Opioids are effective in pain-management, but long-term opioid users can develop prescription opioid use disorder (OUD). One treatment strategy in patients with OUD is rotating from a short-acting opioid to a long-acting opioid  or methadone). Both BuNa and methadone have been shown to be effective strategies in patients with OUD reducing opioid misuse, however data on head-to-head comparison in patients with chronic non-malignant pain and prescription OUD are limited.This two-armed open-label, randomized controlled trial aims to compare effectiveness between BuNa and methadone in patients with chronic non-malignant with prescription OUD (n = 100). Participants receive inpatient rotation to either BuNa or methadone with a flexible dosing regimen. The primary outcome is opioid misuse 2 months after rotation. Secondary outcomes include treatment compliance, side effects, analgesia, opioid craving, quality of life, mood symptoms, cognitive and physical functioning over 2- and 6 months follow-up. Linear mixed model analysis will be used to evaluate change in outcome parameters over time between the treatment arms.This is one of the first studies comparing buprenorphine/naloxone and methadone for treating prescription OUD in a broad patient group with chronic non-malignant pain. Results may guide future treatment for patients with chronic pain and prescription OUD.Trial registrationhttps://www.trialregister.nl/, NL9781 While opioids are potent analgesics on the short-term, evidence to support long-term analgesic efficacy of opioids is weak , 2. LongPatients with chronic pain and prescription OUD often experience difficulties in tapering their opioids, due to recurrence of increase of their pain, combined with withdrawal symptoms . An alteMethadone and buprenorphine are both first-line recommendations for this purpose, mainly studied in OUD patients without chronic pain . MethadoIt has been suggested that both methadone and buprenorphine have beneficial effects on OIH, although through differential mechanisms . OIH refThe distinct pharmacological profiles of methadone and buprenorphine may have clinical relevance. Though both methadone and buprenorphine have been shown to be effective in reducing opioid-related harm like misuse, overdosing, and mortality, as well as increasing quality of life in patients with illicit OUD , 9, 20, Buprenorphine has a more favorable safety profile than methadone, due to its partial agonism, which results in a ceiling of the effects of opioid and lesser risk for overdose, as well due to its high affinity for the μ-OR, making it competes with other agonists at the μ-OR . MethadoOST with BuNa or methadone is also effective in patients with prescription OUD and chronic pain, and effectively reduces opioid (mis)use and craving while maintaining analgesia –36. Yet,Though pharmacologically both rotation strategies might have benefits over the other in terms of safety, adverse effects and analgesia, currently available data cannot guide clinicians when treating chronic pain patients with prescription OUD on the preferred rotation strategy. Given the ongoing (prescription) opioid crisis, this research is urgently needed. The primary aim of the current study is to compare effectiveness between BuNa and methadone rotation in reducing opioid misuse in patients with chronic non-malignant pain and prescription OUD. Secondary aims of this study include assessing domains that are often affected by long-term opioid use, including side effects, analgesia, opioid craving, quality of life, mood symptoms, and cognitive and physical functioning. Based on the data from Nielsen et al. , we hypoThis study is an open-label randomized controlled trial comparing rotation to methadone with BuNa in chronic pain patients with OUD. Staff collecting data will be blinded, whereas study participants and medical staff will be aware of the intervention.This study will be performed at the medical psychiatric unit of the Radboud University Medical Center, Nijmegen, The Netherlands. Patients are admitted two to three weeks  for this rotation to allow careful titration of the medication. During this period, patients can participate in daily  activities organized at the clinic.The primary objective of this study is to compare the effect of rotation to methadone and buprenorphine/naloxone on self-reported opioid misuse 2 months after baseline (prior to rotation). Secondary objectives include comparing the effects of both medications on treatment retention, total prescribed  opioid dose, opioid craving, pain intensity, pain sensitivity, quality of life, depression, anxiety, stress, cognitive and physical functioning, and presence and severity of side effects.All patients with chronic non-malignant pain who are referred to the department of psychiatry for treatment of OUD will be asked to participate in this study. We will include one hundred (100) patients.Participants are eligible if they meet all of the following inclusion criteria; (1) age 18 years or over, (2) meet ICD-11 criteria for chronic non-malignant pain , (3) usePatients will be excluded it they meet one or more of the following exclusion criteria; (1) current pregnancy, lactating, or planning to become pregnant during the study period, (2) have already used buprenorphine or methadone in the last 4 weeks, (3) use other substances of abuse that prevents safe participation in the study , (4) have acute psychiatric comorbidity , (5) have severe respiratory insufficiency or depression, such as chronic obstructive pulmonary disease GOLD 3 or 4, (6) have serious medical disease, such as severe liver dysfunction (Child–Pugh B or C), severe renal dysfunction (eGFR (MDRD) ≤ 29), heart failure, or current brain trauma, (7) have increased risk for torsade de pointes; a Q-T interval of ≥ 450 ms on an electrocardiograph (ECG), (8) have a hypersensitivity or allergy for buprenorphine, naloxone, methadone, or (9) have another medical or psychiatric condition not specified above that prevents safe participation according to the study physician.Patients will be rotated from their current opioid medication to either methadone or BuNa. With either medication, patients are hospitalized to titrate the new medication to a dose appropriate for them (flexible dosing). No placebo will be used, as it has already been established that in patients with OUD rotation to methadone or buprenorphine is more effective than placebo , 11. AlsPatients will be randomized into two treatment arms of equal size (2 × 50), using a block design with blocks of varying sizes using the randomization module in CastorEDC . Clinica®) will be administered in sublingual form. For rotation to BuNa we will use the same dosing protocol as in our previous study [BuNa , and after two (t1) and six (t2) months. All other measures will be conducted in-person.The following baseline characteristics are collected at the start of the study (t0);Demographic variables; Age, gender, ethnic background, marital status, educational level, and employment status.Medical history; Duration of pain, location of pain, cause of pain, type of pain, presence of neuropathic pain, presence of illnesses, and surgical history. Presence of neuropathic pain will be assessed using the Douleur Neuropathique 4 (DN4). The DN4 is a 10-item clinician-administered questionnaire. It has 7-interview questions and 3 small sensory tests. Every item is answered with yes (1 point) or no (0 points); a score of ≥ 4 out of 10 indicates the presence of neuropathic pain [hic pain . In the hic pain , 49. We hic pain .Current medication use; Type and dose of opioid(s), use of non-opioid medication.Use of other substances; Alcohol, tobacco, and drugs. These are measured with the MATE, chapter 1 (substance use).Presence of psychiatric diagnoses; These are measured with the Mini International Neuropsychiatric Interview Plus (MINI-plus). The MINI plus is a standardized, validated, diagnostic interview to assess presence of DSM-4 disorders [isorders –52.Intellectual functioning; Reading capabilities are measured by the Dutch National Adult Reading test Nederlandse Leestest voor Volwassenen (NLV) [en (NLV) .Influence of reward related cues on one’s actions: Pavlovian to instrumental transfer (PIT); PIT refers to the interference of Pavlovian conditioning on independently learned instrumental behavior. In alcohol research, higher scores on PIT-tasks have been associated with higher alcohol consumption [sumption . In our sumption .This measure is collected at t0, t1 and t2.Misuse is measured by the Current Opioid Misuse Measure (COMM). The COMM is a 17-item self-report questionnaire of aberrant opioid use. It is a reliable and valid tool to monitor opioid misuse in chronic pain patients [patients . Each quThe measures are collected at t0, t1 and t2 is measured by the percentage of patients that use their allocated treatment at follow up.Pain is assessed by;The visual analog scale for pain (VAS-pain). The VAS-pain consist of a 100-mm line with “no pain” at 0 mm and “worst pain imaginable” at 100 mm, on which patients have to indicate their pain intensity. The VAS-pain is highly correlated with the numeric rating scale for pain .The Brief Pain Inventory (BPI). The BPI is a self-report questionnaire measuring pain intensity and the extent to which pain interferes with 7 domains of functioning . The BPI has been validated for patients with chronic non-malignant pain .The Central Sensitization Inventory (CSI). The CSI is an indirect measure of central sensitization  . Patient(Quantitative) sensory testing (QST). Sensory testing uses sensory stimuli such as cold, electricity and pressure to assess (changes in) pain sensitivity. We include testing of thermal pain thresholds using an ice-water test, and a Tip-Therm stored on ice). Thermal QST can be used to detect opioid-induced-hyperalgesia (OIH) after chronic opioid exposure . We furtWhen using standardized procedures, (Q)ST has good intra-observer and test–retest reliability .Wellbeing is assessed by;A visual analog scale for quality of life (VAS-QOL). The VAS-QOL consist of a 100-mm line with the “lowest imaginable QOL” at 0 mm and the “best imaginable QOL” at 0 mm.The World Health Organization Quality of Life Questionnaire- abbreviated version (WHOQOL-BREF). The WHOQOL-BREF is a 26-item questionnaire measuring quality of life. It provides QoL scores on four domains; physical, psychological, social relationships, and environmental QoL . The DutThe Depression, Anxiety, Stress scale (DASS). The DASS is a 42-item questionnaire reporting scores on three subscales  and a total score . The DASA visual analog scale for opioid craving (VAS-craving). The VAS-craving consist of a 100-mm line with “no craving” at 0 mm and “worst imaginable craving” at 100 mm.The Global Perceived Effect questionnaire (GPE). This is a one-question questionnaire asking patients to what extent their condition has improved since the start of treatment. The GPE has excellent test–retest reliability, but scores are highly affected by current health status .Functioning is assessed byThe Cognitive Failures Questionnaire (CFQ). The CFQ measures self-reported, subjective cognitive functioning. Patients are asked about the frequency in which they make small errors relating to forgetfulness and absentmindedness . The CFQThe Montreal Cognitive Assessment (MoCA). The MoCA is a one-page test with tasks on short-term memory recall, working memory, visuospatial abilities, executive functioning, attention, and orientation to time and space . The avaThe Rey Auditory Verbal Learning Test (RAVLT), also known as the 15 Word Test (15WT) . In thisThe Stroop Color-Word Test (SCWT). The SCWT is a task to measure attention and information processing. In this task, a list of words is presented in different colored fonts. Patients are asked to name all the colors being seen, while ignoring the actual content of the word . OutcomeThe Paced Auditory Serial Addition Task (PASAT). The PASAT is a neuropsychological test and asses several aspects of attention. The primary measure is speed of information processing. PASAT scores are highly affected by age, IQ, and math ability, but is highly sensitive to change over time and has good psychometric properties .The 6-min walk test (6WT). Patients are asked to walk as fast and as far as they can within six minutes. They may use walking aid or take rests. The total distance walked is the outcome measure. It is an inexpensive test with good reproducibility and is correlated with questionnaires on physical functioning , 79.Side effects are measured with the Opioid-Related Symptom Distress Scale (ORSDS). This self-report measure asks whether patients have experienced the most common side effects of opioids . Frequency, severity and bothersomeness of the side effects are also measured [measured .Utilization of other medication or therapies is assessed by self-report. We ask participants about use of concomitant medication and utilization of any other type of therapies, such as pain education, or psychological interventions.Opioid dose is measured at every follow up and is converted to oral morphine equivalent dose (OME).substance misuse is assessed by urine-toxicology for buprenorphine, methadone, fentanyl, morphine, oxycodone, tramadol, amphetamines, benzodiazepines, methamphetamines, and cannabis as well as self-report for alcohol and nicotine use.Next to the COMM, Data collected for regular care, such as withdrawal severity during rotation, may also be used for scientific analysis.Our primary outcome is to compare mean scores on the COMM two months post rotation (t2) between the BuNa and methadone treatment arms. In our recent study, we rotated 43 patients with chronic pain and prescription OUD to BuNa , 32. In Descriptive statistics will be used to summarize demographic variables and to analyze the baseline measures of the primary and secondary outcome parameters. The relationship between the OME of the drug at baseline and the OME of buprenorphine or methadone at follow-up be analyzed using Pearson’s r correlation. The analyses of the primary and secondary parameters will be based on superiority hypotheses and will be conducted with intention to treat analyses. Scores on the primary and secondary study outcomes will be compared between both treatment arms (between subject factor), as well as over time (within subject factor), using a linear mixed model analysis, with the scores on the outcome measures as the dependent factor.For data collection, we utilize electronic case report forms (CRF) in CastorEDC , which cEvaluating effectiveness of Mindfulness-Based Cognitive therapy (MBCT) as a regular care co-intervention; patients are asked to participate in an 8 week-MBCT training and to fill a few questionnaires to evaluate effectiveness of this intervention.Validation study of a 15 SNPs polygenetic test on predicting OUD in the Dutch Setting and explorative study on predictive value of the test for predicting the effectiveness of OST in these patients. Genetic data from patients will be collected by a single cheek-swab at the start of the study. The informed consent form of the main study has a choice whether patients agree in collection and sharing in their genetic data or not.Questionnaire validation study. Questionnaires that are used to asses opioid (mis)use will be validated for the Dutch context.There will be three ancillary studies to the current one. Participants may or may not choose to participate in these studies without it affecting participation in the main study;This study will compare effectiveness between methadone and buprenorphine/naloxone on reducing opioid misuse in prescription OUD in patients with chronic non-malignant pain. In a randomized controlled trial, 2 × 50 patients will be randomized to BuNa or methadone treatment. Both medications will be flexibly dosed, to a dose appropriate to the individual patient. The primary outcome is opioid misuse at the two-month follow up. Secondary outcomes include treatment retention, treatment adherence, analgesia, opioid craving, opioid side effects, quality of life, mood symptoms, cognitive and physical functioning at the two- and six months follow-up. Linear mixed model analysis will be used to evaluate change in outcome parameters over time between the treatment arms.This is one of the first studies directly comparing BuNa and methadone head-to-head in patients with prescription OUD and will provide valuable insights for clinicians. Responses to BuNa and methadone potentially differ in patients with prescription OUD and pain compared to patients with illicit OUD as the provided analgesia is more important for patients with pain. Both buprenorphine and methadone provide analgesia and reduce OIH through differential mechanism. In earlier research, analgesic effectivity of both was close , 34, 37.Individual pharmacokinetics and pharmacodynamics of buprenorphine and methadone will affect individual dosing and effectivity, as bioavailability of both medications is highly intervariable , 84. We A strength of our study is that we are able to hospitalize our patients for the OST as part of regular medical care. Hospitalization allows for precise titration to a dose appropriate for the individual patient. Buprenorphine has often been dosed insufficiently high in earlier OUD studies , 33, 86 Another strength of our study is the use of a wide variety of secondary outcome measures to cover a large number of clinical domains that might be important for patients’ well-being. For the pain/analgesia assessment, self-report questionnaires are supported by standardized quantitative sensory testing. Sensory thermal measures are one of the most effective methods to asses hyperalgesia .A limitation of our study is that we compare effectiveness of both medications on a group-level. The current trial will not have enough power to investigate individual predictions of treatment outcome for both medications beyond any explorative analyses, which might be a direction for future studies. Another limitation of our study is the open-label design which may introduce bias. It is not feasible to blind our patients or medical staff, as both medications are administered and titrated individually, and are prescribed to use at home during the follow-up phase. Staff collecting data will however be blinded to prevent bias in data collection.Despite these limitations, the current study is among the first studies comparing BuNa and methadone treatment in patients with prescription OUD and chronic pain. Results may guide future treatment for patients with chronic pain and prescription OUD.


Adequate pain management for preterm born neonates suffering from the extremely painful disease necrotizing enterocolitis (NEC) is essential, since neonatal exposure to pain is related to negative short-term and long-term consequences. The aim of this study was to describe the current pain management and its effectiveness in NEC patients.In this single-center, retrospective study, neonates  with NEC Bell’s stage II or III were included. Information on pain (based on COMFORTneo and NRS scores) and analgesic therapy was collected and analyzed for the acute disease period.Of 79 patients included, 74 (94%) received intravenous analgesic therapy: most commonly morphine, fentanyl, and acetaminophen. The median COMFORTneo score was 11 (IQR 10–11), however, 49 patients had at least one COMFORTneo score ≥ 14 indicating pain. Nineteen patients had persistent high pain scores ≥ 14 with a median duration of 7.2 h (IQR 2.8–14.0).This study showed that despite analgesic therapy, most NEC patients showed signs of pain, and in some, pain persisted for several hours. It suggests that current analgesic therapy frequently failed to prevent pain and existing pain was often insufficiently treated. This supports the urgent need for individualized pain management guidelines for NEC patients.This study is unique in reporting on pain management in neonates suffering from necrotizing enterocolitis (NEC) during the full acute disease period.Despite analgesic therapy, the majority of NEC patients experience pain, and in some patients, pain persists for several hours.These findings highlight the need for improvement of neonatal pain management in NEC patients, including better pain monitoring and guidelines for individualized analgesic therapy.Improved pain management guidelines may help to prevent short-term and long-term consequences of neonatal exposure to pain, as well as excessive exposure to opioids. An essential aspect of NEC treatment is adequate pain management, since it is a very painful disease due to the ongoing inflammation and ischemia in the intestine. In contrast to what clinicians once thought, preterm neonates can experience pain and it is important to adequately treat their pain in order to prevent discomfort and severe short-term metabolic and circulatory complications.4 Exposure to pain during the neonatal period not only threatens short-term comfort and recovery, but can also have negative long-term consequences by harming neurodevelopment.5 Rodent studies suggest that exposure to pain during the neonatal period affects brain development and induces long-term behavioral changes.11 In humans, neonatal exposure to pain has been associated with changes in brain morphology, impaired cognitive development, and altered pain sensitivity.22 These negative effects were already found in children who had been exposed to mild procedural pain during NICU admission. NEC, on the other hand, causes severe visceral pain, and is therefore expected to have even more negative long-term consequences.23 Additionally, NEC patients are often very preterm, which makes them specifically vulnerable to the negative effects of pain due to the immaturity of the developing nociceptive system. On top of that, seeing your vulnerable child experiencing pain is very stressful for parents.24Treatment of NEC primarily consists of medical treatment, including abdominal decompression, broad-spectrum intravenous antibiotics, no enteral feeding, and therefore total parenteral nutrition.25 When treating neonates with opioids, caution is needed, as animal studies have shown that neonatal exposure to opioids could potentially harm neurodevelopment.10 However, these rodent studies found that exposure to opioids in the presence of pain has a neuroprotective effect.10 In humans, contradictory effects of neonatal opioid exposure on brain morphology and cognition have been suggested.5Opioids such as morphine and fentanyl are most commonly used for treating pain in neonates suffering from NEC.26 To find out whether current pain management for NEC patients is well-balanced or if patients receive too little or too much analgesic therapy, this study aims to describe current pain management in preterm neonates suffering from NEC.Since both exposure to pain and to opioids during the neonatal period could have negative short-term and long-term effects, it is essential to adequately treat pain in NEC patients, while avoiding overtreatment and side effects. In other words: getting the balance right. Currently, it is unknown whether pain in neonates with NEC is treated adequately or whether these neonates are exposed to excessive pain or overtreatment with opioids. Importantly, it has been suggested that the current pain treatment of neonates suffering from NEC is not balanced yet. For instance, Van Ganzewinkel et al. found that NEC survivors had a decreased pain threshold and pain tolerance in adolescence, which may reflect the effects of neonatal exposure to excessive pain.27 NEC diagnosis and staging according to these criteria was based on clinical symptoms, radiographic findings, surgical and pathology reports and decided on in expert consensus meetings. Infants with spontaneous intestinal perforation (SIP) were excluded. Surgical NEC was defined as NEC with a surgical indication within 7 days after NEC onset.In this single-center, retrospective study, all neonates diagnosed with NEC who were admitted to the level III-IV neonatal intensive care unit of the Erasmus MC—Sophia Children’s Hospital, Rotterdam, The Netherlands, between January 1, 2015, and December 31, 2020, were included. Only patients with NEC stage ≥ II, according to modified Bell’s criteria, were included.The Erasmus MC—Sophia Children’s Hospital is a teaching hospital with open-bay units and 24-h accessibility of the ward for parents, who participate in the care for their child and generally provide kangaroo care for a few hours daily if the child’s condition allows.This study was embedded in the Risk NEC Study, an ongoing local cohort study on risk factors, treatment, and outcomes related to NEC in very preterm infants. The Risk NEC Study started in 2008 and includes patients with a birth weight < 1500 grams and/or a gestational age < 32 weeks who are admitted to the NICU of the Erasmus MC—Sophia Children’s Hospital. This study aims to assess risk factors and outcomes of NEC. The institutional medical ethical review board waived the need for specific approval for this study according to the Dutch law (MEC-2013-409), based on the observational nature of the study. No specific informed consent was deemed necessary for the use of the retrospective data in this study.Demographics were extracted from the existing database of the ongoing Risk NEC Study. Pain and pharmacological data were additionally retrieved from the electronic patient management systems HiX©  and Picis©  for each individual NEC disease period. The onset of the disease period was defined as the day of prescription and the start of antibiotic treatment as part of (suspected) NEC . The last day of the NEC disease period was defined as the second day after the administration of intravenous analgesics had been discontinued or until death. If a patient had not received intravenous analgesic therapy, the NEC disease period ended on the second day after re-initiation of minimal enteral feeding (MEF).The effectiveness of the analgesic therapy was determined using the neonates’ COMFORTneo, NRS pain, and NRS distress scores. These pain scores were collected for each patient for the total disease period. Patients were treated according to the local pain guideline  and represent a nurse’s subjective estimate of the patient’s pain and distress. An NRS pain score of 4 or higher indicates pain and an NRS distress score of 4 or higher indicates distress.Nurses in our NICU have been trained to assess the COMFORTneo, NRS pain, and NRS distress score and enter these in the electronic patient management system. The COMFORTneo score  or numbers (percentages). The number of patients with a COMFORTneo score ≤ 8 was calculated among patients who received intravenous analgesics. The median doses of analgesics were calculated among patients receiving those analgesics.In order to evaluate the agreement between different pain scores used in our NICU, the positive and negative percent agreement between these scores were calculated. The positive percent agreement between the COMFORTneo score and the NRS pain and NRS distress score was calculated by dividing the number of times both scores indicated pain by the number of times the COMFORTneo score indicated pain. The negative percent agreement was calculated by dividing the number of times both scores indicated no pain by the number of times the COMFORTneo score indicated no pain.To look further into different patterns of pain, a subgroup analysis was performed, based on three pain score patterns: persistent high scores, persistent low scores, and recurrent high scores. Persistent high scores were defined as at least two consecutive COMFORTneo scores ≥ 14 with at least 1 h between these scores. Recurrent high scores were defined as at least 3 COMFORTneo scores ≥ 14 with normal scores  in between. Persistent low scores were defined as at least two consecutive COMFORTneo scores ≤ 8 with at least 1 h between these scores. The number of patients with persistent low scores was calculated among patients receiving analgesic therapy. The association between COMFORTneo score and analgesic therapy was visualized for the patient with the most illustrative pain patterns, selected based on an independent review of all patient plots by three neonatologists. Analyses were conducted using RStudio version 1.4.1106  and SPSS version 25.0 .During the study period, 4074 neonates were primarily admitted to the NICU of the Erasmus MC—Sophia Children’s Hospital, of whom 1524 neonates were born at a gestational age < 32 weeks. Seventy-nine preterm neonates diagnosed with NEC were included, corresponding to a NEC rate of 5.2% among very preterm neonates. Table The duration of the NEC disease period ranged from 1 to 47 days  and the total number of pain score measurements per patient ranged from 0 to 195 . At least one COMFORTneo score, NRS pain score or NRS distress score was available for 76 patients (96%). In three patients, no pain score was available, likely because these patients died shortly after the diagnosis of NEC. Summary statistics for the pain scores are shown in Table The total cumulative doses and daily cumulative doses of the administered analgesics are shown in Table Daily cumulative doses of morphine, fentanyl, acetaminophen, and midazolam and the percentage of patients receiving these analgosedatives are shown in Fig. Persistent high COMFORTneo scores were found in 19 patients 24%), recurrent high scores in 24 patients (30%), and persistent low scores in 18 patients (23%) .30 They found that NEC patients on average experienced 16 painful procedures per day. However, the pain scores were not presented in this paper and nurses’ compliance with the pain assessment was low. The other paper, from our own research group, studied pain scores and analgesic therapy of NEC patients around the surgical intervention and showed that the median COMFORTneo score was 10 pre-operatively and 11 post-operatively and that most patients had at least one high pain score.25 Our current study confirms the earlier findings that pain scores are overall acceptable, but that the majority of NEC patients at least once have a high pain score. The current study additionally shows that pain occurs during the entire disease course of NEC, not just in the first days or around surgery, and that pain often persists. Acknowledging that NEC is likely the most painful condition in neonatal care, it is disappointing that no further studies on pain management in NEC have been published. There is a gap in knowledge, and consequently lack of consensus, on adequate drugs, doses, and pain assessment for these vulnerable patients. Larger prospective multi-center studies are highly needed.To our knowledge, this study is unique in longitudinally exploring pain and analgesic therapy during complete NEC disease episodes. Only two previous papers have been published on pain and analgesic therapy in NEC patients.28 Unfortunately, other scores for assessing prolonged pain, such as the EDIN scale (Échelle Douleur Inconfort Nouveau-Né) and the N-PASS scale , have not been validated specifically in NEC patients either.32 The validation studies of the COMFORTneo, EDIN, and N-PASS score all included too few NEC patients to assess validity in this group specifically.32 More research is needed to determine the validity of prolonged pain scores in NEC patients.A strength of our study is the complete and comprehensive overview of pain and pain management during the entire NEC disease period, in a substantial cohort of preterm infants that suffer from the rare disease NEC. A limitation of our study is the retrospective design, with the number of pain measurements differing between patients. The number of measurements may not only be related to the disease duration, but also to the severity of pain, since pain scores tend to be measured more frequently after high scores. This reflects good clinical practice, but may have led to over-representation of the painful periods, and may therefore have biased our results. The retrospective design also limited our ability to evaluate effectiveness of specific therapeutic interventions. As systematic pre- and post-intervention pain scores were lacking, this study describes the overall effect of analgesic therapy on pain scores. Another limitation of our study is that the COMFORTneo score has been validated in preterm infants, but not specifically in NEC patients.31 Therefore, the NRS pain and NRS distress score were evaluated as well, which represent nurses’ subjective estimates of pain and distress. We found a poor positive percent agreement between the COMFORTneo score and the NRS pain and NRS distress score, with the COMFORTneo score indicating pain more frequently than the NRS scores. This contradicts the results from a previous validation study of the COMFORTneo score by Van Dijk et al., which found a good agreement between the COMFORTneo score and the NRS pain and NRS distress score.28 The low positive percent agreement compared with the negative percent agreement might reflect the difficulty of detecting pain in NEC patients. Perhaps a different approach is needed, which integrates pain scores and other clinical parameters such as heart rate. A bedside pain dashboard, as has been suggested by Vinks et al., might enable the integration of different sources of information regarding a patient’s real-time pain level and trends and might benefit the implementation of personalized pain management.33 Current pain scores being repeatedly outside the normal window, suggest that analgesic therapy was not adequately tailored to the individual patient’s needs. Furthermore, pain persisting for several hours suggests suboptimal adherence to the local pain guideline, which prescribes considering extra medication in case of a high pain score and reassessing the pain score within an hour. Pain measurements being missed could have resulted in delayed analgesic therapy and thereby higher pain scores.The COMFORTneo score might be less reliable in NEC patients, since NEC patients are often severely ill and therefore less reactive showing a blank face and few movements, which could result in a normal or low COMFORTneo score in presence of pain.9 In humans, exposure to procedural pain during NICU admission has been associated with impaired brain development and cognitive development and with altered pain sensitivity later in life.19 The long-term consequences of intense visceral pain, as is caused by NEC, are largely unknown. It has been shown that NEC survivors have a lower pain tolerance and pain threshold at adult age, which might be explained by their exposure to pain during the disease.26The finding that most NEC patients experience pain is of clinical importance, since there is evidence that neonatal exposure to pain could have negative long-term consequences. For instance, rodent studies have shown that exposure to pain during the neonatal period causes neurodegeneration and has negative effects on adult behavior.10 Thus, in rodents, both neonatal pain and neonatal opioid exposure solely could be harmful to the developing brain, but in the presence of pain, exposure to opioids could have a neuroprotective effect. Conflicting effects of neonatal opioid exposure have been found in humans regarding brain development and cognition.5 These conflicting results might reflect differences in the balance between exposure to pain and analgesics.Most NEC patients in our study were treated with opioids, which may also harm neurodevelopment. Studies in rodents have shown that neonatal exposure to morphine in absence of pain causes neuronal damage and learning impairment, while exposure to morphine in presence of pain does not.Thus, it is important to find the right balance in the pain management of NEC patients: on the one hand, pain should be prevented by adequate analgesic therapy and on the other hand, excessive exposure to opioids should be prevented. NEC patients’ pain level should be measured regularly, and physicians should pay attention to pain scores and adequately adapt the analgesic therapy based on the pain score.Despite the use of acetaminophen and opioids, most NEC patients still experienced pain at some point. The analgesic therapy regimen often failed to relieve pain after a high pain score, resulting in pain persisting for hours in some patients. There is a lack of pain management guidelines for NEC patients. More research is needed to determine how the current analgesic therapy regimen can be adapted to improve the prevention and treatment of pain in NEC patients.Supplementary Material


Background and aimsPeripheral neuropathy is a frequent complication of long-standing diabetes mellitus that adversely affects the quality of life. Pregabalin (anticonvulsant) and duloxetine (antidepressant) are often prescribed for diabetic peripheral neuropathic pain. This study aimed to determine and compare the efficacy and safety of pregabalin and duloxetine in patients with diabetic peripheral neuropathic pain.Materials and methodsThis prospective observational study was conducted at District Headquarter (DHQ) Hospital, Daggar, Buner district, Pakistan, from February 15 to July 15, 2022, after approval from the Institutional Research and Ethical Review Board. Confirmation of diabetic peripheral neuropathy was based on the history of diabetes mellitus and vibration perception threshold (VPT) using a biothesiometer. The cut-off was set at 15 volts. VPT of more than 15 volts was considered confirmatory for peripheral neuropathy. Patients were divided equally into two groups. Baseline visual analog scale (VAS) score was recorded for all patients. Tablet pregabalin 300 mg daily was administered for four weeks to one group, while tablet duloxetine in 60 mg strength daily was administered to the other group. VAS score after four-week treatment was recorded and compared. Adverse events experienced by the patient were also noted.ResultsA total of 86 patients were enrolled. The patient ages ranged from 30 to 80 years. Baseline characteristics, including mean age, mean BMI, and mean disease duration of duloxetine versus pregabalin group, were 50.30 ± 8.55 versus 48.20 ± 8.99 years, 23.47 ± 1.23 versus 23.10 ± 1.59 kg/m2 and 21.64 ±7.41 versus 20.04±6.37 months respectively. Duloxetine effectively controlled peripheral neuropathic pain in 81.4% of patients compared to pregabalin in 74.4% of patients. Severe drug-related adverse reactions were observed in 4.6% of patients with duloxetine compared to 0% with pregabalin.ConclusionDuloxetine and pregabalin effectively reduce diabetes-related peripheral neuropathic pain. However, duloxetine has slightly better outcomes than pregabalin. The safety profile of pregabalin is better than duloxetine. Diabetes mellitus, often referred to as the epidemic of the 21st century, is a significant public health problem. As of 2019, the global prevalence of diabetes mellitus worldwide was approximately 9.3%, with a large portion of the population having asymptomatic impaired glucose tolerance [The clinical spectrum of diabetes-related complications is vast . PersistObjectives and settingThis study aims to determine and compare the efficacy and safety of PGB and DLX in diabetic peripheral neuropathic pain. This prospective observational study was conducted at the Department of Internal Medicine, District Headquarter (DHQ) Hospital, Daggar, Buner district, Pakistan, from February 15 to July 15, 2022, after approval from its Institution Research and Ethical Review Board SamplingDiagnosis of diabetic peripheral neuropathy was confirmed based on history . Confirmation of peripheral neuropathy was based on vibration perception threshold (VPT) using a biothesiometer. The cut-off for peripheral neuropathy was set at 15 volts. VPT 15 volts or below was considered normal, 16 to 25 volts was called grade 1 (mild) neuropathy, and more than 25 volts was called grade 2 (severe) neuropathy. Both male and female patients aged 30 to 80 years with diabetic peripheral neuropathic pain >4) were included. Patients with type 1 diabetes, diabetic foot ulcer, patients with a history of peripheral vascular diseases, or those who were already taking PGB or DLX were excluded.Data collection and analysisA total of 86 patients with diabetic peripheral neuropathy were recruited. Patients were arbitrarily allocated into two groups. Forty-three patients were allocated to the PGB group, and 43 were allocated to the DLX group. PGB and DLX were administered orally in a dose of 300 mg and 60 mg, respectively. Efficacy in terms of symptom relief was plotted on the VAS, with a VAS 0 referring to no pain and 10 to severe pain. Baseline VAS was noted on the day of treatment initiation and then after four weeks of treatment. VAS 0 and 1 were called significant improvements. Safety was assessed in terms of unwanted events experienced by study participants during treatment. These were grouped as mild , moderate , and severe , renal function tests (RFTs) leading to discontinuation of treatment.Data was recorded using the statistical analysis program IBM SPSS Statistics for Windows, Version 23.0 . Mean ± standard deviation was computed for quantitative variables. For qualitative variables, frequencies and percentages were calculated. Statistical tests of significance student t-test were applied for comparing means of continuous variables while Chi-square test was applied for categorical variables. P-value ≤0.05 was considered statistically significant.2 and 23.10 ± 1.59 kg/m2 was calculated in the DLX and PGB groups, respectively. Table The study participants were in the age group of 30-80 years, with age of 50.30 ± 8.55 years for the DLX group and 48.20 ± 8.99 years for the PGB group. A mean BMI of 23.47± 1.23kg/mThe mean baseline VAS of the DLX group was 7.3±0.9, while post-treatment VAS was 1.6±0.3. The mean baseline and post-treatment VAS in the PGB group were 6.8±0.5 and 1.9±0.4, respectively, as shown in Table The observed efficacy of DLX after four weeks of treatment was 81.4%, while PGB was effective in reducing diabetic neuropathic pain in 74.4% of patients, as shown in Table None of the factors, including age, gender, BMI, disease duration, and HbA1c, significantly affected the efficacy .Tables Regarding the safety profile, PGB was comparatively safer than DLX. Nausea, vomiting, and epigastric discomfort were the most common adverse events reported with DLX while somnolence and dizziness were more common with PGB. Adverse events leading to treatment withdrawal were experienced by two patients 4.6%) in the DLX group. Table % in the Peripheral neuropathy is a frequent complication of long-term uncontrolled diabetes mellitus. The pathogenesis of diabetic peripheral neuropathic pain is attributed to the ion channel changes, which affect the function of nerve cells to transmit pain signals. The pain is debilitating and adversely affects the quality of life. Moreover, other complications are also attributed to it, including diabetic foot ulcers and diabetic foot deformities ,13. DLX This prospective observational study comparing the efficacy of DLX and PGB was the first of its kind in our population. In this study, DLX was observed to reduce diabetes-related peripheral neuropathic pain in 81.4% of patients as compared to 74.4% efficacy of PGB but the results were not significant as the p-value was greater than 0.05. Both DLX and PGB were found to reduce diabetic peripheral neuropathic pain. However, the safety profile of PGB was better than that of DLX. In a study by Joharchi and colleagues, DLX and PGB were found equally effective in reducing diabetes-related peripheral neuropathic pain. However, DLX was associated with more severe adverse reactions as compared to PGB . Our stuThe observations regarding the safety profile of DLX are variable. A meta-analysis by Quilici and colleagues, comprising 11 studies comparing the safety and efficacy of DLX, PGB, gabapentin, and amitriptyline, observed that DLX was better tolerated as compared to other drugs administered for peripheral neuropathic pain . This isOur study has limitations like a small sample size and the descriptive nature of the study. Therefore, randomized controlled trials with a large sample size should be performed to better assess the efficacy and safety of DLX and PGB in our population.DLX and PGB effectively improve diabetes-related peripheral neuropathic pain; however, DLX has better efficacy (81.4%) compared to PGB (74.4%) in reducing diabetes-related peripheral neuropathic pain. In contrast to efficacy profile, safety profile of PGB is better than DLX. Patients taking DLX for diabetic peripheral neuropathy should be monitored for adverse effects.


The aim of this study is to investigate the pattern of changes in activities of daily living (ADLs), sleep disturbance, and pain in the early postoperative period following a total shoulder arthroplasty (TSA).Prospective data on patterns of limitation in ADLs, sleep disturbance, and pain were collected from patients undergoing elective TSA preoperatively and at specific time points postoperatively . At each time point, patients were asked regarding the major limitation affecting their shoulder. Limitations in ADLs and sleep disturbances were scored on a 3-point scale  modeled after the ADL which require active external rotation score and visual analog scale scores were used for pain. Patient responses were analyzed with respect to patient factors , and living situation .Shoulder pain (43%) and inability to perform ADLs (38%) were the 2 most commonly reported limitations prior to undergoing TSA. Patients noticed progressive improvements in pain with 37% reductions in visual analog scale scores at 2 weeks and 67% reduction at 3 months. At 2 weeks after TSA, sleep disturbances were the most disabling issue in 33% of the cohort, with considerable improvements (104%) in sleep scores at 3 months compared to pre-op. The ADLs involving forward elevation and working at the waist level improved considerably between 6 weeks and 3 months, but activities involving rotation including reaching behind the back, across the chest, and use of strength showed mild improvements by 3 months.This prospective study demonstrates the chronology of improvements in pattern of limitations experienced by patients with respect to pain, sleep, and ADLs in the early postoperative period after TSA. Majority of patients can expect to have 2/3 resolution of pain, improved sleep, and improvement in ADLs involving forward elevation and waist level function by 3 months. The primary objectives of shoulder arthroplasty are to reduce pain, restore function, and improve the quality of life. Numerous studies have demonstrated long-term improvements in these parameters compared to baseline (preoperative) after TSA.,,,Although short-, mid-, and long-term outcomes of TSA have been extensively published, there is limited literature on the chronological pattern and extent of limitations incurred with respect to postoperative pain, sleep disturbances, and activities of daily living (ADLs) limitations in first few months after TSA. There are substantial dynamic improvements and changes that occur during the first several weeks after TSA with respect to pain relief, sleep cycle changes, and ability to perform ADLs. During this time patient’s interaction with the surgeon are more frequent and questions regarding recovery are more common. Although improvements in outcomes scores and pain scores during the early postoperative period are helpful for patients to understand the big picture of their recovery, it has been our observation that information about chronology of improvements in pain and function are lacking. Prior studies have focused on characterizing improvements in shoulder specific outcomes after TSA but these outcome scores do not take into consideration the important limitations specific to ADLs, sleep disturbances and extent of pain relief in the first several weeks after shoulder arthroplasty.In this prospective study from September 2018 to May 2019, consecutive patients who underwent TSA (anatomic or reverse) by 1 of 3 fellowship trained orthopedic surgeons were included in the study. Patients were included in the study if they were over 18 years of age, had undergone either anatomic or reverse TSA (rTSA), and have follow-up visits at the 2 weeks, 6 weeks, and 3 months. Patients were excluded if the arthroplasty indication was acute fracture, or if they were unable or unwilling to complete the study questionnaire.,Each patient gave informed consent and completed a questionnaire preoperatively and at the 2-week, 6-week, and 3-month postoperative time points assessing the level of daily and athletic activity, sleep disturbances, and level of pain following shoulder arthroplasty. The questionnaire included demographics , pain scores, operative information, and questions regarding ADLs. These included clothing related activities (5 questions), personal hygiene activities (5 questions), food preparation (4 questions), household activities (4 questions), general mobility (4 questions), and general activities (3 questions). Patient responses to the ADLs questions were scored on a 3-point scale ranging from a lower functioning (0 = unable to do) to a higher functioning (3 = no difficulty) level modeled after the ADL which require active external rotation score.Response data were tabulated for the entire study group including both numerical data and respondent written answers. Data were divided into subgroups based on time of follow-up at 2 weeks, 6 weeks, or 3 months. The data was further subdivided categorically based both on the aforementioned activity groups in the ADLs as well as by primary motion required . Additional subdivisions were made dependent on whether the patient underwent an anatomic TSA or an rTSA.During the defined study period patients with primary or secondary arthritis who were indicated for TSA (anatomic or reverse) were included in the study. All patients underwent TSA via a deltopectoral approach. In the anatomic TSA (aTSA), subscapularis tenotomy was performed in all cases and repaired at the end of the procedure. Three different anatomic implant types  were used by the surgeons. For rTSA, subscapularis tenotomy was performed when subscapularis was intact or partially torn. The tenotomy was repaired at the end of procedure unless it was not reparable. Both inlay (DJO Inc.) and onlay (Exactech Inc. and Tornier Inc.) designs implants were used by the surgeons.The arm was placed in a sling for 4-6 weeks in patients that underwent aTSA. For rTSA the sling use varied as per surgeon’s preference (2 weeks vs. 6 weeks). Physical therapy was started on all TSAs on day 1 after surgery. TSA precautions were followed in a similar fashion for all shoulder arthroplasties for at least 6 weeksIn this study the primary outcome of interest is the pattern of restoration of the ability to complete ADLs following TSA. This was represented using 2 novel clinical outcome indexes, the total ADLs score and the percentage adjusted ADLs score. Subgroup analysis was performed to assess patient’s ability to perform a subset of activity type, giving insight on when patient can return to normal function. The statistical analysis was performed using R studio .This study included a total of 154 patients, all of whom met the aforementioned inclusion and exclusion criteria. Of these patients, 154 completed the preoperative survey, 105 completed the 2-week survey, 105 completed the 6-week survey, and 101 completed the 3-month survey. The cohort was split almost evenly by gender , and 60% were retired . The patP = .03). Patients who were operated on their right arm (P = .05) and had higher preoperative visual analog scale (VAS) pain scores had significantly lower preoperative ADL scores (P = .03).The preoperative questionnaire was completed by 154 patients prior undergoing either aTSA or rTSA. Of the 105 patients that completed the 2 week postoperative questionnaire underwent 81 aTSA and 24 rTSA. There were no significant differences in preoperative ADL scores with respect to gender,  race, marital status, arm dominance, and ethnicity. Employment was one factor that showed to affect ADL scores. Patients who were retired and unemployed had a significantly lower ADL scores compared to patients who were employed either full time or part time, or self-employed. Patients in the lowest income bracket of less than 25,000 of annual income were shown to have statistical impactful lower ADL scores compared to patients with higher annual income  and 6-week (3% reduction) after shoulder arthroplasty. However, there was a considerable improvement (34% reduction) in these limitations at 3 months after TSA. The mean ADL score improved to 61 at 3 months from a preoperative score of 47 .Figure 3The mean functional score improved from 1.59 preoperatively to 2.23 (70% increase) at 3 months, with specifically a 19% and 23% improvement in activities performed at work and while taking part in hobbies, respectively .The ADL scores related to clothing tasks that showed a similar trend with gradual improvement by 10% and 19% at 6 weeks and 3 months, respectively. The subgroup analysis demonstrated that most difficult task reported by the cohort was putting on a shirt with an average score of 1.70, which improved to 1.84 and 2.27 at 6 weeks and 3 months, respectively .The ADL scores related to personal hygiene showed a decrease at 2-week time point but there was considerable improvement in this score at the 6 weeks (18.7% improvement) and 3 months (41.2% improvement) time points. However, patients consistently demonstrated difficulty reaching the opposite shoulder/arm pit, and reaching behind the back during activities of personal hygiene at 3 months .The ADL scores related to the food preparation demonstrated a 36% reduction at 2 weeks after surgery compared to preoperative scores. At the 6-week time point, the majority of patients reported restoration to preoperative function and at 3 months there was 16.8% further improvement compared to preoperative scores. Opening a tight jar was the most difficult task reported by the cohort preoperatively and at 3 months . The ADLIn this prospective cohort study, we describe the chronology of improvements that occur with regards to pain, sleep disturbances, and performing ADLs in the first three months following a TSA. We found that pain with or without limitations in ADLs was the most common preoperative reason to undergo a shoulder arthroplasty. Postoperatively, patients can expect a 2/3 reduction in their pain in first 3 months of recovery with some residual sleep disturbances at 3 months. The ADLs involving forward elevation (reaching shoulder level shelf in the forward plane), general mobility, and working at the waist level (food preparation) improves considerably at 3 months but activities involving rotation including reaching behind the back and across the chest, and activities involving use of strength show mild improvements by 3 months.TSA has shown good-excellent short- and long-term outcomes for treatment of shoulder arthritis with considerable improvements in pain and functional outcome scores. There are considerable improvements that occur during the first several weeks after TSA with respect to pain relief, sleep cycle changes, and ability to perform ADLs, but chronology and frequency of these limitation and improvements are less well described in literature. In this prospective study, we investigated the challenges experienced by patients during first 12 weeks after TSA. We believe that this data will serve as a resource for counseling patients, as to what to expect in first 3 months after TSA.It is important to note that chronology and extent of pattern of limitations after shoulder arthroplasty are not identical compared to after rotator cuff repair or instability repair even though the sling time may be similar. Postoperative pain levels after arthroscopic instability repair are less than those undergoing a shoulder arthroplasty. Although patients with arthroplasty have early onset of range of motion (ROM) exercises, the pattern of limitations and its recovery with respect to ROM and ADLs are likely to be different between post arthroplasty and rotator cuff repair or instability repair. A more objective insight into the aforementioned differences will require additional study including postsurgical patients with different surgical proceduresShoulder pain was reported as the most common reason and limited function as the second most common reason to undergo a shoulder arthroplasty by our study cohort. Previous studies have demonstrated that TSA is a predictable operation for pain relief. Tashjian et al reported a 5.9-fold decrease in pre- and postoperative VAS scores following TSA, which was statistically significant.Shoulder pathology has been correlated to have significant impact on sleep quality, sleep duration, and habitual sleep efficiency.,Limitations in ROM following shoulder arthroplasty is a reasonable concern of patients after TSA. Although patients with shoulder arthritis have limited function prior to surgery, sling use in first 4-6 weeks after surgery makes the patient one handed for most part. Our study demonstrates that function involving forward elevation improves much faster than ADLs that required internal rotation behind the back or reaching across the body. ADLs involving rotation behind the back remain quite limited for a longer period of time due to the pattern of recovery of ROM after shoulder surgery and also in part due to restrictions imposed by the surgeons. Razmjou et al showcased statistically significant improvement of ROM at the 6-month postoperative mark, which continued to the 2-year postoperative follow-up compared to preoperative baseline.The construct of this study has several strengths and limitations. In this study we focused on the chronological sequence of presentation of the 3 most important limitations (as determined by the patients) and were able to determine the frequency and progression of the extent of improvement of these limitations at three time points (2 weeks/6 weeks/3 months). Study strengths include a large cohort, prospective standardized data collection, and a prior categorization of primary outcomes, and presentation of important clinical improvements with regards to ADLs, sleep, and pain management. In addition, there was limited recall bias because the data collection was on regular scheduled bias. However, there are also several important limitations. First, the sleep disturbances were subjectively determined and not objectively assessed. Second, the study duration was short (3 months) but because prior studies have reported on one-year outcomes, we wanted the focus of this study on first 3 months. Third, we did not have enough numbers to evaluate the differences in pattern of recovery in patients undergoing aTSA or rTSA. Finally, we did not have adequate control groups with respect to shoulder pathology  to determine differences in pattern of recovery in early phases after TSA.This prospective study demonstrates the chronology of improvements in pattern of limitations experienced by patients with respect to pain, sleep, and ADLs in the early postoperative period after TSA. The majority of patients can except to have 2/3 resolution of pain, improved sleep, and improvement in ADLs involving forward elevation and waist level function by 3 months.Funding: The authors received no financial support for the research, authorship, and/or publication of this article.Conflicts of interest: The authors, their immediate families, and any research foundation with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.


To study the effects of modified Lamaze breathing on abdominal pain experienced during colonoscopy. n = 40) and a control group (n = 45). Their basic clinical information was collected, and the bowel cleanliness, the time for the endoscope to reach the ileocecal junction, and the degree of abdominal pain of the two groups were compared.  Eighty-five patients who underwent common colonoscopy at our hospital between March 2021 and May 2021 were selected and randomly divided into the Lamaze group  was significantly lower in the Lamaze group compared with the control group.  Modified Lamaze breathing demonstrated promising effectiveness in reducing abdominal pain during colonoscopy and improving the quality of the examination. Colonoscopy, despite being a modern minimally invasive procedure with high accuracy in diagnosing colorectal diseases , may stiLamaze breathing originates from the “Lamaze method of childbirth,” first developed by French obstetrician Ferdinand Lamaze . It is aDuring a colonoscopy, the colon is stretched after a gas injection, which may cause pain and discomfort in the patients. The mechanisms of labor pain and colonoscopy-caused pain may be similar to a certain extent since the colon and uterus contain smooth muscles .In this study, we made patients undergoing colonoscopy to perform a modified Lamaze breathing technique and assessed its effects on the degree of abdominal pain to provide a new research direction for improving the quality of clinical enteroscopy.n = 40) and control group (n = 45). In the control group, routine nursing interventions for colonoscopy were performed, while for the Lamaze group, modified Lamaze breathing was performed in addition to routine nursing interventions.The data of 85 patients who underwent colonoscopy at the Digestive Endoscopy Center of our hospital between March 2021 and May 2021 were collected and randomly classified into the Lamaze group (Inclusion criteria of participants were as follows : (1) norThis technique was performed based on the following steps:Step A: thoracic breathing at the beginning of the examination: (1) complete relaxation; (2) staring at one point; (3) inhaling through the nostrils and exhaling through the mouth, with the abdomen relaxed; and (4) 6-9 times of inspiration and exhalation per minuteStep B: shallow and slow accelerated breathing when the colonoscopy passed through the descending sigmoid colon junction (mild pain): (1) complete relaxation; (2) staring at one point; (3) inhaling through the nostrils and exhaling through the mouth; and (4) accelerating breathing with increasing pain and slowing it down with decreasing painStep C: shallow breathing when the colonoscopy passed through the splenic flexure and hepatic flexure (pain above moderate degree): (1) complete relaxation; (2) staring at one point; (3) exhaling with a slightly opened mouth (emitting “hee hee” sounds), making noise from the larynx; (4) adjusting respiratory rate according to the intensity of pain, with the amount of air inhaled and exhaled kept the same to avoid hyperventilation; and (5) 4-6 continuous rapid breaths followed by forced exhalation. This step was repeated until the pain disappearedStep D: halitus movement when feeling pain but unable to gather strength: to open the mouth and breathe rapidly like gasping with the body relaxedAll examined patients took the same laxative for bowel preparation, and the quality of preparation was graded as follows: grade I, excellent with no visible feces; grade II, satisfactory with a small amount of visible feces, but did not block the visual field; and grade III, unsatisfactory with feces blocking the visual field and/or colonoscopy passage.After the colonoscopy, the patients' intraoperative pain was measured with the Wong-Baker faces pain rating scale . Patientt-test was used for comparison between the two groups and Wilcoxon rank-sum test for nonnormal distribution variables. Enumeration data were expressed as frequency (n) and percentage (%), and the chi-square test was used for statistical analysis. P < 0.05 was considered statistically significant.The SPSS 24.0 software was used for data analysis. Measurement data were expressed as mean ± standard deviation (SD), and the The general data of the patients included were analyzed. According to the results, there were no significant differences between the Lamaze group and control group in terms of gender, age, and history of colonoscopy , indicatBowel preparation was evaluated in both groups of patients during colonoscopy. The results showed that the intestinal tract of patients in both groups was clean without stool accumulation; there was no significant difference in bowel cleanliness between the two groups , indicatThe duration of colonoscopy was compared between the two groups. It was revealed that there was no significant difference in the time to reach the ileocecal junction between the two groups .The degree of abdominal pain caused during colonoscopy was compared between the two groups. The results showed that patients in the control group experienced significantly more intense pain in the anal region, descending sigmoid colon junction, splenic flexure, and hepatic flexure than those in the Lamaze group , suggestColonoscopy, as the main means of examination for colorectal diseases worldwide, is of great value for the early detection of colorectal lesions . HoweverThe pain arising from colonoscopy falls into the category of visceral pain, often caused by stimuli such as mechanical traction, intestinal smooth muscle spasm, ischemia, and inflammation, leading to unpleasant feelings accompanied by nausea, vomiting, and changes in cardiovascular and respiratory activities. As reported, to provide an effective field of view during colonoscopy, air injection is required to dilate the intestinal cavity, but excessive air can cause the intestinal lumen to be overinflated and stretched, stimulating nerve endings to produce pain. Since the colon is relatively free in the abdominal cavity, abdominal pain, abdominal distension, nausea, and vomiting can be triggered when the endoscope passes through bends such as the descending sigmoid colon junction, hepatic flexure, and splenic flexure. When the bowel is stimulated during colonoscopy, smooth muscle spasm of the bowel wall can occur, thus producing pain , similarIn this study, the pain-relieving effects of modified Lamaze breathing during colonoscopy were observed due to the advantages of Lamaze breathing and the characteristics of colonoscopy. The study results showed that there was no significant difference in age, gender, colonoscopy history, occurrence of complications, and time of the endoscope to reach the ileocecal junction between the two groups. Compared with routine nurse interventions for colonoscopy, Lamaze colonoscopy could significantly reduce the pain score of anal pain, descending sigmoid colon junction, splenic flexure, and hepatic flexure, which was consistent with findings of Yu et al. and T. Voiosu et al. , 21.Bowel cleanliness is also associated with the degree of abdominal pain in patients. Fecal water and bubbles in the enteric cavity can directly affect endoscopists' visual field, increasing the risk of missed diagnosis and treatment difficulties. Multiple repeated irrigation will increase the operation time and cause discomfort. Thus, poor intestinal cleanliness leads to more time for endoscopists to intubate, which could result in a higher rate of failure . HoweverPerforming modified Lamaze breathing preoperatively under proper guidance could subdue abdominal pain during colonoscopy, increase patients' tolerance, and enhance their experience during medical treatment.


Traumatic Spinal cord injury (SCI) is a devastating condition that results in life long disability. Impairments associated with traumatic SCI such as sensory, motor, and autonomic dysfunctions lead to an array of secondary SCI-specific complications. Neuropathic pain is one of the most common medical complications of traumatic SCI which significantly affects motor function and activities of daily living (ADL) in people with traumatic SCI. Neuropathic pain is one of the main factors for dependency, decreased quality of life (QOL), poor rehabilitation outcomes, and depression in traumatic SCI individuals. The main aim of the current study was to determine the frequency of neuropathic pain and its effects on rehabilitation outcomes, balance function, and QOL in people with traumatic SCI.A cross-sectional survey was carried out at PCP from March to August 2020. Overall, 123 participants were added to the study using a non-probability convenience sampling technique. Information was collected using an adapted, validated questionnaire. Both male and female traumatic SCI patients with age between 18-60 years who received at least two weeks of rehabilitation, 42 days after diagnosis of traumatic SCI were included in current study while patients with Acute SCI, SCI patients with any other condition which can affect neuropathic pain such as traumatic brain injury, diabetic neuropathy, amputation, etc. and progressive neurological diseases such as multiple sclerosis and Guillain barre syndromes were excluded. Patients who have received at least two weeks of rehabilitation, 42 days after diagnosis of traumatic SCI. Patients with traumatic SCI.Overall, 123 traumatic SCI patients were included in the study. The majority of the  participants were male and 83 (67.5%) were from urban areas. Eighty-Seven (70.73%) participants had neuropathic pain. Neuropathic pain was significantly associated  with rehabilitation outcomes, balance function, and quality of life.It can be concluded that more than two-third of SCI patients suffer from neuropathic pain. Moreover, neuropathic pain is significantly associated with rehabilitation outcomes, balance function, and quality of life. Traumatic SCI is a devastating condition that results in lifelong disability.7The symptoms of neuropathic pain generally persist for long durations.14Neuropathic pain is a disabling condition that restricts patients from performing ADLs and affects the patient’s QOL.17st, 2020 to August 30th, 2020).A cross-sectional study was conducted in PCP, Khyber Pakhtunkhwa, Pakistan. This hospital is a semi-government hospital located at the center of Khyber Pakhtunkhwa. This hospital covers 80% of the SCI population of the KPK province and considers a hub for all rehabilitation sector hospitals. Participants who fulfilled the inclusion criteria have been selected from different departments of that hospital. The study was conducted in six months  Feeding (2) Bathing (3) Dressing (4) Grooming while the second portion was about the mobility of the patients. It had two parts. The first part was about indoor activity and other part was about outdoor activity.Section “D” also consisted of two portions. The first portion was about the forward reach of both the right and left side of the patients while the second portion was about the lateral reach of the right and left side of the patients.Section “E” was divided into four domains. These four domains included the physical health of the patients, psychological state of the patients, social relationship of the patients and the environment of the patients.Overall included participants in this study were 123 in which no participant quit the study. All the participants were traumatic SCI patients admitted in different units of PCP, Khyber Pakhtunkhwa. The maximum age of the participants was 60 years while the minimum age of the participants was 18 years. The mean age of the participants is 33.52 with a standard deviation of ±11.52. Analysis of the study showed that the majority (82.11%) of the study participants were male while (17.9%) were female.Results declared that the majority (67.5%) of the study participants were reported from the urban area while (32.5%) SCI patients were noted from rural areas. The majority (30.09%) of the cause of injury of the participants was fall from a height, followed by road traffic accident (28.5%), fire arm injury (21.1%), hit by falling object (12.2%), coal mine accident (4.1), and fall on the ground .The majority (70.73%) of the traumatic SCI patients had neuropathic pain; followed by (29.27%) of traumatic SCI had no neuropathic pain .The majority of the participants responded that their rehabilitation outcomes were affected by neuropathic pain because the study analysis shows that his p-value was below 0.05.et. al that neuropathic pain effect QOL in SCI patients.26The current study conducted shows that majority of the participants level injury is paraplegic and the ASIA impairment scale is complete. The basic purpose of the current study was to assess the frequency of neuropathic pain in traumatic SCI patients. The current study revealed that the majority n =87 (70.73%) patients had average signs and symptoms regarding neuropathic pain in traumatic SCI patients. As discussed earlier 70.73% of patients suffered from neuropathic pain in traumatic spinal cord injury while 29.27% had no pain. This rate was found to be higher at 17.73% than the previously reported study (53%) conducted by Burke D et al.Traumatic SCI patients from paraplegic center Peshawar were included in the study, nearly half of the traumatic SCI population admitted in tertiary care hospitals and private hospitals. It would be good if data were collected from traumatic SCI patients admitted in tertiary care hospitals.Time constraint is another limitation of the study.The research findings showed that neuropathic pain is one of the main issue among traumatic SCI patients.It can effect the rehabilitation outcomes, balance function and quality of life which can ultimately effect the general health status of such patients. Proper management and prognosis of neuropathic pain is important to improve the individual’s quality of life.This study will help in the management of effective therapeutic options by understanding the relevance of neuropathic pain among these patients.MIK: Concept and study design, literature search and literature review,acquisition of data,drafting the manuscript,final approval of the version to be published. He is responsible for the accuracy or intergerity of the work. AA: Overall supervision,drafting the manuscript,analysis and interpretation of data. IA: Literature search and literature review,critical revision. AKF:Concept and study design,critical revision.


Acute hepatic porphyria (AHP) is a family of four rare genetic diseases, each involving deficiency in a hepatic heme biosynthetic enzyme. Resultant overproduction of the neurotoxic intermediates δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) leads to disabling acute neurovisceral attacks and progressive neuropathy. We evaluated the AHP disease burden in patients aged ≥ 12 years in a post hoc analysis of the Phase 3, randomized, double-blind, placebo-controlled ENVISION trial of givosiran (NCT03338816), an RNA interference (RNAi) therapeutic that targets the enzyme ALAS1 to decrease ALA and PBG production. We analyzed baseline AHP severity via chronic symptoms between attacks, comorbidities, concomitant medications, hemin-associated complications, and quality of life (QOL) and evaluated givosiran (2.5 mg/kg monthly) in patients with and without prior hemin prophylaxis on number and severity of attacks and pain scores during and between attacks.Participants  included patients with low and high annualized attack rates . At baseline, patients reported chronic symptoms (52%), including nausea, fatigue, and pain; comorbidities, including neuropathy (38%) and psychiatric disorders (47%); concomitant medications, including chronic opioids (29%); hemin-associated complications ; and poor QOL . A linear relationship between time since diagnosis and AAR with placebo suggested worsening of disease over time without effective treatment. Givosiran reduced the number and severity of attacks, days with worst pain scores above baseline, and opioid use versus placebo.Patients with AHP, regardless of annualized attack rates, have considerable disease burden that may partly be alleviated with givosiran. Acute hepatic porphyria (AHP) is a family of rare genetic diseases, each arising from a deficiency in an enzyme involved in hepatic heme biosynthesis . These eAHP is a multisystem disease characterized by disabling acute neurovisceral attacks, most often including severe abdominal pain, vomiting, muscle weakness, hypertension, and changes in mental status . ChronicEarly treatment is important to prevent disease progression , 15. TheIntravenous (IV) hemin is the standard of care for confirmed acute attacks , 20, 21.Liver transplantation is considered a last resort for patients with severe recurrent attacks that do not respond to hemin , 26, 27.P < 0.001) [Thus, treatment options for recurrent AHP were limited before the approval of givosiran, a subcutaneously administered RNA interference (RNAi) therapeutic that specifically targets ALAS1 messenger RNA in the liver to reduce production of ALA and PBG , 30. Giv< 0.001) . Givosir< 0.001) . The pro< 0.001) . The saf< 0.001) , 36.This post hoc analysis used data from the ENVISION trial to evaluate the disease burden associated with AHP, including patients with a low rate of acute attacks . The efficacy of givosiran in patients with and without prior hemin use was also assessed, including patient-reported pain scores during and between attacks.The study population was defined as patients aged ≥ 12 years with a diagnosis of AHP, an elevated level of urinary ALA or PBG , and either a confirmed pathogenic mutation associated with AHP or biochemical and clinical criteria consistent with a diagnosis of AHP . PatientThirty-six study sites in 18 countries participated in the study . PatientThe primary endpoint was AAR  among patients with AIP . SecondaDaily worst pain and daily worst fatigue scores were measured using the Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory-Short Form (BFI-SF) numerical rating scales (NRS), respectively. An NRS was also used for daily worst nausea score. All NRS ranged from 0 to 10, with higher scores indicating more severe symptoms; scores were captured using a daily eDiary from screening through Month 12.QOL assessments included the 12-Item Short-Form Health Survey, version 2 (SF-12), and the EuroQol-5 Dimension-5 Level Questionnaire (EQ-5D-5L) and were collected throughout the study. The SF-12 generates 8 domains of functional health and well-being, including bodily pain, in addition to physical component summary (PCS) and mental component summary (MCS) scores. Low scores on the PCS indicate limitations in physical functioning, high bodily pain, and poor general health. The EQ-5D-5L assesses 5 dimensions, as well as patient’s global impression of their overall health on a visual analog scale (EQ VAS), which ranges from 0  to 100 .A review of ENVISION trial data was undertaken to fully examine the severity of AHP disease burden at baseline, including the prevalence of chronic symptoms, comorbidities, concomitant medications, prophylactic hemin use and associated complications, and patient QOL. Additional measurements included lost days of work due to AHP and hours of caregiver support required. The association between time since diagnosis and AAR was also examined. Furthermore, post hoc analyses were undertaken to examine the effects of givosiran treatment on the number and severity of attacks in patients with AHP according to prior hemin prophylaxis, and on daily worst pain scores and analgesic use during attack-free periods. These analyses were not protocol-defined, and therefore no formal statistical comparisons were undertaken.A total of 94 patients with AHP were enrolled in the ENVISION trial, of whom 46 were assigned to receive placebo and 48 to receive givosiran . The medAt baseline, 52% of patients were experiencing chronic symptoms of porphyria, defined as symptoms between attacks daily or on most days . ChronicPatients had a poor QOL at baseline, as measured using the SF-12 PCS, SF-12 MCS, and EQ VAS  , with ma0% , withP < 0.01). This suggests that AHP disease worsening likely occurs over time.There was a linear relationship between longer time since diagnosis of AHP and higher AAR in the placebo group during the 6-month double-blind treatment period of the ENVISION trial  were considerably higher than those reported in earlier US and Swedish observational studies (18–22%) 5% were c, 35, 39.The diagnosis of AHP is frequently delayed for years due to the non-specific nature of AHP symptoms . In the Despite the high historical AAR, only about 50% of patients in ENVISION met the European Porphyria Network (EPNET) classification criteria for recurrent attacks, which are used as a marker for disease severity . EPNET dOur study also examined disease burden at baseline according to prior hemin use in ENVISION trial patients and showed that disease burden remained high in patients who had not received hemin prophylaxis; approximately 60% experienced chronic symptoms between attacks, with a median historical AAR of 6 in the placebo group and 8 in the givosiran group.In ENVISION, the number of porphyria attacks and attack severity were both reduced in patients receiving givosiran compared with those receiving placebo, regardless of prior hemin use. Givosiran recipients had fewer days with daily worst pain scores above baseline than placebo recipients, and nearly 50% fewer days with severe pain during attack-free periods. Pain is one of the key factors associated with diminished QOL among patients with AHP . The SF-A strength of our study is that, unlike the observational EXPLORE study , all potIn conclusion, the current study highlights the severe disease burden associated with AHP, even in patients with a relatively low rate of attacks, and supports the effectiveness of givosiran for the management of certain acute and chronic porphyria symptoms.