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(182) Baseline pain and analgesic consumption over time as a determinant of post-op pain severity
Abstracts
Other (180) Plasma endogenous enkephalin levels in systemic sclerosis patients
P21 (182) Baseline pain and analgesic consumption over time as a determinant of post-op pain severity
T McNearney, K Sluka, M Fischbach, C Ahn, M Mayes; University of Texas Medical Branch, Galveston, TX Met-and leu-enkephalins are endogenous opioid neuropeptides with potent analgesic, vasoactive and immunomodulatory properties. We hypothesized that clinical or immunological abnormalities of systemic sclerosis (SSc) patients might be correlated to plasma enkephalin levels. Plasma samples were collected from people with SSc (N⫽17) and matched normal controls (N⫽16). Plasma met-enkephalin and leu-enkephalin levels (ug/ml) were measured by high performance liquid chromatography (HPLC). Additionally, plasma samples collected at study entry of the Genetics versus Environment in Scleroderma Outcomes Study (GENISOS) cohort (early SSc, N⫽136) were measured and correlated to database parameters. Statistical analyses were performed by Student’s t-tests and Pearson correlation coefficients. The results were as follows: 1. SSc patient vs matched normal controls study: SSc patients had significantly lower plasma met-enkephalin levels (0.16⫹0.10 vs 0.28⫹0.14 ug/ml, p⫽0.05) and lower plasma leu-enkephalin levels (1.04⫹0.90 vs 2.45⫹0.10 ug/ml, respectively, p⬍0.03). 2. GENISOS samples: Significantly lower plasma met-enkephalin levels were associated with anti-topoisomerase I seropositivity (6⫹8.3 vs 14.9⫹22.8 ug/ml, p⫽0.02). Plasma leu-enkephalin levels were significantly higher in SSc patients with digital pulp loss (95.6⫹130 vs 64.9⫹101 ug/ml, p⫽0.02). Generally, plasma leu-enkephalin levels were severalfold higher than plasma met-enkephalin levels. Lower mean plasma met-enkephalin levels and inversely higher leu-enkephalin levels were noted (p⫽NS) in SSc patients with Raynaud’s phenomena, digital gangrene, pulmonary fibrosis and pulmonary hypertension. Lower plasma levels of endogenous enkephalins in small SSc vs matched control groups may reflect depressed synthesis or increased degradation related to ongoing neurogenic, vasogenic or fibrogenic processes. The associations of plasma enkephalin levels to immunologic or clinical pathologies may underscore their physiologic significance in SSc. Supported by NIH Specialized Center of Research (SCOR) Grant in Scleroderma P50AR44888 (TAM, CA, MDM), NIH Centers for Research Translation (CORT) P50AR054144 (TAM, CA, MDM), University Clinic Research Center Grants M01-RR00073 (UTMB), M01RR02558 (UTH-HSC), M01-RR01346 (UT-SA), NIH K0202201 (KAS), NS39734 (KAS), AR052316 (KAS).
D Solorio, D Baum, M Kuss; SCIREX Research Centers, Austin, TX There has been much discussion in the context of analgesic drug development regarding which surgical procedures produce mild, moderate and severe pain. Furthermore, related discussion as to what constitutes major or minor surgery often confuses drug developers attempting to select appropriate inclusion/exclusion criteria for acute pain studies. The authors have compiled from numerous published study results various surgical selection criteria such as baseline pain one should consider when designing analgesic clinical trials. The authors reviewed and selected over 20 published analgesic clinical trials in an effort to catalog specific surgical criteria to better explain pain severity and durability of various surgical procedures. Surgical procedures evaluated include third molar extraction, hysterectomy, bunionectomy, hip and/or knee replacement, hernia repair, and hammertoe repair. In addition to using baseline pain scores and analgesic consumption over time to compare between surgical procedures the authors also used established efficacy end-points (PI, PID, PR, TOTPAR, SPID) to compare drug response within a clinical study, between studies utilizing the same model, or between models. Comparisons are aided by transforming these variables into quantities known as effect sizes. An effect size is defined as the difference between two means divided by an estimate of the common standard deviation. By looking at differences of means rather than individual means, effect sizes may account for systematic “shifts” due solely to variations in mean starting pain. For several recent investigations on treatments for acute pain, the authors matched studies using the same active treatments, both compared to placebo, and measuring the same efficacy variables, where one study was in a specific post-surgical setting, and the other was in another post-surgical pain setting. Effect sizes were calculated for each study comparing the active treatment to placebo. Meaningful differences exist between various surgical procedures which could significantly impact analgesic trial outcomes.
(181) Psychological impairment influences pain duration following surgical injury
Treatment Approaches (Medical/Interventional)
I Carroll, J Wang, C Wang, M Gillespie, P Barelka, K Humphreys, J Trafton, F Dirbas, S Goodman, R Whyte, W Cannon, G Yang, J Pollard, S Mackey; Stanford University, Stanford, CA To date, numerous studies have investigated the severity of post-operative pain, but few have characterized the duration of pain following surgery. We studied time-to-pain resolution following surgery to establish the natural history of pain cessation following five specific surgeries and to identify factors that predict persistent pain following surgery. A prospective, longitudinal observational study was conducted with 77 patients who underwent five distinct surgical procedures: thoracotomy, total hip replacement, total knee replacement, radical mastectomy, lumpectomy. Patients were consented before their surgery and asked to complete baseline assessments for psychological items implicated as risk factors for chronic pain. In addition, patients were given the Brief Pain Inventory (BPI) beginning with post-operative Day 1 and daily thereafter until their pain resolved (defined as five consecutive days of zero average pain). Time to pain resolution was analyzed using both univariate and multivariate survival analysis models, stratified by surgery type. Median time to pain resolution was 64 days, and 21% of patients reported ongoing pain at the surgical site 150 days post operation. Univariate analysis revealed that a number of risk factors were significantly associated with delayed pain resolution, independent of surgery type. Multivariate analysis identified preoperative PTSD symptomatology, self-perceived addiction-susceptibility, and elevated levels of Post-Operative Day 1 pain severity as predictors of delayed pain resolution even when controlling for all other variables. In contrast, anxiety, depression, and preoperative opioid use did not predict delayed pain resolution in multivariate models. This study identifies risk factors that influence pain resolution and has facilitated development of a useful, practical methodology by which to investigate factors that promote pain persistence following injury.
Anticonvulsants (183) Evaluation of lacosamide in diabetic neuropathic pain trials A Shaibani, S Bongardt, K Sommerville; Nerve and Muscle Center, Houston, TX To evaluate efficacy and safety of the investigational antinociceptive, anticonvulsant drug lacosamide in the treatment of diabetic neuropathic pain, data from Phase II and III double-blind, randomized, placebo-controlled trials were evaluated. Three fixed-dose trials (SP742, SP743, SP768) consisted of a 12-week maintenance phase in which participants were administered 200, 400 or 600 mg/day lacosamide or placebo. A Phase II flexible-dose trial (SP614), in which patients were allowed a maximum of 400mg/day lacosamide or placebo, consisted of a 4-week maintenance phase. The primary outcome was within-subject change in average daily pain score (11-point Likert) from baseline to the last 4-weeks of maintenance for the fixed-dose trials and from baseline to the end of maintenance for the flexible-dose trial. In all trials, lacosamide at all doses (n⫽1023) numerically reduced pain scores versus placebo (n⫽291). Results were statistically significant for 400mg dose in two trials (SP614, P⫽.04; SP742, P⫽.01) and at the level of significance in SP768 (P⫽.0507). Significance was not reached in SP743 due to a strong placebo effect at the final visit. When evaluating the secondary variable of change from baseline to the entire maintenance phase, in the fixed-dose trials both 400 and 600mg/day lacosamide significantly reduced pain over placebo (P⬍.02 for both doses in each trial). Adverse event data from these trials were pooled. Treatment with 400 and 600 mg/day had the following frequencies of adverse events ⬎5% in either group: dizziness (13.6% for 400 mg/day vs 25.3% for 600 mg/day), fatigue (7.7% in each group), nausea (6.8% with 400 mg vs 14.9% for 600 mg), tremor (5.9% vs 9.4%), headache (8.5% vs 10.5%), vertigo (3.3% vs 7.2%), somnolence (4.2% vs 5.8%), and balance disorder (2.6% vs 5.5%). In clinical trials of diabetic neuropathic pain, lacosamide treatment 400mg/day offered an optimal combination of efficacy and safety, with significant pain reductions.
Other (180) Plasma endogenous enkephalin levels in systemic sclerosis patients
P21 (182) Baseline pain and analgesic consumption over time as a determinant of post-op pain severity
T McNearney, K Sluka, M Fischbach, C Ahn, M Mayes; University of Texas Medical Branch, Galveston, TX Met-and leu-enkephalins are endogenous opioid neuropeptides with potent analgesic, vasoactive and immunomodulatory properties. We hypothesized that clinical or immunological abnormalities of systemic sclerosis (SSc) patients might be correlated to plasma enkephalin levels. Plasma samples were collected from people with SSc (N⫽17) and matched normal controls (N⫽16). Plasma met-enkephalin and leu-enkephalin levels (ug/ml) were measured by high performance liquid chromatography (HPLC). Additionally, plasma samples collected at study entry of the Genetics versus Environment in Scleroderma Outcomes Study (GENISOS) cohort (early SSc, N⫽136) were measured and correlated to database parameters. Statistical analyses were performed by Student’s t-tests and Pearson correlation coefficients. The results were as follows: 1. SSc patient vs matched normal controls study: SSc patients had significantly lower plasma met-enkephalin levels (0.16⫹0.10 vs 0.28⫹0.14 ug/ml, p⫽0.05) and lower plasma leu-enkephalin levels (1.04⫹0.90 vs 2.45⫹0.10 ug/ml, respectively, p⬍0.03). 2. GENISOS samples: Significantly lower plasma met-enkephalin levels were associated with anti-topoisomerase I seropositivity (6⫹8.3 vs 14.9⫹22.8 ug/ml, p⫽0.02). Plasma leu-enkephalin levels were significantly higher in SSc patients with digital pulp loss (95.6⫹130 vs 64.9⫹101 ug/ml, p⫽0.02). Generally, plasma leu-enkephalin levels were severalfold higher than plasma met-enkephalin levels. Lower mean plasma met-enkephalin levels and inversely higher leu-enkephalin levels were noted (p⫽NS) in SSc patients with Raynaud’s phenomena, digital gangrene, pulmonary fibrosis and pulmonary hypertension. Lower plasma levels of endogenous enkephalins in small SSc vs matched control groups may reflect depressed synthesis or increased degradation related to ongoing neurogenic, vasogenic or fibrogenic processes. The associations of plasma enkephalin levels to immunologic or clinical pathologies may underscore their physiologic significance in SSc. Supported by NIH Specialized Center of Research (SCOR) Grant in Scleroderma P50AR44888 (TAM, CA, MDM), NIH Centers for Research Translation (CORT) P50AR054144 (TAM, CA, MDM), University Clinic Research Center Grants M01-RR00073 (UTMB), M01RR02558 (UTH-HSC), M01-RR01346 (UT-SA), NIH K0202201 (KAS), NS39734 (KAS), AR052316 (KAS).
D Solorio, D Baum, M Kuss; SCIREX Research Centers, Austin, TX There has been much discussion in the context of analgesic drug development regarding which surgical procedures produce mild, moderate and severe pain. Furthermore, related discussion as to what constitutes major or minor surgery often confuses drug developers attempting to select appropriate inclusion/exclusion criteria for acute pain studies. The authors have compiled from numerous published study results various surgical selection criteria such as baseline pain one should consider when designing analgesic clinical trials. The authors reviewed and selected over 20 published analgesic clinical trials in an effort to catalog specific surgical criteria to better explain pain severity and durability of various surgical procedures. Surgical procedures evaluated include third molar extraction, hysterectomy, bunionectomy, hip and/or knee replacement, hernia repair, and hammertoe repair. In addition to using baseline pain scores and analgesic consumption over time to compare between surgical procedures the authors also used established efficacy end-points (PI, PID, PR, TOTPAR, SPID) to compare drug response within a clinical study, between studies utilizing the same model, or between models. Comparisons are aided by transforming these variables into quantities known as effect sizes. An effect size is defined as the difference between two means divided by an estimate of the common standard deviation. By looking at differences of means rather than individual means, effect sizes may account for systematic “shifts” due solely to variations in mean starting pain. For several recent investigations on treatments for acute pain, the authors matched studies using the same active treatments, both compared to placebo, and measuring the same efficacy variables, where one study was in a specific post-surgical setting, and the other was in another post-surgical pain setting. Effect sizes were calculated for each study comparing the active treatment to placebo. Meaningful differences exist between various surgical procedures which could significantly impact analgesic trial outcomes.
(181) Psychological impairment influences pain duration following surgical injury
Treatment Approaches (Medical/Interventional)
I Carroll, J Wang, C Wang, M Gillespie, P Barelka, K Humphreys, J Trafton, F Dirbas, S Goodman, R Whyte, W Cannon, G Yang, J Pollard, S Mackey; Stanford University, Stanford, CA To date, numerous studies have investigated the severity of post-operative pain, but few have characterized the duration of pain following surgery. We studied time-to-pain resolution following surgery to establish the natural history of pain cessation following five specific surgeries and to identify factors that predict persistent pain following surgery. A prospective, longitudinal observational study was conducted with 77 patients who underwent five distinct surgical procedures: thoracotomy, total hip replacement, total knee replacement, radical mastectomy, lumpectomy. Patients were consented before their surgery and asked to complete baseline assessments for psychological items implicated as risk factors for chronic pain. In addition, patients were given the Brief Pain Inventory (BPI) beginning with post-operative Day 1 and daily thereafter until their pain resolved (defined as five consecutive days of zero average pain). Time to pain resolution was analyzed using both univariate and multivariate survival analysis models, stratified by surgery type. Median time to pain resolution was 64 days, and 21% of patients reported ongoing pain at the surgical site 150 days post operation. Univariate analysis revealed that a number of risk factors were significantly associated with delayed pain resolution, independent of surgery type. Multivariate analysis identified preoperative PTSD symptomatology, self-perceived addiction-susceptibility, and elevated levels of Post-Operative Day 1 pain severity as predictors of delayed pain resolution even when controlling for all other variables. In contrast, anxiety, depression, and preoperative opioid use did not predict delayed pain resolution in multivariate models. This study identifies risk factors that influence pain resolution and has facilitated development of a useful, practical methodology by which to investigate factors that promote pain persistence following injury.
Anticonvulsants (183) Evaluation of lacosamide in diabetic neuropathic pain trials A Shaibani, S Bongardt, K Sommerville; Nerve and Muscle Center, Houston, TX To evaluate efficacy and safety of the investigational antinociceptive, anticonvulsant drug lacosamide in the treatment of diabetic neuropathic pain, data from Phase II and III double-blind, randomized, placebo-controlled trials were evaluated. Three fixed-dose trials (SP742, SP743, SP768) consisted of a 12-week maintenance phase in which participants were administered 200, 400 or 600 mg/day lacosamide or placebo. A Phase II flexible-dose trial (SP614), in which patients were allowed a maximum of 400mg/day lacosamide or placebo, consisted of a 4-week maintenance phase. The primary outcome was within-subject change in average daily pain score (11-point Likert) from baseline to the last 4-weeks of maintenance for the fixed-dose trials and from baseline to the end of maintenance for the flexible-dose trial. In all trials, lacosamide at all doses (n⫽1023) numerically reduced pain scores versus placebo (n⫽291). Results were statistically significant for 400mg dose in two trials (SP614, P⫽.04; SP742, P⫽.01) and at the level of significance in SP768 (P⫽.0507). Significance was not reached in SP743 due to a strong placebo effect at the final visit. When evaluating the secondary variable of change from baseline to the entire maintenance phase, in the fixed-dose trials both 400 and 600mg/day lacosamide significantly reduced pain over placebo (P⬍.02 for both doses in each trial). Adverse event data from these trials were pooled. Treatment with 400 and 600 mg/day had the following frequencies of adverse events ⬎5% in either group: dizziness (13.6% for 400 mg/day vs 25.3% for 600 mg/day), fatigue (7.7% in each group), nausea (6.8% with 400 mg vs 14.9% for 600 mg), tremor (5.9% vs 9.4%), headache (8.5% vs 10.5%), vertigo (3.3% vs 7.2%), somnolence (4.2% vs 5.8%), and balance disorder (2.6% vs 5.5%). In clinical trials of diabetic neuropathic pain, lacosamide treatment 400mg/day offered an optimal combination of efficacy and safety, with significant pain reductions.