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Recruitment and retention in pain studies: experience from a clinical trial involving behavioral and pharmacological therapies
S40
F11 Neural Stimulation - Humans (256) Spinal cord stimulation improves pain intensity and interference, irrespective of pain site, device manufacturer or primary vs. revised implantation status L Nguyen, A Wilson, T Palermo, and B Stacey; Oregon Health & Science University, Department of Anesthesiology and Perioperative Medicine Portland, OR Spinal cord stimulation (SCS) provides relief by sending electrical stimulation to the spinal cord via electrodes implanted in the epidural space. SCS is known to improve neuropathic pain, but contention remains regarding use for other varieties of pain, such as back pain. Two primary aims of this study were to 1) assess changes in pain intensity and interference after SCS implantation, and 2) evaluate predictors of pain outcome (pain site, device manufacturer, primary vs. revised SCS implantation). Data were obtained from retrospective chart review at a multidisciplinary pain clinic. Over a 2.5 year period, 51 of 86 adults receiving new or revised SCS implantations had complete Brief Pain Inventory (BPI) data available to include in this analysis. Patients completed the BPI at baseline and at two post-implant visits, occurring at approximately 2 weeks and 6 months. Patients were on average 49 years old with a mean pain duration of 9.3 years; 51% were male with average BMI in the overweight range (M=29.9). Primary pain sites included lower back (n=27), extremity (n=14), chest wall/abdominal (n=6), groin/pelvic (n=3), and neck (n=1) pain. Most of the sample (62.8%) had $ 2 pain diagnoses; 21.6% were concurrently diagnosed with complex regional pain syndrome. Repeated measures ANOVAs showed reductions in pain intensity, F=4.94, p=.01 and pain interference, F=7.68, p=.001 over time, with contrasts showing both follow up assessments significantly improved from baseline. Neither SCS device manufacturer nor primary vs. revision SCS implantation status predicted outcome. Back pain and non-back pain patients had similar improvements in pain intensity and interference, suggesting SCS efficacy for a variety of pain sites. This uncontrolled study suggests that SCS may effectively reduce pain intensity and interference for patients with a variety of pain conditions and changes do not depend on device manufacturer or SCS implantation status.
Abstracts (258) Duloxetine and placebo alter different gray matter regions in chronic low back pain patients N Chatterjee, N Noor, A Crowell, and S Mackey; Stanford University, Palo Alto, CA Chronic lower back pain (CLBP) affects millions of people and cost billions of dollars per year in the United States alone. Recent evidence indicates that chronic back pain may cause structural changes in brain gray matter (GM), suggesting that GM changes may be an important metric in evaluating the efficacy of pain treatments. In this double-blind crossover study, we used tensor based morphometry (TBM) to test our hypothesis that treatment with duloxetine (a specific serotonin-norepinephrine reuptake inhibitor) would cause GM changes that are distinct from those caused by treatment with placebo. 14 male subjects with CLBP were recruited. They rated pain as at least 4/10 on average for the two weeks prior to the start of the study and were not on pain medications. Study design was a double blind, placebo control, 12 week crossover study utilizing duloxetine as the active drug. Structural scans were conducted at baseline and at the end of each drug period. Tensor based morphometry was used to evaluate structural changes between baseline and follow-up scans in a method similar to that outlined by Kipps et al (Kipps, J Neurol Neurosurg Psychiatry, 2005). Significant clusters were defined at p<0.05 corrected for multiple comparisons. Both duloxetine and placebo caused changes in localized brain GM. These changes were distinct in that duloxetine led to increases in GM in bilateral caudate and decreases in GM in orbitofrontal and ventromedial prefrontal cortex, while placebo led to increases in GM in left anterior insula and bilateral caudate. Correlations with behavioral measurements are ongoing. Our study suggests separate brain mechanisms for duloxetine and placebo effects in chronic low back pain patients. (Supported by a research grant from Eli Lilly.)
F12 Non-Opioid Analgesics - Other
F13 Novel Therapeutic Agents
(257) Recruitment and retention in pain studies: experience from a clinical trial involving behavioral and pharmacological therapies
(259) Prolonged analgesic effect of RTX on A-delta type II fibers following peripheral administration
S Bounds, B Klick, L Buenaver, M Smith, R Edwards, E Grace, S Raja, and J Haythornthwaite; Johns Hopkins University, Baltimore, MD A vital aspect of executing a clinical trial is successful recruitment and retention of the target population. The occurrence of subject refusal and rates of particular exclusions is an under investigated area in pain research, especially in comparison to psychosocial literature. The current study examined the rates of rule outs at four phases of a study investigating pain in temporomandibular disorder (TMD) patients. We aimed to illuminate factors that influence participation, while also explicating the individuals who successfully matriculated into the study. 886 potential subjects were screened for participation with an initial telephone screen, followed by three baseline screening visits to ensure study eligibility and willingness. Exclusions and refusals were documented at each screening phase. For the purposes of this analysis, callers who were considered ‘‘non-serious’’ (e.g. those who did not have pain or TMD, N = 302) were excluded from the descriptive calculations. The analysis of the initial phone screen revealed that out of the 643 exclusions, subjects were most likely to decline participation for the following reasons: 21% were not interested in taking a study medication, 13% were concerned about the time commitment, and 7% were apprehensive about the travel required for study visits. Participants were excluded for the following reasons: 16% were currently taking antidepressants, 9% did not have high enough pain ratings, and 8% were presently being treated with opioids or other contraindicated medications. The current findings suggest that a relatively high proportion of potential participants either declined participation or were excluded for a disproportionate amount of reasons; perhaps implying that a large number of pain patients are not receiving a prospective treatment that might be highly effective. Such high rule-outs and refusals to participate suggest that clinical trials (i.e., efficacy studies) may be inadequately sampling the population for which these treatments will be translated.
K Mitchell, B Bates, J Keller, M Nemenov, A Mannes, and M Iadarola; NIDCR, NIH, Bethesda, MD Peripheral injections of resiniferatoxin (RTX) can be used to achieve analgesia by temporarily removing TRPV1-expressing pain fibers. A goal of the present study was to determine the minimal amount of RTX needed to obtain hypoalgesia. Additionally, we sought to determine whether C-fibers and A-delta type II fibers are differentially affected by RTX. Using a laser to stimulate rat hind paws, we observed that 0.5 ng failed to induce hypoalgesia, whereas 5.0 ng and 50 ng resulted in C-fiber hypoalgesia for nearly 2 weeks. When observing A-delta type II fiber response, both 5 and 50 ng injections resulted in potent hypoalgesia within the first week whereas no hypoalgesia was observed with the vehicle and 0.5 ng injections. Unexpectedly, A-delta type II hypoalgesia remained for as long as 2 months, although there was a partial return of behavior. Molecularly, we observed that mRNA encoding ATF-3 and galanin, markers of regeneration, were dramatically increased in the dorsal root ganglia (DRG) 24 h and 10d after RTX injection. In contrast, the transcript encoding MCP-1, a putative indicator of nociception when induced in DRG, was significantly elevated by 24 h but returned immediately thereafter. In the spinal cord, increased expression of c-Fos protein was detected by 6h but returned to baseline by 24 h. Taken together, these data indicate that the more prolonged hypoalgesic response for A-delta type II is due to a slowed regeneration as compared to C-fibers.
F11 Neural Stimulation - Humans (256) Spinal cord stimulation improves pain intensity and interference, irrespective of pain site, device manufacturer or primary vs. revised implantation status L Nguyen, A Wilson, T Palermo, and B Stacey; Oregon Health & Science University, Department of Anesthesiology and Perioperative Medicine Portland, OR Spinal cord stimulation (SCS) provides relief by sending electrical stimulation to the spinal cord via electrodes implanted in the epidural space. SCS is known to improve neuropathic pain, but contention remains regarding use for other varieties of pain, such as back pain. Two primary aims of this study were to 1) assess changes in pain intensity and interference after SCS implantation, and 2) evaluate predictors of pain outcome (pain site, device manufacturer, primary vs. revised SCS implantation). Data were obtained from retrospective chart review at a multidisciplinary pain clinic. Over a 2.5 year period, 51 of 86 adults receiving new or revised SCS implantations had complete Brief Pain Inventory (BPI) data available to include in this analysis. Patients completed the BPI at baseline and at two post-implant visits, occurring at approximately 2 weeks and 6 months. Patients were on average 49 years old with a mean pain duration of 9.3 years; 51% were male with average BMI in the overweight range (M=29.9). Primary pain sites included lower back (n=27), extremity (n=14), chest wall/abdominal (n=6), groin/pelvic (n=3), and neck (n=1) pain. Most of the sample (62.8%) had $ 2 pain diagnoses; 21.6% were concurrently diagnosed with complex regional pain syndrome. Repeated measures ANOVAs showed reductions in pain intensity, F=4.94, p=.01 and pain interference, F=7.68, p=.001 over time, with contrasts showing both follow up assessments significantly improved from baseline. Neither SCS device manufacturer nor primary vs. revision SCS implantation status predicted outcome. Back pain and non-back pain patients had similar improvements in pain intensity and interference, suggesting SCS efficacy for a variety of pain sites. This uncontrolled study suggests that SCS may effectively reduce pain intensity and interference for patients with a variety of pain conditions and changes do not depend on device manufacturer or SCS implantation status.
Abstracts (258) Duloxetine and placebo alter different gray matter regions in chronic low back pain patients N Chatterjee, N Noor, A Crowell, and S Mackey; Stanford University, Palo Alto, CA Chronic lower back pain (CLBP) affects millions of people and cost billions of dollars per year in the United States alone. Recent evidence indicates that chronic back pain may cause structural changes in brain gray matter (GM), suggesting that GM changes may be an important metric in evaluating the efficacy of pain treatments. In this double-blind crossover study, we used tensor based morphometry (TBM) to test our hypothesis that treatment with duloxetine (a specific serotonin-norepinephrine reuptake inhibitor) would cause GM changes that are distinct from those caused by treatment with placebo. 14 male subjects with CLBP were recruited. They rated pain as at least 4/10 on average for the two weeks prior to the start of the study and were not on pain medications. Study design was a double blind, placebo control, 12 week crossover study utilizing duloxetine as the active drug. Structural scans were conducted at baseline and at the end of each drug period. Tensor based morphometry was used to evaluate structural changes between baseline and follow-up scans in a method similar to that outlined by Kipps et al (Kipps, J Neurol Neurosurg Psychiatry, 2005). Significant clusters were defined at p<0.05 corrected for multiple comparisons. Both duloxetine and placebo caused changes in localized brain GM. These changes were distinct in that duloxetine led to increases in GM in bilateral caudate and decreases in GM in orbitofrontal and ventromedial prefrontal cortex, while placebo led to increases in GM in left anterior insula and bilateral caudate. Correlations with behavioral measurements are ongoing. Our study suggests separate brain mechanisms for duloxetine and placebo effects in chronic low back pain patients. (Supported by a research grant from Eli Lilly.)
F12 Non-Opioid Analgesics - Other
F13 Novel Therapeutic Agents
(257) Recruitment and retention in pain studies: experience from a clinical trial involving behavioral and pharmacological therapies
(259) Prolonged analgesic effect of RTX on A-delta type II fibers following peripheral administration
S Bounds, B Klick, L Buenaver, M Smith, R Edwards, E Grace, S Raja, and J Haythornthwaite; Johns Hopkins University, Baltimore, MD A vital aspect of executing a clinical trial is successful recruitment and retention of the target population. The occurrence of subject refusal and rates of particular exclusions is an under investigated area in pain research, especially in comparison to psychosocial literature. The current study examined the rates of rule outs at four phases of a study investigating pain in temporomandibular disorder (TMD) patients. We aimed to illuminate factors that influence participation, while also explicating the individuals who successfully matriculated into the study. 886 potential subjects were screened for participation with an initial telephone screen, followed by three baseline screening visits to ensure study eligibility and willingness. Exclusions and refusals were documented at each screening phase. For the purposes of this analysis, callers who were considered ‘‘non-serious’’ (e.g. those who did not have pain or TMD, N = 302) were excluded from the descriptive calculations. The analysis of the initial phone screen revealed that out of the 643 exclusions, subjects were most likely to decline participation for the following reasons: 21% were not interested in taking a study medication, 13% were concerned about the time commitment, and 7% were apprehensive about the travel required for study visits. Participants were excluded for the following reasons: 16% were currently taking antidepressants, 9% did not have high enough pain ratings, and 8% were presently being treated with opioids or other contraindicated medications. The current findings suggest that a relatively high proportion of potential participants either declined participation or were excluded for a disproportionate amount of reasons; perhaps implying that a large number of pain patients are not receiving a prospective treatment that might be highly effective. Such high rule-outs and refusals to participate suggest that clinical trials (i.e., efficacy studies) may be inadequately sampling the population for which these treatments will be translated.
K Mitchell, B Bates, J Keller, M Nemenov, A Mannes, and M Iadarola; NIDCR, NIH, Bethesda, MD Peripheral injections of resiniferatoxin (RTX) can be used to achieve analgesia by temporarily removing TRPV1-expressing pain fibers. A goal of the present study was to determine the minimal amount of RTX needed to obtain hypoalgesia. Additionally, we sought to determine whether C-fibers and A-delta type II fibers are differentially affected by RTX. Using a laser to stimulate rat hind paws, we observed that 0.5 ng failed to induce hypoalgesia, whereas 5.0 ng and 50 ng resulted in C-fiber hypoalgesia for nearly 2 weeks. When observing A-delta type II fiber response, both 5 and 50 ng injections resulted in potent hypoalgesia within the first week whereas no hypoalgesia was observed with the vehicle and 0.5 ng injections. Unexpectedly, A-delta type II hypoalgesia remained for as long as 2 months, although there was a partial return of behavior. Molecularly, we observed that mRNA encoding ATF-3 and galanin, markers of regeneration, were dramatically increased in the dorsal root ganglia (DRG) 24 h and 10d after RTX injection. In contrast, the transcript encoding MCP-1, a putative indicator of nociception when induced in DRG, was significantly elevated by 24 h but returned immediately thereafter. In the spinal cord, increased expression of c-Fos protein was detected by 6h but returned to baseline by 24 h. Taken together, these data indicate that the more prolonged hypoalgesic response for A-delta type II is due to a slowed regeneration as compared to C-fibers.