Efficacy and safety of dorsal root ganglion stimulation for tretment of different pain conditions in humans and in animal pain models

Cilj: Na sustavan način prikupiti dokaze i sintezom dokaza analizirati učinkovitost neurostimulacije na parametre i ishode povezane s boli u životinjskim modelima boli te učinkovitost i sigurnost primjene električne stimulacije i pulsne radiofrekvencije za liječenje različitih bolnih stanja u ljudi. Temeljem rezultata dobivenih provedbom sustavnih pregleda razviti neurostimulator i metodologiju koja se može korsititi u translacijskim istraživanjima posebno otkrivanju mehanizma neuromodulacije i testiranja novih modaliteta liječenja. Metode: Za svaki od sustavnih pregleda pretražene su najmanje tri bibliografske baze podataka, a za sustavni pregled o intervenciji u ljudi dodatno i registri kliničkih istraživanja. Kvalitea uključenih istraživanja analizirana je korištenjem Cochraneovog alata za procjenu rizika pristranosti za randomizirana kontrolirana istraživanja i ROBINS-I alata za rizik pristranosti u nerandomiziranim istraživanjima. U eksperimentalnom istraživanju posebno dizajniran Neuromod stimulator korišten je za implantraciju u Sprague-Dawley (SD) štakorie težine 300-400 g. Ukupno je korišteno 45 životinja raspoređenih u jednu od skupina: skupina s podvezanim spinalnim živcem (SNL) (N=6), skupina s kroničnom kompresijskom ozljedom spinalnog ganglija (CCD) (N=9), SNL skupina s ugrađenim stimulatorom (N=11), netaknuta kontrolna skupina (N=6), skupina s ugrađenim lažnim stimulatorom (N=8) i lažnom elektrodom (N=7). Rezultati: U tri provedena sustavna pregleda o učinkovitosti i sigurnosti neurostimulacije u ljudi ukupno su ukjučena 74 istraživanja. Iako su imala generalno pozitivne zaključke o učinku neurostimulacije za različita bolna stanja, istraživanja su bila loše kvalitete s malim brojem uključenih ispitanika dok meta-analiza nije bila moguća zbog velike heterogenosti. U sustavni pregled na životinjskim modelima uključeno je 14 istraživanja koja su također pokazala pozitivan učinak neurostimulacije na koncentracije parametara i ponašanje povezano s boli, ali su bili loše metodološke kvalitete. U eksperimentalnom istraživanju razvijen je funkcionalni stimulator za korištenje u životinjskim modelima boli čija je funkcionalnost potvrđena u zdravih i ozlijeđenih životinja. U životinja sa izazvanom ozljedom spinalnog živca pokazano je da neurostimulacija utječe na smanjenje ponašanja povezanog s boli, dok postavljena elektroda ne uzrokuje kompresiju spinalnog ganglija. Zaključak: Do sada objavljena istraživanja pokazuju da neurostimulacija spinalnog ganglija može pomoći pacijentima koji nisu postigli odgovarajuće smanjenje boli drugim farmakološkim i nefarmakološkim metodama. Dostupni dokazi o učinkovitosti i sigurnosti električne i PRF stimulacije za liječenje kronične boli trebaju se smatrati preliminarnim i potrebno ih je potvrditi provođenjem visokokvalitetnih randomiziranih kontroliranih ispitivanja s dovoljnim brojem sudionika. Eksperimentalno razvijeni stimulator omogućava širok spektar istraživačkih primjena od prilagođavanja parametara stimulacije različitim uvjetima boli, proučavanja novih načina stimulacije poput visokofrekventne stimulacije do dobivanja odgovora o analgetskim mehanizmima stimulacije spinalnog ganglija.Objectives: Collect evidence about effecacy of neurostimulation in a systematic way for the parameters and outcomes associated with pain in animal models of pain and the effeicacy and safety of electrical stimulation and pulsed radiofrequency for the treatment of various painful conditions in humans. Based on the results obtained by conducting systematic reviews, develop a neurostimulator and a methodology that can be used in translational research, especially for the discovery of the mechanism of neuromodulation and testing of new treatment modalities. Methods: At least three bibliographic databases were searched for each of the systematic reviews, and clinical trials registers were additionally searched for the systematic reviews of the intervention in humans. The quality of the included studies was analyzed using the Cochrane risk of bias tool for randomized controlled trials and the ROBINS-I risk of bias tool in nonrandomized trials. In the experimental study, a specially designed Neuromod stimulator was used for implantation in Sprague-Dawley (SD) rats weighing 300-400 g. A total of 45 animals were used divided into one of the groups: the group with spinal nerve ligation (SNL) (N=6), the group with chronic compression injury (CCD) (N=9), the SNL group with implanted stimulator (N=11), intact control group (N=6), group with implanted false stimulator (N=8) and false electrode (N=7). Results: A total of 74 studies were included in three systematic reviews of the efficacy and safety of neurostimulation in humans. Although they had generally positive conclusions about the effect of neurostimulation for different painful conditions, the studies were of poor quality with a small number of participants involved while meta-analysis was not possible due to high heterogeneity. A systematic review in animal models included 14 studies that also showed a positive effect of neurostimulation on pain-related parameters and pain-related behavior, but were of poor methodological quality. In an experimental study, a functional stimulator was developed for use in animal models of pain whose functionality was confirmed in healthy and injured animals. In animals with spinal nerve ligation, neurostimulation has been shown to reduce pain-related behavior, while the electrode does not cause dorsal root ganglion compression. Conclusion: Research published so far shows that neurostimulation of the spinal ganglion can help patients who have not achieved adequate pain reduction by other pharmacological and nonpharmacological methods. Available evidence on the efficacy and safety of electrical and PRF stimulation for the treatment of chronic pain should be considered preliminary and should be confirmed by conducting high-quality randomized controlled trials with a sufficient number of participants. The experimentally developed stimulator enables a wide range of research applications from adjusting stimulation parameters to different pain conditions, studying new stimulation methods such as high-frequency stimulation to obtaining answers about analgesic mechanisms of dorsal root ganglion stimulation

Efficacy and safety of dorsal root ganglion stimulation for tretment of different pain conditions in humans and in animal pain models

Cilj: Na sustavan način prikupiti dokaze i sintezom dokaza analizirati učinkovitost neurostimulacije na parametre i ishode povezane s boli u životinjskim modelima boli te učinkovitost i sigurnost primjene električne stimulacije i pulsne radiofrekvencije za liječenje različitih bolnih stanja u ljudi. Temeljem rezultata dobivenih provedbom sustavnih pregleda razviti neurostimulator i metodologiju koja se može korsititi u translacijskim istraživanjima posebno otkrivanju mehanizma neuromodulacije i testiranja novih modaliteta liječenja. Metode: Za svaki od sustavnih pregleda pretražene su najmanje tri bibliografske baze podataka, a za sustavni pregled o intervenciji u ljudi dodatno i registri kliničkih istraživanja. Kvalitea uključenih istraživanja analizirana je korištenjem Cochraneovog alata za procjenu rizika pristranosti za randomizirana kontrolirana istraživanja i ROBINS-I alata za rizik pristranosti u nerandomiziranim istraživanjima. U eksperimentalnom istraživanju posebno dizajniran Neuromod stimulator korišten je za implantraciju u Sprague-Dawley (SD) štakorie težine 300-400 g. Ukupno je korišteno 45 životinja raspoređenih u jednu od skupina: skupina s podvezanim spinalnim živcem (SNL) (N=6), skupina s kroničnom kompresijskom ozljedom spinalnog ganglija (CCD) (N=9), SNL skupina s ugrađenim stimulatorom (N=11), netaknuta kontrolna skupina (N=6), skupina s ugrađenim lažnim stimulatorom (N=8) i lažnom elektrodom (N=7). Rezultati: U tri provedena sustavna pregleda o učinkovitosti i sigurnosti neurostimulacije u ljudi ukupno su ukjučena 74 istraživanja. Iako su imala generalno pozitivne zaključke o učinku neurostimulacije za različita bolna stanja, istraživanja su bila loše kvalitete s malim brojem uključenih ispitanika dok meta-analiza nije bila moguća zbog velike heterogenosti. U sustavni pregled na životinjskim modelima uključeno je 14 istraživanja koja su također pokazala pozitivan učinak neurostimulacije na koncentracije parametara i ponašanje povezano s boli, ali su bili loše metodološke kvalitete. U eksperimentalnom istraživanju razvijen je funkcionalni stimulator za korištenje u životinjskim modelima boli čija je funkcionalnost potvrđena u zdravih i ozlijeđenih životinja. U životinja sa izazvanom ozljedom spinalnog živca pokazano je da neurostimulacija utječe na smanjenje ponašanja povezanog s boli, dok postavljena elektroda ne uzrokuje kompresiju spinalnog ganglija. Zaključak: Do sada objavljena istraživanja pokazuju da neurostimulacija spinalnog ganglija može pomoći pacijentima koji nisu postigli odgovarajuće smanjenje boli drugim farmakološkim i nefarmakološkim metodama. Dostupni dokazi o učinkovitosti i sigurnosti električne i PRF stimulacije za liječenje kronične boli trebaju se smatrati preliminarnim i potrebno ih je potvrditi provođenjem visokokvalitetnih randomiziranih kontroliranih ispitivanja s dovoljnim brojem sudionika. Eksperimentalno razvijeni stimulator omogućava širok spektar istraživačkih primjena od prilagođavanja parametara stimulacije različitim uvjetima boli, proučavanja novih načina stimulacije poput visokofrekventne stimulacije do dobivanja odgovora o analgetskim mehanizmima stimulacije spinalnog ganglija.Objectives: Collect evidence about effecacy of neurostimulation in a systematic way for the parameters and outcomes associated with pain in animal models of pain and the effeicacy and safety of electrical stimulation and pulsed radiofrequency for the treatment of various painful conditions in humans. Based on the results obtained by conducting systematic reviews, develop a neurostimulator and a methodology that can be used in translational research, especially for the discovery of the mechanism of neuromodulation and testing of new treatment modalities. Methods: At least three bibliographic databases were searched for each of the systematic reviews, and clinical trials registers were additionally searched for the systematic reviews of the intervention in humans. The quality of the included studies was analyzed using the Cochrane risk of bias tool for randomized controlled trials and the ROBINS-I risk of bias tool in nonrandomized trials. In the experimental study, a specially designed Neuromod stimulator was used for implantation in Sprague-Dawley (SD) rats weighing 300-400 g. A total of 45 animals were used divided into one of the groups: the group with spinal nerve ligation (SNL) (N=6), the group with chronic compression injury (CCD) (N=9), the SNL group with implanted stimulator (N=11), intact control group (N=6), group with implanted false stimulator (N=8) and false electrode (N=7). Results: A total of 74 studies were included in three systematic reviews of the efficacy and safety of neurostimulation in humans. Although they had generally positive conclusions about the effect of neurostimulation for different painful conditions, the studies were of poor quality with a small number of participants involved while meta-analysis was not possible due to high heterogeneity. A systematic review in animal models included 14 studies that also showed a positive effect of neurostimulation on pain-related parameters and pain-related behavior, but were of poor methodological quality. In an experimental study, a functional stimulator was developed for use in animal models of pain whose functionality was confirmed in healthy and injured animals. In animals with spinal nerve ligation, neurostimulation has been shown to reduce pain-related behavior, while the electrode does not cause dorsal root ganglion compression. Conclusion: Research published so far shows that neurostimulation of the spinal ganglion can help patients who have not achieved adequate pain reduction by other pharmacological and nonpharmacological methods. Available evidence on the efficacy and safety of electrical and PRF stimulation for the treatment of chronic pain should be considered preliminary and should be confirmed by conducting high-quality randomized controlled trials with a sufficient number of participants. The experimentally developed stimulator enables a wide range of research applications from adjusting stimulation parameters to different pain conditions, studying new stimulation methods such as high-frequency stimulation to obtaining answers about analgesic mechanisms of dorsal root ganglion stimulation

Efficacy and safety of dorsal root ganglion stimulation for tretment of different pain conditions in humans and in animal pain models

Cilj: Na sustavan način prikupiti dokaze i sintezom dokaza analizirati učinkovitost neurostimulacije na parametre i ishode povezane s boli u životinjskim modelima boli te učinkovitost i sigurnost primjene električne stimulacije i pulsne radiofrekvencije za liječenje različitih bolnih stanja u ljudi. Temeljem rezultata dobivenih provedbom sustavnih pregleda razviti neurostimulator i metodologiju koja se može korsititi u translacijskim istraživanjima posebno otkrivanju mehanizma neuromodulacije i testiranja novih modaliteta liječenja. Metode: Za svaki od sustavnih pregleda pretražene su najmanje tri bibliografske baze podataka, a za sustavni pregled o intervenciji u ljudi dodatno i registri kliničkih istraživanja. Kvalitea uključenih istraživanja analizirana je korištenjem Cochraneovog alata za procjenu rizika pristranosti za randomizirana kontrolirana istraživanja i ROBINS-I alata za rizik pristranosti u nerandomiziranim istraživanjima. U eksperimentalnom istraživanju posebno dizajniran Neuromod stimulator korišten je za implantraciju u Sprague-Dawley (SD) štakorie težine 300-400 g. Ukupno je korišteno 45 životinja raspoređenih u jednu od skupina: skupina s podvezanim spinalnim živcem (SNL) (N=6), skupina s kroničnom kompresijskom ozljedom spinalnog ganglija (CCD) (N=9), SNL skupina s ugrađenim stimulatorom (N=11), netaknuta kontrolna skupina (N=6), skupina s ugrađenim lažnim stimulatorom (N=8) i lažnom elektrodom (N=7). Rezultati: U tri provedena sustavna pregleda o učinkovitosti i sigurnosti neurostimulacije u ljudi ukupno su ukjučena 74 istraživanja. Iako su imala generalno pozitivne zaključke o učinku neurostimulacije za različita bolna stanja, istraživanja su bila loše kvalitete s malim brojem uključenih ispitanika dok meta-analiza nije bila moguća zbog velike heterogenosti. U sustavni pregled na životinjskim modelima uključeno je 14 istraživanja koja su također pokazala pozitivan učinak neurostimulacije na koncentracije parametara i ponašanje povezano s boli, ali su bili loše metodološke kvalitete. U eksperimentalnom istraživanju razvijen je funkcionalni stimulator za korištenje u životinjskim modelima boli čija je funkcionalnost potvrđena u zdravih i ozlijeđenih životinja. U životinja sa izazvanom ozljedom spinalnog živca pokazano je da neurostimulacija utječe na smanjenje ponašanja povezanog s boli, dok postavljena elektroda ne uzrokuje kompresiju spinalnog ganglija. Zaključak: Do sada objavljena istraživanja pokazuju da neurostimulacija spinalnog ganglija može pomoći pacijentima koji nisu postigli odgovarajuće smanjenje boli drugim farmakološkim i nefarmakološkim metodama. Dostupni dokazi o učinkovitosti i sigurnosti električne i PRF stimulacije za liječenje kronične boli trebaju se smatrati preliminarnim i potrebno ih je potvrditi provođenjem visokokvalitetnih randomiziranih kontroliranih ispitivanja s dovoljnim brojem sudionika. Eksperimentalno razvijeni stimulator omogućava širok spektar istraživačkih primjena od prilagođavanja parametara stimulacije različitim uvjetima boli, proučavanja novih načina stimulacije poput visokofrekventne stimulacije do dobivanja odgovora o analgetskim mehanizmima stimulacije spinalnog ganglija.Objectives: Collect evidence about effecacy of neurostimulation in a systematic way for the parameters and outcomes associated with pain in animal models of pain and the effeicacy and safety of electrical stimulation and pulsed radiofrequency for the treatment of various painful conditions in humans. Based on the results obtained by conducting systematic reviews, develop a neurostimulator and a methodology that can be used in translational research, especially for the discovery of the mechanism of neuromodulation and testing of new treatment modalities. Methods: At least three bibliographic databases were searched for each of the systematic reviews, and clinical trials registers were additionally searched for the systematic reviews of the intervention in humans. The quality of the included studies was analyzed using the Cochrane risk of bias tool for randomized controlled trials and the ROBINS-I risk of bias tool in nonrandomized trials. In the experimental study, a specially designed Neuromod stimulator was used for implantation in Sprague-Dawley (SD) rats weighing 300-400 g. A total of 45 animals were used divided into one of the groups: the group with spinal nerve ligation (SNL) (N=6), the group with chronic compression injury (CCD) (N=9), the SNL group with implanted stimulator (N=11), intact control group (N=6), group with implanted false stimulator (N=8) and false electrode (N=7). Results: A total of 74 studies were included in three systematic reviews of the efficacy and safety of neurostimulation in humans. Although they had generally positive conclusions about the effect of neurostimulation for different painful conditions, the studies were of poor quality with a small number of participants involved while meta-analysis was not possible due to high heterogeneity. A systematic review in animal models included 14 studies that also showed a positive effect of neurostimulation on pain-related parameters and pain-related behavior, but were of poor methodological quality. In an experimental study, a functional stimulator was developed for use in animal models of pain whose functionality was confirmed in healthy and injured animals. In animals with spinal nerve ligation, neurostimulation has been shown to reduce pain-related behavior, while the electrode does not cause dorsal root ganglion compression. Conclusion: Research published so far shows that neurostimulation of the spinal ganglion can help patients who have not achieved adequate pain reduction by other pharmacological and nonpharmacological methods. Available evidence on the efficacy and safety of electrical and PRF stimulation for the treatment of chronic pain should be considered preliminary and should be confirmed by conducting high-quality randomized controlled trials with a sufficient number of participants. The experimentally developed stimulator enables a wide range of research applications from adjusting stimulation parameters to different pain conditions, studying new stimulation methods such as high-frequency stimulation to obtaining answers about analgesic mechanisms of dorsal root ganglion stimulation

Assessments of attrition bias in Cochrane systematic reviews are highly inconsistent and thus hindering trial comparability

Abstract Background An important part of the systematic review methodology is appraisal of the risk of bias in included studies. Cochrane systematic reviews are considered golden standard regarding systematic review methodology, but Cochrane’s instructions for assessing risk of attrition bias are vague, which may lead to inconsistencies in authors’ assessments. The aim of this study was to analyze consistency of judgments and support for judgments of attrition bias in Cochrane reviews of interventions published in the Cochrane Database of Systematic Reviews (CDSR). Methods We analyzed Cochrane reviews published from July 2015 to June 2016 in the CDSR. We extracted data on number of included trials, judgment of attrition risk of bias for each included trial (low, unclear or high) and accompanying support for the judgment (supporting explanation). We also assessed how many Cochrane reviews had different judgments for the same supporting explanations. Results In the main analysis we included 10,292 judgments and supporting explanations for attrition bias from 729 Cochrane reviews. We categorized supporting explanations for those judgments into four categories and we found that most of the supporting explanations were unclear. Numerical indicators for percent of attrition, as well as statistics related to attrition were judged very differently. One third of Cochrane review authors had more than one category of supporting explanation; some had up to four different categories. Inconsistencies were found even with the number of judgments, names of risk of bias domains and different judgments for the same supporting explanations in the same Cochrane review. Conclusion We found very high inconsistency in methods of appraising risk of attrition bias in recent Cochrane reviews. Systematic review authors need clear guidance about different categories they should assess and judgments for those explanations. Clear instructions about appraising risk of attrition bias will improve reliability of the Cochrane’s risk of bias tool, help authors in making decisions about risk of bias and help in making reliable decisions in healthcare