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      Analgesic Drug Development for Children: A History of Shortcomings … Until Now

      1 , 1 , 1 , 2

      Journal of Pain Research

      Dove

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          Abstract

          With hundreds of pharmaceutical companies internationally, each sharing a portion of a global, multi-trillion dollar business, and with international drug approval regulations varying widely in terms of restrictions, timing, and cost, each decision made by pharmaceutical companies in planning the development of a new drug has immense financial consequences. Grünenthal, a family-owned pharmaceutical company that now employs over 4500 individuals, has funded and executed multiple clinical drug trials of the analgesic tapentadol, a novel molecule with both mu-opioid and SNRI-like (serotonin and norepinephrine reuptake inhibitor) properties that have been shown to be effective in the treatment of acute and chronic pain in adults. In taking the necessary steps to demonstrate pharmacokinetics, efficacy and, safety in the pediatric population for their drug, Grünenthal has established a precedent and set the bar for other pharmaceutical companies – one that has remained largely absent from the most recent drug releases. Medical advances and new drug development have grown at a tremendous pace, and continue to reach new heights year after year. In 1996, the United States Food and Drug Administration (FDA) approved a record-breaking 50 new drug approvals.1 In the year 2018, another benchmark was set when the FDA issued approvals for 61 new drugs.1 While used as evidence of the progress of the economies of medically advanced countries, these numbers do not reflect the myopic perspective that predominates the world of pharmaceutical development in ignoring 25% of the population – children. Of the 61 new drug approvals in 2018, only 4 approvals were for the pediatric age group (ages 2–17)2 in spite of the fact that children and adolescents represent one-quarter of the population, suffer from many of the same ailments as do their elders, and from many more that are unique to their age group. Today, only about half of analgesic medications used in either inpatient or outpatient settings have been thoroughly evaluated for efficacy and safety, and have dosing guidelines approved by the international regulatory agencies for use in pediatrics.2 The number of analgesic medications approved in ages less than 2 years, including preterm infants, is even more humbling at only 35%.10 Yet in spite of the lack of clinical trials by industry and thorough evaluation by governmental bodies, analgesics are still widely prescribed in pediatrics and are used “off-label,” which increases the risk to the patient for both toxicity and lack of efficacy, as well as medicolegal exposure for the healthcare provider.5 These statistics hallmark one of the realities of pharmaceutical progress: with competition to be the quickest to bring new medications to market also comes the incentive to bypass important steps that confer benefit to society but are, at the same time, deemed unnecessary for the sake of corporate profit. In the case of pain medication, this means that the pediatric population is overlooked, and is deprived of evidence for safe and effective medication administration. Of course, pharmaceutical research and development for children has many challenges. Ethical considerations, financial burdens, and time constraints make it difficult and expensive for the pharmaceutical industry to allocate their resources to what is, in essence, an ethical and altruistic duty that does not assure their return on investment. To address the problem of the misaligned interests of pharmaceutical companies, who have well-defined fiduciary obligations to their stockholders, and the vulnerable patients and their healthcare providers, it has been necessary to have intervention by governments to align public health and corporate priorities. For example, since 1994 there have been several regulatory programs and statutory requirements put in place by the US FDA and the US Congress in order to realign the visions towards a collective goal. However, experience shows that there is still much more to be done in hopes of reaching the endpoint of safer healthcare practice and overall affordable and accessible healthcare for our vulnerable populations. Today, even with the presence of the FDA requirements (Figure 1), only around 50% of all analgesics used in children are “approved” by the FDA for use in pediatrics. Figure 1 Historical timeline of drug development milestones in the United States of America. Note: Data from these studies.1–4 Grünenthal’s development of tapentadol for the pediatric population has shown very promising safety and efficacy results – comparable to those found in the adult population. By first using simulation models on known volume of distribution and clearance data, an oral, weight-based tapentadol dose was predicted and used for subsequent pediatric clinical trials. Using these models, Grünenthal then used the predicted oral formulation dosing regimens and designed and executed studies that defined pharmacokinetics and efficacy for their trial drug in children. In both single-blind and double-blind randomized control studies, Grünenthal has been able to show short-term benefits of their new pain medication in children. Confirmation of the short-term effects in the pediatric population from these studies allow health care providers to prescribe the oral formulation of tapentadol with confidence in its dose, predicted effects and potential side effects.6 9 In an ideal world, all drugs used in the pediatrics would have strong evidence-based dosing regimens and appropriate drug labelling. History and current data tell us that this vision has many challenges, ranging from simple financial considerations to complex ethical hurdles, all of which have proven difficult to overcome. From the perspective of patients and healthcare providers, maximizing efficacy while concurrently mitigating side effects continues to be the main objective. From the view of the majority of drug development companies, market share, profitability and their fiduciary responsibility to shareholders drive corporate decision-making. In the type of political and economic model that is found in the United States, governmental bodies can only do so much to help bridge the two distinctive goals between the public and drug developers. At some point, we hope that more drug companies, like Grünenthal, will make the difficult but necessary decision to value patient safety and wellbeing of children over corporate profits. Grünenthal has assumed the burden of providing well-designed studies in both the adult and pediatric population to define safe prescription regimens, ideally, before drugs go to market. In the world of pain medicine, this prospective approach will be expected to lead to a reduction of inappropriate prescribing. This will benefit not only the patient but may also reduce the opioid burden that is faced on an international scale.

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          Most cited references 9

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

          Abstract 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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            Pharmacokinetics, safety, and efficacy of tapentadol oral solution for treating moderate to severe pain in pediatric patients

            Background: This trial is part of the global pediatric clinical development program investigating the administration of the strong analgesic tapentadol in children and adolescents. Patients and methods: The single site, open-label phase 2 trial evaluated the pharmacokinetic profile of tapentadol and its major metabolite, tapentadol-O-glucuronide, as well as safety and tolerability and efficacy of a single dose of tapentadol oral solution (1 mg/kg) in patients (2 to <18 years) undergoing dental, ear, nose, or throat surgery. Blood sampling and pain intensity measurements were conducted using age-appropriate schedules and rating scales, respectively. Adverse events were monitored throughout the trial. Results: Sixty-six patients were treated. They were stratified by age: Group 1 (12 to <18 years), n=21; Group 2 (6 to <12 years), n=28; and Groups 3 (3 to <6 years) and 4 (2 to <3 years), n=17. Serum tapentadol concentrations observed in these pediatric patients were within the range observed in adults after administration of a single tapentadol immediate-release dose (50–100 mg), whereas those of the metabolite tapentadol-O-glucuronide were within the same range or lower than in adults who received comparable single doses of tapentadol. Pain intensity improved over time across all age groups. The most common treatment-emergent adverse events were nausea (24.2%), vomiting (16.7%), dizziness (9.1%), and headache (6.1%). Conclusion: A single dose of tapentadol oral solution (1 mg/kg) administered to pediatric patients (2 to <18 years) resulted in serum tapentadol concentrations within the targeted range shown to be safe and efficacious in adults. Tapentadol demonstrated good tolerability and safety; within the limitations of the trial design, improvements in postsurgical pain intensity were observed across the age groups. Tapentadol may provide a new treatment option in the management of moderate to severe pediatric pain.
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              First evaluation of tapentadol oral solution for the treatment of moderate to severe acute pain in children aged 6 to <18

              Background This is the first clinical trial in the global pediatric clinical development program for the use of the analgesic tapentadol in children and adolescents. Patients and methods This multicenter, open-label clinical trial investigated pharmacokinetics, safety and tolerability, and efficacy of tapentadol and its major metabolite tapentadol-O-glucuronide after administration of a single dose of tapentadol oral solution (OS) in pediatric patients aged 6 to <18 years experiencing moderate to severe acute pain after surgery. Efficacy (change in pain intensity after tapentadol intake) was assessed in an exploratory manner using the McGrath Color Analog Scale and Faces Pain Scale-Revised. Adverse events were monitored throughout the trial. Results Forty-four patients who received a single dose of 1 mg/kg tapentadol OS were included in this investigation. Maximum serum concentrations of tapentadol (111 ng/mL) and tapentadol-O-glucuronide (2,400 ng/mL) observed in this trial were within the range of individual maximum concentrations observed in healthy adults administered a comparable dose (range for tapentadol 23.2–129 ng/mL, for tapentadol-O-glucuronide 1,040–4,070 ng/mL). Following tapentadol administration, pain intensity scores improved from baseline at all timepoints. Treatment-emergent adverse events, none of which were serious, were experienced by 45.5% of the patients; the most commonly reported were vomiting (29.5%) and nausea (9.1%). Conclusions Tapentadol OS administered as a single dose of 1 mg/kg in children aged 6 to <18 years was generally well tolerated and produced similar serum concentrations as administration of 50–100 mg tapentadol immediate-release tablets in adults. A decrease in postsurgical pain was observed using exploratory subject-reported pain assessments. Tapentadol OS may provide a new treatment option in the management of moderate to severe acute pain in children and adolescents.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                jpr
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                31 March 2021
                2021
                : 14
                : 867-870
                Affiliations
                [1 ]Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine , Stanford, CA, USA
                [2 ]Department of Pediatrics, Stanford University School of Medicine , Stanford, CA, USA
                Author notes
                Correspondence: Andrew Dinh Email atdinh@stanford.edu
                Article
                291594
                10.2147/JPR.S291594
                8020136
                © 2021 Dinh et al.

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                Page count
                Figures: 1, References: 10, Pages: 4
                Categories
                Editorial

                Anesthesiology & Pain management

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