Periodic Reporting for period 5 - IMI-PainCare (Improving the care of patients suffering from acute or chronic pain)
Berichtszeitraum: 2022-04-01 bis 2023-03-31
Acute and persistent pain represent a common medical and societal burden, and their pharmacotherapy is often inadequate. To advance management of pain patients, prediction of clinical treatment success and translation from preclinical data into the clinic need to be improved. Pharmacodynamic biomarkers could define whether nociceptive signalling is adequately modulated by a new drug, thus predicting clinical efficacy. The pathophysiology of chronic pelvic pain is particularly poorly understood and no adequate preclinical models are available to assess the efficacy of new analgesics.
IMI-PainCare aimed to advance pain management via three mutually supportive subprojects: PROMPT identified Patient Reported Outcome Measures (PROMs) to standardize assessment of treatment success of acute and chronic pain; BioPain validated the translatability of pharmacokinetic (PK) and pharmacodynamic (PD) modelling of functional biomarkers of pain pathways in healthy subjects and preclinical species; TRiPP identified biomarkers and mechanistic pathways of clinical phenotypes of patients with chronic pelvic pain, and back-translated them into preclinical models. The overall objectives of IMI-PainCare, to improve the care of patients with acute or chronic pain by providing a toolbox to streamline the development for novel analgesic drugs; were aligned with the National Institutes of Health (NIH). Conclusions from the action are available as open access publications.
IMI-PainCare aimed to advance pain management via three mutually supportive subprojects: PROMPT identified Patient Reported Outcome Measures (PROMs) to standardize assessment of treatment success of acute and chronic pain; BioPain validated the translatability of pharmacokinetic (PK) and pharmacodynamic (PD) modelling of functional biomarkers of pain pathways in healthy subjects and preclinical species; TRiPP identified biomarkers and mechanistic pathways of clinical phenotypes of patients with chronic pelvic pain, and back-translated them into preclinical models. The overall objectives of IMI-PainCare, to improve the care of patients with acute or chronic pain by providing a toolbox to streamline the development for novel analgesic drugs; were aligned with the National Institutes of Health (NIH). Conclusions from the action are available as open access publications.
Over the fifth year we have made significant progress in achieving our goals, thanks to the close collaborations of all partners, enabled through regular virtual meetings, six General Assemblies, one Scientific Meetings and other smaller scientific project meetings organized within congresses e.g. EFIC 2019.
Subproject PROMPT
Sub-project PROMPT aimed to standardise the assessment of acute and chronic pain and to identify risk factors for development of chronic postsurgical pain. PROMPT evaluated patient-reported outcomes from real world conditions and in controlled trials. This included an extensive systematic literature research on chronic neuropathic and pelvic pain studies, a large multinational observational trial on postsurgical pain (n= 3322, 18 structures involved), activity tracking (AT) recordings of almost 400 patients showing very satisfying quality, and the publication[1] of a consensus process on a final core outcome set of PROMs to assess the effectiveness of perioperative pain management in research and clinical practice with a multi-stakeholder panel including patient representatives. Regarding chronic post-surgical pain (CPSP), findings offered reliable new data in CPSP incidence, characteristics and consequences and showed that CPSP has a low mean incidence.
Subproject BIOPAIN
BioPain aimed to validate several biomarkers for their ability to identify the analgesic effects of drugs. The team used neurophysiological techniques to test functional biomarkers that objectively document the nociceptive signal processing in specific areas of the nociceptive system. After reaching a consensus on three medications (lacosamide, pregabalin, tapentadol)[2], four multicentric randomized clinical trials (RCTs) in healthy volunteers were designed to test the analgesic efficacy through neurophysiological/neuroimaging biomarkers at peripheral (RCT1), spinal (RCT2) and cortical (RCT3-RCT4) level. Pharmacokinetic data were collected to obtain a PK-PD model. Equivalent biomarkers were established in rodents. Two innovative devices were developed and received CE certification. Within five years,preclinical pharmacokinetic models were completed, the four RCTs finalized the multinational enrolment (n=118) despite interruptions by COVID-19 and performed the analysis on primary outcomes. All four studies were successful in producing large datasets that could be used to determine the best biomarker panel for each of the drugs tested (sodium channel blocker, calcium channel modulator, dual mode of action opioid/reuptake inhibitor), for translation between preclinical and clinical phases of drug development, and to get information on test-retest reliability. Primary statistical analysis indicated either positive (for peripheral and EEG biomarkers) or negative (for spinal and brain imaging) trial outcomes, but the most important results are subsequent hierarchical statistical modelling (including patient-reported predictors), PK-PD modelling across species, and refined power calculations for future trials. Three trial designs (RCT1,RCT2, and RCT3) and validation of two spinal excitability measures (RIII reflex, N13 SEP) were published.
Subproject TRiPP
Subproject TRiPP profiled women with chronic pelvic pain (CPP), to identify biomarkers and novel treatment pathways. Despite the high incidence of chronic pelvic pain, both diagnostic tools and our understanding of associated pathologies are unspecific or do not exist at all. TRiPP used questionnaires, genomic (multi-omic) analysis of women with and without CPP, psychophysical testing, nervous system assessment and bladder sensitivity testing, literature review of endometriosis associated pain (EAP) and bladder pain syndrome (BPS) animal models, and home cage analysis as powerful tool to measure a broad spectrum of behavioural parameters in group housed animals during light and dark phase. TRiPP also improved pain models through trials in both humans and animals. Within the 5th year, data analyses were completed with only the final integrated analyses and neuroimaging data remaining to be analysed. Data highlighted the burden of symptoms experienced by women with CPP, especially those with comorbid conditions, and demonstrated similarities with other chronic pain conditions. Back translation of the clinical data allowed the preclinical teams to identify a model with the highest value of translation. A lay editorial article for TRiPP were published[3].
Major dissemination activities were done jointly by the three subprojects including two briefing books submitted to regulatory agencies (EMA). A regular consultation was held with NIH to align research activities across the Atlantic Ocean (INTEGRATE-Pain)[4]. During the entire duration of the project, preliminary results were systematically presented at major International Pain Congresses, to NIH partners and to the public at the EU parliament. Early contacts with FDA and EMA were appreciated by both agencies.
Patient representatives took part in the Delphi-processes, in setting up study designs, as coauthors on publications, and as initiators with ICD-11 pain classification teams.
Subproject PROMPT
Sub-project PROMPT aimed to standardise the assessment of acute and chronic pain and to identify risk factors for development of chronic postsurgical pain. PROMPT evaluated patient-reported outcomes from real world conditions and in controlled trials. This included an extensive systematic literature research on chronic neuropathic and pelvic pain studies, a large multinational observational trial on postsurgical pain (n= 3322, 18 structures involved), activity tracking (AT) recordings of almost 400 patients showing very satisfying quality, and the publication[1] of a consensus process on a final core outcome set of PROMs to assess the effectiveness of perioperative pain management in research and clinical practice with a multi-stakeholder panel including patient representatives. Regarding chronic post-surgical pain (CPSP), findings offered reliable new data in CPSP incidence, characteristics and consequences and showed that CPSP has a low mean incidence.
Subproject BIOPAIN
BioPain aimed to validate several biomarkers for their ability to identify the analgesic effects of drugs. The team used neurophysiological techniques to test functional biomarkers that objectively document the nociceptive signal processing in specific areas of the nociceptive system. After reaching a consensus on three medications (lacosamide, pregabalin, tapentadol)[2], four multicentric randomized clinical trials (RCTs) in healthy volunteers were designed to test the analgesic efficacy through neurophysiological/neuroimaging biomarkers at peripheral (RCT1), spinal (RCT2) and cortical (RCT3-RCT4) level. Pharmacokinetic data were collected to obtain a PK-PD model. Equivalent biomarkers were established in rodents. Two innovative devices were developed and received CE certification. Within five years,preclinical pharmacokinetic models were completed, the four RCTs finalized the multinational enrolment (n=118) despite interruptions by COVID-19 and performed the analysis on primary outcomes. All four studies were successful in producing large datasets that could be used to determine the best biomarker panel for each of the drugs tested (sodium channel blocker, calcium channel modulator, dual mode of action opioid/reuptake inhibitor), for translation between preclinical and clinical phases of drug development, and to get information on test-retest reliability. Primary statistical analysis indicated either positive (for peripheral and EEG biomarkers) or negative (for spinal and brain imaging) trial outcomes, but the most important results are subsequent hierarchical statistical modelling (including patient-reported predictors), PK-PD modelling across species, and refined power calculations for future trials. Three trial designs (RCT1,RCT2, and RCT3) and validation of two spinal excitability measures (RIII reflex, N13 SEP) were published.
Subproject TRiPP
Subproject TRiPP profiled women with chronic pelvic pain (CPP), to identify biomarkers and novel treatment pathways. Despite the high incidence of chronic pelvic pain, both diagnostic tools and our understanding of associated pathologies are unspecific or do not exist at all. TRiPP used questionnaires, genomic (multi-omic) analysis of women with and without CPP, psychophysical testing, nervous system assessment and bladder sensitivity testing, literature review of endometriosis associated pain (EAP) and bladder pain syndrome (BPS) animal models, and home cage analysis as powerful tool to measure a broad spectrum of behavioural parameters in group housed animals during light and dark phase. TRiPP also improved pain models through trials in both humans and animals. Within the 5th year, data analyses were completed with only the final integrated analyses and neuroimaging data remaining to be analysed. Data highlighted the burden of symptoms experienced by women with CPP, especially those with comorbid conditions, and demonstrated similarities with other chronic pain conditions. Back translation of the clinical data allowed the preclinical teams to identify a model with the highest value of translation. A lay editorial article for TRiPP were published[3].
Major dissemination activities were done jointly by the three subprojects including two briefing books submitted to regulatory agencies (EMA). A regular consultation was held with NIH to align research activities across the Atlantic Ocean (INTEGRATE-Pain)[4]. During the entire duration of the project, preliminary results were systematically presented at major International Pain Congresses, to NIH partners and to the public at the EU parliament. Early contacts with FDA and EMA were appreciated by both agencies.
Patient representatives took part in the Delphi-processes, in setting up study designs, as coauthors on publications, and as initiators with ICD-11 pain classification teams.
Improving the care of pain is essential to improve the well being of the overall population. IMI-PainCare-produced literature can bring big steps in the implementation of pain treatment and research. The results from systematic literature reviews, consensus processes, NITs, RCTs, preclinical trials, and the innovative translation and backtranslation between preclinical and clinical work packages, improved the likelihood of successful translation from preclinical to clinical settings and accelerated the future development of new drugs, laying the foundation for future pain research on biomarkers for patients’ stratification and response prediction.
References:
1. doi:10.1097/j.pain.0000000000002254
2. doi: 10.3390/ijms23158295.
3. doi: 10.3390/ijms24032422
4. doi: 10.1093/pm/pnad033
References:
1. doi:10.1097/j.pain.0000000000002254
2. doi: 10.3390/ijms23158295.
3. doi: 10.3390/ijms24032422
4. doi: 10.1093/pm/pnad033