More than three decades of research and study for overcoming the problem of “non-acceptance/non-compliance” of patients has neither resolved nor reduced the severity of this problem. This phenomenological study aimed to identify barriers of adherence to medical advice among type 2 diabetic patients.This study was a qualitative research using phenomenology approach, and the data were analyzed using content analysis approach. Participants were 69 type 2 diabetic patients covered by the diabetes unit of West and East Community Health Centers of Ahvaz, Iran. The views and attitudes of patients about the barriers of adherence to medical advice were elicited by conducting 20–45 min sessions of semi-structured interviews. Data analysis was performed following Colaizzi’s seven-step method.Barriers of adherence to medical advice were classified into systemic and individual barriers. Individual barriers included 11 codes and 5 categories, and systemic barriers contained within 5 codes and 3 categories. Physiologic and physical factors, financial problems, occupational factors, attitudinal problems and lack of knowledge, and social and family problems were identified as individual barriers. Systemic barriers included inadequate publicizing and limited notification, inadequate equipment and facilities, and poor inter-sectional coordination.Generally, problems stated by diabetic patients at the individual level can partly be solved by training patients and the people around them. However, as for the systemic problems, it seems that solving the barriers of adherence to medical advice requires coordination with other organizations as well as intersection coordination. Overall, these problems require not only comprehensive health service efforts, but also the support of policymakers to resolve barriers at infrastructure level. Diabetes has affected millions of people around the world, and there are many concerns about the complications of this disease . Since 1Effective management and control can significantly reduce the risk of disease complications. However, numerous studies conducted across the world have revealed inappropriate control programs and lack of management with regard to diabetes –8. Type While most of the burden of controlling the disease rests on the patient’s shoulders, given the importance of controlling and treating the diabetes, the deputy of health has practically started the prevention, control, and screening programs as well as the diagnosis of the disease since the beginning of 2011 in cities with a population of over one million nationwide .According to the staff of the diabetes unit, after implementation of the diabetes prevention and control programs in diabetes units in Ahvaz, one of diabetic patients’ problems has been lack of disease control despite the provision of services and the necessary therapeutic advice from the staff in the diabetes units. This lack of adherence can have many reasons. Given the high prevalence of diabetes in Ahvaz, this research can help diabetic patients solve their problems in adherence to medical advice based on their own statements. Since no study has been conducted on this topic in Khuzestan province, this study was aimed to identify barriers of adherence to medical advice among type 2 diabetic patients using a phenomenological approach.This study was a qualitative research using phenomenology approach, and the data were analyzed using content analysis approach. The choice of a phenomenology approach was justified by the fact that, based on a logical assumption, individuals are the best reference for describing situations, feelings, and experiences by using their own words.The research population was 69 type 2 diabetic patients covered by the diabetes unit of Community Health Centers in Ahvaz. Ahvaz is the capital of Khuzestan province in southwestern Iran, with a population of more than 1.3 million and hot and dry climate. Ahvaz Jundishapur University of Medical Sciences is the main provider of health services in this city. Participants were selected using purposeful sampling. The inclusion criteria were failure in continuous control of blood sugar, lack of regular visits to the clinic, and patient self-declaration of non-adherence to medical advice. Medical records were used to identify these people, and those patients whose disease was not controlled  and who did not visit the center regularly, were invited to be interviewed. Patients who did not consent to participate in research or those who had moved to other cities were excluded. In this study, none of the participants wanted to discontinue participation, and all selected patients participated in the interviews.The data collection method was semi-structured interview. Two researchers (F.F and M.D) with good experience in this field were selected as interviewers. The interviews were conducted face to face. The subjects who met the inclusion criteria were called to set an appointment for interview and a visit with a specialist; in addition, a visit with nutrition expert visit was arranged for them in health center on the same day. We introduced ourselves and reminded ethical issues for informed consent. The interviews started with more general questions: Are you satisfied with your clinical results? Did you act on the given medical advice? Why didn’t you follow the medical advice and given instructions? and What prevented you from following these pieces of advice? We let the participants freely speak out their answers. We used active listening as well as verbal and nonverbal probes to encourage informants to speak their mind out. After the first few interviews, following the main questions, we probed participants’ thoughts about some delicate points mentioned by other informants. Each interview had a closing question about missing questions and points.In order to collect the required data, each interview lasted from 25 to 45 min. Data collection continued until data saturation where no new concept could be extracted from interviews. This procedure took 8 weeks (from at the beginning of November 2017 by the end of December 2017). All interviews were recorded using a tape recorder, and were then carefully listened to and transcribed verbatim. An attempt was made to conduct the interviews without any bias and to write only the whole content. The content of the interviews after transcription was provided to patients to confirm their accuracy.The data were analyzed following Colaizzi’s seven‑step method. The research team read the transcription of the interviews several times, and after being familiar with the data, they identified significant statements. Then, they extracted and formulated relevant meanings into categories and themes that were common about barriers of adherence to medical advices among participants. In the meantime, the team developed an exhaustive description before producing a fundamental structure of this phenomenon. At the end, this structure was verified by the participants and experts in health center . In addiAfter receiving approval from the Research Ethics Committee of Ahvaz Jundishapur University of Medical Sciences (Ref. ID: IR.AJUMS.REC.1396.626), the researchers introduced themselves to the study settings . In addition, before the beginning of the interview sessions, informed consent was obtained from the participants. The participants were clearly briefed that they had the right to withdraw from the study at any time even after signing the informed consent. The participants were informed about the aims of the study and confidentiality of their personal information. In order to keep the interviewees anonymous and to distinguish them from one another in presenting the findings of the study, a code was assigned to each participant.Lincoln and Guba’s four-criteria  were used to check the trustworthiness of the data . To evalThe interviewees included 37 females and 32 males whose age range was 34–73. The level of education of these people ranged from illiterate to bachelor’s degree. The patients had been diagnosed with T2DM (type two diabetes mellitus) for a duration of one to 30 years. Sixteen codes in 8 categories were extracted from the interviews. These categories were classified into 2 themes of individual and systematic barriers of adherence to medical advice. Individual barriers included 11 codes and 5 categories, and systematic barriers involved 5 codes and 3 categories. T2DM patients’ statements about individual barriers of adherence to medical advice in addition to categories and codes are presented in Table A majority of patients pointed to their comorbidities. In addition to physiological and physical diseases, a number of the participants referred to psychological disorders which resulted from diabetes. “I have a lot of stress which leads to lack of control over my disease, despite adherence to medical advice; so, adherence to medical advice doesn’t work for me” (Participant 6). Physical weakness, aging, digestive system problems, and even chewing problem were barriers to following medical advice. “They ask me to do exercise; I can’t walk or move too much. I love to, but I can’t” (Participant 1). Some of the participants stated that they are intolerant of special kinds of food: “I don’t tolerate dairy, it makes me sick” (Participant 10). Some did not tolerate medication: “…that tablets make me sick; I feel sick all the day long” (Participant 3). However, these are just one side of problem. Another side of personal problems is that patients could not afford to adhere to medical advice. Patients’ remarks show that it is not easy at all to act on medical advice while having financial problems. Repeatedly we received answers like “I’m a retiree and I can’t afford prescribed medications and diets” (Participant 8) or “My husband is a retiree, and he is under medication too; we can’t afford for all these medications” (Participant 12). Some of the participants were worried about the escalating costs “Medication expenses are too high and still rising, I don’t know what we’re going to do?“ (Participant 15).In addition, some wrong thoughts and beliefs get people cold feet to act on medical advice. “These pills are chemical. They aren’t good for health; I think traditional [herbal] medication is better” (Participant 3). “These pills are just plaster, they don’t work” (Participant 27). “I believe that adherence to medical advice is useless. I feel that both adherence and non-adherence to medical advice are the same” (Participant 7). Lack of family and social support was another category extracted from interviews. “My wife can’t make a special food just for me! Children don’t like these diets” (Participant 5). Another participant stated: “The government should provide our medications, why should we pay for medication? We have worked for the government, and now we are retired” (Participant 4).Table Patients were expecting health sector to inform them about diabetes and help them to recognize it at very early stages. While diabetes screening is routinely done in health centers, they were asking for more extensive programs like National Diabetes Week’s festivals that are running in the parks and public places. Some said that they need blood glucose monitors, and there were others who said: “I have the blood glucose monitor but I can’t afford for its kits. I would monitor my blood glucose, if I had these kits “(Participant 14). Quite a number of participants asked for subsidizing foreign medicines or covering them by public insurance companies: “I was using foreign medicines and it was great. Now they [medicines] are scarce and expensive, so I can’t afford to buy them. And medications made in local pharmaceutical manufacturers don’t agree with my stomach” (Participant 19). Another patient said: “I can’t take Iranian medications and I can’t afford foreign ones. The government should force insurance [companies] to cover them” (Participant 15).In general, the results obtained from the interviews can be summarized in two categories: individual barriers and systemic barriers as depicted in Fig. The main reasons for T2DM patients’ non-adherence to medical advice can be divided into two major categories. In the first place, there are individual factors that include physical problems, financial problems, occupational factors, attitudinal problems and lack of knowledge, and finally, social and family problems. The second major reason is related to the health system problems which include cases such as limited and inadequate notification, lack of adequate governmental facilities for patients, and lack of inter-sectional coordination. These issues can help the managers in making decisions on how to provide services and remove the existing barriers to increase patients’ adherence to medical advice.In the conducted interviews, an individual barrier that was repeatedly raised by patients was the physical barriers. According to Worlming et al.’s results, co-morbidity in diabetic patients with diseases such as arthritis, stroke, cardiovascular disease, respiratory diseases, and myocardial infarction was associated with a reduction in physical health, and an increase in the number of comorbid diseases led to a decline in the quality of life, indicating the more pronounced role of doctors in the treatment and health behaviors of diabetic patients .Considering that many patients mentioned stress as an important factor in their failure to follow medical advice, mindfulness-based cognitive therapy can be a solution. According to this therapy, by increasing the peace of mind and reducing negative thoughts about the disease and futility of treatment, the patients will be more likely to follow their doctor’s advice . The resAge of the patients was mentioned as a physical barrier. According to Kriska et al., more physically active people are less likely to develop diabetes, and physical activity decreases by age . ReducedMore than half of the interviewees stated that they could not act on a given advice because of financial problems. Abdoli et al.’s study showed that participants who were aware of self-care behaviors were overwhelmed by the cost and pressure of getting hold of the medications, controlling blood sugar, and dealing with complications of self-care . In a crCurrently, the high consumption of calories, fat, sugar and salt/sodium is increasing among people, and many do not include enough fruits, vegetables and fibers in their diets. A diverse, balanced and healthy diet will vary according to the individual’s needs, cultural backgrounds and food traditions. However, some healthy, diversified, and safe diets need to be considered in every stage of life . EducatiThe diabetic patients in their interviews stated that lack of family and community support was a barriers of adherence to medical advice. According to Meredith et al., family and the social context in which people live is one of the most effective factors in facilitating the management of disease in diabetic patients. Social support may directly strengthen the immune system by increasing self-esteem and positive emotions, thereby leading to accelerated disease improvement and reduced vulnerability to the disease . In manyDiabetic patients had wrong beliefs and attitudes about diabetes and they did not take the risk of disease progression seriously, or they felt that adherence to medical advice would be useless. Hasliza Abu et al. concluded that the evaluation of the patient’s concerns and beliefs about diabetes and insulin are very important in helping doctors to provide patient-centered care. Understanding the perceptions of patients, doctors can encourage their patients to take insulin therapy by dealing with changing misconceptions. In addition, continuous education and emotional support can greatly improve the patient’s misconceptions about diabetes .As far as individual factors were concerned, the patients mentioned their type of job as the reason for lack of mobility and physical activity. Physical activity increases mental health and moderates health risk factors such as obesity, high cholesterol, and high blood pressure . Lewis eOne of the problems that diabetic patients in our study indicated was the lack of sports facilities and inappropriate distribution of facilities in Ahvaz. The Ministry of Health, Welfare and Sports in the Netherlands developed a lifestyle intervention called “BeweegKuur” (Dutch for Exercise Therapy) which incorporated sport and physical activity into the lifestyle of individual patients by focusing on changes in physical activity behavior and diet behavior to prevent and treat type 2 diabetes. The results showed that the program was successful in controlling the disease of the studied patients . TherefoAccording to the diabetic patients in our study, publicizing and notifying are very important in adherence to advice. This was considered as a systematic factor. The results of the study of Xianglong et al. showed that anti-smoking television advertising could affect the knowledge about and attitude towards smoking. In other words, television, as one of the most influential mass media, can directly or indirectly influence health-related behaviors among population . TherefoAnother systemic problem that diabetic patients noted was the lack of appropriate insurance coverage in using the needed healthcare services. Limited income and lack of insurance coverage are commonly perceived as barriers to the effectiveness of self-management education for diabetic patients . In someOne of the limitations of this study was the reluctance of some patients to be interviewed. They later accepted to be interviewed by explanations given to them regarding the benefits of this study in consultations with the personnel at the diabetes unit.Major problems contributing to T2DM patients’ non-adherence to medical advice are divided into two areas of individual and systemic problems. Improving health culture and providing education through mass media and health centers seem to be effective in coping with individual problems and providing self-care and social support for diabetic patients. Implementing targeted interventions in lifestyle, promoting the culture of healthy life through mass media, and particularly, increasing the financial support for services required by diabetics can ultimately lead to improvements in diabetic patients’ adherence to advice. These measures, of course, require an increase in health education activities and the development of inter-sectional health systems as well as a high commitment of society and organizations to improve public health. Policymakers should prioritize the issues raised above.


Determining the optimal dosing regimen for pediatric patients is a challenge due to the lack of dosing guidelines and studies. In addition, many developmental pharmacology changes that occur throughout childhood that have profound impacts on the absorption, distribution, metabolism, and elimination of medications are commonly used in palliative care. Adding to that complexity, certain medications have different effects in the pediatric patient compared to the adult patient. Being aware of the pharmacokinetic changes, impact on neurodevelopment and unique medication factors that are present in pediatric patients helps clinicians treat the pediatric palliative care patient in the best and safest way possible. Working in pediatric palliative care (PPC) is very rewarding but is not without its challenges, especially in the realm of pharmacotherapy. The treatment of pain in children is complex. The first challenge faced by those in pediatrics is the vast neurodevelopmental spectrum that leads to widely variable expressions of pain. Additionally, the lack of dosing guidelines, studies, and commercially available formulations make creating the optimal dosing regimen for pediatric patients a challenge, particularly when combined with the many developmental pharmacology changes that occur throughout childhood. In addition, certain medications have different effects on the pediatric patient compared to the adult patient. Specific examples will be covered in this article, including fentanyl-related chest wall rigidity, methadone prolongation of the corrected QT (QTc) interval, neurodevelopmental impairment from benzodiazepines, and tramadol effects on respiratory function. Being aware of these unique factors helps clinicians treat the PPC patient in the best and safest way.Large-scale, randomized clinical trials are rare, causing us to sometimes rely on case series or case reports. This leads to hesitance to use medications that have not been well studied due to lessons learned from past tragedies, such as birth defects from thalidomide, gray baby syndrome from chloramphenicol, and kernicterus from trimethoprim/sulfamethoxazole. As a result, it is important to be familiar with the concepts of developmental pharmacology and to be able to apply them to the medications commonly used in palliative care.Most clinicians that work with pediatrics have heard the statement “Children are not just small adults”. Further, it is important to remember that neonates are not just small children and premature neonates are not just small neonates. This is important to understand because most of the changes in developmental pharmacology occur in the first year of life, so neonates and infants will be the focus of this section. Developmental pharmacology concepts are broken down into absorption, distribution, metabolism, and elimination (ADME) categories .Intestinal Integrity: Premature neonates have immature intestinal integrity. Commercially available formulations of oral medications often contain high amounts of sugars, preservatives, and flavorings, which increases the osmolality of medications. In all age patients, these high osmolar medications can cause diarrhea, cramping, abdominal distention, and vomiting. In the youngest population, it can also increase their risk of developing necrotizing enterocolitis . TherefoIntestinal Permeability: Neonates also have altered permeability of intestinal mucosa, which plays a role in medication absorption, notably increased absorption. Oral bioavailability (BA) of morphine is 19–47% 23.9%) in adults but 45–50% in term neonates [3.9% in aGastric Transit Time: Gastric emptying time is prolonged in the premature neonate, which can slow the absorption rate and onset of medication effect. As a clinical application of this, clinicians need to make sure to give oral medications enough time to work when using them for procedural pain or sedation.Volume of Distribution: Determining the dose needed to obtain certain plasma concentrations is the concept of volume of distribution. This is often affected by the fluid status in a patient. The percentage of total body water and extracellular water is highest in our premature neonatal population and decreases as they get larger such as term neonates and young infants . As a reProtein Binding: Only the free (unbound) portion of a medication can exert its effects. Neonates not only have lower amounts of binding proteins but the proteins may have less affinity for medications . The resBlood–Brain Barrier (BBB): Neonates have an immature BBB, which can result in faster and greater medication uptake into the CNS. This can cause increased sensitivity to both the therapeutic and toxic effects of a medication. For example, typically lipophilic medications cross the BBB more easily than hydrophilic medications. Since morphine is a hydrophilic medication, it does not cross over to a great extent in older patients; however, it will cross over in neonates due to the immature BBB. This may be why neonates are more sensitive to the CNS effects of morphine.Metabolism occurs in many sites in the body, but the major site of drug biotransformation is the liver. Neonates are born with much lower amounts of cytochrome p450 system enzymes compared to adults, which results in reduced clearance of some medications, especially in the first weeks of life . Even thMorphine, acetaminophen, lorazepam, and dexmedetomidine all undergo 3-glucuronidation. The activity of this process is reduced at birth and reaches close to adult levels by 2–6 months of age . Almost Another pathway that is decreased in newborns is glycine conjugation, although it does increase to adult levels around 8 weeks of age. In the first two months, products that contain the preservative benzyl alcohol should be avoided if possible. Benzyl alcohol is oxidized to benzoic acid, conjugated with glycine, and excreted as hippuric acid. Since conjugation is reduced, benzoic acid accumulates, causing metabolic acidosis and possible neonatal gasping syndrome . Some prUnlike glucuronidation and glycine conjugation, the sulfotransferase system is well developed at birth such that it can compensate for the limited function of other pathways. For example, acetaminophen is mostly metabolized by glucuronidation in adults; however, neonates shift some of the metabolism to the sulfation pathway . As a reAfter a medication is metabolized, it needs to be eliminated from the body. The most common way is via the kidneys. Glomerular filtration rate (GFR) for full-term neonates at birth is approximately 20% of adult values and doubles around Week 2 of age. Premature neonates have an even lower GFR, since nephrogenesis is not complete until around 34 to 36 weeks’ gestation . Serum cAs a result, many medications have much longer half-lives in neonates. For example, the half-life of morphine can be as long as 10–12 h in preterm neonates yet decreases to 2–4 h in adults [Animal studies have demonstrated that brain development is negatively affected by benzodiazepines, and that is starting to be confirmed with neonatal studies . MidazolA concerning side effect of fentanyl is chest wall rigidity. This is commonly observed in adult patients after administration of large doses and rapid infusions. However, in the Neonatal Intensive Care Unit (NICU), it has been seen with commonly administered doses for pain and sedation (3–6 mcg/kg) administered as a slow bolus over 2–3 min . While tTramadol is a medication that is typically viewed as an opioid, albeit a “weak” mu-agonist. It is perceived to have the same potency as codeine and, as such, is often prescribed when health care providers want to avoid “stronger” opioids such as morphine, oxycodone, or hydromorphone. Pharmacological data suggest that the affinity of tramadol for the mu-receptor is approximately 10 times less than codeine and 6000 times less than morphine . The affSo how does tramadol relieve pain? Essentially tramadol works in two ways. The first is through an active metabolite of tramadol, O-desmethyltramadol. Tramadol is metabolized to O-desmethyltramadol via the CYP2D6 cytochrome P450 enzyme system, and O-desmethyltramadol binds to mu-opioid receptors.The second way tramadol relieves pain is by blocking the reuptake of serotonin and norepinephrine, much duloxetine and venlafaxine, which are serotonin-norepinephrine reuptake inhibitors (SNRIs). Both duloxetine and venlafaxine are used for neuropathic pain, and there is some evidence that they may also have an anti-inflammatory effect.In addition to its unique mechanisms of action, tramadol also has some safety concerns in the pediatric population. As mentioned above, tramadol is metabolized by CYP2D6 into its active metabolite. There is variable expression of CYP2D6 across humans. Some people are ultrarapid metabolizers, some are poor metabolizers, and many have normal metabolism. Ultrarapid CYP2D6 metabolizers are individuals who have more than two copies of functional CYP2D6 alleles. In these patients, a higher percentage of tramadol is metabolized to active metabolites, causing a greater risk of respiratory depression and/or death.From 1969 to 2016, the Federal Drug Administration (FDA) discovered nine cases of respiratory depression in children less than 18 years of age, three of them involving deaths. As a result, they released warnings and contraindications to the use of tramadol in pediatric patients . ContraiCommonly known side effects of tramadol include seizures, hypoglycemia, and serotonin syndrome. Interestingly, despite its low affinity for opioid receptors, tramadol has a somewhat higher risk of prolonged use compared with other short-acting opioids.The potential benefits of tramadol must be weighed against its side effect profile before administering.Gabapentin was initially developed in the 1970s to treat spasticity. It was approved by the United States Federal and Drug Administration in the 1990s to treat postherpetic neuralgia. Yet, there are thousands of citations on PubMed for the treatment of pain with gabapentin. Gabapentin is extensively used in PPC, and children with severe neurologic injury often utilize these services. Gabapentin has been shown to be helpful for neuropathic pain and “neuroirritability”.Gabapentinoids  function by binding to presynaptic neuronal alpha-2-delta subunits of voltage-gated calcium channels. This leads to downregulation and decreased production of substance P, glutamate, and calcitonin-related gene peptide, which are thought to initiate and maintain neuropathic pain states.One of the more common side effects of gabapentinoids is somnolence. The drowsiness associated with gabapentinoids is thought of as occurring in the initial days of treatment, after which the patient becomes accustomed to the drug and somnolence improves. Due to case reports of prolonged hypoventilation in postoperative patients receiving gabapentinoids , the proThere is limited evidence to support the use of gabapentinoids for cancer-related neuropathic pain due to the low quality of published data and a lack of efficacy when compared to opioids alone. In fact, the clinical practice guideline of the American Society of Clinical Oncology recommends the use of duloxetine over tricyclic antidepressants and gabapentinoids. Given the potential risk of unintentional overdose when gabapentinoids are used with opioids, it may be prudent for palliative care physicians to consider alternative medications for the first-line treatment of neuropathic pain in patients with cancer who also are taking opioids. For children 7 years of age or older, duloxetine is equally as efficacious as gabapentin without the untoward side effect profile.Methadone is a unique opioid in that it modulates pain via multiple receptors. Methadone provides agonist activity at the μ-, δ-, and κ-opioid receptors, antagonism at the N-methyl-D-aspartate receptor, and is also a serotonin-norepinephrine reuptake inhibitor. In addition to its high bioavailability, long half-life, and no active metabolites, it is particularly attractive to those in pediatrics, as it is the only long-acting opioid that comes as a liquid. This allows even the youngest patient, or one with impaired swallowing and can only receive medications through a nasogastric or gastric tube, to access the benefits of long-acting opioids.Unfortunately, there is a great amount of trepidation in prescribing this opioid. The long half-life leads many to believe it is a difficult medication to titrate—patience, however, is often rewarded with superior analgesia than other pure mu-agonists, especially in those with mixed nociceptive and neuropathic pain. Perhaps the biggest barrier to prescribing methadone is its fabled association with a prolonged corrected QT interval (QTc) that can lead to Torsade de Pointes, a fatal cardiac arrhythmia. There are generally two misconceptions that perpetuate the concern with methadone: (1) what constitutes a “normal” QTc interval and (2) the frequency of a prolonged QTc interval.Most pediatric health care providers define a “prolonged” QTc interval as greater than 450 milliseconds (ms) ; data suIn general, methadone is exceedingly well tolerated in children, with little evidence of clinically significant prolongation of the QTc interval. Caution, however, is warranted when using in critically ill children, those on azole antifungal medications, or with electrolyte abnormalities. In these children, vigilance with frequent ECG monitoring is recommended.Often, we escalate doses of opioids when a patient appears uncomfortable. This might be the correct path if tolerance or untreated pain is present; however, keep in mind the potential for opioid-induced hyperalgesia (OIH).Hyperalgesia is hypothesized to occur via many mechanisms; one main contributor may be glutamate-associated activation of NMDA receptors, which causes an augmented excitatory response . Risk faWith hyperalgesia, the pain quality, location, and distribution pattern are likely to be different from their original pain condition. The pain is usually diffuse, has neuroexcitatory effects, and may be accompanied by myoclonus, hyperesthesia, or allodynia . ManagemIf OIH is suspected, the dose of the opioid should be reduced; however, it is usually a challenge to get patients/caregivers to agree with this because the patient is often experiencing their highest peak of pain. Clinicians should always have a backup plan in place in case the pain worsens.Codeine, hydromorphone, morphine, and other structurally similar opioids in the phenanthrene class undergo glucuronidation to a NMDA receptor-activating metabolite. Since NMDA activation promotes hyperalgesia, switching to an opioid that is structurally unique (outside of the phenanthrene class like fentanyl) could reduce the hyperalgesia ,25.The use of adjunctive agents should also be considered in order to block the activation of the NMDA receptor to reduce the spinal neuron sensitization. Methadone and ketamine can block NMDA receptors and provide pain relief via different receptors than the opioid from which the patient is experiencing OIH. Adding an adjunctive agent, even outside of NMDA antagonism such as acetaminophen or ketorolac, should be considered for the goal of being able to administer lower opioid doses.When one considers the aspects of developmental pharmacology as well as unique metabolic patterns and the lack of clinical studies regarding medications that can be commonly used to treat pain in children, the treatment of pain can almost feel overwhelming. As with most things in medicine, start with the initial conservative dose (never be ashamed to consult your pharmacopeia of choice), assess the response, observe for side effects, and titrate accordingly!


Objective: Functional gastrointestinal disorders (FGIDs) are common in children and adolescents. During 2016 and 2019, we investigated the experiences among parents of children with FGIDs and interviewed their children and adolescents during 2020. The aim of the present study was to explore the experiences among general practitioners (GPs) who treat this patient group.Design: Individual interviews with open-ended questions were audio recorded and transcribed, and subsequently analysed using descriptive content analysis.Setting: Urban and rural areas in two municipalities in Southern Norway. Participants: Twelve GPs practicing in the region were interviewed.Results: GPs generally feel competent treating these patients without referring them to hospital or specialists. Having known the patients and their families over time is important. Providing psycho-educational resources to the patients and parents is essential for their understanding that the pain is not dangerous. The importance of attending school was emphasised.Conclusions: The GPs' biopsychosocial focus and long-term follow-up care are essential in treating children and adolescents with FGIDs and their parents.Current awarenessAbdominal pain is a common symptom in children and adolescents, for which an organic cause is seldom found.Main statementsGPs feel competent to treat children and adolescents who have functional gastro-intestinal disorders (FGIDs) without referring them to hospital or specialists. • A main task for GPs is to inform children, adolescents, and their parents that FGIDs are not a serious organic disease and that everyday life should continue. Children and adolescents with functional gastro-intestinal disorders (FGIDs) are frequently seen by general practitioners (GPs ). In NorGPs often follow these patients the entire course of the disease. Either they remain in primary health care or they are referred to a specialist and return with no somatic diagnosis. The patients’ family histories are often well-known to the GPs, who can be important informants about this patient group over time. It may be demanding for GPs to provide meaningful help to their young patients with FGIDs, as long as there is no physical explanation for their pain . They stIn 2016, the first author interviewed the parents of children and adolescents aged 5–15 years with FGIDs who had been referred to a local hospital by their GPs, and who was later discharged without a somatic diagnosis . In 2019The aim of the present study was to investigate GPs’ experiences with treating children and adolescents with FGIDs. How did the GPs succeed to balance the biopsychosocial aspects, the somatic examinations, and the maintenance of trust in the doctor-patient relationship? We also addressed the GPs’ views on the types of approach and treatment these patients and their families may need.The Regional Committee for Medical and Health Research Ethics determined that the study did not need their approval (reference no. 2020/184272). The Norwegian Centre for Research Data approved the study (reference no. 2020/349340). The GPs gave written consent to participate.We chose a qualitative study design based on individual interviews with Norwegian GPs. The qualitative research interview tries to understand the world from the interviewee’s side and to bring out the meaning of their experiences . BecauseConsolidated Criteria for Reporting Qualitative Studies (COREQ) criteria [The study was designed according to the criteria .A semi-structured interview guide with 14 open-ended questions and additional follow-up questions was developed . The queDuring autumn 2020, GPs working in the same region as the children and parents whom we previously interviewed were selected from a regional list and contacted by telephone by the first author for an interview. Fourteen GPs were contacted and asked to participate. Eight female and four male GPs aged 36–67 years accepted the invitation and were interviewed. These were not the GPs of the specific patients whom we had interviewed previously. Two GPs who had accepted the invitation withdraw without giving any reason. This was a strategic sample based on age, gender, urban or rural practice, and predominance of immigrants or Norwegian inhabitants see .In the Norwegian list system, the patient chooses a GP and then ‘belongs’ to this physician. The relationship usually lasts several years and, consequently, the GP generally knows the family’s histories well and can use these experiences as valuable information in the consultations. In Norway, GPs’ consultations usually last 15–20 min.The first author, a female former GP, and child and adolescent psychiatrist, interviewed the GPs. They were informed that she was interviewing them in her role as a researcher. The GPs determined an appropriate time for the telephone interview. Written information about the study was sent to the GPs before the interview. The interviews were conducted during October and November 2020 and lasted 16–40 min. During the last 2–3 interviews, we got no more information or details. Data saturation was thus achieved, and recruitment was concluded .The interviews were audiotaped and transcribed by the first author. Qualitative content analysis was conducted based on the work by Graneheim and Lundman . No softThe idea for the study was conceived by AB and MB. MB applied for the approvals. AB carried out the interviews and transcribed the text, and both authors participated in the analysis. AB drafted the article, and MB revised it critically.The GPs’ practices were in both rural and urban regions, and one included a predominantly immigrant population . The GPsWe identified three main themes:Building an alliance with the patient and the parents in a complex situation.Healthy children with abdominal pain- expanding the patients’ and parent’s understanding of FGIDs.The pain should not control their life-changing the patients’ and parent’s reaction to FGIDs.The participating GPs highlighted the importance of trust and alliance between them, the patients, and their parents as being a prerequisite for making any progress in handling abdominal pain. Their approaches to these patients had the underlying aim of building and enforcing such an alliance. Even if dealing with the families’ complex problems could be challenging, the GPs were clear that children with FGIDs should be followed up in primary care.All GPs emphasised that a physical examination, including blood tests, urine, and stool samples, was absolutely necessary to exclude organic disease when a child presented with abdominal pain. If the examination showed organic disease, the patient was referred for further evaluation. All GPs claimed that the medical examination seldom showed organic abnormalities that could explain the abdominal pain. Anyhow, it was important to be able to inform the patients that the pain was not dangerous. To do an examination was also essential for building an alliance with the family.A conversation with the child or adolescent and parents about the symptoms was highlighted as important toward deciding how to proceed. Questions about family conditions, siblings, school, friends, and other possible stressors were asked. The GPs tried to have a brief, private conversation with adolescents and children from 5–10 years, when possible. A trustful relationship between the doctor and the family was highlighted by the GPs as essential for the patients and parents to follow their advice. The GPs stated that although abdominal pain in children generally has no organic cause, it affects the lives of the child and family, and they emphasised showing empathy and support during difficult times, thus showing that they took the pain seriously. Children and adolescents with FGIDs often presented complex problems. Some GPs stated that these consultations could be challenging, especially when the patient returned from the hospital without findings of any somatic diagnosis:We do not struggle with the patients who have a disease, it is the patients without a diagnosis who can be challenging (Interview 10).Yet, the GPs referred few patients with FGIDs to the hospital. They argued that these patients belong in general practice:These patients belong here with me, but if the dialogue is complicated, I refer them to hospital for a second opinion (Interview 1).Other reasons for referrals were alarm or ‘red flag’ symptoms, a diffuse or long-term pain situation, the parents demanding to see a specialist, often a paediatrician, or the GP needing support from a colleague:Intensity and chronicity determine whether they are referred. As a doctor, I may need colleague support, because the patient and families become so dissatisfied if they don‘t get well (Interview 10).Toilet habits and constipation were factors that the GPs saw as problematic for many of these patients. Teaching them about how the body functions, which is really a parenting task, often helped the children. Concrete advice about daily toilet routines, as well as about food and exercise, was also needed:A gut reaction to strawberries does not mean intolerance and does not mean that it is impossible for the child to eat this food (Interview 4).The GPs received requests for diet advice and ‘quick fix’ treatments from patients and parents, who wanted medicine that would eliminate the pain once and for all. The GPs spent a great deal of time explaining to the patients and the parents that their advice must be followed for a long time to be effective, as there is no quick and easy way out of FGIDs.They returned for a new consultation after some month. The advices I had given them earlier had not been followed. They asked for a referral to hospital for a quick treatment (Interview 9).Some of the GPs wanted better access to child and adolescent psychiatrists as well as nutritionists outside the hospital. They expressed that a few hours of guidance from a specialist could probably help keep the patient out of the hospital and accelerate improvements. All GPs in our study mentioned that most of these child and adolescent patients with FGIDs disappeared from their practice after some time. When this occurred, the GP concluded that the patient had recovered. However, some returned, even years later, with the same symptoms. Others returned with mental health problems, such as anxiety or depression. The GPs emphasized that trust and alliance were necessary for these patients to consult them with mental symptoms.By using the biopsychosocial model, the GPs could bring in other dimensions than the physical disease when it came to understanding and treating the FGIDs.Their stomach controls their life. They are quite healthy children, except from having abdominal pain (Interview 9).Some patients and their families consulted the GP often and as soon as the child felt pain or had any digestive symptoms. They were afraid of serious diseases and needed their GPs’ reassurance. Some of the GPs in our study had been their family doctor for many years and recognised the parents’ approach to pain symptoms. When the clinical examination was normal, the GPs emphasized other causes than the organic disease. They highlighted that the patients’, parents’, and teachers’ understanding of the pain in a biopsychosocial context is crucial. This would move the families’ away from the fear of serious somatic illness and allow them to explore the context in which the pain occurs. One GP in our study claimed that saying the words ‘this is not cancer’ (Interview 9) was important. Hearing this was sometimes sufficient, after which both the patient and parents stopped worrying about the symptoms and the pain improved:Not everything that hurts is dangerous. However, children are honest, and we need to take them seriously. (Interview 4).The GPs were also concerned with somatization in both parents and patients because pain can be an expression of mental or social difficulties:Children feel through the stomach. The cause of the pain often is multifactorial, the child’s way of signalising problems is through pain. (Interview 8).Being able to understand the child’s life situation through the biopsychosocial model, gave the GPs in our study tools to help the children and their families. Receiving an explanation for FGIDs and a diagnosis was described by the GPs as being among the most important factors for recovery or living a high-quality life with the symptoms:In the second consultation, I always ask about school/work, friends, family and mental symptoms and at last I ask what they believe is the cause of the pain (Interview 2).The GPs seemed to see the pain in a holistic view. Their tasks would be to get the parents as well as the patients to see its connection with psychosocial factors. The GPs took on the task to expand the families’ views and understanding, which could be challenging.Challenges at school often reinforced FGIDs, however, having morning abdominal pain should not mean staying home from school for the rest of the day. The parents needed the courage to send the child with abdominal pain to school. Providing teachers with an explanation about FGIDs and information about the child’s situation, was also important. An essential message was that the prognosis for FGIDs does not improve if the child stayed home from school. Narrowing the patient’s life based on their symptoms could negatively affect their daily experiences. The GP’s task was to guide the patients and parents to this understanding:We need to get the parents and the teachers on the team. They all need more health competence. The next task will then be how to deal with the pain (Interview 4).Parents are their children’s and adolescents’ teachers, so it is important to learn them to interpret bodily signs and how to respond to them. The GPs in our study, therefore, claimed that one of their important tasks was educating children and adolescents, as well as parents, in interpreting and handling abdominal pain:The parents need knowledge about the symptoms. They contribute to the child’s fear by becoming anxious themselves (Interview 10).The children ‘inherit’ their parents’ bodily reaction to stress and their anxiety for serious disease. Knowing the families made it easier for the GPs to explore the situation through the biopsychosocial model:The children adopt their parents’ ways of handling the pain (Interview 4).The GPs in our study thought that children and adolescents could be symptom carriers for the families’ problems. This was perceived as a complex situation that only emerged after exploring these problems for some time. The GPs emphasized that it was important for them to capture possible mental problems in these children and adolescents.Making the parents understand that this is a mental reaction and not a physical illness, is important (Interview 1).The children and adolescents need to have fun and experience a good life. That is maybe the most important treatment for these children with abdominal pain (Interview 10).Twelve GPs were interviewed about their experiences with treating children and adolescents with FGIDs. Our findings stated that it is their responsibility to follow up with these patients and that they feel competent handling the symptoms and seldom refer these patients to the hospital. The patients and parents need reassurance that the pain is not caused by a dangerous illness. They must also be taught the connections between FGIDs, emotions, and life situations.via telephone is thought to result in loss of contextual and non-verbal data and to compromise report, probing, and interpretation of responses compared to face-to-face interviews. However, the telephone may allow respondents to feel more relaxed and able to disclose sensitive information [The first author and interviewer is a child and adolescent psychiatrist who previously worked for many years as a GP. We considered this an advantage during the interviews, as the GPs felt at ease talking to a colleague. In-person interviews may have allowed more detailed information, than a telephone interview. The absence of visual cues ormation . A longeormation . Despiteormation . There wFor qualitative research, theories are especially important as tools to understand, interpret, and elaborate on empirical observations beyond description . The bioThough organic pathology is seldom found, the GPs in our study saw physical investigations as important, in combination with conversation. Lowth concluded that an examination should be conducted to exclude organic disease . This wiWhether further examinations should be conducted, the GPs in our study thought it depends on clinical findings, such as alarm or ‘red flag’ symptoms. Chiou and Nurko stated that in the absence of red flag symptoms, extensive investigations are usually unjustified . This coIn our study, the GPs observed a pattern in which some parents themselves had visited the GP with FGIDs or other pain symptoms for years. This pain approach seemed to have been inherited by their children or adolescents and could also be an expression of the parents’ worries, anxiety, or bodily reaction to stress. This tendency has been noted previously. Shraim reported that consultations for non-specific physical symptoms (NSPS) in mothers were a risk factor for repeated consultations for NSPS in their children . OverallThe GPs in our study stated that both parents and teachers need to change their reactions to the child’s or adolescent’s abdominal pain. A study from 2009 confirmed the view that the parent’s job now is to be a ‘coach’, to encourage and support . The chiGPs in our study felt comfortable serving as the primary care provider for children and adolescents with FGIDs. Continuity, knowing the patients and their families over years, and having the opportunity to observe all their symptoms were considered important to GPs. Children can inherit their parents’ bodily reactions to stress and carry the family’s problems. Both the child and parents must learn that most pain is not dangerous. Instead, the focus should be on normality and mastering everyday life. The GPs in our study made it clear that investigation and treatment of children and adolescents with FGIDs does not have to be complicated, and that understanding the symptoms through the biopsychosocial model is essential.Click here for additional data file.


The aim of the present study was to evaluate and compare the postoperative pain and periapical healing after root canal treatment using three different base endodontic sealers.Primary root canal treatment was initiated in 63 patients diagnosed with necrotic pulp and apical periodontitis, cleaning and shaping was completed in two visit and different base endodontic sealers were used for obturation were selected based on the random allocation of the participants to the following groups; Tubli-Seal, AH Plus and BioRoot RCS. Postoperative pain was recorded by using 100 mm visual analog scale at 24 h, 48 h, 72 h and 7 d after obturation. Digital periapical radiographic evaluation was done to assess rate of periapical healing at baseline, 1, 3 and 6 months. Statistical analysis was done using Kruskal Wallis test and one-way ANOVA.The mean difference in the size of periapical lesions for Tubli-Seal , AH Plus  and BioRoot RCS  at 3 months and 6 months respectively. The mean pain scores at 24 h for Tubli-Seal (17.94 ± 11.35), AH Plus (11.57 ± 11.18), BioRoot RCS (4.73 ± 7.72). At 48 h, Tubli-Seal (5.26 ± 9.04), AH Plus (1.57 ± 3.74) and BioRoot RCS (1.57 ± 3.74) respectively. The mean pain score at 72 h for Tubli-Seal was 2.63 ± 7.33 whereas none of the patients had reported pain in AH Plus and BioRoot RCS group. None of the patients had pain after 7 d of treatment.BioRoot RCS showed less postoperative pain compared to AH Plus and Tubli-Seal and showed better periapical healing compared to AH Plus and Tubli-Seal at 3 and 6 months intervals respectively. Key words:BioRoot RCS, root canal obturation, root canal sealers, periapical periodontitis, Periapical healing, postoperative pain. Apical periodontitis is an inflammatory lesion around the periapical region and can have significant influence on the endodontic treatment prognosis. Teeth with apical periodontitis are considered to be an entombment of various pathological flora which can influence the success rate of the treatment . The aimPeriapical healing is seen to be structural and functional replacement of the bone considered to be an intricate interplay between the osteoclasts and osteoblasts allowing the bone formation to occur seen to be influenced by the host’s intrinsic and extrinsic mechanisms . Root caPostoperative pain is considered to be another significant clinical outcome exhibiting a multifactorial response to treatment related factors such as maintaining the working length to the apical constriction, finishing the endodontic treatment in single visit or multiple visit, instrumentation technique and the type of endodontic sealer used for obturation . PostopeIn regard to all this prior discussed factors, the present study aimed to address both these issues by conducting a comparative evaluation of the incidence and intensity of postoperative pain and post obturation healing of periapical lesions after primary root canal treatment using representatives of different base endodontic sealers such as zinc oxide eugenol sealer , resin-based sealer (AH Plus) and bioceramic sealer (BioRoot RCS) in patients with diagnosed with necrotic pulp and apical periodontitis. The null hypothesis was considered that there was no significant difference in the incidence and intensity of postoperative pain and periapical healing after root canal treatment using BioRoot RCS, AH Plus and Tubli-Seal as endodontic sealers.-Ethical clearance and protocol registrationThe present study adhered to the Consolidated Standards of Reporting Trials (CONSORT) statement of reporting . Ethical approval was obtained from the Institutional Review Board (SRB/SDMDS11/17ODS/09). The protocol for the present clinical trial was registered with the clinical trials registry – India (CTRI) with registration number (CTRI/2018/10/015919) before the clinical trial began. All the patients consented to an informed consent form discussing the details of this trial as well as benefits and risks of the study.-Trial DesignThis study was conducted under a university setting which followed a double blinded parallel randomized clinical trial design with allocation ratio of 1:1 in which the patient and the assessors were blinded from the process. The treating operator could not be blinded since treatment protocol with different endodontic sealers could not be concealed from the operator used in the present study.-Sample size calculationA priori sample size calculation was done using G*Power 3.1.2 software based on a previously published study . Using a-Study groupsFor the present study, 3 groups were taken which were representatives of different base endodontic sealers; Group 1: ZOE based sealer , Group 2: epoxy resin based sealer , Group 3: Bioceramic based sealer .-Inclusion/Exclusion criteriaParticipants undergoing endodontic therapy in maxillary anterior teeth within the age group of 18-60 years categorized under American society of Anesthesiologists (ASA) - 1 giving a tooth diagnosis of necrotic pulp with chronic apical periodontitis confirmed using sensibility test [cold test  and electrical pulp testing ] with a periapical index (PAI) score of 2 or more diagnosed using digital radiography as well as a patient’s VAS Score of 30 mm and above were taken into inclusion criteria for the present study since the present study aimed to evaluate two clinical parameters; postendodontic pain and periapical healing. Patients classified other than ASA -1, immature permanent tooth, tooth exhibiting endodontic-periodontic lesions, dystrophic calcifications within the tooth as well as more than 20° curvature, pregnant or lactating women, root fracture cases, patients who consumed analgesics before 12-24 h prior to the primary root canal treatment were excluded from the present study.-Randomizationp < 0.05). The calibration process was continued in a timeframe of 4 d, 7d, 21 d in order to maintain the calibration between the evaluators prior to the start of trial. In case of disagreement, a third specialist who had sufficient experience for more than 10 years on interpreting radiographs was consulted to achieve an agreement. A piece of paper containing the randomized group number was sealed in the dark-colored envelope containing the respective serial and treatment protocol for only the sealer groups prepared by the respective third person (A.P). Study numbers were sequentially assigned to patients by an individual not related to the present study. The envelope was opened once the intervention was assigned. Respective treatment was carried out based on the group assigned in the paper by a single operator (A.K) conducted the treatment.Computer generated random Table of numbers was conducted using an online service (random.org) was used for the randomization process to assign the participants to different study groups. Block randomization method was advocated using the SNOSE  method for allocation concealment. Two experienced endodontists  who were not involved in the treatment process assessed these periapical radiographs and came to consensus regarding the scoring outcome for the size of the lesion. The endodontists prior to evaluation of the radiographs were calibrated based on a set of 100 predetermined radiographs as a calibration exercise and had come to an agreement based on consensus with a 0.70 cohen kappa statistic , if required. Access cavity preparation was conducted using Endo Access Kit  followed by which debridement of pulp chamber contents was done using a spoon excavator and 3% sodium hypochlorite (NaOCl) . An ISO size 10 K-File (Mani Corp. Japan) was used to obtain for initial patency filing and working length was recorded using an electronic apex locator  such that it was measured at 0.5 mm short of the apical canal terminus (‘0’ reading). The confirmation of the working length was done by using digital periapical radiograph.The canals were shaped using the Protaper Gold rotary system  for all the teeth. The apical preparation was carried out by using ISO stainless steel hand K files  starting with the file which was initially binded till the working length, the final instrumentation was carried out 3 sizes larger than the first file followed by which a similar taper instrumentation technique using Protaper Gold till the working length. During the instrumentation process, 3% NaOCl  was used during each cycle of instrumentation and the canal patency was maintained by passing ISO 15 No. K file approximately 1 mm beyond the determined working length after each instrumentation cycle. In order to effectively remove the smear layer, an irrigation of 17% EDTA  followed by a final irrigation of 3% NaOCl was conducted. All the irrigation process was conducted using a 30-gauge double side vented needle  and 2 ml syringe barrel . During the irrigation process each cycle was intermittently activated using sonic activation for a period of 60 s .Post biomechanical preparation procedure, the canals were dried using sterile paper points according to corresponding taper and freshly mixed calcium hydroxide paste was placed into the prepared canals using a lentulospiral  followed by which a temporary seal was done using intermediate restorative cement . The patients were recalled after a week and patients who were asymptomatic exhibiting a VAS Score of 0 and dry canals on evaluation with sterile paper points after removal of the intra canal medicament were further treated. The teeth were obturated according to the randomly allocated groups, Group 1: Tubli-Seal; Group 2: AH Plus; Group 3: BioRoot RCS.Manufacturer’s instructions were followed for mixing the respective sealer on a sterile glass slab. The apical extent of the master cone was confirmed radiographically by digital radiograph. The canals were dried using sterile paper points and were coated with the sealer using lentulospiral  in a slow speed handpiece  followed by which the obturation process was performed with respective sealers using the lateral compaction technique.Post treatment occlusal reduction of 1 mm was done in all the treated teeth and permanent restorations was done with composite resin  and the periapical healing and postoperative pain was assessed. All the clinical procedures were performed by one operator of similar endodontic clinical experience. A partial coverage or a full coverage prosthetic management was done for all the teeth as indicated.-Outcome assessmentPeriapical healing assessmentp<0.05) in regard to periapical diagnosis. The presence or absence of sealer extrusion was also noted. The size of the periapical lesion was calculated with the help of a grid, X-ray mesh gauge  such that the entire proximity of the periapical lesion was covered under the mesh gauge and the same observers  confirmed the size of the lesion at repeated intervals and mean scores were taken. Subsequent radiographs were taken for each patient at 1, 3 and 6 months using and evaluated using the similar technique. In an event of sealer extrusion during the treatment procedure, the rate of sealer extrusion and pain was assessed separately.All the digital radiograph was carried out using parallel cone technique using RVG sensor  with the help of a sensor positioning system  and was evaluated for baseline data. The data was analyzed by two experienced endodontists  who were not involved in the treatment protocol such that prior images were seen so the interobserver agreement was seen at 0.90 using Cohen kappa  consisting of a 100 mm line divided into 10 equal parts from 0 indicating no pain to 100 indicating extremely severe pain. This provided a range of score from 0-100, score 1-29 was graded as mild pain, 30-69 was regarded as moderate pain and 70-100 were regarded as severe pain. The patients were asked to record at 24 h, 48 h, 72 h, and 7 d after treatment followed by which the patients were recalled to give the diary to the investigators. In case of consumption of analgesics, the type and quantity after treatment was also recorded.-Statistical analysisp value of less than 0.05 is to be considered a significance level.Data was entered in Microsoft excel spreadsheet and analyzed using SPSS software . The normality tests Kolmogorov-Smirnov and Shapiro-Wilk’s test results reveal that all variables did not follow normal distribution. Therefore, a non-parametric test was applied to analyze the data. Chi Square test was used to assess the difference in the extrusion rates among the groups. Mann Whitney U Test was used to assess the differences in the mean pain scores at different time intervals based on extrusion. Kruskal Wallis test was used to assess the differences in mean periapical lesion area and pain score between the various groups. Friedman’s Two-way Analysis of Variance was used to assess the difference between the mean area of periapical lesions measured within each group at different time intervals. For the test, a p=0.909) whereas there was a correlation seen based on the gender of the patients (p=0.358).600 patients were checked for eligibility over a period of six months, out of which 520 did not meet the inclusion criteria and 17 were excluded because of exclusion criteria; 1 patient was pregnant, 5 had history of diabetes mellitus and 11 patients refused to participate. A total of 63 patients were available for further analysis Fig. , there wp=0.001). The mean difference in the size of periapical lesions from baseline to 1 month were Tubli-Seal (0.833) (p=0.137), AH Plus (1.08) (p=0.09) and BioRoot RCS (1.41) (p=0.029); from baseline to 3 months for Tubli-Seal (4.05) (p=0.000), AH Plus (3.86) (p=0.000) and BioRoot RCS (6.27) (p=0.000); from baseline to 6 months, Tubli-Seal (10.22) (p=0.000), AH Plus (9.80) (p=0.000) and BioRoot RCS (13.41) (p=0.000) respectively and shows a significant difference in the reduction of mean area of periapical lesion at 3 months and 6 months in all the three groups.In Tubli-Seal group, at 24 h, 5.3% of patients showed no pain, 68.4% showed mild pain and 26.3 % showed moderate pain; at 48 h, 84.2% of patients showed no pain, 10.5% showed mild pain and 5.3 % showed moderate pain; At 72 h, 84.2% of patients showed no pain, 10.5% showed mild pain and 5.3 % showed moderate pain; At 7 d, none of the patients reported with pain. In AH Plus treated group, at 24 h 31.8% of patients showed no pain, 50% showed mild pain and 18.2 % showed moderate pain; at 48 h, 81.8% of patients showed no pain and 18.2% showed mild pain; at 72 h and 7 d, none of the patients reported with pain. In BioRoot RCS, at 24 h, 68.4% of patients showed no pain,15.8% showed mild pain while 15.8 % showed moderate pain; at 48 h, 85% of patients showed no pain and 15% showed mild pain; at 72 h and at 7 d, none of the patients had pain.p=0.001). In regard to sealer extrusion none of the groups showed significant difference (p=1.00) with sealer extrusion rate rated at 21.1% for all the test groups. There was no significant difference in the mean pain score on the basis of presence or absence of sealer extrusion except for BioRoot RCS treated patients at 24 h (p=0.028) and 48 h (p=0.040) time intervals , suggesting better periapical healing with BioRoot RCS compared to AH Plus and Tubli-Seal. The results of this study can be supported by the fact that BioRoot RCS demonstrated the ability to release calcium ions (721 ppm at 3 h); B type carbonated apatite deposits were found on aged BioRoot RCS (biointeractive-related CaP-forming ability) compared to MTA Fillapex, pulp canal sealer and AH Plus sealer  scoring was used in the present study since it gives semi-quantitative results that do not allow powerful comparison among groups . Thus, ifindings . Recent p ˂ 0.05). A significant healing of periapical lesions in all the three groups at 3 months, suggests that the initial signs of the process of healing can be seen at 3 months interval. These results go in correlation with previously reported clinical study by Huumonen et al. reporting that three month control was adequate in establishing significant healing in cases of apical periodontitis when zinc oxide eugenol and silicone based sealers were used (Bone deposition can be considered as a clinical sign radiographically in the case of healing apical periodontitis post endodontic treatment . Predictere used .A 100 mm VAS scale used in the present study is considered to be an effective method for the measurement of postoperative pain in clinical research . AlthougWithin the limitations of this study, the postoperative pain after root canal treatment using BioRoot RCS as endodontic sealer was less compared to AH Plus and Tubli-Seal. There was no significant difference in post-operative pain based on the extrusion of sealer except for BioRoot RCS at 48 hrs. BioRoot RCS showed better periapical healing compared to AH Plus and Tubli-Seal at 3 and 6 months. A period of 3 months was adequate to establish significant periapical healing in all the three groups. Further studies are required with other different base endodontic sealers to further justify the results obtained in this study.


This study aims to develop an evidence-based clinical practice guideline of acupuncture in the treatment of patients with moderate and severe cancer pain.JAMA Oncology in 2020. We searched databases and websites for evidence on patient preferences and values, and other resources of using acupuncture for treatment of cancer pain. Recommendations were developed through a Delphi consensus of an international multidisciplinary panel including 13 western medicine oncologists, Chinese medicine/acupuncture clinical practitioners, and two patient representatives. The certainty of evidence, patient preferences and values, resources, and other factors were fully considered in formulating the recommendations. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was employed to rate the certainty of evidence and the strength of recommendations.The development of this guideline was triggered by a systematic review published in The guideline proposed three recommendations: (1) a strong recommendation for the treatment of acupuncture rather than no treatment to relieve pain in patients with moderate to severe cancer pain; (2) a weak recommendation for the combination treatments with acupuncture/acupressure to reduce pain intensity, decrease the opioid dose, and alleviate opioid-related side effects in moderate to severe cancer pain patients who are using analgesics; and (3) a strong recommendation for acupuncture in breast cancer patients to relieve their aromatase inhibitor-induced arthralgia.This proposed guideline provides recommendations for the management of patients with cancer pain. The small sample sizes of evidence limit the strength of the recommendations and highlights the need for additional research.The online version contains supplementary material available at 10.1186/s13020-021-00558-4. Cancer is the second leading cause of death globally with an estimated mortality of 10.0 million in 2020 , 4.The World Health Organization (WHO) provides recommendations on pharmacologic and radiotherapeutic management of cancer pain, emphasizing the appropriate application of opioids . HoweverCurrently, several guidelines of the clinical management of cancer pain are available. Among them, the guidelines from European Oncology Nursing Society (EONS) and National Comprehensive Cancer Network (NCCN) , 13 suggJAMA Oncology [Delphi method [The international Trustworthy traditional Chinese Medicine Recommendations (TCM Recs) Working Group, an international team aimed to produce rigorous evidence-based traditional Chinese medicine recommendations adhering to the trustworthy standards , has recOncology . Meanwhii method , 17.This guideline is intended for all hospitals and community healthcare services, as well as Chinese medicine physicians, physicians of integrated traditional Chinese and western medicine, clinicians, rehabilitation physicians, acupuncturists, and related researchers. The target population is cancer patients with moderate to severe pain.The design and development of this guideline are in accordance with the “World Health Organization Handbook for Guideline Development” . The guiJAMA Oncology systematic review) did not participate in voting on the recommendations . We rated the certainty of evidence for each outcome using GRADE approach [The evidence review group closely collaborated with the core authors of the approach , 22, whiapproach .Delphi method to explore the rule of acupuncture point selection for cancer pain [Delphi survey were conducted among 34 Chinese and international experts in the field of acupuncture and cancer.We adopted literature review and cer pain . We searWe searched eight databases from the inception to June 2020 to include primary quantitative , qualitative , and mixed method studies on the preferences and values of patients with cancer pain. Quantitative studies used an adapted version of the GRADE approach to assess risk of bias of studies  and qualWe used GRADE approach to formulate the recommendations, and categorized the strength of recommendations as “strong” and “weak” , by comprehensively considering the balance of benefits and harms, the certainty of evidence, the patient preferences and values, resources, and other factors , 22. We Delphi method to reach consensus for all recommendations. The consensus was reached when more than 70% experts agreed with the strength and direction of recommendation. We obtained the feedback regarding the recommendation from 2 patients and 12 experts (one expert did not vote). The acupuncturist first explained to patients the content that needs consensus, and then the patients independently complete the consensus voting on recommendations.We used Delphi survey, all recommendations reached a consensus. Thirteen of 14 experts voted for recommending the treatment of acupuncture to relieve pain and suggesting a combination treatment of acupuncture/acupressure and analgesics to relieve pain and reduce opioid dose in patients with cancer pain. Ten of 14 experts voted for suggesting the treatment of acupuncture rather than no treatment to relieve pain in breast cancer patients with aromatase inhibitor-induced arthralgia. The consensus was also reached for the acupuncture point selection, manipulation and course. The details are shown in Additional file In the first round of WeChat and Facebook.The guideline was drafted by the academic secretariat. After an internal review, a document was developed for open discussion. After receiving feedbacks from experts, the guideline was finalized by another round of peer review facilitated by the journal editor. The guideline will be disseminated by peer-reviewed academic journals, presented at conferences, and promoted in public media outlets such as As new evidence is published, the TCM Recommendations group will assess the new evidence and make a judgment on the extent that it would be expected to alter the recommendation. Updated guideline will follow the Checklist for the Reporting of Updated Guidelines (CheckUp) .The recommendations are summarized in Fig. We recommend the treatment of acupuncture rather than no treatment to relieve pain in patients with moderate to severe cancer pain .1.1There was no significant difference in relieving cancer pain using different acupuncture techniques .1.2Personalized acupoint selection is suggested. The main acupoints are Hegu (LI4), Taichong (LR3), Ashi-point, Zusanli (ST36), Sanyinjiao (SP6), and Yanglingquan (GB34).1.3ManipulationManual acupuncture: The needling consisted of swabbing all acupoints with alcohol. Needles were inserted to a proper depth as determined by standard point locations, and a “De qi” sensation was obtained at all standardized full-body acupuncture points. During the time of acupuncture, the acupuncturist returned to stimulate needles once, to re-elicit the “De qi” sensation. The course is recommended twice a week, 30 min each time for 6 weeks. Due to limited available evidence, it is recommended to consider specific clinical situation in clinical practice.Electroacupuncture: Two pairs of electrodes were connected at the needles adjacent to the site of pain with two frequencies (hertz) of electro-stimulation provided by a TENS (Transcutaneous Electric Nerve Stimulation) unit. The course is recommended twice a week for 2 weeks, and then weekly for 6 weeks. The needles were left in place for 30 min each time. Due to limited available evidence, it is recommended to consider specific clinical situation in clinical practice.Auricular acupuncture: Use sterile, disposable, semi-permanent needles for 40 min per session, with the needle remaining in the auricle for 3 days. Due to limited available evidence, it is recommended to consider specific clinical situation in the clinical practice.Eight randomized controlled trials (RCTs) –35, withThree types of acupuncture including manual acupuncture, electroacupuncture, and auricular acupuncture were identified in included RCTs .Acupoint selection and manipulation of acupuncture treatment could refer to the recommendation 1. For acupressure, we suggest Shenmen (HT7), Subcortex, and Sympathetic Nerve acupoints. The manipulation is: the patient takes the supine position, and the acupoint skin was routinely disinfected with 75% alcohol. A small piece of tape sticks the cowherb seeds tightly on the acupoints and replaces them daily. Use the index finger and thumb to twist and press the ear points on both sides of the ears, starting from light to heavy. It is suggested that this procedure be performed 3 to 5 times a day in the morning, afternoon, and evening, each time for 3 to 5 min. The pressing force should be an acid bilge feeling in the local point, and 3 days as one course. Due to limited available evidence, the procedure should consider specific clinical practice.Three RCTs addressed 224 patients –38, and The systematic review included 3 RCTs with 166 patients with severe cancer pain –41 showeThe certainty of evidence for all outcomes above were low .Acupoint selection and procedure of acupuncture treatment could refer to the recommendation 1.The systematic review included 2 RCTs involving 197 patients with moderate to severe cancer pain , 33. TheEight –49 crossMost of cancer patients (ranged from 79 to 97%) thought that acupuncture was worthwhile, important, or effective. Around one third of cancer pain patients (ranged 27% to 42%) preferred acupuncture over medication for pain management. For the patients who received acupuncture treatment, most of them (ranged from 70 to 87%) stated that the course of acupuncture met their expectations; and most of them (ranged 90% to 100%) were willing to receive acupuncture treatment again and were willing to recommend acupuncture to others. The main attitudinal barriers to receive acupuncture treatment included the lack of knowledge of acupuncture, expensive, and needling pain.JAMA Oncology’s systematic review showed that the adverse events consisted predominantly the skin and subcutaneous tissue disorder or slight pain from the application of treatment to the skin. No dropouts were attributed to adverse effects associated with acupuncture treatment [The evidence of from the reatment . A studyreatment . The mosreatment . A systereatment . A reviereatment .A systematic review included 8 studies on cost-utility and cost effectiveness of acupuncture for chronic pain showed that the cost per quality-adjusted life-year gained was below the thresholds used by the UK National Institute for Health and Clinical Excellence for “willingness to pay” . A studyAcupuncture is receiving increasing policy support around the world, especially in the area of health insurance.In USA, acupuncture has been recommended as a non-pharmacologic therapy of the most evidence-based and immediately available choice by the Food and Drug Administration (FDA) as well as the National Academies of Sciences, Engineering, and Medicine (NASEM) in coping with the opioid crisis . AcupuncIn Australia, the practice of acupuncture has been nationally regulated since 2012. Acupuncture services can be reimbursed by private health funds, and when practiced by medical practitioners, covered by the Australia’s Medicare Benefits Schedule . The MedChinese medicine in Switzerland is supported by basic and additional medical insurance, which is one of the countries with the greatest support for acupuncture programs . The cosIn China, National Administration of Traditional Chinese Medicine issued a document, including acupuncture and moxibustion, therapeutic massage, scrapping, cupping and other TCM non-drug diagnosis and treatment technologies into the new rural cooperative medical insurance, 60% reimbursement for township hospitals, 40% for secondary hospitals, and 30% for tertiary hospitals [Acupuncture has been widely accessible in many countries. The American Academy of Medical Acupuncture (AAMA) has more than 1300 medical doctors trained to offer acupuncture services, and has approved nine programs for medical doctor certification in acupuncture , 61. WitIn Australia, there are 4921 registered Chinese medicine practitioners in 2020, and 97.9% of them registered as an acupuncturist . In the On the other hand, with the development of integrative oncology around the world –70, acupCancer pain is one of the most common symptoms in cancer patients, especially in advanced cancer patients. However, there were limited effective strategies for pain management for most patients with moderate to severe cancer pain, which significantly reduce the quality of life of patients. Acupuncture can be effective in the management of not only pain, but also symptoms such as insomnia, anxiety, and joint pain . The nonJAMA Oncology in 2020. We conducted meta-analyses to adopt different clinical questions and rated the certainty of evidence with GRADE approach. We focused on the breast cancer patients with aromatase inhibitor-induced arthralgia because of sufficient evidence. Secondly, we recruited 12 international multidisciplinary experts to perform Delphi consensus and formulated guideline recommendations by comprehensively considering the magnitude of effect measures, certainty of evidence, patient preferences and values, cost, policy, and accessibility. Thirdly, we considered patient preferences and values based on a systematical review and 2 patient representatives.This is the first evidence-based guideline for acupuncture in the treatment of cancer pain, and is expected to improve quality of life and care quality for moderate and severe cancer patients. The development of this guideline aims to standardize the clinical practice of acupuncture and ensure its safe and effective application. These guideline recommendations were developed with some strength. Firstly, the evidence was mainly based on a high-quality systematic review published in JAMA Oncology systematic review searched evidence up to March 31, 2019. We did not update this systematic review because only one additional relevant study [However, there were some limitations in this study. Firstly, most of the evidence was of low certainty, and therefore we made weak recommendations. Second, nt study  was publFuture research should prioritize to address: (1) if the efficacy of acupuncture varies in alleviating cancer pain for different types of cancer; (2) the efficacy of acupressure to relieve cancer pain; (3) the patient preferences, values and attitude barriers of acupuncture for cancer pain from different countries.In conclusion, we proposed the first evidence-based guideline recommendations for the management of cancer patients with moderate to severe pain. This guideline will benefit patients with cancer pain using acupuncture treatment. Dissemination and implementation of this guideline are integral components of our goals to address the management of cancer pain. The lack of high-quality evidence limits the strength of the recommendations and highlights the need for additional research.Additional file 1: Appendix S1. The professional field of the steering committee and the expert consensus group. Appendix S2. Details of panel members’ declarations of interests. Appendix S3. Grading the certainty of evidence and the strength of recommendations. Appendix S4. Details of patients preference and values. Appendix S5. Details of expert consensus. Appendix S6. Summary of findings table.