The prevalence of chronic pain in children and adolescents is high. In some patients, it can be severe and refractory to conventional treatment options. There is increasing interest in the use of cannabinoids for therapeutic purposes in children and adolescents. Nabilone, a synthetic cannabinoid, is approved in Canada for the treatment of nausea and vomiting associated with chemotherapy. It can also be used off label for treatment of chronic pain.This study aims to characterize the use of nabilone for severe chronic pain in a pediatric population.This is a retrospective cohort study of patients 18 years or younger who were prescribed nabilone for chronic pain in a tertiary multidisciplinary pediatric chronic pain clinic between July 1, 2013, and June 30, 2017.During the 4-year study period, we screened the charts of 507 patients and identified a total of 28 patients (5.5%) who were treated with nabilone as part of their chronic pain treatment. Common indications for nabilone treatment include mixed neuropathic/nociceptive pain, abdominal pain, neuropathic pain, and spasticity. In all patients, nabilone was prescribed as an adjunctive treatment. Seven patients (25%) reported a slight improvement in pain symptoms. Side effects were reported by 21.4% of patients. The most common reported side effects were sedation and cognitive slowing.Adjunctive treatment with nabilone may improve pain symptoms in a subset of pediatric chronic pain patients. Further research investigating the long-term safety and efficacy of nabilone in the treatment of chronic pain in children is needed. It can lead to debilitating effects beyond pain, impacting many aspects of daily life, including sleep, emotions, school attendance, social interactions, and physical activities. The total cost of chronic pain in adolescents is estimated to be $19.5 billion annually in the United States.2 The optimal treatment model for chronic pain in children involves a multidisciplinary approach involving pharmacological, physical, and psychological strategies. However, severe chronic pain in children can be challenging to treat despite these treatment strategies. Response to current pharmacological treatment strategies is highly variable. There is very little literature available examining the efficacy and outcomes of pharmacological interventions in young people with chronic pain.3 In adults, only one out of every three patients who receive treatment for neuropathic pain experiences an analgesic effect, defined as ≥30% pain reduction.5 Alternative treatment strategies are needed for patients who are refractory to conventional treatment options.Chronic pain is highly prevalent among children and adolescents, affecting approximately one in five children.6 Cannabinoids are also currently recommended as a third-line treatment option for chronic neuropathic pain in the 2014 revised Canadian Pain Society neuropathic pain guidelines.7Cannabinoids are biologically active constituents of cannabis or synthetic compounds with an affinity for or activity at the cannabinoid receptors. There is evidence in adults that cannabinoids can be helpful in the treatment of human immunodeficiency virus neuropathy, diabetic neuropathy, posttraumatic or postsurgical neuropathic pain, and mixed central and peripheral neuropathic pain states.8Nabilone is an orally administered synthetic cannabinoid and analogue of delta-9-tetrahydrocannabinol (THC), which is the main psychoactive component in cannabis. It is licensed in Canada and United States as an antiemetic for management of nausea and vomiting associated with cancer chemotherapy. The use of nabilone for treatment of chronic pain is off-label. Nabilone acts as an agonist of two endogenous cannabinoid receptors, CB1 and CB2. Stimulation of the CB1 receptor, which is located in neuron terminals throughout the nervous system, reduces neuronal excitability. Stimulation of the CB2 receptor results in anti-inflammatory effects. Nabilone has also been shown to improve sleep in adults likely due to the sedative effects of THC.9 Cannabinoids were found to be well tolerated in a systematic review of randomized trials of cannabinoids for treatment of chronic noncancer pain in adults. Adverse effects were generally mild to moderate in severity.10 Current evidence on the use of medical cannabinoids for pain in children is limited to only one case report in children with complex regional pain syndrome (CRPS) and a small trial in children with complex motor disorders.12The 2018 legalization of medical marijuana in Canada and 18 U.S. states has led to a gap between increased interest in this treatment modality by patients and families and limited evidence for its use in the pediatric population. A 2017 systematic review to identify the evidence base of cannabinoids as a medical treatment in children and adolescents showed that evidence for benefit was strongest for chemotherapy-induced nausea and vomiting, with increasing evidence of benefit for epilepsy. However, there is insufficient evidence for its use in chronic pain conditions such as spasticity and neuropathic pain.13 In this study, we present a retrospective chart review of a single-center clinical experience on the use of nabilone for a small series of pediatric patients with severe chronic noncancer pain over a 4-year period.There is a paucity of literature available to guide clinicians on the use of medical cannabinoids in children and adolescents. The American Academy of Pediatrics currently opposes dispensing medical cannabis to children and adolescents; however, it does recognize that it may be an option for children with severely debilitating conditions and for whom current therapies are inadequate.The study design was a retrospective cohort study, analyzing data on all patients aged ≤18 years followed in our chronic pain clinic who were prescribed nabilone between July 1, 2013, and June 30, 2017, at a single tertiary pediatric teaching hospital . This study was approved by the institutional research ethics board (No. 1000059383) and consents were waived given the deidentified and retrospective nature of the data collected.The pediatric chronic pain clinic at The Hospital for Sick Children provides interdisciplinary pain management to children and adolescents. Patients were identified through a search of all new patients seen in clinic during this time period through the clinic database. Patients were selected for review if they were (1) prescribed nabilone for pain treatment and (2) ≤18 years old at the time of prescription. Patients prescribed nabilone for indications other than chronic pain  were excluded from the study.Data were collected from hospital electronic medical records, including clinic notes, letters, and scanned prescriptions. For each patient, we collected data including patient’s age, sex, weight, primary pain diagnosis, location of pain, and any concurrent medical diagnosis. Information on nabilone prescriptions included dose prescribed and duration of treatment. Nabilone’s effect on pain and other symptoms, reported side effects, and reasons for discontinuation were collected from patient and family reports that were documented in the clinic notes. We also collected information on other pain medications used including other forms of prescribed cannabinoids such as cannabidiol (CBD) oil and nonpharmacological treatments provided. All comments related to nabilone treatment in the chart were captured. The chronic pain clinic includes a total of four physicians who all prescribed nabilone as part of their practice. There was no formal treatment protocol established for nabilone in the chronic pain clinic. It was introduced as an adjunctive treatment for patients at the discretion of the prescribing pain physician. All data were extracted from charts and entered into an anonymized database. For this study, the initial visit is considered the chronic pain clinic visit where nabilone was prescribed. If nabilone was prescribed between clinic visits, the chronic pain clinic visit immediately prior to the prescription was used as the initial visit.Descriptive statistics are presented. Numerical variables are displayed as median and interquartile range (IQR) and categorical variables are presented as numbers and percentages.During the 4-year study period, we screened charts from 507 patients and identified a total of 28 patients (5.5%) who were treated with nabilone as part of their chronic pain treatment. The median age of our patient cohort at the start of nabilone treatment was 14.0 years (IQR:11.8–16) and 75% of patients were female .Table 1.The most common primary pain diagnosis associated with nabilone treatment was mixed neuropathic/nociceptive pain (32.1%), followed by abdominal pain (21.4%), neuropathic pain (17.9%), and spasticity (14.3%). The pain location was most commonly described as generalized (42.9%), followed by abdominal (21.4%) and lower extremity (14.3%). The patients frequently had coexisting mental health disorders, including anxiety (35.7%) and depression (21.4%).Patients were concurrently taking between one and five other pain medications while on nabilone. The number of patients taking one, two, three, and four or more concomitant medications was seven, eight, five, and eight patients, respectively. The most common concurrent pharmacological treatments include anti-epileptics, nonsteroidal anti-inflammatory drugs, opioids, and antidepressants . In one The duration of treatment varied widely, from less than one week to more than 12 months in 13 patients. The longest duration of treatment was 29 months. None of the patients started nabilone treatment less than 3 months from the time of chart review. Side effects and effectiveness were evaluated at follow-up visits, which varied between 1 and 6 months after initiation of therapy. Patients had between one and ten follow-up visits prior to terminal of therapy or discharge from care. Nabilone dosing ranged from 0.25 mg once daily up to 2 mg twice daily. The median daily nabilone dose prescribed was 1.5 mg. Due to limited documentation of follow-up pain scores, only 13 patients had documented pain scores both at the start of treatment and at follow-up visits. Seven patients showed a small reduction of between 0.5 and 1.5 on the Numeric Rating Scale in pain scores. Three patients had pain scores that were unchanged. Three patients reported increased pain scores during treatment. Side effects were documented in 6 of the 28 patients. Side effects reported include sedation, cognitive slowing, agitation, nightmares, and dry mouth .Table 3.The objective of this study was to describe the use of nabilone in a small cohort of children and adolescents with severe chronic pain that was refractory to other treatment strategies. In this retrospective analysis of nabilone prescribing practice over a 4-year period in a pediatric multidisciplinary chronic pain clinic, we found that 5.5% of patients were prescribed a trial of nabilone. In our cohort, there was a slight improvement in pain in a small subset of patients treated with nabilone. It was tolerated without side effects in a majority of the patients, with 21.4% of patients reporting side effects. The most common reported side effects were sedation and cognitive slowing.14–16 In other studies, treatment with THC-containing cannabinoids decreased pain in patients with rheumatoid arthritis and neuropathic radiculopathy.18 The THC-induced analgesia was correlated with a reduction in functional connectivity between the anterior cingular cortex and sensorimotor cortex in functional magnetic resonance imaging.18 A Canadian Agency for Drug and Technologies in Health rapid review specifically evaluating the use of nabilone for management of chronic pain found limited evidence that nabilone may be better than placebo or medications such as amitriptyline in relieving chronic pain.19Several clinical trials have shown inconclusive results on the use of selective cannabinoid products containing THC for the treatment of chronic neuropathic pain in adults.11 A second small randomized trial examined the use of CBD enriched oil extract with two different CBD-to-THC ratios on children with complex motor disorders. Participants from both groups reported a statistically significant improvement in pain (12 Our study adds to the limited available information on the use of nabilone for chronic pain in children and adolescents.Information on the use of synthetic cannabinoids for chronic pain in children and adolescents is currently limited to only case report and one small randomized trial. Rudich et al. reported the use of dronabinol in two adolescents with neuropathic pain and comorbid major depressive disorder. Dronabinol reduced the affective component of pain by 40% and improved psychosocial functioning after 4 months, although there was a gradual dissipation of effectiveness after 6 months that led to discontinuation. in pain .12 Our s20 The scarce data available concerning the pediatric population require clinicians to extrapolate data from adult studies. A simplified Canadian guideline for prescribing medical cannabinoids in primary care recommends the use of pharmaceutically developed products such as nabilone or nabiximols as initial agents because dosing is more consistent.21 They suggested that clinicians could consider medical cannabinoids for refractory neuropathic pain if patients have had a reasonable therapeutic trial of at least three prescribed analgesics and have persistent problematic pain despite optimized analgesic therapy. They should be given as an adjunct to other prescribed analgesics. The findings of our study were largely in accordance with these recommendations. The patients in this series had all trialed multiple medications and still experienced pain that was poorly managed by conventional multidisciplinary treatment options prior to starting nabilone. Nabilone was prescribed as an adjunct to other pharmacologic and nonpharmacologic treatments in all patients.The use of medical cannabis has become increasingly popular. Studies have shown that 10% to 15% of adult patients with chronic pain use cannabis to improve pain, sleep, and mood.22 There is evidence from recreational cannabis users suggesting that the chronic use of cannabis may have adverse effects on the developing brain. Neuroimaging studies show that individuals who began using recreational cannabis regularly in adolescence tend to have differences in cortical and subcortical volumes, white matter integrity, and functional connectivity compared to nonusers.23 There is also epidemiological evidence to support the view that regular or heavy cannabis use among adolescents and young adults may increase the risk of developing psychotic disorders.24 However, there are significant differences between recreational use and medical use of synthetic cannabinoids use, including frequency, potency, route of administration, and number of active ingredients. The lack of research limits our understanding of the long-term effects of medical cannabinoids in children and adolescents.The decision to trial cannabinoids for chronic pain in children and adolescents needs to be carefully balanced with the potential risk of cannabinoids, in particular their risk to the developing brain. The CB1 receptors are particularly concentrated in brain regions critical for executive functioning, reward processing, and memory.25Currently, there is limited evidence from randomized controlled trials to inform the practice of treating children and adolescents with chronic pain using cannabinoids to improve pain intensity and disability. The potential benefit of cannabinoids in pediatric populations must be balanced with the associated risks. The Canadian Pediatric Society recommends that the use of cannabis for medical purposes in children be evaluated on a case-by-case basis and always with a comprehensive discussion of potential benefits, risks, and goals of treatments.A comprehensive biopsychosocial pain assessment needs to be performed, including a psychological assessment for history of psychotic disorder, anxiety, and substance abuse and family history of psychotic disorders.When considering cannabinoids, physicians must engage patients and families in an informed consent discussion that includes risks and benefits of the medication, including the potential impact of cannabinoids on the developing brain.Medical cannabinoids should be prescribed as an adjunct to other analgesics and nonpharmacological management strategies, including physical and psychological strategies.Close follow-up is required to evaluate the efficacy and potential adverse drug reaction of the medication and the risk–benefit ratio needs to be regularly reassessed.Without a pediatric guideline that provides specific recommendations on the use of cannabinoids for children and adolescents with chronic pain, we suggest the following steps be considered when prescribing cannabinoids for chronic pain:This is the largest cohort study yet reported on the use of nabilone in children and adolescents for chronic pain indications. We hope to stimulate discussion of therapeutic options for children with severe pain and for whom current therapies are inadequate, which may lead to increased research in this area.Limitations of this study include its retrospective design and data collection. The data collection was limited to the documentation available in patients’ medical records. We were unable to exact pain ratings and detailed information about patients’ function from all clinic visits due to incomplete documentation in the outpatient setting. We included subjective data collected from clinicians’ notes, which may be subject to reporting bias. Other limitations include the small number of patients in this study and lack of a control group, which makes it difficult to draw conclusions. The effectiveness of nabilone reported in this study needs to be interpreted with caution, because it was used concurrently with multiple other medications and nonpharmacological treatments that may have contributed to pain control. This study was performed at a single academic tertiary children’s hospital and our results may not be widely generalized to other centers.


This retrospective study aimed to evaluate midterm outcomes of surgical management of multi-segment thoracic spinal tuberculosis by single-stage posterior transforaminal debridement and interbody fusion with instrumentation. From January 2007 to October 2015, 42 adult patients with thoracic spinal tuberculosis involving three or more levels underwent single-stage posterior transforaminal debridement, interbody fusion and instrumentation At a mean follow-up of 73.5 ± 9.6 months, all patients were eligible for final evaluation. All displayed improved biochemical markers and pain scores at 3 months and improved physiologic levels at the end of treatment. Visual analogue and 36-Item Short-Form Health Survey scores were significantly improved compared with preoperative values. All 30 patients with preoperative neurological deficits experienced neurologic improvement. Thoracic kyphosis angle decreased significantly from 34.4° ± 4.5° to 22.0° ± 2.6°. A mean kyphotic angle loss of 1.7° ± 1.1° was recorded at the final follow-up, and bone fusion was observed at a mean of 10.6 ± 2.1 months, with no instrumentation failures. One patient experienced delayed incisional healing and five patients suffered postoperative intercostal neuralgia that were cured by conservative treatment. There were no graft failures or implant breakages. This study showed the utility of a single-staged procedure combining posterior transforaminal debridement and interbody fusion with instrumentation, and demonstrated promising results. Significant challenges in spinal TB arise from osteolysis that may cause deformity, neurological deficit, and even paraplegia2. Anti-TB chemotherapy remains the mainstay of treatment for spinal TB3. Options include drug therapy alone, surgery followed by medical therapy, or concomitant use of both modalities5. Conservative medical management cannot fully prevent the potential progression of kyphosis, which often results in chronic back pain, residual deformity, or both6. Although its incidence is relatively low, multi-segment thoracic spinal TB can cause acute symptoms and disability. Consequently, treatment is difficult, and surgical procedures are indicated more often than for single-segment thoracic spinal TB8. The lack of a consensus-based management protocol for these infections has been noted in the literature. The central segment of the vertebral body often develops extensive osteolysis with sequestrum fragments and massive cold abscesses, which can easily invade the spinal canal9. The location of vital organs near the thoracic spine, confounds surgery for multi-segment thoracic spinal TB. Adjacent organs should be protected from injury, and attention should be paid to the restoration of spinal stability after the lesion is cleared.Skeletal tuberculosis (TB) imposes a formidable disease burden, especially in the developing world11. Transforaminal thoracic interbody fusion aims to avoid retraction of neural elements that is inevitable during the anterior approach12. Due to a lack of evidence-based guidelines for optimal treatment and management strategies, the therapy of multi-segment thoracic spinal TB remains controversial. We present our experience with a midterm follow-up of management that uses a single-stage debridement through the posterior transforaminal approach coupled with stabilization using fusion and instrumentation.With the development of advanced treatments and surgical options, stabilization through posterior instrumentation remains the mainstay for the correction of angular deformities and provides stabilization; however, fusion across spinal segments has been reported when the anterior approach is indicated for easier access to diseased segments of vertebral bodies13; and (iv) no pain relief or progressive vertebral destruction after anti-TB therapy, indicating poor response to conservative treatment. Exclusion criteria were (i) large paravertebral abscess or gravity abscess formation; (ii) previous thoracic spinal surgery ; and (iii) limited osteolysis and abscess, with neither spinal cord compression nor spinal instability. Twenty-five patients were male and 17 were female. The average age at the time of surgery was 45.8 ± 13.8 years. Lesions involved three levels in 19 patients, four levels in 14 patients, five levels in eight patients, and six levels in one patient. Of these, 11 patients exhibited skip lesions. All patients presented with at least one constitutional symptom, such as back pain, weakness, malaise, night sweats, low-grade fever, or weight loss. Disease-specific presentations were noted in 22 patients (52.4%) with intercostal neuralgia, 30 patients (71.4%) with paraparesis, and one patient (2.4%) with paraplegia. Initial working diagnoses of TB were based on biochemical and radiological parameters. Diagnoses were confirmed by histopathologic findings or a culture of tissue samples that yielded Mycobacterium tuberculosis.From January 2007 to October 2015, 178 patients with multi-segment (three or more level involvement) thoracic spinal TB were evaluated at our center. In total, 76 patients did not undergo surgical management, and 42 patients were not candidates for a single-stage posterior approach procedure due to clinical characteristics (exclusion criteria are listed below). In total, 60 patients underwent a single-stage posterior approach debridement through the transforaminal corridor and stabilization using interbody fusion as well as instrumentation. A total of 42 patients were eligible for final evaluation at a minimum 5-year follow-up and were included in this study  and c-reactive protein (CRP) levels, neurological function , Visual Analog Scale (VAS) pain scores, quality of life , and measurements of thoracic kyphotic angles.Each patient was placed in a prone position after the administration of general anesthesia. A soft cushion was placed under the chest and pelvis so that the abdomen could hang freely, which reduced kyphosis. For patients undergoing an upper thoracic spine procedure, intraoperative halo traction was performed to reduce kyphosis. The diseased segment was localized under an image intensifier and a posterior midline approach was centered over the affected levels. Posterior elements including lamina, facet joints, and transverse processes were exposed , followed by dissection at the level of decompression and extended bilaterally to expose costotransverse articulations. Subsequently, the placement of screws was performed. Generally, longer segmental fixation was preferred, between at least two levels superior and inferior to the level of decompression. Affected vertebral bodies with limited destruction of the disc and adjacent vertebral bodies  were often incorporated into the instrumentation system. A hemi-laminectomy or laminectomy was conducted on the most severely involved aspect of the diseased segment. Exposure was increased as appropriate by sacrificing the thoracic nerve roots on the most affected side to allow a more thorough debridement when offering a > 270° decompression  with a two-tailed p-value significant at p < 0.05.Statistical analysis was performed using SPSS version 18.0  for descriptive data as well as comparative analysis using a paired This study protocol was approved by the Ethics Committee of Xiangya Hospital Central South University, We also followed the Declaration of Helsinki and its later amendments. Written informed consent was obtained from all patients.M. tuberculosis. None of the isolates were drug-resistant.In total, 42 patients with a mean follow-up of 73.5 ± 9.6 months were analyzed at the final follow-up. All patients had pathologic diagnoses of TB demonstrated by either tuberculous granulomas or caseous necrosis. Cultures from 11 patients yielded p < 0.05) than those obtained at the 3-month postoperative and final assessments.The average intraoperative bleeding volume and surgical case duration were 842.9 ± 182.7 mL and 182.2 ± 26.0 min, respectively. The average pretreatment ESR and CRP were 60.6 ± 18.6 mm/h and 43.9 ± 11.2 mg/L, which significantly decreased to 11.4 ± 2.7 mm/h and 4.4 ± 1.2 mg/L 3 months after surgery, respectively. Furthermore, at the final follow-up, ESR and CRP values returned to 4.2 ± 1.5 mm/h and 1.8 ± 0.7 mg/L respectively. Preoperative ESR and CRP values were significantly higher . Single-level debridement and interbody fusion were performed in 28 patients, and two-level procedures were completed in 14 patients. Spontaneous intervertebral bone fusion was achieved 10.6 ± 2.1 months after surgery , and reconstruction of anterior load support by interbody fusion that is also achieved by the thoracic reconstruction techniqueWe agree that the posterior-only approach might be radical and requires careful patient selection. We advocate the following considerations when managing multilevel thoracic spinal TB: (1) whenever possible and in the presence of adequate bone stock, the affected vertebrae should be incorporated into the instrumentation system; (2) enough graft should be impacted into the defect, and the intervertebral graft should be fixed to promote fusion; (3) temporary rod stabilization of the spinal cord should be provided during transforaminal thoracic debridement; (4) careful patient selection is required for this method, which is used primarily in spinal TB with limited osteolysis of the middle column; (5) careful monitoring to prevent intraoperative spinal cord injury (stretching or distraction); intraoperative spinal monitoring could be added for safety. During the entire follow-up process, all patients achieved bone fusion, and no bone nonunion or recurrence caused by insufficient debridement was observed.This study is limited by its small size and its retrospective study design. In addition, 18 patients were lost to follow-up. However, multilevel spinal TB remains rare, and therefore, these numbers might not be disregarded. Despite the favorable outcomes of this study, the authors would recommend a larger multicenter study to compare results between the various surgical approaches before advocating a single-stage posterior approach for all patients.This midterm retrospective study of the management of multilevel thoracic spinal TB in adults showed the utility of a single-stage procedure combining posterior debridement, interbody fusion, and instrumentation; and demonstrated promising results.


Isolated otolith dysfunction and vertigo”. The collection includes four original papers that discuss issues toward the establishment of this clinical entity.The otolith organs, saccule, and utricle sense linear acceleration, while the semicircular canals, lateral, anterior, and posterior semicircular canal sense angular acceleration –3. It isWaissbluth and Oyarzún reported a case that was considered to have “isolated unilateral saccular dysfunction”. A 20-year-old woman presented with frequent episodic dizziness. She showed unilateral absence of cVEMP with normal oVEMP and normal vHIT. This report outlines some important points for the diagnosis of “vertigo/dizziness due to isolated otolith dysfunction”. As this patient was young and showed a unilateral absence of cVEMP, it was convincing that her findings were pathological. However, one should also note that appropriate cVEMP recording requires adequate SCM (sternocleidomastoid muscle) contraction without left-right difference and preferably, normalization of amplitudes according to muscle activation levels  with normal test results of canal function  should not be enough for diagnosis of “vertigo/dizziness due to isolated otolith dysfunction”. Especially for the diagnosis of idiopathic vertigo/dizziness due to isolated otolith dysfunction, thorough exclusion of various known vestibular diseases and spinning vertigo episodes is required.Murofushi et al. report on isolated otolith dysfunction in patients with persistent postural-perceptual dizziness (PPPD). The majority of PPPD patients in this study had otolith dysfunction and many of them included isolated otolith dysfunction. Idiopathic vertigo/dizziness due to isolated otolith dysfunction could be a precipitating condition of PPPD. This study suggested that the association of PPPD with isolated otolith dysfunction should be further clarified. However, this study included patients older than 65 years of age. These patients should be carefully diagnosed.Xu et al. reported vestibular disorders in patients with obstructive sleep apnea syndrome (OSAS). Patients with OSAS had much higher abnormality rates in otolith tests (cVEMP and oVEMP) than canal tests . Although their study did not directly mention isolated otolith dysfunction, it suggested that the otolith organ might be more vulnerable than the semicircular canal to hypoxic events. One should be careful with the placement of electrodes in OSAS patients because their obesity might make proper placement difficult.What is required to establish a new clinical entity “Idiopathic vertigo/dizziness due to isolated otolith dysfunction (IOV/D)”? As Suh and Murofushi propose, both subjective symptoms such as non-spinning, translation, tilt, floating, or flipping-over sensation without spinning vertigo attacks, and objective test findings such as abnormal cVEMP and/or oVEMP with normal vHIT, will be required . While sThe credibility of VEMP test results is an essential aspect of developing this field. To exclude false positivity, at the current stage, only patients younger than 70 (or 65) years of age with unilateral abnormal findings should be enrolled as IOV/D, because VEMP responses could be affected by aging and bilateral abnormal findings might be due to non-vestibular factors . Proper TM wrote the manuscript. M-WS and LM edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Transinguinal preperitoneal (TIPP) single-layer mesh herniorrhaphy has been proven effective. Mesh manufacturers make either a single-unit, two-layer mesh design or a separate optional onlay with the pre-peritoneal mesh. For peace of mind, most surgeons still incorporate the optional onlay. This study evaluated any counterproductive effects of adding the onlay to single-layer TIPP mesh herniorrhaphy and compared the long-term efficacy. This prospective, single-surgeon, single-center, randomized trial compared two groups of 50 consecutive patients at a 1 to 1 ratio. The control group received a single-layer modified Kugel mesh in the preperitoneal space, while the study group received the optional onlay mesh in the inguinal canal with preperitoneal mesh placement. A single surgeon performed the same operation to place the preperitoneal mesh in both groups, the only difference being the placement of the optional onlay mesh in the study group. A blinded researcher performed post-operative interviews using a series of questions at 1, 3, 6, and 12 months after surgery, and another unblinded researcher organized and performed statistical analysis of the peri-operative and post-operative data. The primary endpoints included foreign body sensation, pain, and any other discomfort in the inguinal region following surgery; and the secondary endpoints included recurrence and any complications related to surgery. The patient demographics were similar between the two groups. The average follow-up period was 29 months. Two patients in the 1-layer group and one patient in the 2-layer group were lost to follow-up. Postoperative pain, numbness and soreness were similar between groups. No patients experienced a foreign body sensation after 3 months in the 1-layer group, while five patients still had a foreign body sensation at 12 months in the 2-layer group. No recurrence was noted in either group during the follow-up period. Adequate dissection of the preperitoneal space is the key to a successful single-layer TIPP herniorrhaphy. With decreased materials in the inguinal canal, single-layer TIPP has a lower rate of long-term postoperative discomfort without increasing the risk of future recurrence.Trial registration: ISRCTN 47111213 The invention of polypropylene mesh improved the recurrence rate but increased post-herniorrhaphy chronic pain (> 3 months). Due to simplicity, Lichtenstein mesh repair is easy to learn, but post-herniorrhaphy chronic pain is a major drawback, with some studies reporting an incidence of up to 40%4. Explanations for the high rate of chronic herniorrhaphy pain include periosteum damage during mesh positioning, nerve damage  or inflammation from surrounding mesh materials6. Careful nerve dissection and manipulation during inguinal canal preparation before mesh placement can help to reduce the chance of chronic pain, but mesh placed in the vicinity of inguinal canal nerves can cause inflammation, fibrosis and granuloma formation9. Mesh manufacturers either make a single-unit, two-layer design  or a preperitoneal mesh with a separate optional onlay mesh to strengthen the posterior wall . Some surgeons performing transinguinal preperitoneal (TIPP) mesh repair routinely place the optional onlay in the inguinal canal for fear of future recurrence. In our retrospective study, we noted that 1-layer preperitoneal mesh placement did not put patients at risk of future recurrence (< 1%). The key to TIPP mesh placement is adequate dissection of the preperitoneal space, which results in flat mesh placement covering the hernia defects. Most recent studies have compared different types of mesh and different mesh placements. In this prospective study, we investigated whether the use of the optional onlay mesh included in the modified Kugel mesh is associated with long-term complications and examined the efficacy of single-layer TIPP herniorrhaphy in terms of preventing recurrence.Before the introduction of polypropylene mesh, tissue repair was the main form of herniorrhaphy, but a poor long-term efficacy (> 10% recurrence in 10 years) and immediate postoperative pain were the main drawbacksThe institutional review board at Changhua Christian Hospital approved the trial protocol (IRB number 140312) of this study. The trial was registered online with ISRCTN (online registry number: 47111213 assigned on: 2017/03/21). In the preoperative outpatient clinic, all participants were informed in detail about the method of randomization and surgical method before informed consent was obtained according to the IRB protocol.The study population included patients undergoing elective inguinal hernia surgery using MK mesh at Changhua Christian Hospital. The exclusion criteria included: (1) recurrent hernia, (2) femoral hernia, (3) hernia defects larger than the Posiflex® memory ring diameter, and (4) patients refusing to participate in the randomization protocol. Of the 110 patients eligible during the study period, seven patients did not meet the inclusion criteria and three patients refused to participate in the study. One-hundred patients were allocated into two groups, with 50 patients in each group. During the follow-up period, two patients in the 1-layer group and two in the 2-layer group were lost to follow-up due to changes in telephone number.This randomized, prospective clinical trial aimed to investigate the reduction in post-operative complications associated with mesh herniorrhaphy and determine the long-term effectiveness of single-layer preperitoneal mesh placement as compared with two-layer. The primary endpoint was to evaluate patients’ chronic postoperative complications . The secondary objective was to determine the overall success of the hernia operation .This was a prospective, double-blind (patients and observer blinded), single-center, randomized study with a two-arm parallel-group design. A series of 100 consecutive patients undergoing elective inguinal hernia surgery were randomized by computer-generated allotment into two groups at a 1:1 ratio Fig. . The man10. Intraoperative findings, such as depth of subcutaneous fat , perispermatic cord lipomas, nerves identified in the inguinal canal, and type of hernia defect (Nyhus classification) were recorded. After the flat placement of the MK mesh and securing of the positioning strap, the digital timer was stopped, and the time was recorded  were given at least 30 min prior to incision. The operative field was shaved with electric clippers and disinfected with 2% chlorhexidine + 75% ethanol . Operative time was calculated using the digital operating room timer and was recorded from the initial skin incision until the last suture securing the mesh. The surgical method, preperitoneal dissection and mesh placement were as described in our previous retrospective studyAfter the initial post-operative clinical examination, a blinded research assistant (Y.C.H.) followed-up with the patients via a series of telephone interviews. A set of questions Table  was desip-value < 0.05 considered statistically significant. Post-operative discomfort and pain after 3 months was reported in 40% of patients11 who received mesh herniorraphy with onlay mesh. We estimated a postoperative rate of less than 10% for single-layer TIPP mesh herniorrhaphy from reported studies and our retrospective study16. With an α of 0.05 and a power of 0.8, the sample size was estimated to be 47 in each group . With an expected dropout rate of 10 to 15%, the study was initially estimated to require 110 patients randomized into two groups . During long-term follow-up, two patients in the 1-layer and one patient in the 2-layer group were lost. The average onlay placement time was 451 s (7 min 30 s). Upon reviewing the recorded data, we noted that the average duration for onlay placement in the initial 10 cases was10.9 min, with a range of 10–15 min. After the initial 10 cases, the average onlay placement duration decreased to 6.7 min, with a range of 3–10 min. Increased repetition most likely contributed to the decrease in the onlay placement duration. Pain, soreness and numbness complications were similar between the two groups (Table p > 0.5). The number of reported foreign body sensation occurrences was slightly lower in the 1-layer group from POD-7 to the 3-month follow-up, but this was not statistically significant . Although both groups had similar rates of spinal anesthesia and patients with benign prostatic hyperplasia requiring medication, the 2-layer group had a higher rate of post-operative urine retention needing catheterization . When analyzing different variables and the relation to operative time, the experience of the assistant  and EHS classification were not related to an increased operative time. There was a linear correlation between operative time and skin thickness . There was no recurrence in either group.The patients’ general information, peri-operative and in-hospital data are presented in Tables 15. Tissue repair lacks long-term efficacy, with a reported recurrence rate of more than 10% at the 10-year follow-up point2, while mesh repair has a recurrence of less than 5%11. During our follow-up period , we did not treat any patients for recurrence, and saw no signs of suspected recurrence that needed additional clinical hours for physical examination to confirm the diagnosis. In our previous retrospective experience and clinical experience, one recurrence was noted, and TEP was used to repair the hernia protrusion17. In that recurrence case, inadequate preperitoneal dissection resulted in suboptimal mesh placement19. We have since standardized our dissection with 7 wet surgical gauzes, and no recurrence was noted in the time (2012–2017) spanning from the previous study to this study10. Surgical plane disruption in anterior TIPP mesh herniorrhaphy is a concern regarding future recurrence. Prevention of recurrence should be the priority, with adequate preperitoneal dissection, identification of lipoma and occult peritoneal reflection being important aspects in prevention19. Pre-operative imaging can help identify recurrence and also identify other anatomical anomalies 21. In our experience, with recurrence in anterior preperitoneal mesh placements (< 1% of cases), either the anterior or laparoscopic approach are feasible depending on the surgeon’s preference and experience.The emphasis of earlier hernia repair studies has been on lowering the operative time, future recurrence rate, wound infection rate, and rates of other morbidities 31. Surrogate end points such as post-operative discomfort  have been used to quantify post-operative QoL. Even though the short form-36 (SF-36) questionnaire has been used to evaluate QoL in different diseases and treatments, few hernia studies have incorporated SF-36 to quantify post-operative QoL. Iftikhar et al. used SF-36 to show that post-operative physical and emotional function improved after hernia surgery31. Currently lacking an inguinal hernia-specific QoL questionnaire, Huang et al. proposed the HERQL questionnaire, which aimed to assess post-herniorrhaphy QoL; this needs to be validated in future studies32.With a longer follow-up period, the focus of recent studies has shifted towards evaluating post-operative quality of life (QoL) and minimizing long-term post-operative pain/discomfort28. Many factors can influence post-operative pain, such pre-operative pain, intra-operative nerve manipulation/damage, and mesh-related inflammatory processes35. Pre-operative pain and discomfort are good indicators of post-operative discomfort35. Mier et al. used the SF-12 questionnaire and pre-operative visual analog SPS score to determine post-operative QoL35. In that study, patients with SPS ≤ 12 had an improved long-term QoL. Manangi et al. showed that 27% of patients without pre-operative pain developed chronic pain, while 77% with pre-operative pain developed chronic pain34. Wright et al. studied the reasons for pain in inguinal hernia patients at the histological level, and found that compression neuropathy of the inguinal nerve is a culprit for pre-operative pain. On a microscopic level, increased pain is correlated with an increased nerve diameter, fascicle count, and more myxoid material within the perineurium and endoneurium36. These factors are all innate to patients and can only be identified during surgery. Some intraoperative factors that surgeons can be wary of include nerve identification/manipulation and minimizing foreign materials around the nerves. Some studies have suggested that placement of the mesh in the pre-peritoneal space while minimizing nerve involvement  are related to a decrease in the rate of chronic herniorrhaphy pain39. After implanting prosthetic material, the body will start to undergo acute inflammation and subsequent chronic fibroblastic change, which lead to scarring and fibrosis. In some cases, the inflammatory process can also cause damage to the surrounding tissues8. Nienhuijs et al. compared the Prolene Hernia System (PHS), mesh plug, and Lichtenstein methods for open hernia repair, and found that there was no difference in postoperative pain (39.7% at 3 months and 43.3% long-term) between the three groups11. One possible culprit for the high rate of post-operative pain is the presence of foreign materials in the inguinal canal near the inguinal nerves. In a study by Nienhuijs et al., the rate of chronic pain increased from 39 to 43%, which might suggest the presence of “late-onset chronic pain”. Chronic pain is usually defined as post-operative pain for longer than 6 months, while late-onset chronic pain is usually initially asymptomatic but increasingly more symptomatic after 6 months. Reinpold et al. reported the nerve management of all different open herniorrhaphy procedures with a follow-up duration of at least 5 years6. The study concluded that neurolysis, nerve contact with mesh and the Lichtenstein method are related to the development of chronic herniorrhaphy pain6. The study also stated the need to differentiate between short-term and long-term chronic pain in future studies. The hypothesis of the cause of late persistent chronic pain is the presence of foreign materials in the inguinal canal, causing progressive chronic inflammatory irritation and fibrotic changes leading to nerve traction. In our study, the rate of neuropathy  at 3-months post-op was similar in both groups, but the complaint of a foreign body sensation was statistically significantly different (no patients in the single-layer group complained of this sensation at the 6-month follow-up point). An additional patient complained of a foreign body sensation at 12 months in the 2-layer group. We hypothesized that chronic inflammation might be the reason for the increase in the number of patients experiencing a foreign body sensation in the 2-layer group.With all the advantages of the Lichtenstein method , the debilitating effect of post-herniorrhaphy chronic pain is a major drawbackThe first limitation in our study is the initial sample size. The reported postoperative pain/discomfort for MK mesh with onlay is not available, therefore we used the 40% reported rate in Lichtenstein studies. In assuming the rate of 40%, the sample size would be underpowered. Second limitation would be the telephone interview as form of follow-up. In our current clinical practice and healthcare environment, telephone interviews are the most effective way of following these patients for periods of more than 3 months. The follow-up period is also a limitation to determine any late recurrence patients. Single surgeon design of this study is a limitation but also maintain the same quality of surgeon throughout the study period. The single surgeon design limits the generalizability of the study to surgeons with different experience and training.In this randomized, prospective study, we demonstrated that 1-layer preperitoneal mesh placement is equally effective as 2-layer placement, with a similar recurrence rate. In eliminating the use of onlay mesh, we decreased the manipulation and implantation of foreign material in the inguinal canal. The decreased foreign material also led to a decrease in foreign body sensation (0% after 6 months) and an improved post-operative QoL. Therefore, we strongly believe that properly-placed, single-layer TIPP MK mesh provides the advantage of open mesh repair without the drawback of chronic herniorrhaphy pain associated with Lichtenstein repair.


DPYD gene are associated with decreased dihydropyrimidine dehydrogenase activity. However, only ∼25% of DPYD variant carriers show a decreased dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells.Decreased dihydropyrimidine dehydrogenase enzyme activity is associated with severe fluoropyrimidine-associated toxicity. Four clinically relevant variants in the DPYD genotyping in predicting fluoropyrimidine-related toxicity.To investigate if dihydropyrimidine dehydrogenase phenotyping has added value when combined with DPYD variants and phenotyped using an ex vivo peripheral blood mononuclear cell assay.Retrospective cohort study in which treatment and toxicity data were collected of 228 patients genotyped for four Severe toxicity occurred in 25% of patients with a variant and normal dihydropyrimidine dehydrogenase activity, in 21% of patients without a variant and with decreased dihydropyrimidine dehydrogenase activity, and in 29% of patients without a variant and with normal dihydropyrimidine dehydrogenase activity (controls). The majority of patients with a variant or a decreased dihydropyrimidine dehydrogenase activity received an initial dose reduction (68% and 53% vs 19% in controls) and had a lower mean dose intensity (75% and 81% vs 91% in controls). Fifty percent of patients with a variant and decreased enzyme activity experienced severe toxicity, despite the lowest initial dose and whole treatment dose intensity. They also experienced more grade 4/5 toxicities.Our results indicate that a combined genotype–phenotype approach could be useful to identify patients at increased risk for fluoropyrimidine-associated toxicity (e.g. patients with a variant and decreased dihydropyrimidine dehydrogenase activity). Because the group sizes are too small to demonstrate statistically significant differences, this warrants further research in a prospective study in a larger cohort. Many different factors including age, sex, renal function, liver function, co-medication, and other environmental factors are thought to influence the risk of toxicity.9Fluoropyrimidines (fluorouracil (5-FU) and its prodrug capecitabine) are commonly used in the treatment of several types of malignancies.10 The most important enzyme in the metabolism of fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD).11 At least 3–5% of the Caucasian population has a decreased or absent DPD enzyme activity.13 As these findings strongly depend on methods used to measure DPD activity, considerably higher numbers of patients with decreased DPD activity have also been reported.14 Several studies have shown a link between a decreased DPD enzyme activity and severe fluoropyrimidine toxicity. Between 36 and 59% of the patients who experience severe fluoropyrimidine toxicity (grade ≥3) have a decreased DPD enzyme activity.1517 Only in a minority of individuals, the reduced DPD activity can be explained by genetic variants in the DPYD gene.19Over 80% of the active 5-fluorouracil (5-FU) is metabolized in the liver.DPYD genotyping prior to fluoropyrimidine treatment after publication of a prospective trial, demonstrating that DPYD genotype-based dose reductions improved patient safety during fluoropyrimidine treatment.20 The four clinically relevant genetic variants in the DPYD gene that are known to be associated with a decreased DPD activity are DPYD*2A, DPYD*13, c. 2846A>T, and c.1129-5923C>G.21 The allele frequency of these variants is relatively low in the Caucasian population (between 0.03% and 1.35%).22 The gene activity score (GAS) is often used to translate the DPYD genotype into a DPD phenotype to describe DPD activity and for dose recommendations.23 This translation of DPYD genotypes to their functional activity is based on in vitro and in vivo studies and the subsequent GAS ranges from 0 (no DPD activity) to 2 . For heterozygous carriers of any of the clinically relevant variants, the Dutch Pharmacogenetics Working Group (DPWG) guidelines now recommend a dose reduction of 50%,25 instead of 50% for variants with a GAS of 1.0 and 25% for a GAS of 1.5 as was recommended before.23 This change in dose recommendation is supported by the Clinical Pharmacogenetics Implementation Consortium (CPIC) in the most recent update of their guideline for fluoropyrimidines and DPYD.26 Other rare and common DPYD genetic variants have been reported but are not included in the current international dosing guidelines due to insufficient evidence for functionality.27 When it is not possible to calculate the GAS based on DPYD genotype, for example when two variants might be located on the same allele, the DPWG recommends to determine DPD activity and adjust the initial dose based on available data.The European Medicines Agency recommends DPYD genotyping is widely used globally. However, DPD enzyme activity has been underexplored. We previously showed that only 25% of patients with a decreased DPD enzyme activity carries one of the four DPYD variants.18 So although DPYD genotyping (of four variants) has proven to be useful in preventing toxicity and is cost-effective,29 the majority of the patients with a reduced enzyme activity might remain unidentified and are possibly susceptible to severe fluoropyrimidine toxicity.14 In this prospective trial, the occurrence of severe toxicity (early grade 4–5 toxic events) was compared between two groups. The first group was screened for DPD deficiency using a multi-parametric approach: determining uracil and dihydrouracil concentrations in blood, along with demographic characteristics, and DPYD genotyping. In the second group no pre-treatment testing was performed. The authors conclude that multiparametric pre-therapeutic DPD deficiency screening significantly avoided early severe life threatening toxic events. To our knowledge, no publications exist investigating the added value of the combined genotype–phenotype approach compared to DPYD genotyping alone, which is already widely implemented. Therefore, the aim of our retrospective study was to describe the value of combined DPYD genotyping and DPD phenotyping in predicting fluoropyrimidine-related toxicity in an existing hospital population, reflecting clinical practice.So far, one trial describing a combined genotype–phenotype approach has been published.DPYD and DPD enzyme activity.18 All patients in this study were genotyped for the four clinically relevant DPYD variants and phenotyped with a DPD enzyme-activity assay using ex vivo peripheral blood mononuclear cells (PBMCs). The present study subsequently analysed treatment and toxicity data of these  patients. Patients with incomplete results of genotyping and phenotyping were excluded.This retrospective cohort study was performed in a single academic hospital in the Netherlands. It was approved by the local medical ethical committee. All 228 participants in this study were adults (≥18 years) diagnosed with cancer that were treated with fluoropyrimidines, either with capecitabine or 5-FU intravenously. The patients in this study were of different ethnic backgrounds, although the majority was Caucasian. Details on ethnicities will not be discussed because this was poorly reported. Fluoropyrimidine treatment was only given when the treating physician assessed the patient's condition to be sufficient, based on clinical presentation and laboratory parameters. Previous systemic therapy was allowed with resolved adverse events to grade ≤1. The patients received treatment in the period from January 2014 to December 2019. In case patients received more than one fluoropyrimidine treatment line in this period, all treatments were included in the analysis. This patient cohort is partly overlapping with the cohort described in a previous study which investigated the relationship between genetic variants in 25 In our analysis, the dose recommendations from the DPWG guidelines valid at the time of treatment were used. In some patients, due to clinical urgency, treatment had to be started right away without the genotyping and phenotyping results available; these patients were given a “safe start” .Dose adjustments were made based on genotype and phenotype results by the treating physicians according to national guidelines.DPYD gene analysis and enzyme activity test were performed in one academic hospital. DNA was isolated according to standard methods and DNA of the patients was analyzed using Sanger sequencing for the four clinically relevant DPYD variants: DPYD*2A (NM_000110.4(DPYD):c.1905+1G>A), DPYD*13 (NM_000110.4(DPYD):c.1679T>G), c. 2846A>T (NM_000110.4), and c.1129-5923C>G (NM_000110.4). An extensive description of the genotyping methods was previously published.18 In our study *1/*1 refers to patients who are not carriers of any of the four tested variants.Both the ex vivo PBMCs was performed with isolated lymphocytes. Patients were classified as having a decreased DPD enzyme activity when the enzyme activity was below 8.69 nmol/mg protein/h . The reference cohort and phenotyping methods are described in a previous publication.18The DPD enzyme-activity assay using 4 All adverse events that were possibly, probably, or definitely related to the fluoropyrimidine treatment, as described by the physician or qualified nurse practitioner, were registered. Severe toxicity refers to CTCAE grade 3 or higher. All ≥ grade 3 events were included, clinical as well as laboratory abnormalities. Radiotherapy was mentioned as concomitant treatment when this was applied during fluoropyrimidine treatment or up to two weeks before treatment.The toxicity was graded on a 1–5 scale according to the CTCAE criteria, version 5.0.DPYD variants and DPD enzyme activity measured in PBMCs, the patient cohort was divided into four groups. The first group was the control group, consisting of patients who carry none of the four tested DPYD variants and in whom a normal DPD activity was measured in PBMCs . The patients of the second group carried one of the four clinically relevant DPYD variants and had a normal DPD activity in PBMCs . The third group consisted of patients who did not carry one of the four DPYD variants, but did have a decreased DPD activity in PBMCs (DPYDvariant_no-DPDlow_activity). The fourth group contained the patients who carried one of the four DPYD variants, as well as a decreased DPD activity in PBMCs (DPYDvariant_yes-DPDlow_activity).Based on the presence of DPYDvariant_yes, the total group of patients with decreased DPD activity (with or without a DPYD variant) was designated DPDlow_activity.The total group of patients carrying a variant (regardless of DPD activity) was designated DPYDvariant_no-DPDnormal_activity group, 16 in the DPYDvariant_yes-DPDnormal_activity group, 24 in the DPYDvariant_no-DPDlow_activity group, and 6 in the DPYDvariant_yes-DPDlow_activity group. We included all patients with a DPYD variant and/or decreased DPD activity, and the majority of DPYDvariant_no-DPDnormal_activity patients who were randomly selected. No significant difference in demographics, tumor type, number of treatment cycles, or occurrence of radiotherapy treatment was found between the groups .30Colorectal cancer was the most frequent cancer reported in 66% of the patients, followed by pancreatic and breast cancer. The vast majority of the patients received treatment with capecitabine (82%), while a smaller proportion was treated with intravenous 5-FU. Standard initial treatment dose was received by 74% of the patients, while 26% of the patients received an initial dose reduction, median 75% (range 25–84%). The average body surface area (BSA) was 1.9 mDPYD gene variants associated with decreased DPD activity and 32 patients had a decreased DPD activity measured in PBMCs. No homozygous DPYD variant carriers were identified in our cohort, nor patients with zero DPD enzyme activity. 6/22 heterozygous DPYD variant carriers (27%) showed a decreased DPD enzyme activity measured in PBMCs (DPD activity was below 8.69 nmol/per mg protein/hour)  . More spSupplemental Table 2.Dose reductions and the occurrence of severe toxicity in the different patient groups are shown in DPYDvariant_no-DPDnormal_activity group (91%), followed by 84% in the DPYDvariant_no-DPDlow_activity, 78% in the DPYDvariant_yes-DPDnormal_activity, and 67% in the DPYDvariant_yes-DPDlow_activity group. The majority of the DPYDvariant_yes and DPDlow_activity patients received an initial dose reduction .The mean dose intensity was highest in the DPYD variant carriers (DPYDvariant_yes), 27% in patients with decreased DPD activity (DPDlow_activity), and 29% in the DPYDvariant_no-DPDnormal_activity group. More specifically, ≥grade 3 toxicity occurred in 25% of the DPYDvariant_yes-DPDnormal_activity group and in 21% of the DPYDvariant_no-DPDlow_activity group. In the DPYDvariant_yes-DPDlow_activity, severe toxicity occurred in 3/6 (50%) of patients. The latter are discussed in more detail below. Overall, the percentage of patients who developed severe toxicity was 32% in DPYDvariant_no-DPDnormal_activity group, 21% of patients with initial dose reduction experienced severe toxicity versus 30% treated with a standard initial dose. About half of the DPYDvariant_no-DPDnormal_activity patients who received an initial dose reduction (18/34) had a “safe start” (a lower dose awaiting genotyping and phenotyping results), the remaining for other reasons, for example general condition of the patient or laboratory abnormalities .In the DPYDvariant_yes-DPDnormal_activity group, results were similar: 20% of patients with an initial dose reduction experienced severe toxicity, which was 33% in patients treated with a standard initial dose. In the DPYDvariant_no-DPDlow_activity group, however, 27% of patients treated with a lower initial dose experienced severe toxicity, versus 15% of patients who were treated with a standard initial dose.In the DPYDvariant_yes-DPDlow_activity group) experienced severe toxicity; even though they received the lowest initial dose and whole treatment dose intensity. Furthermore, 50% (3/6) of the patients in this group completely discontinued fluoropyrimidine treatment due to adverse events. This is much less frequent in the other groups, in which 23–31% of patients discontinued treatment due to adverse events . In the other groups, grade 4 and 5 toxicity was very rare . Of note, two of these three patients from the DPYDvariant_yes-DPDlow_activity group who experienced severe toxicity, initially received a higher dose than recommended at that time by the DPWG guidelines . The patients who have a GAS of 1.0 were recommended to receive an upfront dose reduction of 50%; however, two of the three patients with a GAS of 1.0 received 75% and 100% of the standard dose, respectively. In both patients, this was because test results were not available prior to treatment (because treatment had to be started immediately). The patient who received the initial dose of 75% (awaiting results of genotyping and phenotyping) died. When the patient was identified as a variant carrier with reduced DPD enzyme activity, capecitabine was stopped completely. Shortly thereafter the patient was admitted because of deteriorating condition, neutropenic, and thrombocytopenic. The patient died of sepsis. This was likely secondary to intestinal mucositis, but the cause of the fulminant infection could not be identified with autopsy. The patient who received the standard initial dose (100%) was tested for DPD deficiency after development of serious toxicity and capecitabine was discontinued.Of the three patients with severe toxicity in the DPYD variant who also have a decreased DPD enzyme activity, might have a high risk of toxicity even with a reduced fluoropyrimidine dose intensity. These patients also seem to have more grade 4–5 toxicity. Our results indicate that in patients with a known DPYD variant, the risk of severe toxicity could be even higher when the DPD enzyme activity is also low.There are very few studies investigating toxicity in patients who are genotyped and phenotyped for DPD prior to fluoropyrimidine treatment. The results of this retrospective cohort study suggest that patients carrying a DPYD variant carriers with a decreased DPD enzyme activity. Formal conclusions with regards to the added value of pre-treatment phenotyping in patients without a DPYD variant in individualizing fluoropyrimidine treatment require a larger sample size. Currently, a prospective clinical trial is ongoing in the Netherlands to investigate this . In addition, information about cost-effectiveness of additional DPD phenotying is lacking. Nevertheless, there are important advantages of phenotyping, one being able to identify patients at risk of severe toxicity who cannot be identified with standard DPYD genotyping (which was 9% of patients in a previous study18). These include patients with rare DPYD variants or patients of other ethnic backgrounds. Phenotyping is also useful when a patient carries two DPYD variants associated with decreased DPD activity; in this case phenotyping is recommended by the DPWG.25Our results indicate that DPD phenotyping is beneficial in identifying 19 The ex vivo PBMC assay is considered a labor-intensive method for which one needs special equipment, which is not available in every hospital, which makes it difficult to implement this method on a large scale. A cut-off value of <70% below the population mean is used to classify patients as having a decreased DPD activity,15 which predicts fluoropyrimidine-associated toxicity,17 but no prospective study has been performed to determine whether this is the optimal threshold. For patients with a decreased DPD activity but no DPYD variant, there is little evidence with regards to optimal dosing strategies. The CPIC guidelines recommend a dose reduction in patients with a DPD enzyme activity <70% of normal DPD activity in the population, but no clear cut-off values are available to determine the optimal starting dose.26 In one review several phenotype-based approaches are compared.19 Only for DPD enzyme measurement in PBMCs a dosing strategy is established. This method calculates the starting dose in patients with decreased DPD activity using the following formula; the percentage remaining DPD activity compared to normal/average multiplied by the standard dose . This method, however, has not yet been validated. In summary, the clinical validity of PBMC DPD activity has been well established, but there is no clear consensus on the optimal dose adjustment strategy based on the enzyme activity.Some drawbacks exist with regards to the utility of the DPD phenotyping method in the clinic.DPYD gene variants correlate differently with phenotypic DPD enzyme activity. Although the groups are small, we found that carriers of the c.2846A>T or c.1129-5923C>G variant rarely have a decreased DPD activity measured in PBMCs (29% and 10%), while carriers of the DPYD*2A or DPYD*13 variant more frequently have a DPD activity below the threshold (67% and 50%). This is in agreement with a previous study, in which it is shown that DPYD*2A and DPYD*13 carriers have a significantly lower Dihydrouracil/Uracil ratio indicative of DPD deficiency.23The four clinically relevant DPYDvariant_yes group, 32% (7/22) experienced severe toxicity. Only 27% of the patients who are carriers of a clinically relevant DPYD variant have a decreased DPD activity measured in PBMCs. In a larger study, also including the patients from this study, we observed the same.18 For the patients with a variant and a normal DPD activity it might be possible to treat with a higher dose as the activity is in the normal range despite the variant. This is something that warrants additional research.In the total DPYDvariant_yes and DPDlow_activity patients, the initial dose was reduced more frequently and the whole treatment dose intensity was lower, compared to the DPYDvariant_no-DPDnormal_activity patients. Despite this, the differences in overall grade ≥3 toxicity seem to be small between these groups. This could be caused by the reduced dose; if DPYDvariant_yes and DPDlow_activity patients would be treated with standard doses, more toxicity would be expected. No large difference in treatment alterations due to adverse effects in patients with and without initial dose reduction seem to be present, but the groups are too small to demonstrate significance .In DPYDvariant_no-DPDlow_activity group who started treatment with the standard initial dose unexpectedly experienced less severe toxicity than DPYDvariant_no-DPDlow_activity patients with a standard initial dose. This could be due to chance as a result of the small group sizes or perhaps an indication that the threshold for low DPD activity is not optimal. The difference in severe toxicity between patients with or without initial dose reduction in the different groups cannot be explained by concomitant treatment with radio-chemotherapy (known to result in decreased risk of toxicity). Moreover, the difference cannot be explained by other factors such as whole treatment dose intensity, type of medication used, or DPD activity relative to the cut-off value .Patients in the DPYDvariant_no-DPDnormal_activity patients were included; however, the included patients were randomly selected and there is no significant difference in group characteristics. Another limitation of this study is that patients with a variant or decreased DPD activity did not always receive the recommended dose reduction according to existing guidelines, because sometimes DPYD/DPD testing was performed after start of treatment. Ideally, treatment should be started after obtaining genotyping and phenotyping results, but this is not always possible due to the urgency of chemotherapeutic treatment in case of severe illness. In these cases, dose adjustments are made in the second cycle based on test results.Our study has several limitations. First of all, the number of patients is too small for statistical analyses. This is an observational study, and our results warrant further research in a larger, prospective study. There might be a selection bias because not all Nevertheless, other aspects of our study are very important. This study was performed using an existing hospital population, which reflects common practice . Finally, this is one of the few study populations combining genotype and phenotype data, as well as treatment and toxicity data.DPYD genotyping prior to fluoropyrimidine treatment is standard practice nowadays. DPD enzyme activity measurement is used less frequently in the Netherlands. Using a combined genotype–phenotype approach could be useful in identifying patients with a DPYD variant that have an even higher risk of severe fluoropyrimidine-induced toxicity. Furthermore, phenotyping can identify patients who do not carry one of the four DPYD variants but do have a decreased, or no DPD activity . Further studies in larger cohorts are needed to provide statistical substantiation and to investigate which starting dose alterations should be considered in the DPYD variant patients with decreased DPD enzyme activity. Finally, our results underscore the importance of obtaining genotyping and phenotyping results before start of treatment, although this might not be possible in all cases.In most hospitals, Click here for additional data file.DPYD variant and decreased dihydropyrimidine dehydrogenase enzyme activity by Charlotte W Ockeloen, Aron Raaijmakers, Manon Hijmans-van der Vegt, Jörgen Bierau, Judith de Vos-Geelen, Annelieke ECAB Willemsen, Bianca JC van den Bosch and Marieke JH Coenen in Journal of Oncology Pharmacy PracticeSupplemental material, sj-docx-1-opp-10.1177_10781552211049144 for Potential added value of combined DPYD/DPD genotyping and phenotyping to prevent severe toxicity in patients with a


There are few effective conservative therapies for acute lumbar disc herniation (LDH), and the choice of nonsteroidal anti-inflammatory drugs is not recommended for all patients. The purpose of this study was to compare the effect of Yaobitong capsule with celecoxib capsule, and to further confirm the safety and efficacy of Yaobitong capsule.This study is a large sample multicenter randomized controlled trial. Eight hospitals served as sub centers to recruit patients. A total of 258 patients are divided into Yaobitong group and celecoxib group according to the ratio of 1:1. Celecoxib or Yaobitong capsule was taken orally for 14 days. Patients will complete the trial after 3 months of follow-up, and independent statisticians who are blinded to random assignment will analyze the data using SAS 9.3 software. The primary outcome was the visual analogue scale (VAS) score after 14 days of treatment, and Japanese Orthopaedic Association (JOA), Oswestry Disability Index (ODI), and SF-12 will be regarded as secondary outcomes. Safety indexes will be recorded before and after treatment, and adverse events (AEs) will be recorded throughout this trial.This study will evaluate the efficacy and safety of Yaobitong capsule in treating LDH. The experimental results will provide evidence support to treat LDH with Yaobitong capsule. One study suggests that patients who fail to respond to conservative treatment for 6 weeks meet the surgical indications. At present, although the surgical treatment schemes such as percutaneous endoscopic lumbar discectomy are gradually improved, conservative treatment is still the first choice considering the acceptability of surgical treatment and postoperative complications.–8Lumbar disc herniation (LDH) is a frequently occurring disease in orthopedics, which seriously endangers the physical and mental health of patients.–13 However, a network meta-analysis showed that the effect of oral Chinese medicine is lower than that of acupuncture and massage, but there is insufficient evidence to this conclusion for acute LDH. Recent animal studies have shown that Yaobitong capsule can inhibit the inflammatory response and neuropathy of herniated intervertebral disc. However, there are few clinical studies on the treatment of lumbar process with lumbago, and there is a lack of clinical evidence.A large number of meta-analysis and randomized controlled trials showed that acupuncture, massage, traditional Chinese medicine, epidural injections and non steroidal anti-inflammatory drugs have a clear curative effect on LDH, which provides an optional treatment scheme for patients. Although celecoxib capsules are widely used in the treatment of low back pain, there is evidence that celecoxib does not completely cure these lesions. Moreover, celecoxib lacks sufficient evidence to prove their effectiveness in improving daily function. As we know, celecoxib also has adverse reactions. The most common adverse reactions are gastrointestinal reactions, which increases the risk of gastrointestinal bleeding and perforation. In addition, patients with cardiovascular disease may not be suitable for celecoxib.–20 Therefore, this study compared Yaobitong capsule with celecoxib capsule to further confirm the efficacy and safety of Yaobitong capsule, which may provide optional oral drugs for patients with acute LDH.Guidelines of the North American Spine Society and the American College of Physiologists recommend celecoxib as the first-line treatment for acute LDH.This study is a multi-center, randomized controlled trial with a superiority design. Subjects who met the inclusion conditions will be allocated to the experimental group and the control group in a ratio of 1:1. The experimental group will be treated with Yaobitong capsule and the control group will be treated with Celecoxib capsule. The subjects in the 2 groups have no other basic treatment, and the treatment period is 14 days and the follow-up period was 3 months. The trial process is shown in Figure This study was approved by the ethics committee of Changchun University of traditional Chinese medicine on June 11, 2021 (Permission number CCZYFYLL2020 Shenzi-016-02), and is valid until June 11, 2023. We will follow the International Conference Guideline for Good Clinical Practice to ensure that the data and the results are credible. Before starting the study, Patients will be informed of the treatment plan and ethical approval number, and they have the right to know the intervention measures of the trial. Informed consent will be signed by the patients. The patients will sign the informed consent (see appendix 1) if they agree to participate in the clinical trial. This study is registered on September 22, 2020 with the Chinese Clinical Trial Registry, and the registration number is ChiCTR2000038405.The study began to recruit patients on November 8, 2021. The first volunteer was recruited on November 29, 2021. It is expected to complete the patient recruitment in November 2022.Eight sub centers from different provinces in China participated in the implementation of the project. The First Affiliated Hospital of Tianjin University of traditional Chinese medicine, Gansu Hospital of traditional Chinese medicine, and Dong zhimen Hospital of Beijing University of traditional Chinese medicine were respectively responsible for the recruitment of 24 patients; Henan Luoyang orthopedic hospital, the Affiliated Hospital of Shanxi University of traditional Chinese Medicine and the First Affiliated Hospital of Hunan University of traditional Chinese Medicine were responsible for recruiting 36 patients respectively; Shandong Medical Biotechnology Research Center was responsible for recruiting 40 patients; Suzhou Hospital of traditional Chinese medicine was responsible for recruiting 38 patients. Each sub center will recruit volunteers through local advertising.,21 The diagnostic criteria are as follows:The diagnostic criteria of LDH refer to an evidence-based clinical guideline for the diagnosis and treatment of LDH with radiculopathy and The diagnostic efficacy standard of TCM syndrome of the people’s Republic of China.Medical history: with or without a definite history of lumbar injury.Symptoms and signs: low back pain radiates to buttocks and lower limbs, abdominal pressure increases, such as cough, sneezing, etc; There was tenderness and radiation to the lower limbs, and the lumbar movement was limited; There may be hypersensitivity or dullness in the affected innervated area of the lower limbs. Muscle atrophy may occur in patients with a long course of the disease. Tendon reflex and dorsiflexion of the toe may be weakened.Physical examination: positive muscle strength and sensation test; Straight leg raising or strengthening test was a positive result.Auxiliary examination: MRI showed LDH.The patient was aged between 18 and 70 years old. The clinical symptoms were leg pain extending below the knee, which was consistent with the corresponding nerve root distribution area of the MRI.The first course of low back pain or leg pain was less than 3 months, or the latest acute recurrence time was less than 3 months.This study will compare the efficacy and safety of Chinese patent medicine and Western medicine in the treatment of LDH.The VAS scores of leg pain were more than or equal to 4.0.The patient had a history of lumbar surgery.Patients have received oral or epidural steroid therapy in recent 3 months.Severe diabetes with peripheral neuropathy, severe osteoporosis, gastric ulcer, gastrointestinal bleeding, spinal tumor, spinal tuberculosis, spinal compression fracture.Allergic to non-steroidal drugs.There are symptoms of cauda equina nerve damage or parenchymal and progressive loss of motor function.Patients with litigation or legal claims.This study will apply the central randomization method by using the interactive Web response system to randomly assign the subjects to any group. The personnel providing the random sequence do not participate in the implementation of the whole trial. All clinical trial researchers evaluating outcomes can only get random numbers to assign patients by using computer, and neither the researchers nor the patients know which group the patients will be assigned. The independent statisticians will be blinded to random assignment.The treatment regimen was divided into treatment and controlled groups according to randomization. The treatment group(T) was given oral Yaobitong capsules for 14 days. Usage and dosage: oral administration, 3 capsules each time, 3 times a day after meals. Main functions: promoting blood circulation and removing blood stasis, removing wind and dampness, promoting qi, and relieving pain. Indications: low back pain caused by blood stasis and qi stagnation and closed vein.The controlled group (C) was given oral Celecoxib capsules for 14 days. Usage and dosage: oral administration, the recommended dosage is 400 mg for the first dose on the first day, which can be increased by 200mg if necessary, and then 200 mg twice a day according to the medication instructions.–27 It is expected that after 2 weeks of treatment, the difference between the experimental group (Yaobitong capsule) and the control group is 0.5 points, and the standard deviation of the 2 groups is the same (standard deviation = 1.1). It was hypothesis α = 0.05 , 1-β = 0.90. According to the calculation of PASS 11 software, at least 206 cases were collected in this study. Assuming a loss of follow-up rate of 20%, 258 patients need to be included in this study.This study is a randomized controlled trial with parallel control and superiority design. According to previous literature, the VAS score of the control group (celecoxib capsule) after treatment was 5 points. Patients choose the score according to the degree of leg pain, which is the VAS score to evaluate the degree of pain.VAS  score of leg pain on the 14th day of treatment was the main evaluation index of curative effect. VAS adopts a 10 cm scale divided into 1 to 10 points, of which 10 points are the maximum pain and 0 points are painless. The lower the score, the lower the degree of functional restriction, and vice versa.Oswestry disability index (ODI) was used to assess dysfunction. The ODI has 10 main items, including 60 sub-items, to evaluate dysfunction from multiple dimensions. The JOA total score is 29 and the lowest is 0. The lower the score, the more obvious the dysfunction. The improvement index and improvement rate were used to assess the degree of improvement after treatment.Japanese Orthopaedic Association (JOA) was used to assess dysfunction and degree of improvement.Improvement index = post-treatment score - pretreatment score.Improvement rate = [(post-treatment score - pretreatment score)/ 29 - pretreatment score] × 100%. The higher the score, the better the patient’s quality of life.SF-12 scale is a simplified version of SF-36, which contains 12 items with a full score of 100 to evaluate the physiological and psychological status of patients.Secondary outcomes included the ODI score, JOA score, and SF-12 score of all visits. In addition, VAS scores at other visit times were also secondary outcomes. All visit points and evaluation indexes are presented in Table In this study, 8 visit points were designed  and an electronic data management system. The study staff will collect basic subject information, observational indicators, laboratory indicators, and AEs. Data collators will fill in the above data in the case report form and study medical record.P value of bilateral test is less than 0.05. Multivariate imputation by chained equations method will be used for analysis and data processing of those who violated the trial protocol. Data analysis will be conducted by independent statisticians.All outcomes were analyzed based on intention-to-treat analysis. The analysis will be carried out with SAS 9.3 software. It is statistically significant that the ,32 Although some clinical guidelines highly recommend nonsteroidal anti-inflammatory drugs such as celecoxib and ibuprofen as first-line drugs to low back pain, Yaobitong, as a Chinese patent medicine, has been widely used in the clinical treatment of low back pain in China.Conservative therapy is the first choice for patients with acute low back pain. Some studies pointed out that physical therapy such as traction, laser, and ultrasound can effectively treat acute LDH, which may provide effective external therapy for patients in the acute stage. Traditional Chinese medicine believes that Yaobitong capsule has the effects of promoting blood circulation, hemostasis, detumescence, and analgesia, and can effectively treat patients with acute low back pain. Recent studies on the determination of rat plasma components found that the Yaobitong capsule mainly contains ginsenoside Rg1, ginsenoside Rb1, osthol, tetrahydropalmatine, paeoniflorin, paeoniflorin, and ferulic acid, among which the content of ginsenoside from Panax notoginseng is the highest,in recent years, Ginsenoside Rg1 and ginsenoside Rb1 are considered to be effective components for the treatment of LDH. Previously, several randomized controlled trials showed that oral Yaobitong capsule could significantly reduce VAS score, IL-1β and TNF- α in serum, the total effective rate of LDH is more than 95%.–37However, the intervention of these trials adopted the scheme of Yaobitong combined with other therapies . At present, there is deficient evidence of efficacy on the alone application of Yaobitong capsule.Yaobitong capsule contains Panax notoginseng, Ligusticum chuanxiong, Rhizoma Corydalis, Radix Paeoniae Alba, Achyranthes bidentata, Cibotium barometz, cooked Rhubarb and Angelica pubescens.Overall, the current evidence shows that oral Yaobitong capsules have a good effect on LDH, but this conclusion is not confirmed by large sample randomized controlled trials, especially in the treatment of acute LDH. The purpose of this study is to further explore the efficacy and safety of Yaobitong capsules in the treatment of acute LDH and to provide reference evidence for health decision-making. Referring to the guidelines on low back pain, we developed a control group celecoxib, which is recommended as a first-line treatment for acute low back pain. We adopted internationally recognized efficacy measurement methods, including VAS, JOA, ODI, and SF-12 scale. The lumbar dysfunction, degree of pain, and quality of life of all participants will be assessed by these scales. In addition, based on the large sample study of 258 patients, we can explore adverse reactions and safety indexes of Yaobitong capsules to evaluate the safety of Yaobitong in patients with acute LDH.This study is a large sample multi-center randomized controlled trial, but there are limitations: the blinding is not implemented for participants and outcome assessors in this trial, which may produce potential bias factors. The statisticians who pool all results will be blinded throughout this trial, which may effectively reduce bias. The conclusions of this trial will provide the decision maker with valid information concerning the effect and safety of Yaobitong capsules in patients with acute LDH.Conceptualization: Zhenhua Li, Xianshuai Zhang, Kexin Yang, Bin Tang, Siyi Wang.Data curation: Xianshuai Zhang, Siyi Wang, Kexin Yang, Changwei Zhao, Shaojun Li, Zhenhua Li.Formal analysis: He Yin, Guohui Zhou, Siyi Wang, Mingyu Gu.Investigation: Xianshuai Zhang, Siyi Wang.Methodology: Zhenhua Li.Project administration: Xianshuai Zhang.Software: Bin Tang, Kexin Yang.Supervision: Zhenhua Li.Writing – original draft: Xianshuai Zhang, Kexin Yang, Siyi Wang.Writing – review & editing: Zhenhua Li.


Data on the adverse events of opioids for cancer-related pain in Sudanese patients are limited. We conducted this study to evaluate the pattern and severity of adverse events of immediate release morphine, and tramadol used in the treatment of cancer-related pain. A secondary aim was to determine the response rate to opioids for pain control in cancer patients treated at the National Cancer Institute-University of Gezira (NCI-UG), Sudan.p value < 0.05 was considered statistically significant in all analyses.This descriptive cross-sectional study was conducted at NCI-UG between 12 March 2019 and 12 May 2019. A pre-designed questionnaire was used to collect the clinical data of cancer patients on oral opioids for pain control during the study periods. Chi square test was applied to determine whether there is a significant association between the adverse events and the demographic/clinical variables. p value < 0.005). Pain was controlled in 36% of patients, improved in 53% and not controlled in 11% of them.One-hundred and thirteen patients were screened in the study. Of these, three suffered from cognitive dysfunction and ten patients declined to participate in the study. Thus, 100 patients met the criteria for inclusion in this study. Breast cancer was the most frequent diagnosis (17%) followed by colorectal cancer (16%). The majority (91%) of patients had advanced or metastatic disease. The most frequently reported opioids-related adverse events were dry mouth (68%), constipation (61%), sedation (49%), nausea (31%) and vomiting (24%). Most of these symptoms were graded as mild to moderate and no patient had grade IV or V adverse events. Constipation and dry mouth were more frequent among patients received morphine compared to patients received tramadol (This study shows a high prevalence of opioids-related adverse events. The majority of the opioids-related adverse events were grade I or grade II. There seem to be differences in the prevalence of opioids-related adverse events between patients receiving tramadol and those treated with morphine. Moreover, suboptimal pain control adds to the burden on already limited health resources. Therefore, the adequacy of cancer pain management in our setting should be systematically evaluated and effective cancer pain management programmes should be developed. Pain is one of the most feared and burdensome symptoms experienced by cancer patients, particularly in the advanced and terminal stages of the disease when the prevalence approaches 80% , 2. CancThe goals of pain management are to reduce pain and improve QOL while limiting excessive adverse events. Opioids-related adverse events can reduce QOL and limit opioids dosage which leads to ineffective cancer pain management . Common Sudan is a low-income country in sub-Saharan Africa with a population of approximately 40 million . The majA previous single institution study conducted in Sudan showed that uncontrolled pain was the most frequent symptom that prompted patients with cancer to attend the outpatient unit without an appointment . Data onNCI-UG specialises in the diagnosis and treatment of cancer patients. It is located in Wad Medani city, the capital of Gezira state, which serves the whole Gezira state and nearby states. Radiotherapy, chemotherapy and palliative care are cancer treatment modalities available at the NCI-UG.This prospective cross-sectional study was conducted to evaluate the pattern and severity of oral opioids related adverse events among cancer patients at the NCI-UG between 12 March 2019 and 12 May 2019. A secondary aim was to determine response rate to opioids for pain control in this cohort of patients.Cancer patients (>16 years old) on oral opioids (short acting morphine or tramadol) for at least 1 week were eligible to be included in the study. Immediate release morphine and tramadol are the only available opioids in our setting. Patients unable to answer the interviewer or patients who refuse to participate in the study were excluded.A predesigned paper-based questionnaire containing eight parts was developed by the principal investigator. The questionnaire was submitted to a panel of three experts to review the content accuracy and internal validity. It was then piloted on ten patients and modifications were made according to the suggestions. The patients were interviewed by the researchers and a questionnaire was filled out based on patients’ responses to the questions. The data collected included: demographics data , clinicopathological variables , types of pain and severity according to a 5-point numerical scale , types of opioid analgesics, response to pain medications and opioids related adverse events according to the Common Terminology Criteria for Adverse Events Version 4.0, National Institute of Health, National Cancer Institute. Consent was obtained from participants prior to their inclusion in the study.p value of less than 0.05 was considered statistically significant in all analyses.Data were entered into and analysed using Excel software and SPSS version 24. Categorical variables are presented as frequencies and percentages. Chi square test was applied to determine whether there is a significant association between the adverse events and the demographic/clinical variables. The study was approved by the ethics committee of the NCI-UG, Sudan. Data were collected anonymously.One-hundred and thirteen patients were screened in the study. Of these, three suffered from cognitive dysfunction, ten patients declined to participate in the study. Thus, 100 patients met the criteria for inclusion in this study. The majority of patients were female (65%). Breast cancer was the most frequent diagnosis (17%) followed by colorectal cancer (16%). The majority (91%) of patients had advanced or metastatic disease. The general characteristics of the study population are presented in Of the included patients, 45% suffered from somatic pain, 45% suffered from visceral pain and 10% suffered from neuropathic pain. As shown in The most frequently reported opioids-related adverse events are shown in p value < 0.005). Thirty patients in the tramadol group (55.6%) and 9 patients (19.6%) in the morphine group were free of constipation during the study period. Among patients who did not reported opioids-related dry mouth, 23 patients were in the tramadol group (42%) and 9 patients (19.6%) in the morphine group. Although not statistically significant, adverse events of opioids on the central nervous systems (CNS) are more frequent among patients treated with tramadol com pared to patients received morphine  were high. The majority of adverse events reported rated as mild to moderate. Constipation, dry mouth and alteration level of consciousness seem to be of particular impact because of high prevalence.In this study, dry mouth was the most frequent (68%) opioids-related adverse event. We found patients who received tramadol experienced significantly less dry mouth compared to those who received morphine. Previous studies showed a large variation (1%–94%) in the occurrence of dry mouth , 18. StuConstipation is estimated to occur in 25%–50% of cancer patients. It is frequently related to opioids analgesics in patients with advanced cancer . HoweverAdverse events of opioids on the CNS are common. In this study, sedation was the most frequent (49%) adverse effect of opioids on CNS followed by drowsiness (13%) and delirium (8%). The incidence of sedation, drowsiness and delirium in patients with advanced or metastatic cancer is high. Moreover, its causes are often multiple and can be attributed to opioids, other medicines and the disease itself. Therefore, it is difficult to define how much of the sedation, drowsiness and delirium seen at the end of life can be attributed to opioids and how much to the other causes. Sedation caused by opioids may be reduced by decreasing the dose or by rotation to alternative opioids , 22. In The incidence of opioids-induced nausea and vomiting is estimated to be 10%–40% . In thisPruritus (itch) is an occasional side effect of opioids use. In this study, pruritus was reported by 18% of our study population. The mechanism underlying the pruritogenic effects of opioids is still not completely understood . DespiteIn the current study, we examined possible differences in the prevalence of opioids-related adverse events between patients receiving tramadol and those treated with morphine. The non-opioids characteristics of tramadol may explain the difference in the spectrum of side effects compared to morphine. Tramadol treatment resulted in statistically significant lesser constipation and dry mouth than morphine. Although not statistically significant, CNS related adverse events appear to occur more frequently with tramadol than morphine. The difference in the spectrum of side effects reported in this study should be confirmed in a prospective randomised controlled trial. Moreover, further studies are required to compare the difference in intensity of side effects of tramadol and morphine in patients with cancer pain in our limited resource setting.The current study is a single institution’s data; we therefore cannot make conclusions for all Sudan and our findings should be generalised with the necessary caution. However, the NCI-UG is the only referral oncology hospital in central Sudan; hence, the current data provide the best indicator of the pattern and severity of oral opioids-related adverse events among cancer patients within this region.This study shows a high prevalence of opioids-related adverse events. These adverse events could be obstacles that hinder pain therapy or cause its termination. Therefore, it is necessary to undertake preventive measures for reducing preventable opioids-related adverse events such as constipation and dryness of mouth which would ensure that the benefits of pain treatment are not threatened by the intensity of negative effects. Moreover, uncontrolled pain adds to the burden on already limited health resources. Therefore, the adequacy of cancer pain management in our setting should be systematically evaluated and effective cancer pain management programmes tailored to our limited resources setting should be developed. Further research should focus on exploring the effect of opioids-related adverse events on adherence to pain medications.M.M.A.E. was the project leader. All authors contributed to the design and implementation of the research, analysis of the results and writing of the manuscript.No funding was received for this study and none of the authors has any conflicts of interest relevant to this work.