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931)
S2 (306/720) Sex differences in the nociceptive processing of temporomandibular disorder (TMD) patients E Sarlani, E Grace, D Rodriguez, D Pennington, J Greenspan; University of Maryland, Baltimore, MD Our previous work demonstrated that female TMD patients exhibit enhanced nociceptive processing compared to age matched, pain-free controls1,2. This enhancement, measured as increased temporal summation of pain, was found on the hand – a body site distant from the clinical pain region. This finding suggested that these patients had a global increase in central nociceptive processing. Our model incorporating these observations was that this central nociceptive hyperexcitability was one component contributing to the pain of TMD, and could explain why minor and even undetectable pathology of the TMJ region could result in a distressing chronic pain. These studies only evaluated women, since a large majority of TMD patients are women. Now, we report results from similar testing of male TMD patients. Our temporal summation of mechanical pain protocol was used as described previously1. Sharp probes are repeatedly pressed against the skin of the finger, while the subject reports the perceived pain intensity for the 1st, 5th, and 10th stimulus of the series. While the stimulus force is the same each time, rapid repetition of the stimuli produces a gradually increasing perception of pain, which is attributable to central nociceptive processing summation. Based on data collected to date (n⫽11), we have observed that male TMD patients do not show temporal summation of pain, which makes them very different from the female TMD patients, who show exaggerated temporal summation of pain. Furthermore, this apparent absence of any temporal summation distinguishes the male TMD patients from healthy male subjects, who demonstrate some temporal summation. The central nociceptive processing upregulation thought to be contributing to TMD pain for women is not present in men. These results suggest a distinct sex difference in the role of altered nociceptive processing for TMD pain. (1. Sarlani, Pain, 2004; 2. Sarlani, Cells Tissues Organs, 2005)
G. Diagnosis, Assessment and Reviews G04 - Clinical Outcomes Measurement (306/931) Cluster analysis of psychosocial and medication use profiles of patients with painful diabetic peripheral neuropathy (DPN) M Gore, N Brandenburg, K Tai, D Leslie; Avalon Health Solutions, Inc., Philadelphia, PA The objective of this analysis was to identify psychosocial and medication use profiles of patients with painful DPN and to compare them with profiles of other chronic pain conditions. Non-hierarchical k-means clustering technique was used to determine patient profiles. Discriminant analysis (posterior probability of assignment [PPA]), kappa reliability coefficient (K) and external validation (against other pain and mood variables) were used to confirm classification accuracy of the cluster analysis. A questionnaire assessing pain severity & interference, sleep problems, symptom levels of anxiety/depression, medication use and treatment satisfaction was completed by 255 community-based DPN patients. Four sub-groups were identified: (a) 73 patients with higher pain severity (PS), higher pain interference (PI), higher affective distress (AD), higher sleep problems (SP), moderate prescription (Rx) medication use (RXMED), and dissatisfied with Rx medications. This group was similar to a sub-group labeled Dysfunctional in previous pain studies; (b) 60 patients with mild PS & PI, normal AD, lower SP, low RXMED, and somewhat satisfied with Rx medications. This group was similar to a previous sub-group labeled Adaptive Copers (ACs); (c) 106 patients with medium PS & PI, mild to normal AD, medium SP, low RXMED, and moderately dissatisfied with Rx medications. This group was labeled Marginal Copers, as it was slightly worse than the ACs on all parameters; (d) 16 patients with medium PS & PI, mild-moderate AD, higher SP, very high RXMED (mean ⱖ14 Rx types in 7 days prior) and somewhat satisfied with Rx medications. We labeled this sub-group as Heavy Medicators. Cluster validation strongly supported the cluster solution (PPI indicated that overall only 1.96% of patients were misclassified; K-value [.9715, p⬍0.0001]; all MANOVA p-values ⬍0.001.) Results suggest 4 distinct patient types; understanding this taxonomy of patients with painful DPN can assist practitioners in adopting differential interventions based on patient characteristics.
Abstracts
Paper Session 312: Clinical Management of Pain C. Disease Entities (Human) C03 - Central Pain (312/692) Fosphenytoin relieves central neuropathic pain following spinal cord injury C Sang, K Jenkins, K Wang, A Sarin, S Coccoli; Brigham and Women’s Hospital, Boston, MA The systemic administration of sodium channel antagonists has been shown to reduce pain in peripheral and central neuropathic pain states in both preclinical and clinical studies. We evaluated the analgesic efficacy of fosphenytoin, the prodrug of the sodium channel blocker phenytoin, in patients with central neuropathic pain following spinal cord injury (SCI). This was a randomized, double-blind, placebocontrolled, crossover clinical trial of a 15 minute intravenous administration of fosphenytoin 12 mg phenytoin equivalents (PE)/kg vs. fosphenytoin 4 mg PE/kg vs. lidocaine 2 mg/kg vs. saline. Subjects were healthy adults with chronic central neuropathic pain of at least moderate pain intensity. Primary endpoint was percent change from baseline in overall pain intensity (21-point log-linear Gracely scale). The primary endpoint was analyzed with linear model containing sequence, subject within sequence, period and treatment. All enrolled subjects were analyzed. Seventeen subjects enrolled in and completed the study. Mean pain intensity was 12/20 (range, 4-16/20). In the fosphenytoin 12 mg PE/kg arm, peak reduction in mean pain intensity was 50% at 45 minutes following the start of the infusion, with a statistically significant reduction compared to placebo in ongoing pain over the entire testing period (mean % change from baseline over 240 minutes, 31%; p⫽0.007). Trends were present but not statistically significant for the fosphenytoin 4 mg PE/kg and lidocaine 2 mg/kg treatments. Both the complete (n⫽7) and incomplete (n⫽10) subgroups showed a significant improvement (complete: 18% mean reduction in pain intensity, p⫽0.007; incomplete: 40% mean reduction in pain intensity, p⫽0.017). Side effects were well tolerated. In conclusion, fosphenytoin 12 mg/kg provides a statistically and clinically significant reduction in pain intensity. These data support the use of sodium channel antagonists for the treatment of central neuropathic pain following spinal cord injury. Acknowledgments: Stacey Kaplan, RN/ Kristie Chin/ John Vetrano/ Mary Sullivan, NP. Support: Christopher Reeve Paralysis Foundation/M01-RR-01066/R01-41503.
D. Treatment Approaches (Medical/Interventional) D04 - Cancer Pain Opioids (312/729) A randomized, placebo-controlled study of fentanyl effervescent buccal tablets for relief of breakthrough pain in opioid-tolerant patients with cancer D Taylor, R Portenoy, J Messina, L Tremmel; Comprehensive Pain Care PC, Marietta, GA Cancer-related breakthrough pain (BTP) typically is managed with a short-acting oral opioid, taken as needed, in addition to an around-the-clock opioid regimen. Since BTP episodes occur unpredictably and peak rapidly, there is benefit in providing faster pain relief. Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and efficiency of fentanyl absorption through the buccal mucosa and may provide rapid-onset analgesia. This double-blind, randomized, placebo-controlled study evaluated the efficacy and tolerability of FEBT for BTP in opioid-tolerant patients with chronic pain associated with cancer. Eighty (65%) of 123 patients identified an effective FEBT dose during initial open-label titration; 77 were randomized to 1 of 18 sequences of 10 tablets (7 FEBT and 3 placebo), and 72 were efficacyevaluable. During BTP episodes (FEBT: n⫽493; placebo: n⫽208), patients recorded pain intensity (PI), pain relief, and global medication performance (GMP) regularly between 15 and 60 minutes postdose. Clinically significant (ⱖ33%) decreases in PI occurred with FEBT in 13% of episodes by 15 minutes and in 48% of episodes by 30 minutes postdose; at all timepoints, the percentage of episodes showing ⱖ33% PI decrease was significantly greater for FEBT than for placebo (P⬍.05). At 30 minutes postdose, PI decreased by ⱖ50% with FEBT in 24% of episodes and with placebo in 16% of episodes (P⬍.05). Mean GMP ratings at 30 minutes were 1.4 (“good”) for FEBT versus 0.9 (“fair”) for placebo, and at 60 minutes were 2.1 (“very good”) for FEBT versus 1.3 (“good”) for placebo. The analgesic effect of FEBT exceeded that of placebo in all measurements, including responder analysis and GMP ratings. Adverse events (nausea, vomiting, dizziness, constipation, and somnolence) were typical of opioids; 2 patients discontinued because of oral tolerability issues. This study provides the first evidence that FEBT are safe and effective for BTP associated with cancer.
G. Diagnosis, Assessment and Reviews G04 - Clinical Outcomes Measurement (306/931) Cluster analysis of psychosocial and medication use profiles of patients with painful diabetic peripheral neuropathy (DPN) M Gore, N Brandenburg, K Tai, D Leslie; Avalon Health Solutions, Inc., Philadelphia, PA The objective of this analysis was to identify psychosocial and medication use profiles of patients with painful DPN and to compare them with profiles of other chronic pain conditions. Non-hierarchical k-means clustering technique was used to determine patient profiles. Discriminant analysis (posterior probability of assignment [PPA]), kappa reliability coefficient (K) and external validation (against other pain and mood variables) were used to confirm classification accuracy of the cluster analysis. A questionnaire assessing pain severity & interference, sleep problems, symptom levels of anxiety/depression, medication use and treatment satisfaction was completed by 255 community-based DPN patients. Four sub-groups were identified: (a) 73 patients with higher pain severity (PS), higher pain interference (PI), higher affective distress (AD), higher sleep problems (SP), moderate prescription (Rx) medication use (RXMED), and dissatisfied with Rx medications. This group was similar to a sub-group labeled Dysfunctional in previous pain studies; (b) 60 patients with mild PS & PI, normal AD, lower SP, low RXMED, and somewhat satisfied with Rx medications. This group was similar to a previous sub-group labeled Adaptive Copers (ACs); (c) 106 patients with medium PS & PI, mild to normal AD, medium SP, low RXMED, and moderately dissatisfied with Rx medications. This group was labeled Marginal Copers, as it was slightly worse than the ACs on all parameters; (d) 16 patients with medium PS & PI, mild-moderate AD, higher SP, very high RXMED (mean ⱖ14 Rx types in 7 days prior) and somewhat satisfied with Rx medications. We labeled this sub-group as Heavy Medicators. Cluster validation strongly supported the cluster solution (PPI indicated that overall only 1.96% of patients were misclassified; K-value [.9715, p⬍0.0001]; all MANOVA p-values ⬍0.001.) Results suggest 4 distinct patient types; understanding this taxonomy of patients with painful DPN can assist practitioners in adopting differential interventions based on patient characteristics.
Abstracts
Paper Session 312: Clinical Management of Pain C. Disease Entities (Human) C03 - Central Pain (312/692) Fosphenytoin relieves central neuropathic pain following spinal cord injury C Sang, K Jenkins, K Wang, A Sarin, S Coccoli; Brigham and Women’s Hospital, Boston, MA The systemic administration of sodium channel antagonists has been shown to reduce pain in peripheral and central neuropathic pain states in both preclinical and clinical studies. We evaluated the analgesic efficacy of fosphenytoin, the prodrug of the sodium channel blocker phenytoin, in patients with central neuropathic pain following spinal cord injury (SCI). This was a randomized, double-blind, placebocontrolled, crossover clinical trial of a 15 minute intravenous administration of fosphenytoin 12 mg phenytoin equivalents (PE)/kg vs. fosphenytoin 4 mg PE/kg vs. lidocaine 2 mg/kg vs. saline. Subjects were healthy adults with chronic central neuropathic pain of at least moderate pain intensity. Primary endpoint was percent change from baseline in overall pain intensity (21-point log-linear Gracely scale). The primary endpoint was analyzed with linear model containing sequence, subject within sequence, period and treatment. All enrolled subjects were analyzed. Seventeen subjects enrolled in and completed the study. Mean pain intensity was 12/20 (range, 4-16/20). In the fosphenytoin 12 mg PE/kg arm, peak reduction in mean pain intensity was 50% at 45 minutes following the start of the infusion, with a statistically significant reduction compared to placebo in ongoing pain over the entire testing period (mean % change from baseline over 240 minutes, 31%; p⫽0.007). Trends were present but not statistically significant for the fosphenytoin 4 mg PE/kg and lidocaine 2 mg/kg treatments. Both the complete (n⫽7) and incomplete (n⫽10) subgroups showed a significant improvement (complete: 18% mean reduction in pain intensity, p⫽0.007; incomplete: 40% mean reduction in pain intensity, p⫽0.017). Side effects were well tolerated. In conclusion, fosphenytoin 12 mg/kg provides a statistically and clinically significant reduction in pain intensity. These data support the use of sodium channel antagonists for the treatment of central neuropathic pain following spinal cord injury. Acknowledgments: Stacey Kaplan, RN/ Kristie Chin/ John Vetrano/ Mary Sullivan, NP. Support: Christopher Reeve Paralysis Foundation/M01-RR-01066/R01-41503.
D. Treatment Approaches (Medical/Interventional) D04 - Cancer Pain Opioids (312/729) A randomized, placebo-controlled study of fentanyl effervescent buccal tablets for relief of breakthrough pain in opioid-tolerant patients with cancer D Taylor, R Portenoy, J Messina, L Tremmel; Comprehensive Pain Care PC, Marietta, GA Cancer-related breakthrough pain (BTP) typically is managed with a short-acting oral opioid, taken as needed, in addition to an around-the-clock opioid regimen. Since BTP episodes occur unpredictably and peak rapidly, there is benefit in providing faster pain relief. Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and efficiency of fentanyl absorption through the buccal mucosa and may provide rapid-onset analgesia. This double-blind, randomized, placebo-controlled study evaluated the efficacy and tolerability of FEBT for BTP in opioid-tolerant patients with chronic pain associated with cancer. Eighty (65%) of 123 patients identified an effective FEBT dose during initial open-label titration; 77 were randomized to 1 of 18 sequences of 10 tablets (7 FEBT and 3 placebo), and 72 were efficacyevaluable. During BTP episodes (FEBT: n⫽493; placebo: n⫽208), patients recorded pain intensity (PI), pain relief, and global medication performance (GMP) regularly between 15 and 60 minutes postdose. Clinically significant (ⱖ33%) decreases in PI occurred with FEBT in 13% of episodes by 15 minutes and in 48% of episodes by 30 minutes postdose; at all timepoints, the percentage of episodes showing ⱖ33% PI decrease was significantly greater for FEBT than for placebo (P⬍.05). At 30 minutes postdose, PI decreased by ⱖ50% with FEBT in 24% of episodes and with placebo in 16% of episodes (P⬍.05). Mean GMP ratings at 30 minutes were 1.4 (“good”) for FEBT versus 0.9 (“fair”) for placebo, and at 60 minutes were 2.1 (“very good”) for FEBT versus 1.3 (“good”) for placebo. The analgesic effect of FEBT exceeded that of placebo in all measurements, including responder analysis and GMP ratings. Adverse events (nausea, vomiting, dizziness, constipation, and somnolence) were typical of opioids; 2 patients discontinued because of oral tolerability issues. This study provides the first evidence that FEBT are safe and effective for BTP associated with cancer.