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Novel therapeutic agents
60
Abstracts
(805) Report on Intra-articular Botulinum Toxin Type A for Refractory Joint pain
(807) A study to assess the maximum tolerated dose of Tiagabine in patients with painful Diabetic Polyneuropathy
M. Mahowald, J. Singh, D. Dykstra; Minneapolis VA Medical Center/Univ Minnesota, Minneapolis, MN The purpose of this work was to report the off-label use of botulinum toxin type A (BoNT/A) as an intra-articular(IA) treatment for refractory joint pain. We conducted a retrospective record review of IA-BoNT/A (20-50units Allergan BOTOX) into 6 joints of 5 patients with moderate to severe chronic knee or ankle joint pain for 3-20y. All had failed IA corticosteroid injections and were not candidates for joint replacement (4 too young, 1 had spastic paraparesis). Pain severity was recorded on a 0-10 scale, and lower extremity (LE) function was measured by the time to stand up from a chair 10 times (10XTST). Two patients had osteoarthritis(1 knee 2 ankles), 1 had psoriatic arthritis (knee) and 2 had rheumatoid arthritis(1 knee 1 ankle). Age range was 42 to 54y; 2 were female & 3 male. Onset of pain relief after IA-BoNT/A was 1.5 d to 2 wks. Pain severity decreased 55% from 6.8⫾1.2 to 2.9⫾2.3 (p⫽.018); 5/6 joints had ⫽30% pain reduction; and 3/6 had ⫽50% pain reduction. Duration of pain relief was 2-6 months in 4/6 joints and 2/6 joints are still under evaluation. IA-BoNT/A was safe - no patient had increased joint swelling, pain, or systemic effects of fever or fatigue. No new leg muscle weakness developed. Lower extremity function improved in 4 patients (1 was wheel chair bound and 1 had both ankles injected) with a 38% decrease in the 10X TST from a mean of 35.7⫾15 sec to 22.5⫾14 sec (2 tailed paired t test p⫽.038). This is the first report of joint pain relief with intra-articular injection of BoNT/A. IA-BoNT/A was safe and also improved lower extremity function. These findings suggest IA-BoNT/A may offer a safe new option for treatment of refractory joint pain. A randomized controlled trial of IA-BoNT/A has been initiated to confirm these findings.
L. Kirby, B. Belleau; Pivotal Research Centers, Peoria, AZ The objective was to evaluate the tolerability, maximum tolerated dose (MTD), and preliminary efficacy of 2 titration regimens of tiagabine in patients with painful diabetic polyneuropathy. Gamma-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the CNS. Loss of GABA tone contributes in part to enhanced pain sensitivity. Tiagabine, a selective GABA reuptake inhibitor (SGRI), increases synaptic GABA levels in pain-modulating regions of the brain and spinal cord. Preclinical and preliminary clinical reports suggest that tiagabine may reduce neuropathic pain. Tiagabine starting dose was 4 mg/d (2 mg bid). The dose was increased by 2 mg/3 d (Group 1) or 4 mg/3 d (Group 2) until a nontolerable or maximum (28 mg/d) dose was reached. MTD was the highest dose tolerated for 7 days. Pain and sleep were assessed at baseline and MTD using the McGill Pain Questionnaire (MPQ) and sleep diary. All patients completed the study (Group 1, n⫽5; Group 2, n⫽5; placebo, n⫽4). Median MTD of tiagabine was 16 mg/d for both groups (4-28 mg/d). 90% of patients had an MTD ⱖ8 mg/d, with 1 patient titrating to 28 mg/d. The most common adverse events that led to determination of a nontolerated dose were dizziness (n⫽8), asthenia (n⫽4), and headache (n⫽4). Tiagabine treatment appeared to reduce pain, as shown by a decrease in mean MPQ scores (Group 1, -3.5; Group 2, -13.8; placebo, -6.0). Tiagabine also appeared to improve sleep, as indicated by an increase in mean sleep diary ratings (Group 1, 8.4; Group 2, 11.6; placebo, -11.2) Treatment with tiagabine was generally well tolerated in patients with painful diabetic polyneuropathy. The median MTD of tiagabine was 16 mg/d (4-28 mg/d). The results suggest that tiagabine may possess analgesic and sleep-facilitating properties in this patient population. Further study in pain is warranted.
(806) Pregabalin dosed BID is efficacious for improving sleep interference in patients suffering from postherpetic neuralgia: results of a large, randomized, placebo-controlled trial
(808) A prospective, randomized, double-blinded trial evaluating varying volumes of diluent with botulinum toxin type A (Botox) in the treatment of refractory myofascial cervicothoracic pain
R. Van Seventer, C. Bladin, B. Hoggart, S. Martin; Amphia Ziekenhuis, Breda, The Netherlands Sleep disturbance is commonly comorbid with neuropathic pain syndromes, including postherpetic neuralgia (PHN). This study evaluated the efficacy of pregabalin given BID (150, 300, or 300/600 mg/d) for the relief of pain and comorbid sleep disturbance in patients with PHN. Following are the results of the effects of pregabalin on sleep disturbance. 368 patients with pain associated with PHN for ⱖ3 months received at least one dose of pregabalin in this multicenter, 13-week, randomized, double-blind, placebo-controlled study. Patients received placebo (n⫽93) or pregabalin 150 mg/d BID (n⫽87), 300 mg/d BID (n⫽98), or 300/600 mg/d BID (n⫽90). On awakening each morning, patients rated, on an 11-point scale, how their pain had interfered with their sleep the previous night. Changes in sleep disturbance were measured by endpoint mean sleep interference score, weekly sleep interference score, and by the Medical Outcomes Study- Sleep Scale (MOS-S). Comparison of mean sleep interference scores at endpoint and weekly for Weeks 1-13 showed significant improvement for patients who received pregabalin (all dosages) vs placebo (endpoint, P⬍0.001; weekly P⬍0.01). All three pregabalin groups also showed greater improvement than placebo in mean MOS-Sleep scale scores for Sleep Disturbance (P⬍0.002) and the Overall Sleep Problem Index (P⬍0.003). (The study also demonstrated statistically significant improvements in its primary efficacy variable, relief of neuropathic pain associated with PHN.) Each of the three BID dosages of pregabalin (150, 300, 300/600 mg/d) was associated with improved patient-reported sleep outcomes in this study of PHN patients. The beneficial effect on sleep interference began by week 1 and was sustained at statistically significant levels throughout the study. This study was funded by Pfizer, Inc.
M. Royal, B. Bhakta, M. Jenson, V. Movva, R. Sorenson, J. Valentino; PETC Research Group, Tulsa, OK A prospective, randomized, double-blinded trial of 72 patients with refractory myofascial pain (MP) involving the upper trapezius (UT) and levator scapulae (LS) muscles refractory to conservative therapy was performed to evaluate the effect of volume of diluent used with Botulinum toxin Type A (BTA, Botox®, Allergan, Inc., Irvine, CA: 200u/cc, 100u/cc or 50u/cc in saline). All patients who entered had short-term responses to standard trigger point (TP) injections.. A single investigator (who was excluded from all follow up assessments) performed the injections by palpation directly into the TP with 25u/site. The total patient dose was 75-150 units for 3-6 TPs into the affected muscles (maximum of 3 per UT and 2 per LS). Pressure algometry, TP tenderness, muscle spasm, pain VAS, McGill Short Form Pain Questionnaire, Oswestry Neck Pain Questionnaire, Beck‘s Depression Inventory and patient and physician global responses were assessed at 2, 4, 6, 8, 12, and 24 weeks by investigators blinded as to the volume received. Essentially, every outcome measure showed highly significant change from baseline lasting up to 24 weeks, but with a few exceptions (right LS algometry and left UT tenderness), the outcome measures demonstrated only a trend toward significance between the different groups with higher volumes demonstrating better responses. The injections were well tolerated with no significant side effects experienced. Increasing volume of diluent appears to play a supportive role in improving outcome when BTA is used to treat MP. Additional, studies are needed to confirm these results.
Abstracts
(805) Report on Intra-articular Botulinum Toxin Type A for Refractory Joint pain
(807) A study to assess the maximum tolerated dose of Tiagabine in patients with painful Diabetic Polyneuropathy
M. Mahowald, J. Singh, D. Dykstra; Minneapolis VA Medical Center/Univ Minnesota, Minneapolis, MN The purpose of this work was to report the off-label use of botulinum toxin type A (BoNT/A) as an intra-articular(IA) treatment for refractory joint pain. We conducted a retrospective record review of IA-BoNT/A (20-50units Allergan BOTOX) into 6 joints of 5 patients with moderate to severe chronic knee or ankle joint pain for 3-20y. All had failed IA corticosteroid injections and were not candidates for joint replacement (4 too young, 1 had spastic paraparesis). Pain severity was recorded on a 0-10 scale, and lower extremity (LE) function was measured by the time to stand up from a chair 10 times (10XTST). Two patients had osteoarthritis(1 knee 2 ankles), 1 had psoriatic arthritis (knee) and 2 had rheumatoid arthritis(1 knee 1 ankle). Age range was 42 to 54y; 2 were female & 3 male. Onset of pain relief after IA-BoNT/A was 1.5 d to 2 wks. Pain severity decreased 55% from 6.8⫾1.2 to 2.9⫾2.3 (p⫽.018); 5/6 joints had ⫽30% pain reduction; and 3/6 had ⫽50% pain reduction. Duration of pain relief was 2-6 months in 4/6 joints and 2/6 joints are still under evaluation. IA-BoNT/A was safe - no patient had increased joint swelling, pain, or systemic effects of fever or fatigue. No new leg muscle weakness developed. Lower extremity function improved in 4 patients (1 was wheel chair bound and 1 had both ankles injected) with a 38% decrease in the 10X TST from a mean of 35.7⫾15 sec to 22.5⫾14 sec (2 tailed paired t test p⫽.038). This is the first report of joint pain relief with intra-articular injection of BoNT/A. IA-BoNT/A was safe and also improved lower extremity function. These findings suggest IA-BoNT/A may offer a safe new option for treatment of refractory joint pain. A randomized controlled trial of IA-BoNT/A has been initiated to confirm these findings.
L. Kirby, B. Belleau; Pivotal Research Centers, Peoria, AZ The objective was to evaluate the tolerability, maximum tolerated dose (MTD), and preliminary efficacy of 2 titration regimens of tiagabine in patients with painful diabetic polyneuropathy. Gamma-aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the CNS. Loss of GABA tone contributes in part to enhanced pain sensitivity. Tiagabine, a selective GABA reuptake inhibitor (SGRI), increases synaptic GABA levels in pain-modulating regions of the brain and spinal cord. Preclinical and preliminary clinical reports suggest that tiagabine may reduce neuropathic pain. Tiagabine starting dose was 4 mg/d (2 mg bid). The dose was increased by 2 mg/3 d (Group 1) or 4 mg/3 d (Group 2) until a nontolerable or maximum (28 mg/d) dose was reached. MTD was the highest dose tolerated for 7 days. Pain and sleep were assessed at baseline and MTD using the McGill Pain Questionnaire (MPQ) and sleep diary. All patients completed the study (Group 1, n⫽5; Group 2, n⫽5; placebo, n⫽4). Median MTD of tiagabine was 16 mg/d for both groups (4-28 mg/d). 90% of patients had an MTD ⱖ8 mg/d, with 1 patient titrating to 28 mg/d. The most common adverse events that led to determination of a nontolerated dose were dizziness (n⫽8), asthenia (n⫽4), and headache (n⫽4). Tiagabine treatment appeared to reduce pain, as shown by a decrease in mean MPQ scores (Group 1, -3.5; Group 2, -13.8; placebo, -6.0). Tiagabine also appeared to improve sleep, as indicated by an increase in mean sleep diary ratings (Group 1, 8.4; Group 2, 11.6; placebo, -11.2) Treatment with tiagabine was generally well tolerated in patients with painful diabetic polyneuropathy. The median MTD of tiagabine was 16 mg/d (4-28 mg/d). The results suggest that tiagabine may possess analgesic and sleep-facilitating properties in this patient population. Further study in pain is warranted.
(806) Pregabalin dosed BID is efficacious for improving sleep interference in patients suffering from postherpetic neuralgia: results of a large, randomized, placebo-controlled trial
(808) A prospective, randomized, double-blinded trial evaluating varying volumes of diluent with botulinum toxin type A (Botox) in the treatment of refractory myofascial cervicothoracic pain
R. Van Seventer, C. Bladin, B. Hoggart, S. Martin; Amphia Ziekenhuis, Breda, The Netherlands Sleep disturbance is commonly comorbid with neuropathic pain syndromes, including postherpetic neuralgia (PHN). This study evaluated the efficacy of pregabalin given BID (150, 300, or 300/600 mg/d) for the relief of pain and comorbid sleep disturbance in patients with PHN. Following are the results of the effects of pregabalin on sleep disturbance. 368 patients with pain associated with PHN for ⱖ3 months received at least one dose of pregabalin in this multicenter, 13-week, randomized, double-blind, placebo-controlled study. Patients received placebo (n⫽93) or pregabalin 150 mg/d BID (n⫽87), 300 mg/d BID (n⫽98), or 300/600 mg/d BID (n⫽90). On awakening each morning, patients rated, on an 11-point scale, how their pain had interfered with their sleep the previous night. Changes in sleep disturbance were measured by endpoint mean sleep interference score, weekly sleep interference score, and by the Medical Outcomes Study- Sleep Scale (MOS-S). Comparison of mean sleep interference scores at endpoint and weekly for Weeks 1-13 showed significant improvement for patients who received pregabalin (all dosages) vs placebo (endpoint, P⬍0.001; weekly P⬍0.01). All three pregabalin groups also showed greater improvement than placebo in mean MOS-Sleep scale scores for Sleep Disturbance (P⬍0.002) and the Overall Sleep Problem Index (P⬍0.003). (The study also demonstrated statistically significant improvements in its primary efficacy variable, relief of neuropathic pain associated with PHN.) Each of the three BID dosages of pregabalin (150, 300, 300/600 mg/d) was associated with improved patient-reported sleep outcomes in this study of PHN patients. The beneficial effect on sleep interference began by week 1 and was sustained at statistically significant levels throughout the study. This study was funded by Pfizer, Inc.
M. Royal, B. Bhakta, M. Jenson, V. Movva, R. Sorenson, J. Valentino; PETC Research Group, Tulsa, OK A prospective, randomized, double-blinded trial of 72 patients with refractory myofascial pain (MP) involving the upper trapezius (UT) and levator scapulae (LS) muscles refractory to conservative therapy was performed to evaluate the effect of volume of diluent used with Botulinum toxin Type A (BTA, Botox®, Allergan, Inc., Irvine, CA: 200u/cc, 100u/cc or 50u/cc in saline). All patients who entered had short-term responses to standard trigger point (TP) injections.. A single investigator (who was excluded from all follow up assessments) performed the injections by palpation directly into the TP with 25u/site. The total patient dose was 75-150 units for 3-6 TPs into the affected muscles (maximum of 3 per UT and 2 per LS). Pressure algometry, TP tenderness, muscle spasm, pain VAS, McGill Short Form Pain Questionnaire, Oswestry Neck Pain Questionnaire, Beck‘s Depression Inventory and patient and physician global responses were assessed at 2, 4, 6, 8, 12, and 24 weeks by investigators blinded as to the volume received. Essentially, every outcome measure showed highly significant change from baseline lasting up to 24 weeks, but with a few exceptions (right LS algometry and left UT tenderness), the outcome measures demonstrated only a trend toward significance between the different groups with higher volumes demonstrating better responses. The injections were well tolerated with no significant side effects experienced. Increasing volume of diluent appears to play a supportive role in improving outcome when BTA is used to treat MP. Additional, studies are needed to confirm these results.