pain relief from the SCS therapy. In this pilot study, the influence of SCS on the non-painful area is intriguing. We found that on the non-painful area (without the preswww.neuromodulationjournal.com
Temperature (Celcius)
49
*
48 47 46
On
45
Off
44 43 42
Figure 6. Heat pain thresholds over the non-painful area while the SCS was off vs. on. SCS, spinal cord stimulation. *p < 0.05.
ence of SCS-induced paresthesia coverage), there were similar increases of the sensory thresholds (HPth and HPto) from the noxious stimuli while the SCS was on. Historically, the pain relief from SCS therapy was thought to be contingent upon the presence of SCS-induced paresthesia. However, from recent research, it is clear that clinical pain relief has been achieved with newer nonparesthesia-based SCS therapy (high-frequency stimulation) (10). In pre-clinical models, SCS is thought to attenuate neuropathic pain behavior through 1) activation of descending serotoninergic pathways secondary to the modulation of spinal GABAergic (γ-aminobutyric acid) interneurons (19–23), 2) reduced spinal release of excitatory amino acid (24) or substance P (25), 3) activa-
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Neuromodulation 2015; 18: 355–360
QUANTITATIVE SENSORY TESTING AND SCS THERAPY
Temperature (Celcius)
Heat Pain Tolerance Non-Pain Site 51.5 *
51 50.5 On 50 Off 49.5 49 48.5
Figure 7. Heat pain tolerance thresholds over the non-painful area while the SCS was off vs. on. SCS, spinal cord stimulation. *p = 0.05.
tion of adenosine receptors (26), and 4) modulation of a cholinergic mechanism (27,28). The supra-spinal descending inhibitory modulation is also believed to play a role in pain reduction during SCS (29–32). We hypothesize that there is a role of the central influence (spinal and/or supra-spinal) for the increased sensory thresholds during noxious heat stimulation on the opposite, non-painful area without the presence of SCS-induced paresthesia. We hope the data generated from this study will promote future studies to further explore the underlying mechanisms of SCS therapy. For example, future studies might use systemic and/or spinal delivery of agonists and antagonists known to influence the antinociceptive function of SCS (e.g., GABA receptor, opioid receptor, cholinergic receptor, adenosine receptors, and NMDA receptor) to explore the role of the humeral influence in modulating nociceptive signals during SCS. A major limitation of this pilot study was the small sample size. In addition, there was significant heterogeneity in the clinical characteristics of the subjects such as duration of pain conditions and their etiology. Nonetheless, this pilot study did find increased sensory threshold to noxious heat measured via QST while the SCS was on.
Authorship Statements Dr. Ahmed designed and conducted the study, including patient recruitment, data collection, and data analysis. Dr. Ahmed also prepared the manuscript with important intellectual input from Drs. Zhang, Chen, and Mao. Ms. Kristin St. Hillary, Abigail Cohen, Trang Vo, and Mary Houghton helped with patient recruitment, data collection, and data storage. They also provided input during the preparation of the manuscript.
How to Cite this Article: Ahmed S.U., Zhang Y., Chen L., St. Hillary K., Cohen A., Vo T., Houghton M., Mao J. 2015. Effects of Spinal Cord Stimulation on Pain Thresholds and Sensory Perceptions in Chronic Pain Patients. Neuromodulation 2015; 18: 355–360
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COMMENTS It is gratifying to see a patient based investigation of the mechanism of SCS. Although a small pilot study, there is important and insightful information gleaned that should be followed up with a larger more rigorous study. It also bolsters the science behind SCS and the potential for increased clinical applications. Marshall Bedder, MD Seattle, Washington, USA
*** It is essential to have strong basic science evidence for the mechanisms of action of any therapy and it has been challenging with SCS therapies, where many mechanisms are proposed. The authors deserve big thanks for their sincere efforts with this pilot project in trying to solve our quest for understanding mechanisms of action of SCS therapy. I shall sincerely hope this will pave the way for many researchers to further pursue basic science research to help better patient selection for this therapy. Kiran Koneti, MBBS Middlesbrough, United Kingdom Comments not included in the Early View version of this paper.
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© 2015 International Neuromodulation Society
Neuromodulation 2015; 18: 355–360
Revised: April 6, 2015
Accepted: April 22, 2015
(onlinelibrary.wiley.com) DOI: 10.1111/ner.12316
Effects of Spinal Cord Stimulation on Pain Thresholds and Sensory Perceptions in Chronic Pain Patients Shihab U. Ahmed, MBBS, MPH; Yi Zhang, MD, PhD, MS; Lucy Chen, MD; Kristin St. Hillary, BS, RN; Abigail Cohen, BS; Trang Vo, BS; Mary Houghton, BS; Jianren Mao, MD, PhD Objective: Spinal cord stimulation (SCS) has been in clinical use for nearly four decades. In earliest observations, researchers found a significant increase in pain threshold during SCS therapy without changes associated with touch, position, and vibration sensation. Subsequent studies yielded diverse results regarding how SCS impacts pain and other sensory thresholds. This pilot study uses quantitative sensory testing (QST) to objectively quantify the impact of SCS on warm sensation, heat pain threshold, and heat pain tolerance. Materials and Methods: Nineteen subjects with an indwelling SCS device for chronic pain were subjected to QST with heat stimuli. QST was performed on an area of pain covered with SCS-induced paresthesia and an area without pain and without paresthesia, while the SCS was turned off and on. The temperature at which the patient detected warm sensation, heat pain, and maximal tolerable heat pain was used to define the thresholds. Results: We found that all three parameters, the detection of warm sensation, heat pain threshold, and heat pain tolerance, were increased during the period when SCS was on compared with when it was off. This increase was observed in both painful and non-painful sites. Conclusion: The observed pain relief during SCS therapy seems to be related to its impact on increased sensory threshold as detected in this study. The increased sensory threshold on areas without pain and without the presence of SCS coverage may indicate a central (spinal and/or supra-spinal) influence from SCS. Keywords: Pain, quantitative sensory testing (QST), spinal cord stimulation (SCS) Conflict of Interest: The authors report no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this study.
INTRODUCTION
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Address correspondence to: Shihab U. Ahmed, MBBS, MPH, MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 101 Merrimac Street, Suite 610, Boston, MA 02114, USA. Email: sahmed@ partners.org MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 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 Sources of financial support: None.
© 2015 International Neuromodulation Society
Neuromodulation 2015; 18: 355–360
355
Gate control theory, described by Melzack and Wall, suggests that when large afferent fibers in the dorsal column are stimulated, pain signals carried by the small fibers are blocked at the spinal cord (1). This was a seminal event in pain research and generated enormous enthusiasm for the treatment of difficult pain conditions through stimulation of large fibers at the spinal level. Spinal cord stimulation (SCS) therapy for refractory pain evolved into a direct clinical application based on this theory. Soon thereafter, Shealy et al. reported the implantation of an electrode to the thoracic dorsal column to relieve refractory pain of a cancer patient, which he describes as providing almost complete resolution of pain without involving sensory or motor systems (2). The earliest observation by Shealy and his colleagues found a significant increase in the pain threshold (50 to 250%) during SCS therapy (3). They also found no change on touch, position, and vibration sensations during the SCS. However, subsequent research studies had conflicting findings on how SCS impacts pain and other sensory thresholds. Indeed, we found only seven studies involving human trials that explored the impact of SCS on sensory and pain thresholds even as it has been used in clinical practice for more than
four decades (Table 1) (3–9). Possible reasons for these conflicting findings could be related to variations in placement of the lead (intrathecal vs. epidural) and/or sensory measurement techniques. Further, the scientific basis of how SCS reduces clinical pain remains unaddressed. Until very recently, the common belief was that the “buzzing” sensation (paresthesia) from the electrical stimulation (SCS) was associated with pain relief (10). Questions arose regarding whether pain relief was due to the change of perception (distraction
AHMED ET AL.
Table 1. The Impact of SCS on Sensory and Pain Thresholds During Its Uses for Pain Control. Study
Findings
Shealy et al., 1970 (six patients); [SCS lead placed in intrathecal space]
Pain threshold increased 50–250% from baseline with SCS but with no significant alteration of light touch, position sense, vibration, motor functions, bowel, bladder control, and sexual function (3). No change of subjective ability to perceive pain, touch, proprioception, or vibration, and no impairment of motor function (4). Patients (11/17) showed decreased perception of pain, touch, and joint rotation along with hyperreflexia. Somatosensory-evoked potential was also reduced. All changes returned to a control level one hour after the cessation of SCS (5). Immediate abolishing of spontaneous pain. SCS increased the touch and vibration thresholds but no change in pinch-induced cutaneous pain (6). Increased perception and pain threshold by electrical stimulation only from chronic SCS (at least several weeks), not immediately after SCS (7). Decreased spontaneous clinical pain and increased cutaneous heat pain threshold (8). No effect on warm and cold thresholds and no effect on heat, cold, and pressure pain thresholds (9).
Nashhold and Friedman, 1972 (30 patients); [SCS lead placed in intrathecal space] Larson et al., 1974 (18 cancer patients); [SCS lead placed in intrathecal space]
Lindblom and Meyerson, 1975 (ten patients); [SCS lead placed in intrathecal space] Doerr et al., 1978, (eight patients); [SCS lead placed in intrathecal space] Marchand et al., 1991 (eight patients); [SCS lead placed in epidural space] Kemler et al., 2001 (54 CRPS patients); [SCS lead placed in epidural space]
Here we highlight the location of lead placement, number of subjects, indications, and findings related to sensory and pain thresholds. CRPS, complex regional pain syndrome; SCS, spinal cord stimulation.
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of the mind from pain sensations) on the patient’s part or if there are changes in the processing of pain signals (e.g., change in pain thresholds). Since the publication of the first report on SCS therapy, there has been much advancement in nearly all aspects of SCS therapy. For example, leads now contain 8, 16, and 32 electrodes. The pulse generator technology also improved significantly. We have now rechargeable indwelling pulse generator (IPG). More recently, we have seen the introduction of IPG capable of generating highfrequency stimulation that does not create stimulation-induced paresthesia. Also, the earlier practice of intrathecal electrode placement has been replaced by the epidural implantation of the SCS leads. Clinically, there have been many studies demonstrating the efficacy of SCS therapy for various chronic pain conditions (11–14). However, complications from this procedure remain high, with an average of 35% (15). It is estimated that in 2008, more than 35,000 SCS cases were performed worldwide (16). With newer indications, the number is expected to rise. The estimated initial cost ranges from $21,595 to $57,800, depending on the payer (16). Although success of this mode of therapy has been reported, the associated complications and significant procedural cost strongly indicate prudence in selecting patients with the most potential benefit for this mode of therapy. An additional challenge in this regard is our limited understanding as to how SCS reduces pain. Our hypothesis is that at least one mechanism of action of SCS for clinical pain relief is due to selective modulation of the sensory response to noxious stimulation (e.g., heat). The goal of our study is to collect preliminary data on the impact of SCS on pain and sensory thresholds using a quantitative sensory testing (QST) method (17). We hope that the data from this pilot study will provide the impetus for a larger study to better understand the mechanisms of SCS therapy and thus improve patient selection and patient care. In this pilot study, we used QST to objectively quantify the impact of SCS on warm sensation (WS), heat pain threshold (HPth), and heat pain tolerance (HPto) over the painful area covered by the SCSrelated paresthesia and compare our results with findings of a nonpainful area with the same subject (no SCS-related paresthesia). www.neuromodulationjournal.com
PATIENTS AND METHODS Patients who were currently treated with SCS (for a minimum of four weeks) for chronic pain at the MGH Center Pain Medicine were invited to participate in our institutional review board (IRB)approved protocol. We included subjects aged 18 years or older and those who had an SCS device implanted for at least one month for pain control. The one month requirement was to ensure that the subject is familiar with the therapy and has recovered from the surgical implantation of the SCS device. We excluded patients who have a neurological disease or a condition causing sensory deficit to the painful area, subjects who had recent therapy that may influence QST results such as a neuroablative procedure within two months, and subjects who are unable to travel to the study center. Subjects were contacted via phone and a phone-screen was performed using an IRB-approved checklist that included our inclusion and exclusion criteria. The etiology and location of their pain for the SCS therapy initiation are listed in Table 2. Once a subject was deemed eligible for the study, and if he or she indicated willingness to participate, they were asked to withhold the SCS and their opioid medications for four hours prior to their appointment time. Figure 1 describes the flow of the subject’s visit. On the day of the visit, the study physician (SUA) explained the study and obtained the informed consent. After the subject signed the consent, we performed 1) a brief medical history, including medication use; 2) pain history including intensity, location, character, duration and, if known, the etiology; 3) identified the primary pain site; 4) performed a sensory examination (e.g., alcohol swab, cotton swab, pinprick, and vibration); and 5) recorded the routine vital signs (blood pressure, pulse, pulse oximetry). The painful area of the limb was outlined and marked for the placement of the QST probe. A nonpainful area on the opposite side without the presence of SCSinduced paresthesia was also identified and marked for the placement of the QST probe. We collected two sets of data: the first set while the SCS was off and the second set with the SCS on. After the completion of the first set of QST data, the patient was asked to
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QUANTITATIVE SENSORY TESTING AND SCS THERAPY
Table 2. The Causes and Locations of Pain for Which SCS Therapy Was Initiated. Subject
Primary pain complaint
How the pain started
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Lower back and leg Left ankle bone and base of tibia Back and leg (mostly right side) Low back and left lower extremity Left lower extremity and right toes Ball of foot Left leg Left foot Back and right leg Left arm and hand Lower back Lower back and left leg Right knee, right ankle, and left leg Lower back and right hip Left lower back, left leg, and left foot Lower back and leg Lower back and leg Lower back and left leg Bilateral distal lower extremity
Injury sustained while in navy Left tibial surgery for sarcoma removal Osteoarthritis in both knees, knee replacement, fracture of right femur Injury sustained from a fall CRPS after foot surgery After foot surgeries CRPS from soccer injury and ankle stabilization surgery (following the injury) CRPS after foot surgery Unknown cause Degenerative condition at cervical spine After a work-related injury After an epidural abscess Injury sustained from a fall on ice After an MVA Pulled back multiple times over the years Unknown cause Injury sustained from a fall FBSS FBSS
CRPS, complex regional pain syndrome; FBSS, failed back surgery syndrome; MVA, motor vehicle accident; SCS, spinal cord stimulation.
Consent History and Physical
QST with SCS Off
Painful area with SCS-paresthesia coverage
Non-painful area on the opposite side, no paresthesia
QST with SCS On
Painful area with SCS-paresthesia coverage
Non-painful area on the opposite side, no paresthesia
Figure 1. Flow diagram of the subject’s visit. QST, quantitative sensory testing; SCS, spinal cord stimulation.
turn the SCS therapy on and we waited for 20 min before initiating the second set of QST (with SCS therapy on). QST QST is a method to assess the psychophysical response to a set of calibrated stimulation (17). In this study, heat stimulation was used in all QST sessions following a protocol detailed in our previous publication (18).
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To Detect HPto A contact thermode was placed at the designated body site. The temperature at the thermode-skin interface rose at 1°C/sec from a baseline of 32°C to a cutoff temperature of 52°C. Subjects were asked to stop stimulation by pressing a computer mouse button when pain was no longer tolerable (i.e., just beyond pain threshold). The stimulation was fully escapable and the subject was able to withdraw from the stimulation at any time. This same test was repeated three times with a three-min interval and the average threshold temperature from the three tests was used as the pain tolerance temperature (in degree Celsius). Statistical Analysis We used paired t-test and Fisher’s exact test in order to compare continuous and categorical outcomes between the study sites. We compared the WS, HPth, and HPto at the two QST sites with the SCS on and off for each subject. We consider 1.2°C in mean temperature to be an important difference between the painful and non-painful sites (18). The statistical package STATA Version 12 (StataCorp LP, College Station, TX, USA) was used for data analysis.
RESULTS Nineteen patients participated and completed the study. Their average age was 53 years (range 29–65 years) and they had, on average, chronic pain for 12 years (range 1.2–42 years). All nineteen
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To Detect WS A contact thermode was placed at a designated body part (e.g., forearm). The subjects were instructed to stop stimulation by pressing a computer mouse button when they first perceived WS as temperature ascended from the neutral temperature (32°C). This same test was repeated three times with a three-min interval and the average WS temperature from the three tests was used as the WS temperature (in degree Celsius).
To Detect HPth A contact thermode was placed at a designated body part. The temperature at the thermode-skin interface rose at 1°C/sec from a baseline of 32°C to a cutoff temperature of 52°C. Subjects were asked to stop stimulation by pressing a computer mouse button when pain was first detected. This same test was repeated three times with a three-min interval and the average threshold temperature from the three tests was used as the pain threshold temperature (in degree Celsius).
AHMED ET AL.
Warm Sensaon Threshold Pain Site
Heat Pain Tolerance Pain Site 51.5
*
* 51
40 39.5 39
On
38.5
Off
38 37.5
Temperature (Celcius)
Temperature (Celcius)
41 40.5
50.5 50
On
49.5
Off
49
37
48.5
36.5
48
Figure 4. Heat pain tolerance thresholds over the painful area while the SCS was off vs. on. SCS, spinal cord stimulation. *p < 0.05.
Heat Pain Threshold Pain Site
Warm Sensaon Threshold Non-Pain Site
49 48.5 48 47.5 47 46.5 46 45.5 45 44.5 44
42
*
*
41
On Off
Temperature (Celcius)
Temperature (Celcius)
Figure 2. Warm sensation thresholds over the painful area while the SCS was off vs. on. SCS, spinal cord stimulation. *p < 0.05.
40 39
On
38
Off
37 36 35
Figure 3. Heat pain thresholds over the painful area while the SCS was off vs. on. SCS, spinal cord stimulation. *p < 0.05.
Figure 5. Warm sensation thresholds over the non-painful area while the SCS was off vs. on. SCS, spinal cord stimulation. *p < 0.05.
subjects were white and 17 self-identified as non-Hispanic. Ten subjects were on disability. Subjects documented both their worst and least mean Visual Analog Scale pain score (0 = no pain and 10 = worst pain imaginable) over the preceding 24 hours as 7.39 ± 2.20 and 3.68 ± 1.95 respectively. They reported their average percent of pain relief while on SCS therapy as 57.78 ± 19.57. We measured the impact of SCS on WS, HPth, and HPto over the painful area covered by SCS-induced paresthesia and compared the same parameters on a non-painful area on the opposite side, without the presence of SCS-induced paresthesia, in each subject. We found that WS, HPth, and HPto were higher on both painful (38.67 vs. 39.87, p = 0.036; 46.52 vs. 47.59, p = 0.009; 50.12 vs. 50.71, p = 0.036) and non-painful areas (38.18 vs. 40.00, p = 0.041; 45.81 vs. 47.75, p = 0.009; 50.18 vs. 50.63, p = 0.052) when the SCS was on compared with when it was off. There were no side-effects or complications related to the uses of QST in this study.
Heat Pain Threshold Non-Pain Site
DISCUSSION
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Our preliminary data demonstrate an increase in all three QST parameters (WS, HPth, and HPto) on both the painful and the nonpainful areas after the SCS was on for 20 min (Figures 2–7). In support of our hypothesis, we found an increased threshold to noxious stimulation (HPth and HPto) while the SCS was turned on, which coincided with patients’ reported percent pain relief from the SCS therapy. In this pilot study, the influence of SCS on the non-painful area is intriguing. We found that on the non-painful area (without the preswww.neuromodulationjournal.com
Temperature (Celcius)
49
*
48 47 46
On
45
Off
44 43 42
Figure 6. Heat pain thresholds over the non-painful area while the SCS was off vs. on. SCS, spinal cord stimulation. *p < 0.05.
ence of SCS-induced paresthesia coverage), there were similar increases of the sensory thresholds (HPth and HPto) from the noxious stimuli while the SCS was on. Historically, the pain relief from SCS therapy was thought to be contingent upon the presence of SCS-induced paresthesia. However, from recent research, it is clear that clinical pain relief has been achieved with newer nonparesthesia-based SCS therapy (high-frequency stimulation) (10). In pre-clinical models, SCS is thought to attenuate neuropathic pain behavior through 1) activation of descending serotoninergic pathways secondary to the modulation of spinal GABAergic (γ-aminobutyric acid) interneurons (19–23), 2) reduced spinal release of excitatory amino acid (24) or substance P (25), 3) activa-
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QUANTITATIVE SENSORY TESTING AND SCS THERAPY
Temperature (Celcius)
Heat Pain Tolerance Non-Pain Site 51.5 *
51 50.5 On 50 Off 49.5 49 48.5
Figure 7. Heat pain tolerance thresholds over the non-painful area while the SCS was off vs. on. SCS, spinal cord stimulation. *p = 0.05.
tion of adenosine receptors (26), and 4) modulation of a cholinergic mechanism (27,28). The supra-spinal descending inhibitory modulation is also believed to play a role in pain reduction during SCS (29–32). We hypothesize that there is a role of the central influence (spinal and/or supra-spinal) for the increased sensory thresholds during noxious heat stimulation on the opposite, non-painful area without the presence of SCS-induced paresthesia. We hope the data generated from this study will promote future studies to further explore the underlying mechanisms of SCS therapy. For example, future studies might use systemic and/or spinal delivery of agonists and antagonists known to influence the antinociceptive function of SCS (e.g., GABA receptor, opioid receptor, cholinergic receptor, adenosine receptors, and NMDA receptor) to explore the role of the humeral influence in modulating nociceptive signals during SCS. A major limitation of this pilot study was the small sample size. In addition, there was significant heterogeneity in the clinical characteristics of the subjects such as duration of pain conditions and their etiology. Nonetheless, this pilot study did find increased sensory threshold to noxious heat measured via QST while the SCS was on.
Authorship Statements Dr. Ahmed designed and conducted the study, including patient recruitment, data collection, and data analysis. Dr. Ahmed also prepared the manuscript with important intellectual input from Drs. Zhang, Chen, and Mao. Ms. Kristin St. Hillary, Abigail Cohen, Trang Vo, and Mary Houghton helped with patient recruitment, data collection, and data storage. They also provided input during the preparation of the manuscript.
How to Cite this Article: Ahmed S.U., Zhang Y., Chen L., St. Hillary K., Cohen A., Vo T., Houghton M., Mao J. 2015. Effects of Spinal Cord Stimulation on Pain Thresholds and Sensory Perceptions in Chronic Pain Patients. Neuromodulation 2015; 18: 355–360
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COMMENTS It is gratifying to see a patient based investigation of the mechanism of SCS. Although a small pilot study, there is important and insightful information gleaned that should be followed up with a larger more rigorous study. It also bolsters the science behind SCS and the potential for increased clinical applications. Marshall Bedder, MD Seattle, Washington, USA
*** It is essential to have strong basic science evidence for the mechanisms of action of any therapy and it has been challenging with SCS therapies, where many mechanisms are proposed. The authors deserve big thanks for their sincere efforts with this pilot project in trying to solve our quest for understanding mechanisms of action of SCS therapy. I shall sincerely hope this will pave the way for many researchers to further pursue basic science research to help better patient selection for this therapy. Kiran Koneti, MBBS Middlesbrough, United Kingdom Comments not included in the Early View version of this paper.
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