The developmental emergence of differential brainstem serotonergic control of the sensory spinal cord

Schwaller, Fred; Kanellopoulos, Alexandros; Fitzgerald, Maria

doi:10.1038/s41598-017-02509-2

Cited by 21 publications

(53 citation statements)

References 61 publications

(65 reference statements)

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“…Identification of a PK/PD relationship across the different age groups is hindered by a multitude of pain scales used in children and adults 3. In spite of the difficulties in measuring pain response in different age groups, the two mechanisms of action of tapentadol (µ-opioid receptor agonism and noradrenaline reuptake inhibition) are well understood in adults, and there is evidence that both mechanisms are functioning even in very young children 25–27. The latter implies that dose levels in children could be optimized by matching the resulting exposures to the levels that are known to be efficacious and safe in adults.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetic modeling to facilitate dose selection of tapentadol in the pediatric population

Watson

Khandelwal

Freijer

et al. 2019

JPR

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ObjectiveThe main aim of this analysis was to characterize the pharmacokinetics (PK) of the strong analgesic tapentadol in 2-year-old to <18-year-old patients with acute pain and to inform the optimal dosing strategy for a confirmatory efficacy trial in this patient population.MethodsThe analysis dataset included tapentadol concentrations obtained from 92 pediatric patients receiving a single tapentadol oral solution (OS) dose of 1.0 mg/kg bodyweight in two single-dose PK clinical trials. Population PK analysis was performed using nonlinear mixed effects modeling. Simulations were performed to identify tapentadol OS doses in pediatric subjects (2 to <18 years) that would produce exposures similar to those in adults receiving safe and efficacious doses of tapentadol IR (50–100 mg every 4 hrs).ResultsTapentadol PK in children aged from 2 to <18 years was best described by a one-compartment model. Mean population apparent clearance and apparent volume of distribution for a typical subject weighing 45 kg were 170 L/h and 685 L, respectively. Clearance, expressed in bodyweight units as L/h/kg, decreased with increasing age whereas total clearance (L/h) increased with increasing age. Model-based simulations suggested that a tapentadol OS dose of 1.25 mg/kg to children and adolescents aged 2 to <18 years would result in efficacious tapentadol exposures similar to those in adults receiving tapentadol immediate release 50–100 mg every 4 hrs. The proposed tapentadol OS dose was subsequently applied in a confirmatory efficacy trial in 2 to <18-year-old patients suffering from acute postsurgical pain.ConclusionThis analysis provides an example of a model-based approach for a dose recommendation to be used in an efficacy trial in the pediatric population. Uniform dosing based on bodyweight was proposed for the treatment of acute pain in children aged from 2 to <18 years.

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Section: Discussionmentioning

confidence: 99%

Population pharmacokinetic modeling to facilitate dose selection of tapentadol in the pediatric population

Watson

Khandelwal

Freijer

et al. 2019

JPR

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“…Experimentally induced background stress or chronic psychosocial stress also results in an increase in pain perception in adult animals [ 5 , 6 , 7 ] and humans [ 8 , 9 , 10 ], but extrapolating from these data to our infant sample is not straightforward. The effects of stress upon pain pathways are mediated through descending brainstem pathways to the spinal cord [ 5 ], and there is evidence of strong descending excitatory drive from serotonergic and other descending pathways over spinal nociceptive circuits in infant and juvenile rats compared to adults [ 36 , 37 , 38 ]. This tonic excitation may therefore increase infant pain reactivity to background stress.…”

Section: Discussionmentioning

confidence: 99%

Nociceptive Cortical Activity Is Dissociated from Nociceptive Behavior in Newborn Human Infants under Stress

et al. 2017

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SummaryNewborn infants display strong nociceptive behavior in response to tissue damaging stimuli, and this is accompanied by nociceptive activity generated in subcortical and cortical areas of the brain [1, 2]. In the absence of verbal report, these nociceptive responses are used as measures of pain sensation in newborn humans, as they are in animals [3, 4]. However, many infants are raised in a physiologically stressful environment, and little is known about the effect of background levels of stress upon their pain responses. In adults, acute physiological stress causes hyperalgesia [5, 6, 7], and increased background stress increases pain [8, 9, 10], but these data cannot necessarily be extrapolated to infants. Here we have simultaneously measured nociceptive behavior, brain activity, and levels of physiological stress in a sample of 56 newborn human infants aged 36–42 weeks. Salivary cortisol (hypothalamic pituitary axis), heart rate variability (sympathetic adrenal medullary system), EEG event-related potentials (nociceptive cortical activity), and facial expression (behavior) were acquired in individual infants following a clinically required heel lance. We show that infants with higher levels of stress exhibit larger amplitude cortical nociceptive responses, but this is not reflected in their behavior. Furthermore, while nociceptive behavior and cortical activity are normally correlated, this relationship is disrupted in infants with high levels of physiological stress. Brain activity evoked by noxious stimulation is therefore enhanced by stress, but this cannot be deduced from observation of pain behavior. This may be important in the prevention of adverse effects of early repetitive pain on brain development.

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“…Despite an age-dependent variation in the antinociceptive potency of µ-opioid agonism after birth, its analgesic activity has been well established also in newborns 30,32,33. Although the descending noradrenergic system does not seem to fully function as a pain inhibitory system at birth, the spinal elements necessary for the functioning of the noradrenaline reuptake inhibition mechanism are developed at birth and can be utilized by tapentadol 151–153. Therefore a similar exposure–response relationship for tapentadol in adults and children was initially assumed.…”

Section: Key Elements Of the Pediatric Programmentioning

confidence: 99%

The challenge of developing pain medications for children: therapeutic needs and future perspectives

Eerdekens

Beuter

Lefeber

et al. 2019

JPR

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It is broadly accepted that children of all age groups including (preterm) neonates and young infants can perceive pain and that there is an absolute need to treat their pain safely and effectively. The approved treatment options for children, particularly (preterm) neonates and young infants, are very limited with only a few medications specifically labelled for this population. This article presents the challenges of developing pain medications for children. A short overview gives information on pain in children, including pain perception, prevalence of pain and the long-term consequences of leaving pain untreated in this vulnerable population. Current pain management practices are briefly discussed. The challenges of conducting pediatric clinical trials in general and trials involving analgesic medications in particular within the regulatory framework available to develop these medications for children are presented. Emphasis is given to the operational hurdles faced in conducting a pediatric clinical trial program. Some suggestions to overcome these hurdles are provided based on our experience during the pediatric trial program for the strong analgesic tapentadol used for the treatment of moderate to severe acute pain.

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The developmental emergence of differential brainstem serotonergic control of the sensory spinal cord

Cited by 21 publications

References 61 publications

<p>Population pharmacokinetic modeling to facilitate dose selection of tapentadol in the pediatric population</p>

<p>Population pharmacokinetic modeling to facilitate dose selection of tapentadol in the pediatric population</p>

Nociceptive Cortical Activity Is Dissociated from Nociceptive Behavior in Newborn Human Infants under Stress

<p>The challenge of developing pain medications for children: therapeutic needs and future perspectives</p>

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