Peter Schmidt

All Publications

• Safety and Efficacy of Pemivibart, a Long-Acting Monoclonal Antibody, for Prevention of Symptomatic COVID-19: Interim Results From a Phase 3 Randomized Clinical Trial (CANOPY). Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Wolfe, C. R., Cohen, J., Mahoney, K., Holmes, A., Betancourt, N., Gupta, D., Tosh, K., Narayan, K., Campanaro, E., Katz, C., Phelan, A. M., Yalcin, I., Wingertzahn, M., Hawn, P., Schmidt, P., Li, Y., Popejoy, M. 2025

  Abstract

  We report an interim analysis of safety and efficacy of pemivibart in individuals with (cohort A) or without (cohort B) significant immunocompromise in the phase 3 CANOPY trial.Eligible participants (≥18 years; negative for current SARS-CoV-2 infection) received 2 intravenous 4500-mg pemivibart infusions (cohort A) or were randomized 2:1 to receive blinded pemivibart or placebo (cohort B) 90 days apart. Safety was a primary endpoint for both cohorts. The primary immunobridging endpoint for cohort A has previously been reported. Composite incidence of reverse transcription-polymerase chain reaction-confirmed symptomatic COVID-19, COVID-19 hospitalization, and all-cause mortality was an exploratory endpoint.In September-November 2023, 306 participants received pemivibart (cohort A); 317 received pemivibart and 162 placebo (cohort B). The most common study drug-related adverse events were infusion-related reactions (cohort A: 11/306 [3.6%]; cohort B: 7/317 [2.2%, pemivibart] and 0/162 [placebo]). Four of 623 (0.6%) participants who received pemivibart experienced anaphylactic reactions (2 serious). In cohort A, the composite COVID-19 incidence through month 6 was 11/298 (3.7%; 2 deaths). In cohort B, 6/317 (1.9%; no deaths) and 19/160 (11.9%; no deaths) pemivibart and placebo participants, respectively, met the endpoint through month 6 (84.1% standardized relative risk reduction [RRR; 95% CI, 60.9-93.5; nominal P<.0001]), and 15/317 (4.7%; 1 death) and 29/160 (18.1%; no deaths) pemivibart and placebo participants, respectively, met the endpoint through month 12 (73.9% standardized RRR [95% CI, 52.8-85.6; nominal P<.0001]). Twelve month protection was conferred with no additional dosing.Pemivibart provided prophylactic efficacy against COVID-19 and was well-tolerated by most participants. Anaphylaxis was an important safety risk.NCT06039449.

  View details for DOI 10.1093/cid/ciaf265

  View details for PubMedID 40410927

• Immunobridging for Pemivibart, a Monoclonal Antibody for Prevention of Covid-19. The New England journal of medicine Schmidt, P., Li, Y., Popejoy, M. 2024; 391 (19): 1860-1862

  View details for DOI 10.1056/NEJMc2404555

  View details for PubMedID 39536235

  View details for PubMedCentralID PMC11687646

• Prevention of COVID-19 Following a Single Intramuscular Administration of Adintrevimab: Results From a Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Trial (EVADE). Open forum infectious diseases Ison, M. G., Weinstein, D. F., Dobryanska, M., Holmes, A., Phelan, A. M., Li, Y., Gupta, D., Narayan, K., Tosh, K., Hershberger, E., Connolly, L. E., Yalcin, I., Campanaro, E., Hawn, P., Schmidt, P. 2023; 10 (7): ofad314

  Abstract

  The prevention of coronavirus disease 2019 (COVID-19) in vulnerable populations is a global health priority. EVADE was a phase 2/3 multicenter, double-blind, randomized, placebo-controlled trial of adintrevimab, an extended-half-life monoclonal antibody, for postexposure (PEP) and pre-exposure prophylaxis (PrEP) of symptomatic COVID-19.Eligible participants (vaccine-naive, aged ≥12 years) were randomized 1:1 to receive a single 300-mg intramuscular injection of adintrevimab or placebo. Primary efficacy end points were reverse transcription polymerase chain reaction (RT-PCR)-confirmed symptomatic COVID-19 through day 28 in the PEP cohort (RT-PCR-negative at baseline) and through month 3 in the PrEP cohort (RT-PCR-negative and seronegative at baseline) among participants randomized before emergence of the severe acute respiratory syndrome coronavirus 2 Omicron variant (November 30, 2021). Safety was assessed through 6 months.Between April 27, 2021, and January 11, 2022, 2582 participants were randomized. In the primary efficacy analysis, RT-PCR-confirmed symptomatic COVID-19 occurred in 3/175 (1.7%) vs 12/176 (6.8%) adintrevimab- and placebo-treated PEP participants, respectively (74.9% relative risk reduction [RRR]; standardized risk difference, -5.0%; 95% CI, -8.87% to -1.08%; P = .0123) and in 12/752 (1.6%) vs 40/728 (5.5%) adintrevimab- and placebo-treated PrEP participants, respectively (71.0% RRR; standardized risk difference, -3.9%; 95% CI, -5.75% to -2.01%; P < .0001). In a prespecified exploratory analysis of 428 PrEP participants randomized after the emergence of Omicron, adintrevimab reduced RT-PCR-confirmed symptomatic COVID-19 by 40.6% (standardized risk difference -8.4%; 95% CI, -15.35% to -1.46%; nominal P = .0177) vs placebo. Adintrevimab was well tolerated, with no serious drug-related adverse events reported.A single intramuscular injection of adintrevimab provided prophylactic efficacy against COVID-19 due to susceptible variants without safety concerns. Clinical trial registration. NCT04859517.

  View details for DOI 10.1093/ofid/ofad314

  View details for PubMedID 37496612

  View details for PubMedCentralID PMC10368201

• Efficacy and Safety of Adintrevimab (ADG20) for the Treatment of High-Risk Ambulatory Patients With Mild or Moderate Coronavirus Disease 2019: Results From a Phase 2/3, Randomized, Placebo-Controlled Trial (STAMP) Conducted During Delta Predominance and Early Emergence of Omicron. Open forum infectious diseases Ison, M. G., Popejoy, M., Evgeniev, N., Tzekova, M., Mahoney, K., Betancourt, N., Li, Y., Gupta, D., Narayan, K., Hershberger, E., Connolly, L. E., Yalcin, I., Das, A. F., Genge, J., Smith, M., Campanaro, E., Hawn, P., Schmidt, P. 2023; 10 (6): ofad279

  Abstract

  Safe and effective treatments are needed to prevent severe outcomes in individuals with coronavirus disease 2019 (COVID-19). We report results from STAMP, a phase 2/3, multicenter, double-blind, randomized, placebo-controlled trial of adintrevimab, an extended half-life monoclonal antibody, for treatment of high-risk ambulatory patients with mild to moderate COVID-19.Nonhospitalized, unvaccinated participants aged ≥12 years with mild to moderate COVID-19 and ≥1 risk factor for disease progression were randomized to receive a single intramuscular injection of 300 mg adintrevimab or placebo. Enrollment was paused due to the global emergence of the Omicron BA.1/BA1.1 variants, against which adintrevimab showed reduced activity in vitro. The primary efficacy endpoint was COVID-19-related hospitalization or all-cause death through day 29 in participants with COVID-19 due to laboratory-confirmed or suspected non-Omicron severe acute respiratory syndrome coronavirus 2 variants.Between 8 August 2021 and 11 January 2022, 399 participants were randomized to receive adintrevimab (n = 198) or placebo (n = 201), including 336 with COVID-19 due to non-Omicron variants. COVID-19-related hospitalization or all-cause death through day 29 occurred in 8 of 169 (4.7%) participants in the adintrevimab group and 23 of 167 (13.8%) participants in the placebo group, a 66% relative risk reduction in favor of adintrevimab (standardized risk difference, -8.7% [95% confidence interval, -14.71% to -2.67%]; P = .0047). Incidence of treatment-emergent adverse events (TEAEs) was similar between treatment groups (33.9% for adintrevimab and 39.5% for placebo). No adintrevimab-related serious TEAEs were reported.Treatment with a single intramuscular injection of adintrevimab provided protection against severe outcomes in high-risk ambulatory participants with COVID-19 due to susceptible variants, without safety concerns. Clinical Trial Registration. NCT04805671.

  View details for DOI 10.1093/ofid/ofad279

  View details for PubMedID 37351456

  View details for PubMedCentralID PMC10284338

• Antibody-mediated protection against symptomatic COVID-19 can be achieved at low serum neutralizing titers. Science translational medicine Schmidt, P., Narayan, K., Li, Y., Kaku, C. I., Brown, M. E., Champney, E., Geoghegan, J. C., Vásquez, M., Krauland, E. M., Yockachonis, T., Bai, S., Gunn, B. M., Cammarata, A., Rubino, C. M., Ambrose, P., Walker, L. M. 2023; 15 (688): eadg2783

  Abstract

  Multiple studies of vaccinated and convalescent cohorts have demonstrated that serum neutralizing antibody (nAb) titers correlate with protection against coronavirus disease 2019 (COVID-19). However, the induction of multiple layers of immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure has complicated the establishment of nAbs as a mechanistic correlate of protection (CoP) and hindered the definition of a protective nAb threshold. Here, we show that a half-life-extended monoclonal antibody (adintrevimab) provides about 50% protection against symptomatic COVID-19 in SARS-CoV-2-naïve adults at serum nAb titers on the order of 1:30. Vaccine modeling results support a similar 50% protective nAb threshold, suggesting that low titers of serum nAbs protect in both passive antibody prophylaxis and vaccination settings. Extrapolation of adintrevimab pharmacokinetic data suggests that protection against susceptible variants could be maintained for about 3 years. The results provide a benchmark for the selection of next-generation vaccine candidates and support the use of broad, long-acting monoclonal antibodies as alternatives or supplements to vaccination in high-risk populations.

  View details for DOI 10.1126/scitranslmed.adg2783

  View details for PubMedID 36947596

• Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial (vol 153, pg 303, 2018) JAMA SURGERY Hah, J., Mackey, S. C., Schmidt, P. 2022; 157 (6): 553

  View details for DOI 10.1001/jamasurg.2022.1392

  View details for Web of Science ID 000809213600033

• Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial (vol 153, pg 303, 2018) JAMA SURGERY Hah, J., Mackey, S. C., Schmidt, P. 2022

  View details for DOI 10.1001/jamasurg.2017.4915

  View details for Web of Science ID 000784959200002

• Chemotherapy Withdrawal Migraine PAIN MEDICINE Prabhakar, N. K., Schmidt, P. C. 2021

  View details for DOI 10.1093/pm/pnab184

  View details for Web of Science ID 000764447900001

  View details for PubMedID 34100947

• Long term safety, tolerability, and efficacy of intracutaneous zolmitriptan (M207) in the acute treatment of migraine. The journal of headache and pain Nahas, S. J., Hindiyeh, N., Friedman, D. I., Elbuluk, N., Kellerman, D. J., Foreman, P. K., Schmidt, P. 2021; 22 (1): 37

  Abstract

  OBJECTIVE: To determine the long-term safety and tolerability profile of M207 in the acute treatment of migraine.BACKGROUND: M207 is an investigational microneedle-based system for intracutaneous delivery of zolmitriptan for the treatment of migraine attacks. Following on the positive results of a Phase 2/3 placebo-controlled efficacy study (ZOTRIP), this study was designed to evaluate the safety of this novel product during repeated use for the treatment of migraine attacks.METHODS: In this 6-12month open-label, multicenter observational study, participants used an eDiary to record headache symptoms and adverse events at specified intervals up to 48h following treatment of a qualifying attack with M207 3.8mg (intracutaneous zolmitriptan). Participants underwent clinical evaluations at specified intervals up to 12months.RESULTS: Among 335 participants who treated ≥1 migraine attack, 257 completed 6months and 127 completed 1year of treatment. The most common reason for withdrawal from the study was a low frequency of reported attacks post randomization. Overall, 5963 migraine attacks were treated. Most participants (96%) experienced at least 1 adverse event, the vast majority of which concerned the application site, and>95% of which were mild. Fifteen participants (4%) withdrew due to adverse events; 4 withdrew due to 7 application site reactions, 6 of which were mild. Participants achieved pain freedom in 2477/5617 (44%) of attacks, most bothersome symptom freedom in 3315/5330 (62%) of attacks, and pain relief 2h post-dose in 4552/5617 (81%) of attacks. Sustained pain freedom 2-24h was seen in 1761/4698 (38%) of attacks, and 2-48h in 1534/4429 (35%) of attacks.CONCLUSIONS: The majority of participants experienced cutaneous adverse reactions such as application site erythema, swelling, and bleeding, and most reactions were scored as mild. These results are consistent with what was observed in the single migraine attack treatment ZOTRIP trial indicating that M207 is well tolerated in the setting of longer-term repeated use. Efficacy findings were also similar to those in the ZOTRIP trial.TRIAL REGISTRATION: Clinicaltrials.gov on September 13, 2017 ( NCT03282227 ).

  View details for DOI 10.1186/s10194-021-01249-z

  View details for PubMedID 34001002

• Building regional anesthesia capacity in limited-resource settings: a pilot study evaluating a 4-week curriculum PAIN MANAGEMENT Moll, V., Schmidt, P. C., Amos, C., Workneh, R. S., Tadesse, M., Mulugeta, E., Abate, A. 2021; 11 (1): 29–37

  Abstract

  Aim: To pilot a 4-week regional anesthesia curriculum for limited-resource settings. Intervention: A baseline needs assessment and knowledge test were deployed. The curriculum included lectures and hands-on teaching, followed by knowledge attainment tests. Results: Scores on the knowledge test improved from a mean of 37.1% (SD 14.7%) to 50.9% (SD 18.6%) (p = 0.017) at 4 weeks and 49% at 24 months. An average of 1.7 extremity blocks per month was performed in 3 months prior to the curriculum, compared with an average of 4.1 per month in 8 months following. Conclusion: This collaborative curriculum appeared to have a positive impact on the knowledge and utilization of regional anesthesia.

  View details for DOI 10.2217/pmt-2020-0044

  View details for Web of Science ID 000579459700001

  View details for PubMedID 33073715

• Erector Spinae Regional Anesthesia for Robotic Coronary Artery Bypass Surgery Is Not Associated With Reduced Postoperative Opioid Use: A Retrospective Observational Study. Journal of cardiothoracic and vascular anesthesia Moll, V., Ward, C. T., Jabaley, C. S., O'Reilly-Shah, V. N., Boorman, D. W., McKenzie-Brown, A. M., Halkos, M. E., Prabhakar, A., Pyronneau, L. R., Schmidt, P. C. 2020

  Abstract

  OBJECTIVE: Regional anesthesia techniques are gaining traction in cardiac surgery. The aim of this study was to compare the analgesic efficacy of erector spinae plane block catheters (ESPBC), serratus anterior plane block catheters (SAPBC), and paravertebral single-shot block (PVB) versus no block after robotic minimally invasive direct coronary artery bypass (MIDCAB).DESIGN: This was a retrospective observational study of routinely recorded data.SETTING: The study was performed at a single healthcare system.PARTICIPANTS: All patients underwent robotic MIDCAB.INTERVENTION: Data were analyzed from 346 patients during a 53-month period. The clinical data warehouse was queried for all robotic MIDCAB surgeries. Variables abstracted included type of nerve block, age, sex, use of adjuncts, Society of Thoracic Surgeons predicted short length of stay (PSLOS), total opioid consumption during the 72 hours after surgery, and postoperative hospital length of stay (LOS). The primary outcome was total oral morphine milligram equivalents (MME) consumed during the first 72 hours after surgery. The secondary outcome was hospital LOS.MEASUREMENTS AND MAIN RESULTS: In a model adjusting for PSLOS, the authors did not observe an association between ESPBC and the reduction of total administered oral MME within 72 hours after surgery. There was no significant difference in MME when comparing patients who received PVB to patients with ESPBC. Older age and female sex were associated with significantly lower MME. Patients who received ESPBC had a significantly shorter hospital LOS than patients with SAPBC.CONCLUSIONS: These findings suggested that postoperative pain after MIDCAB surgery might not be completely covered by ESPBC. Prospective studies are needed to further elucidate the value of this technique for robotic MIDCAB.

  View details for DOI 10.1053/j.jvca.2020.09.112

  View details for PubMedID 33127286

• Preoperative Factors Associated with Remote Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: Post Hoc Analysis of a Perioperative Gabapentin Trial. Journal of pain research Hah, J. M., Hilmoe, H. n., Schmidt, P. n., McCue, R. n., Trafton, J. n., Clay, D. n., Sharifzadeh, Y. n., Ruchelli, G. n., Hernandez Boussard, T. n., Goodman, S. n., Huddleston, J. n., Maloney, W. J., Dirbas, F. M., Shrager, J. n., Costouros, J. G., Curtin, C. n., Mackey, S. C., Carroll, I. n. 2020; 13: 2959–70

  Abstract

  Preoperative patient-specific risk factors may elucidate the mechanisms leading to the persistence of pain and opioid use after surgery. This study aimed to determine whether similar or discordant preoperative factors were associated with the duration of postoperative pain and opioid use.In this post hoc analysis of a randomized, double-blind, placebo-controlled trial of perioperative gabapentin vs active placebo, 410 patients aged 18-75 years, undergoing diverse operations underwent preoperative assessments of pain, opioid use, substance use, and psychosocial variables. After surgery, a modified Brief Pain Inventory was administered over the phone daily up to 3 months, weekly up to 6 months, and monthly up to 2 years after surgery. Pain and opioid cessation were defined as the first of 5 consecutive days of 0 out of 10 pain or no opioid use, respectively.Overall, 36.1%, 19.8%, and 9.5% of patients continued to report pain, and 9.5%, 2.4%, and 1.7% reported continued opioid use at 3, 6, and 12 months after surgery. Preoperative pain at the future surgical site (every 1-point increase in the Numeric Pain Rating Scale; HR 0.93; 95% CI 0.87-1.00; P=0.034), trait anxiety (every 10-point increase in the Trait Anxiety Inventory; HR 0.79; 95% CI 0.68-0.92; P=0.002), and a history of delayed recovery after injury (HR 0.62; 95% CI 0.40-0.96; P=0.034) were associated with delayed pain cessation. Preoperative opioid use (HR 0.60; 95% CI 0.39-0.92; P=0.020), elevated depressive symptoms (every 5-point increase in the Beck Depression Inventory-II score; HR 0.88; 95% CI 0.80-0.98; P=0.017), and preoperative pain outside of the surgical site (HR 0.94; 95% CI 0.89-1.00; P=0.046) were associated with delayed opioid cessation, while perioperative gabapentin promoted opioid cessation (HR 1.37; 95% CI 1.06-1.77; P=0.016).Separate risk factors for prolonged post-surgical pain and opioid use indicate that preoperative risk stratification for each outcome may identify patients needing personalized care to augment universal protocols for perioperative pain management and conservative opioid prescribing to improve long-term outcomes.

  View details for DOI 10.2147/JPR.S269370

  View details for PubMedID 33239904

  View details for PubMedCentralID PMC7680674

• Efficacy of Qtrypta (zolmitriptan intracutaneous system) Before and After the Initiation of CGRP Antibody Therapy in Subjects with Migraine - a Preliminary Assessment Hindiyeh, N., Schmidt, P., Engels, J., Halladay, W., Kellerman, D. SAGE PUBLICATIONS LTD. 2019: 394

  View details for Web of Science ID 000491167100061

• Review of Acute Treatment of Migraine Trial Results With the New FDA Endpoints: Design Implications for Future Trials HEADACHE Hindiyeh, N. A., Kellerman, D. J., Schmidt, P. C. 2019; 59 (5): 819–24

  View details for DOI 10.1111/head.13511

  View details for Web of Science ID 000472202500012

• Review of Acute Treatment of Migraine Trial Results With the New FDA Endpoints: Design Implications for Future Trials. Headache Hindiyeh, N. A., Kellerman, D. J., Schmidt, P. C. 2019

  Abstract

  BACKGROUND: In October 2014, the US Food and Drug Administration released a draft guidance for the development of drugs for the acute treatment of migraine. This guidance offered the option of replacing the previously required 4 co-primary endpoints: pain freedom, freedom from nausea, freedom from photophobia, and freedom from phonophobia, all at 2 hours posttreatment, with 2 co-primary endpoints: pain freedom and freedom from most bothersome symptom (MBS) other than pain, both at 2 hours posttreatment. At the time the new draft guidance was released, no large clinical trials had been undertaken with these 2 co-primary endpoints, posing a challenge in determining the sample size that might be required to achieve statistical significance. As a number of trials have now been completed, we conducted a review of the observed placebo responses, drug effect sizes, and sample sizes to better inform the design of future trials.METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane library for primary publications of phase 3 randomized, placebo-controlled, double-blind acute migraine treatment trials that used pain freedom and MBS freedom as primary or planned secondary endpoints. For each endpoint, placebo response rates were determined and used to generate estimates of sample size, assuming differences between placebo and active treatment groups of 10%, 15%, and 20%. Sample size calculations were based on 80% power using a 2-group continuity corrected chi-square test with a 5% 2-sided significance level.RESULTS: We identified abstracts or full-length papers describing results of 8 clinical trials employing the new co-primary endpoints. The mean placebo response rate for 2-hour pain freedom was 16.75% (range 11.8-21.3%) and treatment effect (difference in response rates between active and placebo groups) ranged from 5.0% to 27.2%. For 2-hour MBS freedom, the mean placebo response rate was 32.8% (range 25.2-48.1%), and the range of treatment effect was 8.9% to 25.4%. Based on a placebo response rate of 17% for pain freedom, the sample sizes that would have been required to achieve statistical significance were n=269, n=128, and n=77, for treatment effect sizes of 10%, 15%, and 20%, respectively. For MBS, assuming a placebo response rate of 33%, the corresponding required sample sizes would have been n=389, n=181, and n=105.CONCLUSIONS: The observed range of placebo response and treatment effect sizes suggests that use of the newly recommended 2 co-primary endpoints could reduce the sample sizes required to achieve significance compared with past trials using 4 primary endpoints (in which mean and median group sizes for recent trials were 375 and 362, respectively). However, the initial trials using the newly recommended co-primary endpoints tended to treat more participants than would have been minimally required. We anticipate that with the growing body of information regarding the use of these new endpoints, samples sizes may be more aligned with treatment efficacy, enabling faster and more cost-effective trials for acute migraine treatment.

  View details for PubMedID 30953576

• Factors Associated With Acute Pain Estimation, Postoperative Pain Resolution, Opioid Cessation, and Recovery Secondary Analysis of a Randomized Clinical Trial JAMA NETWORK OPEN Hah, J. M., Cramer, E., Hilmoe, H., Schmidt, P., McCue, R., Trafton, J., Clay, D., Sharifzadeh, Y., Ruchelli, G., Goodman, S., Huddleston, J., Maloney, W. J., Dirbas, F. M., Shrager, J., Costouros, J. G., Curtin, C., Mackey, S. C., Carroll, I. 2019; 2 (3)

  View details for DOI 10.1001/jamanetworkopen.2019.0168

  View details for Web of Science ID 000465424000048

• Factors Associated With Acute Pain Estimation, Postoperative Pain Resolution, Opioid Cessation, and Recovery: Secondary Analysis of a Randomized Clinical Trial. JAMA network open Hah, J. M., Cramer, E., Hilmoe, H., Schmidt, P., McCue, R., Trafton, J., Clay, D., Sharifzadeh, Y., Ruchelli, G., Goodman, S., Huddleston, J., Maloney, W. J., Dirbas, F. M., Shrager, J., Costouros, J. G., Curtin, C., Mackey, S. C., Carroll, I. 2019; 2 (3): e190168

  Abstract

  Importance: Acute postoperative pain is associated with the development of persistent postsurgical pain, but it is unclear which aspect is most estimable.Objective: To identify patient clusters based on acute pain trajectories, preoperative psychosocial characteristics associated with the high-risk cluster, and the best acute pain predictor of remote outcomes.Design, Setting, and Participants: A secondary analysis of the Stanford Accelerated Recovery Trial randomized, double-blind clinical trial was conducted at a single-center, tertiary, referral teaching hospital. A total of 422 participants scheduled for thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, or shoulder arthroscopy were enrolled between May 25, 2010, and July 25, 2014. Data analysis was performed from January 1 to August 1, 2018.Interventions: Patients were randomized to receive gabapentin (1200 mg, preoperatively, and 600 mg, 3 times a day postoperatively) or active placebo (lorazepam, 0.5 mg preoperatively, inactive placebo postoperatively) for 72 hours.Main Outcomes and Measures: A modified Brief Pain Inventory prospectively captured 3 surgical site pain outcomes: average pain and worst pain intensity over the past 24 hours, and current pain intensity. Within each category, acute pain trajectories (first 10 postoperative pain scores) were compared using a k-means clustering algorithm. Fifteen descriptors of acute pain were compared as predictors of remote postoperative pain resolution, opioid cessation, and full recovery.Results: Of the 422 patients enrolled, 371 patients (≤10% missing pain scores) were included in the analysis. Of these, 146 (39.4%) were men; mean (SD) age was 56.67 (11.70) years. Two clusters were identified within each trajectory category. The high pain cluster of the average pain trajectory significantly predicted prolonged pain (hazard ratio [HR], 0.63; 95% CI, 0.50-0.80; P<.001) and delayed opioid cessation (HR, 0.52; 95% CI, 0.41-0.67; P<.001) but was not a predictor of time to recovery in Cox proportional hazards regression (HR, 0.89; 95% CI, 0.69-1.14; P=.89). Preoperative risk factors for categorization to the high average pain cluster included female sex (adjusted relative risk [ARR], 1.36; 95% CI, 1.08-1.70; P=.008), elevated preoperative pain (ARR, 1.11; 95% CI, 1.07-1.15; P<.001), a history of alcohol or drug abuse treatment (ARR,1.90; 95% CI, 1.42-2.53; P<.001), and receiving active placebo (ARR, 1.27; 95% CI, 1.03-1.56; P=.03). Worst pain reported on postoperative day 10 was the best predictor of time to pain resolution (HR, 0.83; 95% CI, 0.78-0.87; P<.001), opioid cessation (HR, 0.84; 95% CI, 0.80-0.89; P<.001), and complete surgical recovery (HR, 0.91; 95% CI, 0.86-0.96; P<.001).Conclusions and Relevance: This study has shown a possible uniform predictor of remote postoperative pain, opioid use, and recovery that can be easily assessed. Future work is needed to replicate these findings.Trial Registration: ClinicalTrials.gov Identifier: NCT01067144.

  View details for PubMedID 30821824

• Efficacy of ADAM Zolmitriptan for the Acute Treatment of Difficult-to-Treat Migraine Headaches. Headache Tepper, S. J., Dodick, D. W., Schmidt, P. C., Kellerman, D. J. 2019

  Abstract

  To understand the efficacy of zolmitriptan applied with Adhesive Dermally Applied Microarray (ADAM) in treating types of migraine (those with severe headache pain, the presence of nausea, treatment ≥2 hours after migraine onset, or migraine present upon awakening) that are historically considered to be less responsive to oral medications.ADAM is an investigational system for intracutaneous drug administration. In a pivotal Phase 2b/3 study (ZOTRIP, N = 321 in the modified intention-to-treat population), ADAM zolmitriptan 3.8 mg provided superior pain freedom and freedom from patients' usual most bothersome associated symptom (MBS), compared with placebo at 2 hours post-dose. We undertook a post hoc analysis of data from the ZOTRIP trial to examine these same outcomes in subsets of patients whose migraine characteristics have been associated with poorer outcomes when treated with oral medications.The ZOTRIP trial was a multicenter, randomized, double-blind, placebo-controlled, parallel group Phase 2b/3 study conducted at 36 sites in the United States. Presented here are post hoc subgroup analyses of patients with nausea (n = 110) or severe pain (n = 72) at baseline, those whose treatment was delayed 2 or more hours after onset (n = 75), and those who awoke with migraine (n = 80). The Cochran-Mantel-Haenszel test was used to assess whether patients in the ADAM zolmitriptan 3.8 mg group had superior treatment outcomes compared with placebo.In patients with nausea, 2-hour pain freedom was achieved in 44% (26/59) in the ADAM zolmitriptan 3.8 mg group and 14% (7/51) in the placebo group (P = .005) (odds ratio = 5.11, 95% CI: 1.96-13.30), and 2-hour MBS freedom was achieved in 68% (40/59) in the active treatment group and 45% (23/51) of those receiving placebo (P = .009) (odds ratio = 2.86, 95% CI: 1.28-6.43). For those with severe pain, corresponding pain-free values were 26% (10/39) and 15% (5/33) (P = .249) (odds ratio = 2.14, 95% CI: 0.60-7.62), and MBS-free values were 64% (25/39) and 42% (14/33) (P = .038) (odds ratio = 2.86, 95% CI: 1.05-7.79). Among participants who awoke with migraine, 44% (16/36) and 16% (7/44) were pain-free in the ADAM zolmitriptan 3.8 mg and placebo groups, respectively (P = .006) (odds ratio = 4.29, 95% CI: 1.50-12.31), and 72% (26/36) vs 39% (17/44) were MBS-free, respectively (P = .003) (odds ratio = 4.40, 95% CI: 1.61-12.05). In those whose treatment was delayed ≥2 hours, pain freedom in the active treatment group and placebo group were 33% (12/36) and 10% (4/39), respectively (P = .017) (odds ratio = 4.33, 95% CI: 1.24-15.10), and MBS freedom was achieved in 69% (25/36) and 41% (16/39), respectively, in the delayed treatment group (P = .014) (odds ratio = 3.37, 95% CI: 1.27-8.95). No significant effects (overall interaction P = .353) were observed in logistical regression models of treatment by subgroup interaction.Severe pain, delayed treatment, awakening with a headache, and the presence of nausea are factors that predict a poorer response to acute migraine treatment. In these post hoc analyses of subgroups of patients with each of these characteristics in the ZOTRIP trial, participants receiving ADAM zolmitriptan 3.8 mg displayed nearly uniformly better headache responses (2-hour headache freedom and 2-hour MBS freedom) compared with those who received placebo.

  View details for DOI 10.1111/head.13482

  View details for PubMedID 30698272

• Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials: A Post-Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial HEADACHE Dodick, D. W., Tepper, S. J., Friedman, D. I., Gelfand, A. A., Kellerman, D. J., Schmidt, P. C. 2018; 58 (7): 986–92

  Abstract

  To better understand the utility of using pain freedom and most bothersome headache-associated symptom (MBS) freedom as co-primary endpoints in clinical trials of acute migraine interventions.Adhesive dermally applied microarray (ADAM) is an investigational system for intracutaneous drug administration. The recently completed pivotal Phase 2b/3 study (ZOTRIP), evaluating ADAM zolmitriptan for the treatment of acute moderate to severe migraine, was one of the first large studies to incorporate MBS freedom and pain freedom as co-primary endpoints per recently issued guidance by the US Food and Drug Administration. In this trial, the proportion of patients treated with ADAM zolmitriptan 3.8 mg, who were pain-free and MBS-free at 2 hours post-dose, was significantly higher than for placebo.We undertook a post-hoc analysis of data from the ZOTRIP trial to examine how the outcomes from this trial compare to what might have been achieved using the conventional co-primary endpoints of pain relief, nausea, photophobia, and phonophobia.Of the 159 patients treated with ADAM zolmitriptan 3.8 mg or placebo, prospectively designated MBS were photophobia (n = 79), phonophobia (n = 43), and nausea (n = 37). Two-hour pain free rates in those with photophobia as the MBS were 36% for ADAM zolmitriptan 3.8 mg and 14% for placebo (P = .02). Corresponding rates for those with phonophobia as the MBS were 14% and 41% (P = .05). For those whose MBS was nausea, corresponding values were 56% and 16%, respectively (P = .01). Two-hour freedom from the MBS for active drug vs placebo were 67% vs 35% (P < .01) for photophobia, 55% vs 43% (P = .45) for phonophobia, and 89% vs 58% for nausea (P = .04). MBS freedom but not pain freedom was achieved in 28%. Only 1 patient (1%) achieved pain freedom, but not MBS freedom. The proportion with both pain and MBS freedom was highest (56%) among those whose MBS was nausea.In this study, the use of MBS was feasible and seemed to compare favorably to the previously required 4 co-primary endpoints.

  View details for DOI 10.1111/head.13327

  View details for Web of Science ID 000442734800008

  View details for PubMedID 29782049

  View details for PubMedCentralID PMC6174959

• Effects of gabapentin, pregabalin and gastroretentive gabapentin on simulated driving, daytime sedation and cognition PAIN MANAGEMENT Schmidt, P., Rao, S. 2018; 8 (4): 297–306

  Abstract

  Randomized Phase I study examining the effects of gabapentinoids gabapentin, pregabalin and gastroretentive gabapentin on simulated driving performance, sedation and cognitive function in healthy volunteers (n = 32).Driving attentiveness, sleepiness and cognition were evaluated prior to subjects receiving study doses. Blood samples were collected during each treatment.Subjects receiving gastroretentive gabapentin showed less change in variation in lateral lane position (p = 0.0275), less tremor (p = 0.0304) and fewer vision disturbances compared with gabapentin (p = 0.0177). Statistically significant decrease in One Card Learning Test performance was observed after treatment with gastroretentive gabapentin.Gastroretentive gabapentin demonstrated reduced driving impairment and lower scores on key neurotoxicity measures. Further studies in patients with postherpetic neuralgia are needed. Clinical trial number: NCT03179345.

  View details for DOI 10.2217/pmt-2018-0005

  View details for Web of Science ID 000435507400009

  View details for PubMedID 29671676

• Randomized, double-blind, placebo-controlled, parallel-group, multi-center study of the safety and efficacy of ADAM zolmitriptan for the acute treatment of migraine CEPHALALGIA Spierings, E. L. H., Brandes, J., Kudrow, D. B., Weintraub, J., Schmidt, P. C., Kellerman, D. J., Tepper, S. J. 2018; 38 (2): 215–24

  Abstract

  Objective To determine the efficacy, tolerability, and safety of ascending doses of Adhesive Dermally-Applied Microarray (ADAM) zolmitriptan versus placebo for acute migraine treatment. Background ADAM is a novel patient-administered system for intracutaneous drug administration. In a phase 1 pharmacokinetic study, zolmitriptan administered using ADAM had much faster absorption than oral administration with higher exposure in the first two hours. Methods This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 2b/3 study evaluating ADAM zolmitriptan 1 mg, 1.9 mg, and 3.8 mg versus placebo. Co-primary endpoints were pain freedom and freedom from most bothersome other migraine-associated symptom 2 hours post-dose. Results Of patients treated with ADAM zolmitriptan 3.8 mg or placebo, 41.5% and 14.2%, respectively were pain-free 2 hours post-dose ( p = 0.0001) and 68.3% and 42.9% were free from their most bothersome other symptom ( p = 0.0009). Due to the fixed sequential testing methodology, formal statistical significance was not established for secondary endpoints. However, the proportion of patients who were photophobia-free, phonophobia-free, and nausea-free at 2 hours post-dose was higher in the ADAM zolmitriptan 3.8 mg group compared with placebo, as were the percentages of patients who were pain-free, and who experienced pain relief up to 48 hours post-dose. Systemic adverse events were consistent with previous triptan trials, and included dizziness, paresthesia, muscle tightness, and nausea, all of which occurred in < 5% of patients in any group. Application site reactions were generally mild and resolved within 48 hours, although erythema and bruising persisted for longer periods in some patients. Conclusion ADAM zolmitriptan 3.8 mg provides effective relief of migraine headache and associated most bothersome symptoms compared with placebo, and is well-tolerated. ClinicalTrials.gov NCT02745392.

  View details for DOI 10.1177/0333102417737765

  View details for Web of Science ID 000425150600001

  View details for PubMedID 29022755

  View details for PubMedCentralID PMC5815423

• Use of Most Bothersome Symptom as a Co-Primary Endpoint in an Acute Treatment of Migraine Trial Dodick, D. W., Tepper, S. J., Friedaman, D., Gelfand, A., Cowan, R. P., Schmidt, P., Engels, J., Rapoport, A., Kellerman, D. J. SAGE PUBLICATIONS LTD. 2017: 361–62

  View details for Web of Science ID 000416844600055

• Post Hoc Subanalysis of Two Randomized, Controlled Phase 3 Trials Evaluating Diclofenac Potassium for Oral Solution: Impact of Migraine-Associated Nausea and Prior Triptan Use on Efficacy HEADACHE Lipton, R. B., Schmidt, P., Diener, H. 2017; 57 (5): 756–65

  Abstract

  To determine whether baseline nausea or prior triptan treatment for migraine impact the effectiveness of diclofenac potassium for oral solution in treating acute migraine.A great deal of variability exists in patients' response to migraine medications. Migraine-associated nausea is common and debilitating and can reduce the effectiveness of oral medications. It may cause patients to delay taking oral medications, which is known to diminish therapeutic outcomes, or to avoid taking them altogether. Gastroparesis, which may be associated with nausea, also inhibits drug absorption, resulting in lower bioavailability. Studies have shown that having nausea at the time of drug administration predicts a poorer response to triptan treatment. It is of interest to understand how effective other migraine medications are in patients with a poor response to triptans.Data from two randomized, double-blind, placebo controlled trials were pooled and post hoc subgroup analyses were performed in patients with and without nausea at baseline, and in patients with and without prior triptan treatment. Efficacy assessments included the percentage of patients who, at 2 hours postdosing, were headache pain-free (2hPF, primary endpoint), without photophobia, without phonophobia, without nausea, or without a severe degree of disability. A Cochran-Mantel-Haenszel test, stratified by analysis center was used to evaluate treatment effect. Effects of nausea or prior triptan use were determined using logistic regression with factors of treatment group, analysis center, nausea or prior triptan use at time of dosing, and interaction of treatment group by nausea or prior triptan use at time of dosing.The modified intent to treat population consisted of 1272 patients, 644 on active drug and 628 on placebo. The majority of patients (85%) were female. At the time of dosing, 783 (62%) patients reported nausea with the treated attack. Prior triptan use was recorded in 570 (45%). For headache pain, nausea, photophobia, and phonophobia, patients in the active treatment group had a statistically significantly better response than those receiving placebo, regardless of whether they had nausea at baseline. In logistic regression analysis only treatment group predicted a response for these parameters with no detectable group interaction. Baseline nausea, as well as treatment group, predicted whether patients recorded severe disability at 2 hours. While patients in the active treatment group were significantly more likely to be headache pain-free at 2 hours after dosing, whether or not they had previously been treated with triptan, more triptan-naïve patients (30%) than triptan-experienced patients (20%) were headache pain-free. Interestingly, in the placebo groups, triptan-naïve patients were also more likely to be PF (14% vs 7%). In the logistic regression analysis, treatment group predicted a headache pain response, triptan use predicted a lack of response, and there was no interaction between the two. Prior triptan use did not predict any of the other outcome measures.Nausea at the time of dosing does not diminish the effectiveness of diclofenac potassium for oral solution. The rapid absorption profile may enhance the effectiveness in patients with nausea. Prior triptan use predicted poorer headache response at 2 hours postdose, suggesting the possibility of a subset of patients who are more likely to be refractory to both triptans and diclofenac. Diclofenac potassium for oral solution is effective in triptan-naïve patients but no reliable inference can be made from this study as to about how to order treatment.

  View details for DOI 10.1111/head.13073

  View details for Web of Science ID 000400179100009

  View details for PubMedID 28386945

  View details for PubMedCentralID PMC5434944

• Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial. JAMA surgery Hah, J. n., Mackey, S. C., Schmidt, P. n., McCue, R. n., Humphreys, K. n., Trafton, J. n., Efron, B. n., Clay, D. n., Sharifzadeh, Y. n., Ruchelli, G. n., Goodman, S. n., Huddleston, J. n., Maloney, W. J., Dirbas, F. M., Shrager, J. n., Costouros, J. n., Curtin, C. n., Carroll, I. n. 2017

  Abstract

  Guidelines recommend using gabapentin to decrease postoperative pain and opioid use, but significant variation exists in clinical practice.To determine the effect of perioperative gabapentin on remote postoperative time to pain resolution and opioid cessation.A randomized, double-blind, placebo-controlled trial of perioperative gabapentin was conducted at a single-center, tertiary referral teaching hospital. A total of 1805 patients aged 18 to 75 years scheduled for surgery (thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, and shoulder arthroscopy) were screened. Participants were enrolled from May 25, 2010, to July 25, 2014, and followed up for 2 years postoperatively. Intention-to-treat analysis was used in evaluation of the findings.Gabapentin, 1200 mg, preoperatively and 600 mg, 3 times a day postoperatively or active placebo (lorazepam, 0.5 mg) preoperatively followed by inactive placebo postoperatively for 72 hours.Primary outcome was time to pain resolution (5 consecutive reports of 0 of 10 possible levels of average pain at the surgical site on the numeric rating scale of pain). Secondary outcomes were time to opioid cessation (5 consecutive reports of no opioid use) and the proportion of participants with continued pain or opioid use at 6 months and 1 year.Of 1805 patients screened for enrollment, 1383 were excluded, including 926 who did not meet inclusion criteria and 273 who declined to participate. Overall, 8% of patients randomized were lost to follow-up. A total of 202 patients were randomized to active placebo and 208 patients were randomized to gabapentin in the intention-to-treat analysis (mean [SD] age, 56.7 [11.7] years; 256 (62.4%) women and 154 (37.6%) men). Baseline characteristics of the groups were similar. Perioperative gabapentin did not affect time to pain cessation (hazard ratio [HR], 1.04; 95% CI, 0.82-1.33; P = .73) in the intention-to-treat analysis. However, participants receiving gabapentin had a 24% increase in the rate of opioid cessation after surgery (HR, 1.24; 95% CI, 1.00-1.54; P = .05). No significant differences were noted in the number of adverse events as well as the rate of medication discontinuation due to sedation or dizziness (placebo, 42 of 202 [20.8%]; gabapentin, 52 of 208 [25.0%]).Perioperative administration of gabapentin had no effect on postoperative pain resolution, but it had a modest effect on promoting opioid cessation after surgery. The routine use of perioperative gabapentin may be warranted to promote opioid cessation and prevent chronic opioid use. Optimal dosing and timing of perioperative gabapentin in the context of specific operations to decrease opioid use should be addressed in further research.clinicaltrials.gov Identifier: NCT01067144.

  View details for PubMedID 29238824

• Proceedings of the AMCP Partnership Forum: Breaking the Link Between Pain Management and Opioid Use Disorder JOURNAL OF MANAGED CARE & SPECIALTY PHARMACY Botticelli, M. P., Brock, I., Brooks, P., Byram, D., Clark, K. J., Curro, F. A., Daw, J., Duggan, M., Erensen, J., Fan, J., Francis, W., Gammitoni, A., Ghods, M. P., Greenberg, P., Jan, S. A., Jeffrey, P. L., Kowalski, T., Lee, J., McNally, D. L., Nowak, L. E., Peppin, J. F., Schroeder, A., Schmidt, P., Stoddard, J., Tanzman, B., Thomson, H., Wesolowicz, L., Dragovich, C., Eichelberger, B., Mackowiak, J., Oh, S., Sega, T., Singh, P., Singh, R. 2015; 21 (12): 1116-1122

  Abstract

  Prescription drug misuse and abuse, especially with opioid analgesics, is the fastest growing drug problem in the United States. Addressing this public health crisis demands the coordinated efforts and actions of all stakeholders to establish a process of improving patient care and decreasing misuse and abuse. On September 9, 2014, the Academy of Managed Care Pharmacy (AMCP) convened a meeting of multiple stakeholders to recommend activities and programs that AMCP can promote to improve pain management, prevent opioid use disorder (OUD), and improve medication-assisted treatment outcomes. The speakers and panelists recommended that efforts to improve pain management outcomes and reduce the potential for OUD should rely on demonstrated evidence and best practices. It was recommended that AMCP promote a more holistic and evidence-based approach to pain management and OUD treatment that actively engages the patient in the decision-making process and includes care coordination with medical, pharmacy, behavioral, and mental health aspects of organizations, all of which is seamlessly supported by a technology infrastructure. To accomplish this, it was recommended that AMCP work to collaborate with organizations representing these stakeholders. Additionally, it was recommended that AMCP conduct continuing pharmacy education programs, develop a best practices toolkit on pain management, and actively promote quality standards for OUD prevention and treatment.

  View details for Web of Science ID 000369356100003

  View details for PubMedID 26679961

• In reply. Anesthesiology Schmidt, P. C., Ruchelli, G., Mackey, S. C., Carroll, I. R. 2014; 121 (2): 424-426

  View details for DOI 10.1097/ALN.0000000000000299

  View details for PubMedID 25050501

• Sacroiliac Joint Radiofrequency Ablation with a Multi lesion Probe: A Case Series of 60 Patients ANESTHESIA AND ANALGESIA Schmidt, P. C., Pino, C. A., Vorenkamp, K. E. 2014; 119 (2): 460–62

  Abstract

  This retrospective case series of patients with refractory sacroiliac joint (SIJ) pain presents our first 77 SIJ radiofrequency ablation (RFA) procedures performed with a multilesion probe. Of these, 16 (20.8%) provided no relief; 55 (71.4%) provided >50% pain relief at 6 weeks; 42 (54.5%, 95% confidence interval, 42.8%-65.8%) provided >50% pain relief at 6 months; and 12 (15.6%) continued to provide >50% pain relief at 1 year. These results compare favorably to those published using other RFA techniques. In conclusion, more than half of our patients with refractory SIJ pain received some pain relief for at least 6 months after RFA.

  View details for DOI 10.1213/ANE.0000000000000282

  View details for Web of Science ID 000339455900029

  View details for PubMedID 25046790

• Self-Loathing Aspects of Depression Reduce Postoperative Opioid Cessation Rate PAIN MEDICINE Hah, J. M., Mackey, S., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Schmidt, P. C., Carroll, I. R. 2014; 15 (6): 954-964

  Abstract

  We previously reported that increased preoperative Beck Depression Inventory II (BDI-II) scores were associated with a 47% (95% CI 24%-64%) reduction in the rate of opioid cessation following surgery. We aimed to identify the underlying factors of the BDI-II (affective/cognitive vs somatic) associated with a decreased rate of opioid cessation after surgery.We conducted a secondary analysis of the data from a previously reported prospective, longitudinal, observational study of opioid use after five distinct surgical procedures (total hip replacement, total knee replacement, thoracotomy, mastectomy, and lumpectomy) in 107 patients. The primary endpoint was time to opioid cessation. After exploratory factor analysis of the BDI-II, mean summary scores were calculated for each identified factor. These scores were evaluated as predictors of time to opioid cessation using Cox proportional hazards regression.The exploratory factor analysis produced three factors (self-loathing symptoms, motivational symptoms, emotional symptoms). All three factors were significant predictors in univariate analysis. Of the three identified factors of the BDI-II, only preoperative self-loathing symptoms (past failure, guilty feelings, self-dislike, self-criticalness, suicidal thoughts, worthlessness) independently predicted a significant decrease in opioid cessation rate after surgery in the multivariate analysis (HR 0.86, 95% CI 0.75-0.99, P value 0.037).Our results identify a set of negative cognitions predicting prolonged time to postoperative opioid cessation. Somatic symptoms captured by the BDI-II were not primarily responsible for the association between preoperative BDI-II scores and postoperative prolonged opioid use.

  View details for DOI 10.1111/pme.12439

  View details for Web of Science ID 000338025900009

  View details for PubMedCentralID PMC4083472

• Perioperative Gabapentinoids Choice of Agent, Dose, Timing, and Effects on Chronic Postsurgical Pain ANESTHESIOLOGY Schmidt, P. C., Ruchelli, G., Mackey, S. C., Carroll, I. R. 2013; 119 (5): 1215-1221

  View details for DOI 10.1097/ALN.0b013e3182a9a896

  View details for Web of Science ID 000329797900029

  View details for PubMedID 24051389