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Kumar A, Vallabhaneni P. Anxiety disorders presenting as gastrointestinal symptoms in children - a scoping review. Clin Exp Pediatr 2025; 68:344-351. [PMID: 39810509 PMCID: PMC12062388 DOI: 10.3345/cep.2024.01732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/03/2025] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
Functional gastrointestinal disorders (FGID) and their association with anxiety disorders in children significantly impact a child's functioning and treatment response. This study aimed to scope the evidence of anxiety disorders manifesting as FGID in children up to 16 years old. A comprehensive search strategy was conducted on Embase (1974-2024), MEDLINE (via EBSCOHost 1946-2024), and APA PsycINFO (via EBSCOHost 1967-2024). Articles were retrieved, screened, and assessed for bias using the GRADE system. Our initial search yielded 1984 articles. After screening titles and abstracts, 53 articles remained. Full-text screening further narrowed this to 4 eligible studies. The first study found that anxiety indirectly influenced abdominal pain severity in children with irritable bowel syndrome. The second study reported an association between anxiety and abdominal pain but found that anxiety might not predict abdominal pain in later childhood. The third study suggested FGID could be a risk factor for anxiety, with higher anxiety rates in children with FGID compared to those without. The fourth study found no significant difference in pain intensity between children with functional abdominal pain disorders (FAPD) alone and those with FAPD and anxiety. The reviewed studies indicate a relationship between anxiety and FGID but lack clarity on directionality or causation. The limited number of studies calls for more research, including case-control studies with large sample sizes and longitudinal cohort studies to investigate the incidence and causation.
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Boerner KE, Pawliuk C, Heran A, Donaghy B, Moore D, Leong K, Devan H, Oberlander TF. Systematic review of autistic representation in the treatment literature for pediatric chronic pain. THE JOURNAL OF PAIN 2025:105390. [PMID: 40228686 DOI: 10.1016/j.jpain.2025.105390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 03/05/2025] [Accepted: 04/03/2025] [Indexed: 04/16/2025]
Abstract
Chronic pain disproportionately affects autistic children and young people, yet they are underrepresented in pain research. Research on psychological, physical, and pharmacological therapies for other conditions suggests modifications are required to ensure treatment accessibility and efficacy for autistic individuals. However, no such evidence base has been synthesized in pediatric pain. The aim of this review was to (1) review existing "gold-standard" treatment literature for pediatric chronic pain to determine the representation of autistic participants, and (2) review literature on treatment of chronic pain specifically in autistic children and young people to describe the current evidence landscape and identify next directions for research. 16.7% (12/72) of randomized controlled trials included in Cochrane reviews of interventions for pediatric chronic pain explicitly excluded youth with a developmental delay/disability, of which only 8.3% specifically named autism. However, 52.8% of Cochrane-included trials had criteria or protocols which may have disproportionately impacted autistic participants, such as excluding intellectual disability, psychiatric conditions, medical conditions, and/or requiring participants to communicate verbally. Twenty-nine studies of treating chronic pain in autistic children and young people were identified, of which the majority were case reports (k = 27, 93%) with large variation in pain condition, intervention applied, and outcomes measured. Given the high prevalence of chronic pain in autistic children and young people, there is an ethical imperative to ensure their representation in intervention trials, co-develop interventions that address the specific needs of autistic individuals who live with pediatric chronic pain, and to increase accessibility in chronic pain research more broadly. REGISTRATION: PROSPERO: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=491423 registered March 19 2024 Open Science Framework: https://osf.io/8na64/ registered December 18, 2023 PERSPECTIVE: Autistic children and young people (CYP) are not represented in reviews of chronic pain treatments, and the literature on treating chronic pain specifically in this population is so variable no clear conclusions can be drawn. Efforts to increase accessibility of chronic pain interventions and research for autistic CYP is needed.
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Affiliation(s)
- Katelynn E Boerner
- Department of Pediatrics, Faculty of Medicine, University of British Columbia, and BC Children's Hospital Research Institute, Vancouver, Canada; Centre for Gender & Sexual Health Equity, University of British Columbia, Vancouver, Canada; Women's Health Research Institute, BC Women's Hospital and Health Centre, Vancouver, Canada.
| | - Colleen Pawliuk
- Department of Pediatrics, Faculty of Medicine, University of British Columbia, and BC Children's Hospital Research Institute, Vancouver, Canada
| | - Aishwarya Heran
- Department of Pediatrics, Faculty of Medicine, University of British Columbia, and BC Children's Hospital Research Institute, Vancouver, Canada
| | - Bethany Donaghy
- Research Centre for Brain & Behaviour, Liverpool John Moores University, Liverpool, United Kingdom
| | - David Moore
- Research Centre for Brain & Behaviour, Liverpool John Moores University, Liverpool, United Kingdom
| | - Kai Leong
- Department of Pediatrics, Faculty of Medicine, University of British Columbia, and BC Children's Hospital Research Institute, Vancouver, Canada
| | - Hemakumar Devan
- Rehabilitation Teaching and Research Unit (RTRU), Department of Medicine, University of Otago, Wellington, New Zealand
| | - Tim F Oberlander
- Department of Pediatrics, Faculty of Medicine, University of British Columbia, and BC Children's Hospital Research Institute, Vancouver, Canada; School of Population and Public Health, University of British Columbia, Vancouver, Canada
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Shokrnejad-namin T, Amini E, Khakpai F, Zarrindast MR. The additive effect between citalopram and muscimol upon induction of antinociceptive effect in male mice. IBRO Neurosci Rep 2024; 17:58-64. [PMID: 39807389 PMCID: PMC11725972 DOI: 10.1016/j.ibneur.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 05/09/2024] [Accepted: 05/10/2024] [Indexed: 01/16/2025] Open
Abstract
Previous investigations have revealed the role of GABAergic and serotonergic systems in the modulation of pain behavior. This research aimed to examine the effects of intracerebroventricular (i.c.v.) infusion of GABAA receptor agonist and antagonist as well as citalopram on pain behavior in male mice. For i.c.v. microinjection, a guide cannula was surgically implanted in the left lateral ventricle of male mice. Pain behavior was evaluated using a tail-flick test. Tail flick latency was measured in each experimental group of mice every 15 min (for 60 min). I.c.v. microinjection of muscimol (0.5 and 1 µg/mouse; GABAA receptor agonist) into the left lateral ventricle dose-dependently induced an antinociceptive effect. On the other hand, i.c.v. infusion of bicuculline (1 µg/mouse; GABAA receptor antagonist) induced a hyperalgesia response. Moreover, intraperitoneally (i.p.) administration of citalopram (8 mg/kg) produced an antinociceptive effect. Co-treatment of citalopram (8 mg/kg) along with muscimol (0.25 µg/mouse) or bicuculline (0.25 µg/mouse) potentiated the antinociceptive effect produced by citalopram. We found an additive antinociceptive effect of citalopram and muscimol in male mice. In conclusion, our results suggested an interaction between citalopram and GABAergic agents on the modulation of pain behavior in male mice.
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Affiliation(s)
- Taha Shokrnejad-namin
- Department of Physiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Elnaz Amini
- Department of Physiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Khakpai
- Department of Physiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad-Reza Zarrindast
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran
- Institute for Cognitive Science Studies (ICSS), Tehran, Iran
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Alyasi AS, Altawili MA, Alabbadi AF, Hamdi AHA, Alshammery AS, Alfahad MI, Alamri RM, Alanazi TR, Harbi MHA, Alajmi AM, Alabdulrahim JM, Alalshaikh AM, Hanbzazah AM. Pharmacological Management for Pediatric Irritable Bowel Syndrome: A Review. Cureus 2023; 15:e49197. [PMID: 38130553 PMCID: PMC10735276 DOI: 10.7759/cureus.49197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/20/2023] [Indexed: 12/23/2023] Open
Abstract
Irritable bowel syndrome is a multifactorial disease with chronic symptoms that interfere with the quality of life of patients. It represents one of the most common causes of functional abdominal pain in the pediatric population. Various theses with little evidence tried to explain the pathophysiology of the disease. Neurological origin was one of the theories explaining the disease, either by the disturbance of neurotransmitters like dopamine, noradrenaline, and serotonin, which have some evidence of their relation to GI tract functions. Other factors like bio-psycho-social factors that affect the pediatric population are represented in bullying, unrealistic academic expectations from the parents, continuous educational stress, and difficult relationships with peers. Other factors may be genetic abnormalities of the receptors or visceral hypersensitivity. Treatment strategies for the disease varied from physical activity like yoga to a diet like a low-FODMAP diet. Pharmacological treatment of the disease targets the presenting symptoms, represented by antispasmodic drugs treating abdominal pain/discomfort, antipsychotics that regulate the disturbance in the brain-gut axis, and other drugs targeting diarrhea or constipation that present with the patient according to the type of IBS and the condition of the patient.
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Affiliation(s)
- Alaa S Alyasi
- Pediatrics and Neonatology, Maternal and Child Health Care Center, Tabuk, SAU
| | | | | | | | | | | | | | | | | | - Alaa M Alajmi
- General Practice, Primary Health Centers - Dammam Health Network, Dammam, SAU
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Rexwinkel R, Vlieger AM, Saps M, Tabbers MM, Benninga MA. A therapeutic guide on pediatric irritable bowel syndrome and functional abdominal pain-not otherwise specified. Eur J Pediatr 2022; 181:2603-2617. [PMID: 35460383 PMCID: PMC9192445 DOI: 10.1007/s00431-022-04459-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 03/27/2022] [Accepted: 03/29/2022] [Indexed: 12/14/2022]
Abstract
Disorders of the gut-brain interaction negatively impact quality of life and carry a substantial socioeconomic burden. Irritable bowel syndrome (IBS) and functional abdominal pain-not otherwise specified (FAP-NOS) are common functional abdominal pain disorders in childhood. The pathophysiology is not fully understood, and high-quality intervention trials and international guidelines are missing. Therefore, the management of these disorders remains challenging. This review aims to provide an up-to-date overview of therapeutic possibilities for pediatric IBS or FAP-NOS and recommends management strategies. To prevent unnecessary referrals and extensive costs, it is fundamental to make a positive diagnosis of IBS or FAP-NOS in children with chronic abdominal pain with only minimal investigations. A tailor-made approach for each patient, based on the accompanying physical and psychological symptoms, is proposed to date. CONCLUSION Shared decision-making including non-pharmacological and pharmacological interventions should be considered and discussed with the family. WHAT IS KNOWN • Irritable bowel syndrome and functional abdominal pain-not otherwise specified are common in childhood. • Although the number of treatment options has grown recently, managing these disorders can be challenging and unsatisfactory, and no evidence-based international management guidelines are available. WHAT IS NEW • We suggest using a stepwise individualized approach to management, where after first-line management, both non-pharmacological and pharmacological interventions should be discussed.
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Affiliation(s)
- Robyn Rexwinkel
- Emma Children's Hospital, Amsterdam UMC, Pediatric Gastroenterology, University of Amsterdam, Room C2-312, PO Box 22700, 1100 DD, Amsterdam, Netherlands.
| | - Arine M Vlieger
- Department of Pediatrics, St. Antonius Hospital, Nieuwegein, Netherlands
| | - Miguel Saps
- Department of Pediatric Gastroenterology, University of Miami, Miami, FL, USA
| | - Merit M Tabbers
- Emma Children's Hospital, Amsterdam UMC, Pediatric Gastroenterology, University of Amsterdam, Room C2-312, PO Box 22700, 1100 DD, Amsterdam, Netherlands
| | - Marc A Benninga
- Emma Children's Hospital, Amsterdam UMC, Pediatric Gastroenterology, University of Amsterdam, Room C2-312, PO Box 22700, 1100 DD, Amsterdam, Netherlands
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Cordeiro Santos ML, da Silva Júnior RT, de Brito BB, França da Silva FA, Santos Marques H, Lima de Souza Gonçalves V, Costa dos Santos T, Ladeia Cirne C, Silva NOE, Oliveira MV, de Melo FF. Non-pharmacological management of pediatric functional abdominal pain disorders: Current evidence and future perspectives. World J Clin Pediatr 2022; 11:105-119. [PMID: 35433299 PMCID: PMC8985495 DOI: 10.5409/wjcp.v11.i2.105] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 07/19/2021] [Accepted: 02/11/2022] [Indexed: 02/06/2023] Open
Abstract
Functional abdominal pain disorders (FAPDs) are an important and prevalent cause of functional gastrointestinal disorders among children, encompassing the diagnoses of functional dyspepsia, irritable bowel syndrome, abdominal migraine, and the one not previously present in Rome III, functional abdominal pain not otherwise specified. In the absence of sufficiently effective and safe pharmacological treatments for this public problem, non-pharmacological therapies emerge as a viable means of treating these patients, avoiding not only possible side effects, but also unnecessary prescription, since many of the pharmacological treatments prescribed do not have good efficacy when compared to placebo. Thus, the present study provides a review of current and relevant evidence on non-pharmacological management of FAPDs, covering the most commonly indicated treatments, from cognitive behavioral therapy to meditation, acupuncture, yoga, massage, spinal manipulation, moxibustion, and physical activities. In addition, this article also analyzes the quality of publications in the area, assessing whether it is possible to state if non-pharmacological therapies are viable, safe, and sufficiently well-based for an appropriate and effective prescription of these treatments. Finally, it is possible to observe an increase not only in the number of publications on the non-pharmacological treatments for FAPDs in recent years, but also an increase in the quality of these publications. Finally, the sample selection of satisfactory age groups in these studies enables the formulation of specific guidelines for this age group, thus avoiding the need for adaptation of prescriptions initially made for adults, but for children use.
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Affiliation(s)
- Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Bahia, Brazil
| | | | - Talita Costa dos Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Carolina Ladeia Cirne
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Natália Oliveira e Silva
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Márcio Vasconcelos Oliveira
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Pesce M, Puoti MG, Rybak A, Andreozzi M, Bruzzese E, Sarnelli G, Borrelli O. Pharmacological interventions for pediatric irritable bowel syndrome. Expert Opin Pharmacother 2021; 23:91-103. [PMID: 34523358 DOI: 10.1080/14656566.2021.1976753] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Irritable bowel syndrome is a common functional gastrointestinal disorder in children, characterized by recurrent abdominal pain associated with altered bowel habits in terms of both frequency and consistency. According to change in stool consistency it is categorized into 4 subtypes. From the etiological perspective, it is a combination of factors takes part in symptoms' generation, the overall treatment response rate is often unsatisfactory if a multidisciplinary is not pursued. AREAS COVERED The aim of this manuscript is to summarize the current pharmacotherapy in pediatric irritable bowel syndrome in order to aid clinicians in treating this challenging disorder. EXPERT OPINION Most evidence involving pediatric populations rely on open label or retrospective studies and/or are not specifically designed for irritable bowel syndrome but tend to generalize their results to mixed populations of children with functional gastrointestinal disorders. A high placebo response rate combined with poor patients' selection could account for the overall weak evidence supporting the use of pharmacological agents in pediatric irritable bowel syndrome. Given the multifaceted nature of the disorder, multidisciplinary approaches combining pharmacotherapy with alternative treatments is highly recommendable.
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Affiliation(s)
- Marcella Pesce
- Department of Clinical Medicine and Surgery, University "Federico Ii" of Naples, Naples, Italy
| | - Maria Giovanna Puoti
- Division of Neurogastroenterology & Motility, Department of Paediatric Gastroenterology, Great Ormond Street Hospital for children, London, UK
| | - Anna Rybak
- Division of Neurogastroenterology & Motility, Department of Paediatric Gastroenterology, Great Ormond Street Hospital for children, London, UK
| | - Marta Andreozzi
- Department of Clinical Medicine and Surgery, University "Federico Ii" of Naples, Naples, Italy
| | - Eugenia Bruzzese
- Department of Translational Medical Science, University "Federico Ii" of Naples, Naples, Italy
| | - Giovanni Sarnelli
- Department of Clinical Medicine and Surgery, University "Federico Ii" of Naples, Naples, Italy
| | - Osvaldo Borrelli
- Division of Neurogastroenterology & Motility, Department of Paediatric Gastroenterology, Great Ormond Street Hospital for children, London, UK
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Friesen C, Colombo JM, Deacy A, Schurman JV. An Update on the Assessment and Management of Pediatric Abdominal Pain. PEDIATRIC HEALTH MEDICINE AND THERAPEUTICS 2021; 12:373-393. [PMID: 34393542 PMCID: PMC8354769 DOI: 10.2147/phmt.s287719] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 07/15/2021] [Indexed: 12/12/2022]
Abstract
Chronic abdominal pain is very common in children and adolescent and results in high personal and social costs. Most youth with chronic abdominal pain fulfill criteria for a functional abdominal pain disorder (FAPD) as defined by Rome criteria. These are complex conditions with a wide array of biological, psychological, and social factors contributing to the experience of pain. The purpose of the current review is to provide an overview of the pathophysiology of FAPDs and an up-to-date summary of the literature related to FAPDs in children and adolescents, with additional focus on several areas (eg, diet and probiotics) where patients and families frequently have questions or implement self-directed care. We also provide an approach to the assessment and treatment of pediatric FAPDs focusing on the robust literature regarding psychological interventions and much sparser literature regarding medication treatment.
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Affiliation(s)
- Craig Friesen
- Division of Gastroenterology, Hepatology, and Nutrition; Children's Mercy Kansas City, Kansas City, MO, USA
| | - Jennifer M Colombo
- Division of Gastroenterology, Hepatology, and Nutrition; Children's Mercy Kansas City, Kansas City, MO, USA
| | - Amanda Deacy
- Division of Gastroenterology, Hepatology, and Nutrition; Children's Mercy Kansas City, Kansas City, MO, USA
| | - Jennifer V Schurman
- Division of Gastroenterology, Hepatology, and Nutrition; Children's Mercy Kansas City, Kansas City, MO, USA
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Jolly T, Mansuri Z, Trivedi C, Adnan M, Cohen SP, Vu TN. Are Psychotropic Medications Effective in Chronic Pain Management in Children and Adolescents? A Meta-Analysis of Randomized Control Trials. J Pain Res 2021; 14:1915-1924. [PMID: 34194243 PMCID: PMC8238552 DOI: 10.2147/jpr.s310381] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 06/02/2021] [Indexed: 12/11/2022] Open
Abstract
Objective Data defining and subsequently guiding the use of psychotropic medications in children and adolescents is sparse. We conducted a meta-analysis of randomized control trials to examine the effectiveness of psychotropic medications in children and adolescents with chronic pain. Methods We conducted a comprehensive literature search from published studies, and annual scientific sessions of psychiatry conferences. We identified double-blind, randomized control trials (RCTs) in which psychotropic medications were compared to placebo. Data was collected for the total number of patients, baseline characteristics, and changes in pain score. Meta-analysis was performed using a random effect model evaluating average change in pain score and the number of patients with a reduction in pain score for both groups. Pooled data are expressed as standardized mean differences (SMD) and odds ratios (OR) with 95% confidence intervals (CI). Results We found 5 studies that included amitriptyline (n=2), citalopram (n=1), buspirone (n=1) and duloxetine (n=1). In the pooled analysis for the difference in the average change in pain score, 4 RCTs with 395 patients were included. After 12–13 weeks of therapy, reductions in pain score were significantly greater in the psychotropic drug group as compared to placebo (SMD: −0.77, 95% CI −1.54, 0.0001, p= 0.05). For the analysis on the number of patients with a reduction in pain, data were available for 445 patients (224-medication group, 221-placebo group). More patients in the psychotropic drug group experienced a meaningful reduction in pain score at 12–13 weeks of therapy compared to placebo (OR 1.66, 95% CI 1.08–2.54, p= 0.02). Conclusion The results of this meta-analysis demonstrate significant analgesic efficacy of psychotropic medications in the management of children with chronic pain. This review is limited by the small number of studies included for analysis. There is a pressing need for more robust clinical trials to further investigate these promising findings.
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Affiliation(s)
- Taranjeet Jolly
- Department of Psychiatry & Behavioral Health, Penn State University College of Medicine, Inpatient Child and Adolescent Psychiatry, Pennsylvania Psychiatric Institute, Harrisburg, PA, USA
| | - Zeeshan Mansuri
- Department of Psychiatry, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
| | - Chintan Trivedi
- Psychiatry Department, St. David's Medical Center, Austin, TX, USA
| | - Mahwish Adnan
- Department of Psychiatry, Mercy Hospital and Medical Center, Lincolnwood, IL, USA
| | - Steven P Cohen
- Department of Anesthesiology & Critical Care medicine, Neurology and Physical Medicine & Rehabilitation, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - To-Nhu Vu
- Department of Anesthesia & Pain Medicine, Penn State University College of Medicine, Hershey, PA, USA
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10
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Sánchez-Salcedo JA, Cabrera MME, Molina-Jiménez T, Cortes-Altamirano JL, Alfaro-Rodríguez A, Bonilla-Jaime H. Depression and Pain: use of antidepressant. Curr Neuropharmacol 2021; 20:384-402. [PMID: 34151765 PMCID: PMC9413796 DOI: 10.2174/1570159x19666210609161447] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 04/03/2021] [Accepted: 04/03/2021] [Indexed: 11/24/2022] Open
Abstract
Background: Emotional disorders are common comorbid affectations that exacerbate the severity and persistence of chronic pain. Specifically, depressive symptoms can lead to an excessive duration and intensity of pain. Clinical and preclinical studies have been focused on the underlying mechanisms of chronic pain and depression comorbidity and the use of antidepressants to reduce pain. Aim: This review provides an overview of the comorbid relationship of chronic pain and depression, the clinical and pre-clinical studies performed on the neurobiological aspects of pain and depression, and the use of antidepressants as analgesics. Methods: A systematic search of literature databases was conducted according to pre-defined criteria. The authors independently conducted a focused analysis of the full-text articles. Results: Studies suggest that pain and depression are highly intertwined and may co-exacerbate physical and psychological symptoms. One important biochemical basis for pain and depression focuses on the serotonergic and norepinephrine system, which have been shown to play an important role in this comorbidity. Brain structures that codify pain are also involved in mood. It is evident that using serotonergic and norepinephrine antidepressants are strategies commonly employed to mitigate pain Conclusion: Literature indicates that pain and depression impact each other and play a prominent role in the development and maintenance of other chronic symptoms. Antidepressants continue to be a major therapeutic tool for managing chronic pain. Tricyclic antidepressants (TCAs) are more effective in reducing pain than Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs).
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Affiliation(s)
- José Armando Sánchez-Salcedo
- Doctorado en Ciencias Biológicas y de la Salud. Universidad Autónoma Metropolitana-Iztapalapa, UAM-I, Apartado Postal 55 535, C.P. 09340, Ciudad de México, Mexico
| | - Maribel Maetizi Estevez Cabrera
- Doctorado en Ciencias Biológicas y de la Salud. Universidad Autónoma Metropolitana-Iztapalapa, UAM-I, Apartado Postal 55 535, C.P. 09340, Ciudad de México, Mexico
| | - Tania Molina-Jiménez
- Facultad de Química Farmacéutica Biológica, Universidad Veracruzana. Circuito Gonzálo Aguirre Beltrán Sn, Zona Universitaria. C.P. 91090 Xalapa-Enríquez
| | - José Luis Cortes-Altamirano
- División de Neurociencias, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Secretaría de Salud, Ciudad de México, Mexico
| | - Alfonso Alfaro-Rodríguez
- División de Neurociencias, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Secretaría de Salud, Ciudad de México, Mexico
| | - Herlinda Bonilla-Jaime
- Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana-Iztapalapa. Apartado Postal 55 535, C.P. 09340, Ciudad de México, Mexico
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11
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Rexwinkel R, de Bruijn CMA, Gordon M, Benninga MA, Tabbers MM. Pharmacologic Treatment in Functional Abdominal Pain Disorders in Children: A Systematic Review. Pediatrics 2021; 147:peds.2020-042101. [PMID: 34045320 DOI: 10.1542/peds.2020-042101] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/12/2021] [Indexed: 11/24/2022] Open
Abstract
CONTEXT Functional abdominal pain disorders (FAPDs) are common in childhood, impacting quality of life and school attendance. There are several compounds available for the treatment of pediatric FAPDs, but their efficacy and safety are unclear because of a lack of head-to-head randomized controlled trials (RCTs). OBJECTIVE To systematically review the efficacy and safety of the pharmacologic treatments available for pediatric FAPDs. DATA SOURCES Electronic databases were searched from inception to February 2021. STUDY SELECTION RCTs or systematic reviews were included if the researchers investigated a study population of children (4-18 years) in whom FAPDs were treated with pharmacologic interventions and compared with placebo, no treatment, or any other agent. DATA EXTRACTION Two reviewers independently performed data extraction and assessed their quality. Any interresearcher disagreements in the assessments were resolved by a third investigator. RESULTS Seventeen articles representing 1197 children with an FAPD were included. Trials investigating antispasmodics, antidepressants, antibiotics, antihistaminic, antiemetic, histamine-2-receptor antagonist, 5-HT4-receptor agonist, melatonin, and buspirone were included. No studies were found on treatment with laxatives, antidiarrheals, analgesics, antimigraines, and serotonergics. LIMITATIONS The overall quality of evidence on the basis of the Grading of Recommendations, Assessment, Development and Evaluations system was very low to low. CONCLUSIONS On the basis of current evidence, it is not possible to recommend any specific pharmacologic agent for the treatment of pediatric FAPDs. However, agents such as antispasmodics or antidepressants can be discussed in daily practice because of their favorable treatment outcomes and the lack of important side effects. High-quality RCTs are necessary to provide adequate pharmacologic treatment. For future intervention trials, we recommend using homogenous outcome measures and instruments, a large sample size, and long-term follow-up.
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Affiliation(s)
- Robyn Rexwinkel
- Pediatric Gastroenterology, Hepatology, and Nutrition, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands; .,Amsterdam Reproduction and Development Research Institute, Amsterdam University Medical Center, Academic Medical Center and Emma Children's Hospital, Amsterdam, The Netherlands.,Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.,Contributed equally as co-first authors
| | - Clara M A de Bruijn
- Pediatric Gastroenterology, Hepatology, and Nutrition, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.,Amsterdam Reproduction and Development Research Institute, Amsterdam University Medical Center, Academic Medical Center and Emma Children's Hospital, Amsterdam, The Netherlands.,Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.,Contributed equally as co-first authors
| | - Morris Gordon
- School of Medicine, University of Central Lancashire, Preston, United Kingdom
| | - Marc A Benninga
- Pediatric Gastroenterology, Hepatology, and Nutrition, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Merit M Tabbers
- Pediatric Gastroenterology, Hepatology, and Nutrition, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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12
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de Bruijn CMA, Rexwinkel R, Gordon M, Benninga M, Tabbers MM. Antidepressants for functional abdominal pain disorders in children and adolescents. Cochrane Database Syst Rev 2021; 2:CD008013. [PMID: 33560523 PMCID: PMC8094232 DOI: 10.1002/14651858.cd008013.pub3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Functional Abdominal Pain Disorders (FAPDs) present a considerable burden to paediatric patients, impacting quality of life, school attendance and causing higher rates of anxiety and depression disorders. There are no international guidelines for the management of this condition. A previous Cochrane Review in 2011 found no evidence to support the use of antidepressants in this context. OBJECTIVES To evaluate the current evidence for the efficacy and safety of antidepressants for FAPDs in children and adolescents. SEARCH METHODS In this updated review, we searched the Cochrane Library, PubMed, MEDLINE, Embase, PsycINFO and two clinical trial registers from inception until 03 February 2020. We also updated our search of databases of ongoing research, reference lists and 'grey literature' from inception to 03 February 2020. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing antidepressants to placebo, to no treatment or to any other intervention, in children aged 4 to 18 years with a FAPD diagnosis as per the Rome or any other defined criteria (as defined by the authors). The primary outcomes of interest included treatment success (as defined by the authors), pain severity, pain frequency and withdrawal due to adverse events. DATA COLLECTION AND ANALYSIS Two review authors checked all citations independently, resolving disagreement with a third-party arbiter. We reviewed all potential studies in full text, and once again made independent decisions, with disagreements resolved by consensus. We conducted data extraction and 'Risk of bias' assessments independently, following Cochrane methods. Where homogeneous data were available, we performed meta-analysis using a random-effects model. We conducted GRADE analysis. MAIN RESULTS We found one new study in this updated search, making a total of three trials (223 participants) eligible for inclusion: two using amitriptyline (AMI) and one using citalopram. For the primary outcome of treatment success, two studies used reports of success on a symptom-based Likert scale, with either a two-point reduction or the two lowest levels defined as success. The third study defined success as a 15% improvement in quality of life (QOL) ratings scales. Therefore, meta-analysis did not include this final study due to the heterogeneity of the outcome measure. There is low-certainty evidence that there may be no difference when antidepressants are compared with placebo (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.87 to 1.56; 2 studies, 205 participants; I2 = 0%). We downgraded the evidence for significant imprecision due to extremely sparse data (see Summary of findings table 1). The third study reported that participants receiving antidepressants were significantly more likely than those receiving placebo to experience at least a 15% improvement in overall QOL score at 10 and 13 weeks (P = 0.007 and P = 0.002, respectively (absolute figures were not given)). The analysis found no difference in withdrawals due to adverse events between antidepressants and placebo: RR 3.17 (95% CI 0.65 to 15.33), with very low certainty due to high risk of bias in studies and imprecision due to low event and participant numbers. Sensitivity analysis using a fixed-effect model and analysing just for AMI found no change in this result. Due to heterogeneous and limited reporting, no further meta-analysis was possible. AUTHORS' CONCLUSIONS There may be no difference between antidepressants and placebo for treatment success of FAPDs in childhood. There may be no difference in withdrawals due to adverse events, but this is also of low certainty. There is currently no evidence to support clinical decision making regarding the use of these medications. Further studies must consider sample size, homogenous and relevant outcome measures and longer follow up.
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Affiliation(s)
| | | | - Morris Gordon
- School of Medicine, University of Central Lancashire, Preston, UK
| | - Marc Benninga
- Department of Paediatric Gastroenterology, Emma Children's Hospital/AMC, Amsterdam, Netherlands
| | - Merit M Tabbers
- Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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Abstract
Paediatric functional abdominal pain disorders, currently referred to as disorders of gut-brain interaction, comprise irritable bowel syndrome, functional dyspepsia, abdominal migraine and functional abdominal pain not otherwise specified, as defined by the Rome IV diagnostic criteria. Functional abdominal pain disorders are common disorders with a prevalence of 3-16% depending on country, age and sex. A greater understanding of aetiopathogenesis and pathophysiology is emerging and includes intestinal components (inflammation, motility and the microbiota), central factors (psychological aspects, sensitization and/or differences in connectivity or activity of certain brain regions) as well as extrinsic factors (infections). In particular, the timing of disruption of the microbiota-gut-brain axis seems to be important. Diagnosis is challenging but is primarily based on clinical symptoms and exclusion of other organic causes, with an emphasis on avoiding unnecessary invasive diagnostic procedures. The available pharmacological interventions are limited in children and, therefore, management has focused on combined approaches, including mind-targeted interventions (hypnotherapy and cognitive behavioural therapy), diet (probiotics) and percutaneous electrical nerve field stimulation. The evidence for their clinical efficacy, although limited, is favourable, with positive impacts on symptoms and overall quality of life. The coming decades hold promise for improved understanding and management of these enigmatic disorders.
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Nightingale S, Sharma A. Functional gastrointestinal disorders in children: What is new? J Paediatr Child Health 2020; 56:1724-1730. [PMID: 32468619 DOI: 10.1111/jpc.14857] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 02/22/2020] [Accepted: 02/26/2020] [Indexed: 12/20/2022]
Abstract
Abdominal pain-predominant functional gastrointestinal disorders encompass a group of chronic conditions featuring abdominal pain where no serious gastrointestinal or intra-abdominal pathology is present. The Rome IV classification system defines and categorises this group based on symptomatology as: functional dyspepsia, irritable bowel syndrome, functional abdominal pain - not otherwise specified and abdominal migraine. These conditions can impact the functioning of the child and family significantly and are challenging to manage. Although the causes of these conditions are not clear, recent years have seen an improved understanding of underlying pathophysiology and identification of effective management options for these conditions.
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Affiliation(s)
- Scott Nightingale
- Department of Gastroenterology, John Hunter Children's Hospital, Newcastle, New South Wales, Australia.,Priority Research Centre GrowUpWell, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia
| | - Ajay Sharma
- Department of Gastroenterology, Joondalup Health Campus, Perth, Western Australia, Australia.,Perth Paediatrics, Perth, Western Australia, Australia
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Cardwell GS, Findling RL, Robb AS. Psychiatric Diseases in Children and Adolescents. Handb Exp Pharmacol 2020; 261:397-413. [PMID: 31598836 DOI: 10.1007/164_2019_262] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Pharmacotherapy of psychiatric illnesses in children and adolescents has grown significantly over the last few decades. However, the body of research examining pharmacological treatments for psychiatric illnesses is much smaller in children and adolescents than it is in adults. As most treatments for psychiatric disorders are more effective if started early in the course of illness, treatment options for youth are especially important in order to ensure better treatment outcomes. This chapter discusses currently approved medications to treat psychiatric disorders in children and adolescents. Research on medications that may be effective treatments but are not yet FDA approved is also discussed. The medications are broken down into major categories used in youth with psychiatric disorders including antidepressants, mood stabilizers, ADHD medications, and antipsychotics.
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Affiliation(s)
| | - Robert L Findling
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Adelaide S Robb
- Department of Psychiatry, Children's National Health System, Washington, DC, USA.
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16
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Yacob D, Kroon Van Diest AM, Di Lorenzo C. Functional abdominal pain in adolescents: case-based management. Frontline Gastroenterol 2020; 12:629-635. [PMID: 34917320 PMCID: PMC8640410 DOI: 10.1136/flgastro-2020-101572] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/23/2020] [Accepted: 09/29/2020] [Indexed: 02/04/2023] Open
Abstract
Functional gastrointestinal disorders (FGIDs), including functional abdominal pain (FAP), account for a large portion of conditions seen by paediatric gastroenterologists. Despite the commonality of FGIDs, there remains significant stigma around these diagnoses among medical providers, patients and families. This is due to the absence of easily identifiable biological markers in FGIDs and the overlay with psychological and social factors contributing to symptom onset and maintenance. As such, the biopsychosocial model is essential in conceptualising, evaluating and treating FGIDs. The way in which medical providers explain FGIDs and the manner in which they collaborate with other specialists (eg, psychologists, dieticians, physical therapists, school nurses) is paramount to the patient and family acceptance of an FGID diagnosis and the success of subsequent treatment. The following review outlines paediatric FGIDs with a focus on FAP in adolescents, in particular within the context of the biopsychosocial approach to pathophysiology, diagnosis and treatment.
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Affiliation(s)
- Desale Yacob
- Pediatric Gastroenterology, Hepatology and Nutrition, Nationwide Children’s Hospital, Columbus, Ohio, USA,Pediatrics, The Ohio State University, Columbus, Ohio, USA
| | - Ashley M Kroon Van Diest
- Pediatrics, The Ohio State University, Columbus, Ohio, USA,Pediatric Psychology and Neuropsychology, Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Carlo Di Lorenzo
- Pediatric Gastroenterology, Hepatology and Nutrition, Nationwide Children’s Hospital, Columbus, Ohio, USA,Pediatrics, The Ohio State University, Columbus, Ohio, USA
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Comparison of the Efficacy of Buspirone and Placebo in Childhood Functional Abdominal Pain: A Randomized Clinical Trial. Am J Gastroenterol 2020; 115:756-765. [PMID: 32221160 DOI: 10.14309/ajg.0000000000000589] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Pharmacological interventions have not been successful in the treatment of childhood functional abdominal pain (FAP) hitherto. Buspirone is suggested to be efficacious in some of the abdominal pain-related functional gastrointestinal disorders based on evidences from the studies on adults. We aim to investigate the efficacy of buspirone on childhood FAP. METHODS This randomized clinical trial was conducted on 117 patients with childhood FAP aged 6-18 years. We randomly assigned patients to receive buspirone or placebo for 4 weeks, with the adjusted dosage for age. Participants completed the questionnaires assessing pain, depression, anxiety, somatization, and sleep disturbances at baseline, at the end of the 4-week therapy (first follow-up), and at 8 weeks after medication discontinuation (second follow-up). The primary outcome was treatment response rate, defined as reduced pain score of ≥2 or reporting no pain at the follow-up assessments. RESULTS Ninety-five patients completed the 4-week therapy (48 and 47 in buspirone and placebo groups, respectively). Both buspirone and placebo reduced pain after 4 weeks of treatment, and these effects were persistent 8 weeks after medication discontinuation (P < 0.001 for both groups at weeks 4 and 12). Treatment response rates for buspirone and placebo were 58.3% and 59.6% at week 4 (P = 0.902) and 68.1% and 71.1% at week 12 (P = 0.753), respectively. DISCUSSION Buspirone effectively improves pain and associated psychological symptoms including depressive symptoms, anxiety, somatization, and sleep disturbances in childhood FAP but has no superiority over placebo. Further studies, with the higher doses of buspirone and longer follow-ups are recommended.
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18
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Haleem DJ. Targeting Serotonin1A Receptors for Treating Chronic Pain and Depression. Curr Neuropharmacol 2020; 17:1098-1108. [PMID: 31418663 PMCID: PMC7057205 DOI: 10.2174/1570159x17666190811161807] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 07/31/2019] [Accepted: 08/02/2019] [Indexed: 02/07/2023] Open
Abstract
The association of chronic pain with depression is becoming increasingly recognized. Treating both the conditions together is essential for an effective treatment outcome. In this regard, it is important to identify a shared mechanism involved in the association of chronic pain with depression. Central serotonin (5-hydroxytryptamine; 5-HT) neurotransmission has long been known to participate in the processing of signals related to pain. It also plays a key role in the pathogenesis and treatment of depression. Although functional responses to serotonin are mediated via the activation of multiple receptor types and subtypes, the 5-HT1A subtype is involved in the processing of nociception as well as the pathogenesis and treatment of depression. This receptor is located presynaptically, as an autoreceptor, on the perikaryon and dendritic spines of serotonin-containing neurons. It is also expressed as a heteroreceptor on neurons receiving input from serotonergic neurons. This arti-cle targets the 5-HT1A receptors to show that indiscriminate activation of pre and postsynaptic 5-HT1A receptors is likely to produce no therapeutic benefits; biased activation of the 5-HT heteroreceptors may be a useful strategy for treating chronic pain and depression individually as well as in a comorbid condition.
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Affiliation(s)
- Darakhshan Jabeen Haleem
- Neuroscience Research Laboratory, Dr. Panjwani Center for Molecular Medicine & Drug Research (PCMD), International Center for Chemical and Biological Science (ICCBS), University of Karachi, Karachi 75270, Pakistan
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19
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Zeevenhooven J, Timp ML, Singendonk MMJ, Benninga MA, Tabbers MM. Definitions of Pediatric Functional Abdominal Pain Disorders and Outcome Measures: A Systematic Review. J Pediatr 2019; 212:52-59.e16. [PMID: 31277898 DOI: 10.1016/j.jpeds.2019.04.048] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 03/19/2019] [Accepted: 04/24/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To systematically review definitions of functional abdominal pain orders (FAPDs) and outcome measures used in therapeutic randomized controlled trials in pediatric FAPDs adhering to the Outcome Measures in Rheumatology recommendations. STUDY DESIGN Cochrane, MEDLINE, Embase, and Cinahl databases were systematically searched from inception to April 2018. English-written therapeutic randomized controlled trials concerning FAPDs in children aged 4-18 years were included. Definitions of FAPDs, interventions, outcome measures, measurement instruments, and outcome assessors of each study were tabulated descriptively. Quality was assessed using the Delphi List. RESULTS A total of 4771 articles were found, of which 64 articles were included (n = 25, 39% of high methodologic quality). The Rome III (50%), Rome II (17%), Apley (16%), and author-defined (17%) criteria were used to define FAPDs. Fourteen studies (22%) assessed a pharmacologic, 25 (39%) a dietary, and 25 (39%) a psychosocial intervention. Forty-four studies (69%) predefined their primary outcomes. In total, 211 reported predefined outcome measures were grouped into 23 different outcome domains; the majority being patient-reported (n = 27, 61%). Of the 14 studies that evaluated a pharmacologic intervention, 12 (86%) reported on adverse events. CONCLUSIONS Studies on pediatric FAPDs are of limited methodologic quality and show large heterogeneity and inconsistency in defining FAPDs and outcome measures used. Development of a core outcome set is needed to make comparison between intervention studies possible.
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Affiliation(s)
- Judith Zeevenhooven
- Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Pediatric Gastroenterology, Amsterdam, the Netherlands.
| | - Merel L Timp
- Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Pediatric Gastroenterology, Amsterdam, the Netherlands
| | - Maartje M J Singendonk
- Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Pediatric Gastroenterology, Amsterdam, the Netherlands
| | - Marc A Benninga
- Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Pediatric Gastroenterology, Amsterdam, the Netherlands
| | - Merit M Tabbers
- Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Pediatric Gastroenterology, Amsterdam, the Netherlands
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20
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Eccleston C, Fisher E, Cooper TE, Grégoire MC, Heathcote LC, Krane E, Lord SM, Sethna NF, Anderson AK, Anderson B, Clinch J, Gray AL, Gold JI, Howard RF, Ljungman G, Moore RA, Schechter N, Wiffen PJ, Wilkinson NMR, Williams DG, Wood C, van Tilburg MAL, Zernikow B. Pharmacological interventions for chronic pain in children: an overview of systematic reviews. Pain 2019; 160:1698-1707. [PMID: 31335640 DOI: 10.1097/j.pain.0000000000001609] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900.
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Affiliation(s)
- Christopher Eccleston
- Centre for Pain Research, University of Bath, Bath, United Kingdom
- Department of Clinical and Health Psychology, Ghent University, Ghent, Belgium
| | - Emma Fisher
- Centre for Pain Research, University of Bath, Bath, United Kingdom
- Pain, Palliative, and Supportive Care, Oxford University Hospitals, Oxford, United Kingdom
| | - Tess E Cooper
- Faculty of Medicine and Health, School of Public Health, The University of Sydney, Sydney, New South Wales, Australia
| | | | - Lauren C Heathcote
- Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Elliot Krane
- Department of Anesthesiology, Perioperative, and Pain Medicine, Pediatrics, Stanford University School of Medicine, Stanford, Palo Alto, CA, United States
| | - Susan M Lord
- Children's Complex Pain Service, John Hunter Children's Hospital, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
- Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia
| | - Navil F Sethna
- Department of Anesthesiology, Critical Care and Pain Medicine, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | | | - Brian Anderson
- Department of Anaesthesiology, University of Auckland, Auckland, New Zealand
| | - Jacqueline Clinch
- Bristol Royal Children's Hospital, University of Bristol, Bristol, United Kingdom
- Royal National Hospital for Rheumatic Diseases, Bath, United Kingdom
| | - Andrew L Gray
- Division of Pharmacology, Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Jeffrey I Gold
- Anesthesiology, Pediatrics, and Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Pediatric Pain Management Clinic, Children's Hospital Los Angeles, Los Angeles, CA, United States
| | - Richard F Howard
- Department of Anaesthesia and Pain Medicine, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom
| | - Gustaf Ljungman
- Pediatric Oncology, Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - R Andrew Moore
- Pain Research, Nuffield, Department of Clinical Neurosciences, University of Oxford, The Churchill, Oxford, United Kingdom
| | - Neil Schechter
- Department of Anesthesiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Philip J Wiffen
- Pain Research, Nuffield, Department of Clinical Neurosciences, University of Oxford, The Churchill, Oxford, United Kingdom
| | - Nick M R Wilkinson
- Department of Paediatrics, Evelina London Children's Hospital, Kings College London, United Kingdom
| | - David G Williams
- The Anaesthetic Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Chantal Wood
- Department of Rheumatology, Chronic Pain Centre, University Hospital of Limoges, University of Limoges, Haute Vienne, France
| | - Miranda A L van Tilburg
- College of Pharmacy and Health Sciences, Campbell University, Buies Creek, NC, United States
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, United States
| | - Boris Zernikow
- German Paediatric Pain Centre, Children's and Adolescent's Hospital, Datteln, Germany
- Children's Pain Therapy and Paediatric Palliative Care, Faculty of Health, School of Medicine, Witten/Herdecke University, Witten, Germany
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Palermo TM, Kashikar-Zuck S, Friedrichsdorf SJ, Powers SW. Special considerations in conducting clinical trials of chronic pain management interventions in children and adolescents and their families. Pain Rep 2019; 4:e649. [PMID: 31583334 PMCID: PMC6749908 DOI: 10.1097/pr9.0000000000000649] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 02/21/2018] [Accepted: 03/03/2018] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Disabling chronic pain is a common experience for children and adolescents. However, the evidence base for chronic pain interventions for youth is extremely limited, which has hindered the development of evidence-based practice guidelines for most pediatric chronic pain conditions. OBJECTIVES To review and provide recommendations on clinical trial design and evaluation in children and adolescents with chronic pain. METHODS In this article, we summarize key issues and provide recommendations for addressing them in clinical trials of chronic pain interventions in children and adolescents and their families. RESULTS To stimulate high-quality trials of pediatric chronic pain management interventions, attention to key issues including sample characterization, trial design and treatment administration, outcome measurement, and the ethics of intervening with children and adolescents, as opposed to adults with chronic pain, is needed. CONCLUSION Future research to develop interventions to reduce or prevent childhood chronic pain is an important priority area, and requires special considerations in implementation and evaluation in clinical trials.
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Affiliation(s)
- Tonya M. Palermo
- Center for Child Health, Behavior, and Development, Seattle Children's Research Institute, Seattle, WA, USA
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA
| | - Susmita Kashikar-Zuck
- Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Stefan J. Friedrichsdorf
- Department of Pain Medicine, Palliative Care and Integrative Medicine, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA
| | - Scott W. Powers
- Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Rexwinkel R, Zeevenhooven J, van Etten-Jamaludin FS, Benninga MA, Tabbers MM. Side effects associated with pharmacotherapy for pediatric irritable bowel syndrome and functional abdominal pain - not otherwise specified: a systematic review. Expert Opin Drug Saf 2019; 18:111-125. [PMID: 30676113 DOI: 10.1080/14740338.2019.1574295] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION To systematically review the literature regarding the side effects of pharmacotherapy in children with irritable bowel syndrome (IBS) and functional abdominal pain - not otherwise specified (FAP-NOS). Areas covered: Cochrane Library, PubMed, and Embase databases were searched from inception to May 2018. The following inclusion criteria were applied: (1) randomized controlled trials (RCTs), cohort studies or case-control studies; (2) in children aged 4-18 years or adult studies if children are reported separately; (3) reporting a diagnosis of IBS or FAP-NOS as defined by the authors; and (4) reporting the occurrence of side effects of pharmacotherapy. Quality assessment of included studies was conducted. Expert opinion: A total of 4619 articles were identified; 17 were included. In 10/17 (59%) studies, side effects of pharmacotherapy (antispasmodics, antidepressants, antihistaminic agents, serotonergic agents and antibiotics) occurred. The majority of side effects were: (1) limited to the gastrointestinal tract and central nervous system and, 2) mild and transient. No serious adverse events were reported. This systematic review shows that data on safety in children with functional abdominal pain disorders are scarce, and highlights the lack of high-quality research for potential side effects of pediatric IBS and FAP-NOS. Further research by means of large well-designed-follow-up studies is necessary.
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Affiliation(s)
- Robyn Rexwinkel
- a Pediatric Gastroenterology , Emma Children's Hospital, Amsterdam UMC, University of Amsterdam , Amsterdam , The Netherlands
| | - Judith Zeevenhooven
- a Pediatric Gastroenterology , Emma Children's Hospital, Amsterdam UMC, University of Amsterdam , Amsterdam , The Netherlands
| | | | - Marc A Benninga
- a Pediatric Gastroenterology , Emma Children's Hospital, Amsterdam UMC, University of Amsterdam , Amsterdam , The Netherlands
| | - Merit M Tabbers
- a Pediatric Gastroenterology , Emma Children's Hospital, Amsterdam UMC, University of Amsterdam , Amsterdam , The Netherlands
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23
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Abstract
This article provides an overarching view of what is currently known about the physiology of the brain-gut axis in both health and disease and how these concepts apply to irritable bowel syndrome, the most common functional gastrointestinal disorder in pediatrics.
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Affiliation(s)
- Julie Khlevner
- Department of Pediatrics, Columbia University College of Physicians and Surgeons, 630 West 168th Street, PH 17, New York, NY 10032, USA
| | - Yeji Park
- Department of Pediatrics, Columbia University College of Physicians and Surgeons, 630 West 168th Street, PH 17, New York, NY 10032, USA
| | - Kara Gross Margolis
- Department of Pediatrics, Columbia University College of Physicians and Surgeons, 630 West 168th Street, PH 17, New York, NY 10032, USA.
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Bonilla S, Nurko S. Focus on the use of antidepressants to treat pediatric functional abdominal pain: current perspectives. Clin Exp Gastroenterol 2018; 11:365-372. [PMID: 30310301 PMCID: PMC6166750 DOI: 10.2147/ceg.s146646] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Chronic abdominal pain is frequently encountered in pediatric practice. A large proportion of cases meet Rome criteria for abdominal pain-functional gastrointestinal disorders (AP-FGIDs). These disorders are costly and, in some cases, lead to impairment of daily functioning and overall quality of life. Pathophysiologic mechanisms include early stressful events, visceral hypersensitivity, dysmotility, changes in intestinal microbiota, and altered central nervous system processing. They are considered disorders of the brain-gut interaction. The diagnosis is made on clinical grounds using symptom-based criteria (Rome criteria). Anxiety and depressive symptoms are more prevalent in patients with AP-FGIDs. Therefore, attention has been directed to the use of neuromodulators as potential interventions for AP-FGIDs. Antidepressants are one type of neuromodulators, and one of the most studied drugs for the management of AP-FGIDs in adult and pediatric population. Data available in pediatric population have significant limitations including nonuniform methodology with different study designs and primary endpoints. Evidence of the efficacy of antidepressants in the management of pediatric AP-FGIDs is not consistent. There is an urgent need for well-designed randomized clinical trials using age-appropriate validated outcome measures. Careful consideration must be given to adverse effects, particularly increased suicidal ideation.
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Affiliation(s)
- Silvana Bonilla
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital. Boston, MA, USA,
| | - Samuel Nurko
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital. Boston, MA, USA,
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Recurrent Abdominal Pain in Children: Summary Evidence From 3 Systematic Reviews of Treatment Effectiveness. J Pediatr Gastroenterol Nutr 2018; 67:23-33. [PMID: 29470291 DOI: 10.1097/mpg.0000000000001922] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Between 4% and 25% of school-aged children complain of recurrent abdominal pain (RAP) severe enough to interfere with their daily activities. METHODS We carried out a systematic review of randomised controlled trials (RCTs) in eleven databases and 2 trials registries from inception to June 2016. An update search was run in November 2017. All screening was performed by 2 independent reviewers. Included studies were appraised using the Cochrane risk of bias tool and the evidence assessed using GRADE. We included any dietary, pharmacological or psychosocial intervention for RAP, defined by Apley or an abdominal pain-related functional gastrointestinal disorder, as defined by the Rome III criteria, in children and adolescents. RESULTS We included 55 RCTs, involving 3572 children with RAP (21 dietary, 15 pharmacological, 19 psychosocial, and 1 multiarm). We found probiotic diets, cognitive-behavioural therapy (CBT) and hypnotherapy were reported to reduce pain in the short-term and there is some evidence of medium term effectiveness. There was insufficient evidence of effectiveness for all other dietary interventions and psychosocial therapies. There was no robust evidence of effectiveness for pharmacological interventions. CONCLUSIONS Overall the evidence base for treatment decisions is poor. These data suggest that probiotics, CBT, and hypnotherapy could be considered as part of holistic management of children with RAP. The evidence regarding relative effectiveness of different strains of probiotics is currently insufficient to guide clinical practice. The lack of evidence of effectiveness for any drug suggests that there is little justification for their use outside of well-conducted clinical trials. There is an urgent need for high-quality RCTs to provide evidence to guide management of this common condition.
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Devanarayana NM, Rajindrajith S. Irritable bowel syndrome in children: Current knowledge, challenges and opportunities. World J Gastroenterol 2018; 24:2211-2235. [PMID: 29881232 PMCID: PMC5989237 DOI: 10.3748/wjg.v24.i21.2211] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 04/26/2018] [Accepted: 05/11/2018] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common and troublesome disorder in children with an increasing prevalence noted during the past two decades. It has a significant effect on the lives of affected children and their families and poses a significant burden on healthcare systems. Standard symptom-based criteria for diagnosis of pediatric IBS have changed several times during the past two decades and there are some differences in interpreting symptoms between different cultures. This has posed a problem when using them to diagnose IBS in clinical practice. A number of potential patho-physiological mechanisms have been described, but so far the exact underlying etiology of IBS is unclear. A few potential therapeutic modalities have been tested in children and only a small number of them have shown some benefit. In addition, most of the described patho-physiological mechanisms and treatment options are based on adult studies. These have surfaced as challenges when dealing with pediatric IBS and they need to be overcome for effective management of children with IBS. Recently suggested top-down and bottom-up models help integrating reported patho-physiological mechanisms and will provide an opportunity for better understanding of the diseases process. Treatment trials targeting single treatment modalities are unlikely to have clinically meaningful therapeutic effects on IBS with multiple integrating patho-physiologies. Trials focusing on multiple combined pharmacological and non-pharmacological therapies are likely to yield more benefit. In addition to treatment, in the future, attention should be paid for possible prevention strategies for IBS.
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Affiliation(s)
| | - Shaman Rajindrajith
- Department of Paediatrics, Faculty of Medicine, University of Kelaniya, Ragama 11010, Sri Lanka
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Brusaferro A, Farinelli E, Zenzeri L, Cozzali R, Esposito S. The Management of Paediatric Functional Abdominal Pain Disorders: Latest Evidence. Paediatr Drugs 2018; 20:235-247. [PMID: 29497992 PMCID: PMC5954057 DOI: 10.1007/s40272-018-0287-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Recurrent abdominal pain (RAP) is one of the most common health complaints in both children and adults. Although RAP is considered a functional disorder rather than an organic disease, affected children and their families can still experience anxiety and concerns that can interfere with school, sports, and regular daily activities and lead to frequent attendances at pediatric emergency departments or pediatric gastroenterology clinics. Our review shows experts do not agree on a universally proven management that will work on every child presenting with functional abdominal pain (FAP). Treatment strategies include both non-pharmacological and pharmacological options. Non-pharmacological treatments are usually very well accepted by both children and their parents and are free from medication side effects. Nevertheless, they may be as effective as the pharmacological interventions; therefore, according to many experts and based on the majority of current evidence, a non-pharmacological approach should be the first intervention attempt in children with RAP. In particular, the importance of the bio-psychosocial approach is highlighted, as a majority of children will improve with counselling and reassurance that no serious organic pathologies are suspected, especially when the physician establishes a trustful relationship with both the child and their family. Placebo and pharmacological interventions could be attempted when the bio-psychosocial approach is not applicable or not efficacious. In some difficult cases, finding an effective treatment for FAP can be a challenge, and a number of strategies may need to be tried before symptoms are controlled. In these cases, a multidisciplinary team, comprising a pediatric gastroenterologist, dietician, psychologist, and psychotherapist, is likely to be successful.
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Affiliation(s)
- Andrea Brusaferro
- Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Piazza Menghini 1, 06129, Perugia, Italy
| | - Edoardo Farinelli
- Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Piazza Menghini 1, 06129, Perugia, Italy
| | - Letizia Zenzeri
- Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Piazza Menghini 1, 06129, Perugia, Italy
| | - Rita Cozzali
- Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Piazza Menghini 1, 06129, Perugia, Italy
| | - Susanna Esposito
- Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Piazza Menghini 1, 06129, Perugia, Italy.
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Rajindrajith S, Zeevenhooven J, Devanarayana NM, Perera BJC, Benninga MA. Functional abdominal pain disorders in children. Expert Rev Gastroenterol Hepatol 2018; 12:369-390. [PMID: 29406791 DOI: 10.1080/17474124.2018.1438188] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 02/05/2018] [Indexed: 02/06/2023]
Abstract
Chronic abdominal pain is a common problem in pediatric practice. The majority of cases fulfill the Rome IV criteria for functional abdominal pain disorders (FAPDs). At times, these disorders may lead to rather serious repercussions. Area covered: We have attempted to cover current knowledge on epidemiology, pathophysiology, risk factors related to pathophysiology, clinical evaluation and management of children with FAPDs. Expert commentary: FAPDs are a worldwide problem with a pooled prevalence of 13.5%. There are a number of predisposing factors and pathophysiological mechanisms including stressful events, child maltreatment, visceral hypersensitivity, altered gastrointestinal motility and change in intestinal microbiota. It is possible that the environmental risk factors intricately interact with genes through epigenetic mechanisms to contribute to the pathophysiology. The diagnosis mainly depends on clinical evaluation. Commonly used pharmacological interventions do not play a major role in relieving symptoms. Centrally directed, nonpharmacological interventions such as hypnotherapy and cognitive behavioral therapy have shown both short and long term efficacy in relieving pain in children with FAPDs. However, these interventions are time consuming and need specially trained staff and therefore, not currently available at grass root level. Clinicians and researchers should join hands in searching for more pragmatic and effective therapeutic modalities to improve overall care of children with FAPDs.
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Affiliation(s)
- Shaman Rajindrajith
- a Department of Paediatrics, Faculty of Medicine , University of Kelaniya , Ragama , Sri Lanka
| | - Judith Zeevenhooven
- b Department of Pediatric Gastroenterology and Nutrition , Emma Children, Hospital, Academic Medical Centre , Amsterdam , The Netherlands
| | | | | | - Marc A Benninga
- b Department of Pediatric Gastroenterology and Nutrition , Emma Children, Hospital, Academic Medical Centre , Amsterdam , The Netherlands
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Lu PL, Saps M. Advances in the Evaluation and Management of Childhood Functional Abdominal Pain. CURRENT PEDIATRICS REPORTS 2018. [DOI: 10.1007/s40124-018-0159-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Holland KJ, Bennett WE. Narcotic and Antidepressant Use and Hospital Readmission Rates in Children With Functional Abdominal Pain. Clin Pediatr (Phila) 2017; 56:1104-1108. [PMID: 27831525 DOI: 10.1177/0009922816674520] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Functional abdominal pain is a common presentation in the pediatric population, and it carries a large financial and emotional burden. The objective of this study was to describe the association between the use of narcotics and antidepressants and hospital readmission in children admitted for abdominal pain without an organic cause. We analyzed data from the Pediatric Health Information System database. A multivariate logistical regression model was used to assess the association between medication type and hospital readmission rates within 30 and 90 days. There was a positive association between readmission rates. Readmission rates were higher for children who were older, male, Black, had Medicaid insurance, had a longer hospital stay, or were treated with a selective serotonin reuptake inhibitor/tricyclic antidepressant/narcotic. While not standard practice, patients with functional abdominal pain who receive these medications may be at an increased risk for readmission and subsequent health care contacts and are good candidates for future healthcare coordination.
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Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial. Lancet Gastroenterol Hepatol 2017; 2:727-737. [PMID: 28826627 DOI: 10.1016/s2468-1253(17)30253-4] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/07/2017] [Accepted: 07/13/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Development of safe and effective therapies for paediatric abdominal pain-related functional gastrointestinal disorders is needed. A non-invasive, US Food and Drug Administration-cleared device (Neuro-Stim, Innovative Health Solutions, IN, USA) delivers percutaneous electrical nerve field stimulation (PENFS) in the external ear to modulate central pain pathways. In this study, we evaluated the efficacy of PENFS in adolescents with abdominal pain-related functional gastrointestinal disorders. METHODS In this randomised, sham-controlled trial, we enrolled adolescents (aged 11-18 years) who met Rome III criteria for abdominal pain-related functional gastrointestinal disorders from a single US outpatient gastroenterology clinic. Patients were randomly assigned (1:1) with a computer-generated randomisation scheme to active treatment or sham (no electrical charge) for 4 weeks. Patients were stratified by sex and presence or absence of nausea. Allocation was concealed from participants, caregivers, and the research team. The primary efficacy endpoint was change in abdominal pain scores. We measured improvement in worst abdominal pain and composite pain score using the Pain Frequency-Severity-Duration (PFSD) scale. Participants with less than 1 week of data and those with organic disease identified after enrolment were excluded from the modified intention-to-treat population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT02367729. FINDINGS Between June 18, 2015, and Nov 17, 2016, 115 children with abdominal pain-related functional gastrointestinal disorders were enrolled and assigned to either PENFS (n=60) with an active device or sham (n=55). After exclusion of patients who discontinued treatment (n=1 in the PENFS group; n=7 in the sham group) and those who were excluded after randomisation because they had organic disease (n=2 in the PENFS group; n=1 in the sham group), 57 patients in the PENFS group and 47 patients in the sham group were included in the primary analysis. Patients in the PENFS group had greater reduction in worst pain compared with sham after 3 weeks of treatment (PENFS: median score 5·0 [IQR 4·0-7·0]; sham: 7·0 [5·0-9·0]; least square means estimate of change in worse pain 2·15 [95% CI 1·37-2·93], p<0·0001). Effects were sustained for an extended period (median follow-up 9·2 weeks [IQR 6·4-13·4]) in the PENFS group: median 8·0 (IQR 7·0-9·0) at baseline to 6·0 (5·0-8·0) at follow-up versus sham: 7·5 (6·0-9·0) at baseline to 7·0 (5·0-8·0) at follow-up (p<0·0001). Median PFSD composite scores also decreased significantly in the PENFS group (from 24·5 [IQR 16·8-33.3] to 8·4 [3·2-16·2]) compared with sham (from 22·8 [IQR 8·4-38·2] to 15·2 [4·4-36·8]) with a mean decrease of 11·48 (95% CI 6·63-16·32; p<0·0001) after 3 weeks. These effects were sustained at extended follow-up in the PENFS group: median 24·5 (IQR 16·8-33·3) at baseline to 12 (3·6-22·5) at follow-up, compared with sham: 22·8 (8·4-38·2) at baseline to 16·8 (4·8-33·6) at follow-up (p=0·018). Ten patients reported side-effects (three of whom discontinued the study): ear discomfort (n=6; three in the PENFS group, three in the sham group), adhesive allergy (n=3; one in the PENFS group, two in the sham group), and syncope due to needle phobia (n=1; in the sham group). There were no serious adverse events. INTERPRETATION Our results show that PENFS with Neuro-Stim has sustained efficacy for abdominal pain-related functional gastrointestinal disorders in adolescents. This safe and effective approach expands treatment options and should be considered as a non-pharmacological alternative for these disorders. FUNDING American Neurogastroenterology and Motility Society.
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Cooper TE, Heathcote LC, Clinch J, Gold JI, Howard R, Lord SM, Schechter N, Wood C, Wiffen PJ, Cochrane Pain, Palliative and Supportive Care Group. Antidepressants for chronic non-cancer pain in children and adolescents. Cochrane Database Syst Rev 2017; 8:CD012535. [PMID: 28779487 PMCID: PMC6424378 DOI: 10.1002/14651858.cd012535.pub2] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time and relief of pain is now seen as important.We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) from genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, as well as for other unknown reasons.Antidepressants have been used in adults for pain relief and pain management since the 1970s. The clinical impression from extended use over many years is that antidepressants are useful for some neuropathic pain symptoms, and that effects on pain relief are divorced and different from effects on depression; for example, the effects of tricyclic antidepressants on pain may occur at different, and often lower, doses than those on depression. Amitriptyline is one of the most commonly used drugs for treating neuropathic pain in the UK. OBJECTIVES To assess the analgesic efficacy and adverse events of antidepressants used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. SELECTION CRITERIA Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing any antidepressant with placebo or an active comparator. DATA COLLECTION AND ANALYSIS Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed the evidence using GRADE and created three 'Summary of findings' tables. MAIN RESULTS We included four studies with a total of 272 participants (6 to 18 years of age) who had either chronic neuropathic pain, complex regional pain syndrome type 1, irritable bowel syndrome, functional abdominal pain, or functional dyspepsia. All of the studies were small. One study investigated amitriptyline versus gabapentin (34 participants), two studies investigated amitriptyline versus placebo (123 participants), and one study investigated citalopram versus placebo (115 participants). Due to a lack of available data we were unable to complete any quantitative analysis.Risk of bias for the four included studies varied, due to issues with randomisation and allocation concealment (low to unclear risk); blinding of participants, personnel, and outcome assessors (low to unclear risk); reporting of results (low to unclear risk); and size of the study populations (high risk). We judged the remaining domains, attrition and other potential sources of bias, as low risk of bias. Primary outcomesNo studies reported our primary outcomes of participant-reported pain relief of 30% or greater or 50% or greater (very low-quality evidence).No studies reported on Patient Global Impression of Change (very low-quality evidence).We rated the overall quality of the evidence (GRADE rating) as very low. We downgraded the quality of the evidence by three levels to very low because there was no evidence to support or refute. Secondary outcomesAll studies measured adverse events, with very few reported (11 out of 272 participants). All but one adverse event occurred in the active treatment groups (amitriptyline, citalopram, and gabapentin). Adverse events in all studies, across active treatment and comparator groups, were considered to be a mild reaction, such as nausea, dizziness, drowsiness, tiredness, and abdominal discomfort (very low-quality evidence).There were also very few withdrawals due to adverse events, again all but one from the active treatment groups (very low-quality evidence).No serious adverse events were reported across any of the studies (very low-quality evidence).There were few or no data for our remaining secondary outcomes (very low-quality evidence).We rated the overall quality of the evidence (GRADE rating) for these secondary outcomes as very low. We downgraded the quality of the evidence by three levels to very low due to too few data and the fact that the number of events was too small to be meaningful. AUTHORS' CONCLUSIONS We identified only a small number of studies with small numbers of participants and insufficient data for analysis.As we could undertake no meta-analysis, we are unable to comment about efficacy or harm from the use of antidepressants to treat chronic non-cancer pain in children and adolescents. Similarly, we cannot comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.There is evidence from adult randomised controlled trials that some antidepressants, such as amitriptyline, can provide some pain relief in certain chronic non-cancer pain conditions.There is no evidence from randomised controlled trials to support or refute the use of antidepressants to treat chronic non-cancer pain in children or adolescents.
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Affiliation(s)
- Tess E Cooper
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchWestmeadNSWAustralia2145
| | - Lauren C Heathcote
- Stanford UniversityDepartment of Anesthesiology, Perioperative and Pain Medicine1070 Arastradero Road, Suite 300Palo AltoCaliforniaUSA94304
| | - Jacqui Clinch
- Bristol Royal Hospital for ChildrenPaediatric RheumatologyBristolUK
- Bath Centre for Pain ServicesChild/Adolescent PainBathUK
| | - Jeffrey I. Gold
- Keck School of Medicine, University of Southern California / Children’s Hospital Los AngelesAnesthesiology, Pediatrics, and Psychiatry & Behavioral Sciences4650 Sunset Blvd. MS#12Los AngelesCaliforniaUSA90027
| | - Richard Howard
- Great Ormond Street HospitalAnaesthesia and Pain ManagementGreat Ormond StreetLondonUKWC1N 3JH
| | - Susan M Lord
- John Hunter Children’s HospitalChildren’s Complex Pain ServiceNewcastleNew South Wales (NSW)Australia
| | - Neil Schechter
- Boston Children’s HospitalAnesthesiology, Perioperative and Pain Medicine300 Longwood AvenueBostonUSA
| | - Chantal Wood
- University Hospital DupuytrenRheumatologyLimogesFrance
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Treatment of Functional Abdominal Pain With Antidepressants: Benefits, Adverse Effects, and the Gastroenterologist's Role. J Pediatr Gastroenterol Nutr 2017. [PMID: 28644344 DOI: 10.1097/mpg.0000000000001416] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Pediatric functional abdominal pain is often treated with tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). The aim is investigating antidepressant use for treatment efficacy, correlation of response to psychiatric factors, and impact of adverse effects in regard to physicians' prescribing patterns. METHODS Retrospective review (2005-2013) children (5-21 years old) with functional abdominal pain treated with SSRI or TCA. Of the 531 cases with functional abdominal pain, 192 initiated SSRIs or TCAs while followed by gastroenterology. Charts reviewed for symptoms, adverse effects, and response: decreased pain or increased daily functioning. RESULTS Sixty-three of 84 (75%) SSRI patients improved, 56 of 92 (61%) TCA patients improved (P = 0.03). Logistic regression controlling for psychiatric factors: SSRI remained significant over TCA (P = 0.04). Thirty-two of 67 (48%) patients with constipation received TCAs and 26 of 45 (58%) patients with diarrhea received SSRIs (P = 0.64). Three SSRI patients reported gastrointestinal effects, all diarrheal-type symptoms, and 2 TCA patients reported gastrointestinal effects, both constipation, in all it led to discontinuation. Thirteen (29%) of diarrheal-type patients reported adverse effects causing discontinuation as compared to 7 (8%) in the constipation group (P = .01). Twenty-one (25%) SSRI patients reported adverse effects with 5 (6%) mood disturbances. Twenty (22%) TCA patients reported adverse effects, 13 (14%) with mood disturbances (P = .07). Overall, 12 (14%) SSRI patients discontinued medication due to adverse effects, whereas 16 (17%) TCA patients (P = 0.24) did. CONCLUSIONS Patients had significantly greater response to SSRIs than TCAs, remaining significant after controlling for psychiatric factors. Little significance is given to patient's associated gastrointestinal symptoms, frequently resulting in adverse effects and termination of medication.
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Martin AE, Newlove‐Delgado TV, Abbott RA, Bethel A, Thompson‐Coon J, Whear R, Logan S, Cochrane Developmental, Psychosocial and Learning Problems Group. Pharmacological interventions for recurrent abdominal pain in childhood. Cochrane Database Syst Rev 2017; 3:CD010973. [PMID: 28262913 PMCID: PMC6464549 DOI: 10.1002/14651858.cd010973.pub2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Between 4% and 25% of school-aged children at some stage complain of recurrent abdominal pain (RAP) of sufficient severity to interfere with their daily lives. When no clear organic cause is found, the children are managed with reassurance and simple measures; a large range of pharmacological interventions have been recommended for use in these children. OBJECTIVES To determine the effectiveness of pharmacological interventions for RAP in children of school age. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase, and eight other electronic databases up to June 2016. We also searched two trials registers and contacted researchers of published studies. SELECTION CRITERIA Randomised controlled trials involving children aged five to 18 years old with RAP or an abdominal pain-related functional gastrointestinal disorder, as defined by the Rome III criteria (Rasquin 2006). The interventions were any pharmacological intervention compared to placebo, no treatment, waiting list, or standard care. The primary outcome measures were pain intensity, pain duration or pain frequency, and improvement in pain. The secondary outcome measures were school performance, social or psychological functioning, and quality of daily life. DATA COLLECTION AND ANALYSIS Two review authors independently screened titles, abstracts, and potentially relevant full-text reports for eligible studies. Two review authors extracted data and performed a 'Risk of bias' assessment. We used the GRADE approach to rate the overall quality of the evidence. We deemed a meta-analysis to be not appropriate as the studies were significantly heterogeneous. We have consequently provided a narrative summary of the results. MAIN RESULTS This review included 16 studies with a total of 1024 participants aged between five and 18 years, all of whom were recruited from paediatric outpatient clinics. Studies were conducted in seven countries: seven in the USA, four in Iran, and one each in the UK, Switzerland, Turkey, Sri Lanka, and India. Follow-up ranged from two weeks to four months. The studies examined the following interventions to treat RAP: tricyclic antidepressants, antibiotics, 5-HT4 receptor agonists, antispasmodics, antihistamines, H2 receptor antagonists, serotonin antagonists, selective serotonin re-uptake inhibitors, a dopamine receptor antagonist, and a hormone. Although some single studies reported that treatments were effective, all of these studies were either small or had key methodological weaknesses with a substantial risk of bias. None of these 'positive' results have been reproduced in subsequent studies. We judged the evidence of effectiveness to be of low quality. No adverse effects were reported in these studies. AUTHORS' CONCLUSIONS There is currently no convincing evidence to support the use of drugs to treat RAP in children. Well-conducted clinical trials are needed to evaluate any possible benefits and risks of pharmacological interventions. In practice, if a clinician chooses to use a drug as a 'therapeutic trial', they and the patient need to be aware that RAP is a fluctuating condition and any 'response' may reflect the natural history of the condition or a placebo effect, rather than drug efficacy.
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Affiliation(s)
- Alice E Martin
- Royal Devon and Exeter HospitalPaediatricsBarrack RoadExeterEnglandUKEX2 5DW
| | - Tamsin V Newlove‐Delgado
- University of Exeter Medical SchoolNIHR CLAHRC South West Peninsula (PenCLAHRC)St Luke's CampusExeterEnglandUKEX1 2LU
| | - Rebecca A Abbott
- University of Exeter Medical SchoolNIHR CLAHRC South West Peninsula (PenCLAHRC)St Luke's CampusExeterEnglandUKEX1 2LU
| | - Alison Bethel
- University of Exeter Medical SchoolNIHR CLAHRC South West Peninsula (PenCLAHRC)St Luke's CampusExeterEnglandUKEX1 2LU
| | - Joanna Thompson‐Coon
- University of Exeter Medical SchoolNIHR CLAHRC South West Peninsula (PenCLAHRC)St Luke's CampusExeterEnglandUKEX1 2LU
| | - Rebecca Whear
- University of Exeter Medical SchoolNIHR CLAHRC South West Peninsula (PenCLAHRC)St Luke's CampusExeterEnglandUKEX1 2LU
| | - Stuart Logan
- University of Exeter Medical SchoolNIHR CLAHRC South West Peninsula (PenCLAHRC)St Luke's CampusExeterEnglandUKEX1 2LU
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Hoekman DR, Zeevenhooven J, van Etten-Jamaludin FS, Douwes Dekker I, Benninga MA, Tabbers MM, Vlieger AM. The Placebo Response in Pediatric Abdominal Pain-Related Functional Gastrointestinal Disorders: A Systematic Review and Meta-Analysis. J Pediatr 2017; 182:155-163.e7. [PMID: 28081889 DOI: 10.1016/j.jpeds.2016.12.022] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 11/04/2016] [Accepted: 12/06/2016] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To investigate the magnitude and determinants of the placebo response in studies with pediatric abdominal pain-related functional gastrointestinal disorders. STUDY DESIGN The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL were searched for systematic reviews and randomized placebo-controlled trials concerning children 4-18 years of age with an abdominal pain-related functional gastrointestinal disorder. The primary outcome was the pooled proportion of subjects assigned to placebo with improvement as defined by the authors. The effect of trial characteristics on the magnitude of the placebo response was investigated using univariate meta-regression analysis. RESULTS Twenty-one trials were identified. The pooled proportion of subjects with improvement was 41% (95% CI, 34%-49%; 17 studies) and with no pain was 17% (95% CI, 8%-32%; 7 studies). The pooled standardized mean difference on the Faces Pain Scales compared with baseline was -0.73 (95% CI, -1.04 to -0.42; 8 studies). There was significant heterogeneity across studies with respect to both outcomes. Lower dosing frequency (P = .04), positive study (P = .03), longer duration of treatment (P < .001), and higher placebo dropout (P < .001) were associated with higher report of no pain. Response on Faces Pain Scales was greater in studies conducted in the Middle East (P = .002), in studies that did not report the randomization schedule (P = .02), and in studies with a higher percentage of females (P = .04). CONCLUSIONS Approximately 41% of children with abdominal pain-related functional gastrointestinal disorders improve on placebo. Several trial characteristics are correlated significantly with the proportion of patients with no pain on placebo and with the magnitude of the placebo response on Faces Pain Scales. These data could be valuable for the design of future studies.
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Affiliation(s)
- Daniël R Hoekman
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands
| | - Judith Zeevenhooven
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands
| | | | - Iuke Douwes Dekker
- Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Marc A Benninga
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands
| | - Merit M Tabbers
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands
| | - Arine M Vlieger
- Department of Pediatrics, St. Antonius Hospital, Nieuwegein, the Netherlands
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Abstract
UNLABELLED There is little evidence for most of the medications currently used to treat functional abdominal pain disorders (FAPDs) in children. Not only are there very few clinical trials, but also most have significant variability in the methods used and outcomes measured. Thus, the decision on the most appropriate pharmacological treatment is frequently based on adult studies or empirical data. In children, peppermint oil, trimebutine, and drotaverine have shown significant benefit compared with placebo, each of them in a single randomized clinical trial. A small study found that cyproheptadine was beneficial in the treatment of FAPDs in children. There are conflicting data regarding amitriptyline. While one small study found a significant benefit in quality of life compared with placebo, a large multicenter study found no benefit compared with placebo. The antidepressant, citalopram, failed to meet the primary outcomes in intention-to-treat and per-protocol analysis. Rifaximin has been shown to be efficacious in the treatment of adults with IBS. Those findings differ from studies in children where no benefit was found compared to placebo. To date, there are no placebo-controlled trials published on the use of linaclotide or lubiprostone in children. Alpha 2 delta ligands such as gabapentin and pregabalin are sometimes used in the care of this group of children, but no clinical trials are available in children with FAPDs. Similarly, novel drugs that have been approved for the care of irritable bowel with diarrhea in adults such as eluxadoline have yet to be studied in children. CONCLUSIONS Little data support the use of most medications commonly used to treat FAPDs in children. More randomized, placebo-controlled studies are needed to assess the efficacy of pharmacological interventions in the treatment of FAPDs in children.
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Affiliation(s)
- Miguel Saps
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA.
| | - Adrian Miranda
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Wisconsin, Milwaukee, WI, USA
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Gomez-Suarez R. Difficulties in the Diagnosis and Management of Functional or Recurrent Abdominal Pain in Children. Pediatr Ann 2016; 45:e388-e393. [PMID: 27841921 DOI: 10.3928/19382359-20161019-01] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recurrent abdominal pain is a frequent pathology seen in the pediatric gastroenterology practice. In fact, most children with abdominal pain symptoms have functional disorders of the gastrointestinal tract. A focused medical history, comprehensive physical examination, and minimal testing are often enough to establish the diagnosis. The presence of red flags such as rectal bleeding, bilious vomiting, fever, and arthralgia should alert providers as well as direct further diagnostic and therapeutic plans. When patients show no red flags after a complete physical examination, providing the family with information about the pathophysiology and explaining the psychosocial model of pain can help to decrease anxiety around the pain symptoms. This article discusses the challenges in diagnosing and managing abdominal pain in children. [Pediatr Ann. 2016;45(11):e388-e393.].
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Abstract
BACKGROUND The use of psychotropic medications, particularly antidepressants, is common in patients with inflammatory bowel disease (IBD) in spite of a lack of their robust efficacy in this population. This review provides an overview of the use trends of different classes of antidepressant and anti-anxiety medication and their effects on mood, nervous system function, gastrointestinal physiology and immunity drawing from the literature available in the general population, other medical conditions, and when available, patients with IBD. It also covers the evidence base for the actions, efficacy, and potential complications of antidepressants organized by different classes. METHODS We conducted a PubMed search of articles relating the different drug classes probed to the terms above in different populations of interest. All types of articles were accepted including case reports and series, open and randomized trials, reviews, and expert opinion. We also examined the reference lists of the publications found. RESULTS Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are the most commonly prescribed agents for anxiety and depression in patients with IBD, though their efficacy for these conditions in the general population are mild to moderate at best. SSRIs are generally well tolerated, though at higher doses, they, like most antidepressant classes, can be associated with activation, serotonergic syndrome, and increased suicidal ideation. TCAs have many more serious side effects but have some shown efficacy for functional GI symptoms. A newer class, the serotonin noradrenergic reuptake inhibitors (SNRIs), can be effective for refractory depression, anxiety and chronic pain syndromes with a side effect profile similar to both SSRIs and more mild manifestations of TCAs. Mirtazapine has moderate efficacy for depression if sedation and weight gain side effects are tolerated and some small support for use in nausea and vomiting. Bupropion targets dopamine and noradrenaline reuptake and has moderate efficacy for depression, and some small support for use in fatigue and smoking cessation. Buspirone has an indication for generalized anxiety disorder though studies show only a minimal benefit. It has some growing evidence for use in functional dyspepsia. Most of these agents have physiological effects on the brain, immune system, and gastrointestinal tract (with the exception of bupropion) hence their therapeutic and side effects manifested in these systems. CONCLUSION Antidepressant medications are frequently prescribed for depression, anxiety disorders, and chronic pain syndromes, but overall support for their efficacy is modest at best. Psychological interventions have growing support for having much more robust effects without the side effects of antidepressants and should be considered first-line treatment or at least an adjunct to psychotropic medications for these conditions.
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Hyams JS, Di Lorenzo C, Saps M, Shulman RJ, Staiano A, van Tilburg M. Functional Disorders: Children and Adolescents. Gastroenterology 2016; 150:S0016-5085(16)00181-5. [PMID: 27144632 DOI: 10.1053/j.gastro.2016.02.015] [Citation(s) in RCA: 789] [Impact Index Per Article: 87.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Accepted: 02/09/2016] [Indexed: 02/07/2023]
Abstract
Characterization of childhood and adolescent functional gastrointestinal disorders (FGIDs) has evolved during the two decade long Rome process now culminating in Rome IV. The era of diagnosing a FGID only when organic disease has been excluded is waning,as we now have evidence to support symptom-based diagnosis. In child/adolescent Rome IV we extend this concept by removing the dictum that there was "no evidence for organic disease" in all definitions and replacing it with "after appropriate medical evaluation the symptoms cannot be attributed to another medical condition". This change allows the clinician to perform selective or no testing to support a positive diagnosis of a FGID. We also point out that FGIDs can coexist with other medical conditions that themselves result in gastrointestinal symptoms (e.g., inflammatory bowel disease). In Rome IV functional nausea and functional vomiting are now described. Rome III "abdominal pain related functional gastrointestinal disorders" (AP-FGID) has been changed to functional abdominal pain disorders (FAPD) and we have derived a new term, "functional abdominal pain -not otherwise specified", to describe children who do not fit a specific disorder such as irritable bowel, functional dyspepsia, or abdominal migraine. Rome IV FGID definitions should enhance clarity for both clinicians and researchers.
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Affiliation(s)
- Jeffrey S Hyams
- Head, Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, 282 Washington Street, Hartford, CT 06101
| | - Carlo Di Lorenzo
- Head, Division of Digestive Diseases, Hepatology, and Nutrition, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205
| | - Miguel Saps
- Division of Digestive Diseases, Hepatology, and Nutrition, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205
| | - Robert J Shulman
- Baylor College of Medicine, Children's Nutrition Research Center, Texas Children's Hospital, 1100 Bates Street, Houston, TX 77030
| | - Annamaria Staiano
- Department of Translational Science, Section of Pediatrics, University of Naples, Federico II, Via S. Pansini, 5 80131 Naples, Italy
| | - Miranda van Tilburg
- University of North Carolina at Chapel Hill Department of Gastroenterology and Hepatology 130 Mason Farm rd, #4106 CB 7080 Chapel Hill NC
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Korterink J, Devanarayana NM, Rajindrajith S, Vlieger A, Benninga MA. Childhood functional abdominal pain: mechanisms and management. Nat Rev Gastroenterol Hepatol 2015; 12:159-171. [PMID: 25666642 DOI: 10.1038/nrgastro.2015.21] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Chronic abdominal pain is one of the most common clinical syndromes encountered in day to day clinical paediatric practice. Although common, its definition is confusing, predisposing factors are poorly understood and the pathophysiological mechanisms are not clear. The prevailing viewpoint in the pathogenesis involves the inter-relationship between changes in hypersensitivity and altered motility, to which several risk factors have been linked. Making a diagnosis of functional abdominal pain can be a challenge, as it is unclear which further diagnostic tests are necessary to exclude an organic cause. Moreover, large, well-performed, high-quality clinical trials for effective agents are lacking, which undermines evidence-based treatment. This Review summarizes current knowledge regarding the epidemiology, pathophysiology, risk factors and diagnostic work-up of functional abdominal pain. Finally, management options for children with functional abdominal pain are discussed including medications, dietary interventions, probiotics and psychological and complementary therapies, to improve understanding and to maximize the quality of care for children with this condition.
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Affiliation(s)
- Judith Korterink
- Department of Paediatric Gastroenterology &Nutrition, Emma Children's Hospital, Academic Medical Centre, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands
| | - Niranga Manjuri Devanarayana
- Department of Physiology and Department of Paediatrics, Faculty of Medicine, University of Kelaniya, Thalagolla Road, 11010 Ragama, Sri Lanka
| | - Shaman Rajindrajith
- Department of Physiology and Department of Paediatrics, Faculty of Medicine, University of Kelaniya, Thalagolla Road, 11010 Ragama, Sri Lanka
| | - Arine Vlieger
- Department of Paediatrics, St. Antonius Hospital, 3430 EM, Nieuwegein, Netherlands
| | - Marc A Benninga
- Department of Paediatric Gastroenterology &Nutrition, Emma Children's Hospital, Academic Medical Centre, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands
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