Opioids are extensively used in patients with cancer pain; despite their efficacy, several patients can experience ineffective analgesia and/or side effects. Pharmacogenetics is a new approach to drug prescription based on the “personalized-medicine” concept, i.e., the ability of tailoring treatments to each individual’s genetic/genomic profile. Pharmacogenetics aims to identify specific genetic variants that influence pharmacokinetics and pharmacodynamics of drugs, better determining their effectiveness/safety profile. Opioid response is a complex scenario, but some gene variants have shown a correlation with pain sensitivity, as well as with opioid metabolism and clinical efficacy/adverse events. Although questions remain unanswered, some of these gene variants may already be used to identify specific patients’ phenotypes that are more prone to experience better clinical response . Once adopted, this approach to opioid prescription may improve a patient’s outcome. This review summarizes the available data on genetic variants and opioid response: we will focus on basic pharmacogenetic and its impact in the clinical scenario discussing how they may lead to more appropriate opioid prescription in cancer patients. Opioids have been used for years in chronic pain management, both in cancer and non-cancer patients. Even though they are effective in many cases, opioids have some important side effects, which limit their effectiveness in clinical practice. Adverse events such as constipation, nausea, vomiting, itching, and sedation can occur also, even after a single dose. Long-term administration can lead to tolerance and hyperalgesia, reducing effectiveness despite the increasing doses and molecule rotation ,2. The mAs well as for most of the drugs (probably even more for opioids) it is difficult to find the optimal combination between appropriate dose and side effects. The concept of the so-called “personalized medicine” could help to overcome this problem, offering new information to find the best effective and safest dose for a specific patient and to provide maximum efficacy with no/minimum adverse events. The philosophy of “personalized medicine” is to choose medications according not only to patient’s history but also to his genetically determined pharmacokinetic and pharmacodynamics. In fact, the major determinant in defining the specificity of each individual is the genetic profile, which defines any aspect of pharmacology and physiology, including the response to pain medication. Great attention has been paid in the last ten years to the genetic component that influences pain perception and opioid therapies, which may define the most suitable drug for any patient, both to provide adequate pain relief and to improve oncologic outcome .In this narrative review we focus on mechanisms underlying genetic variation in opioid response; starting from the basics of opioids’ pharmacology, we present how genetic profile may determine pharmacokinetics and pharmacodynamics efficacy and safety of opioid medication, helping to choose the “ideal” medication (and adjust the dose) for cancer pain patients according to each individual’s characteristics. Our literature search was conducted in PubMed, using MeSH  and free-text terms. The Boolean operators “OR” and “AND” were used to help search terms for the main subjects. The first subject included terms relating to chronic pain conditions: “chronic pain” or “malignant” or “cancer” or “palliative care”; second, terms relating to pharmacogenetics: “pharmacogenetic” or “genetic” or “genomic” or “genotype” or “cytochrome P450 3A4/A5” or “cytochrome P450 2D6” or “CYP3A4/A5” or “CYP2D6” or “OPRM1” or “mu opioid receptor” or “ABCB1” or “UGT” or “UDP glycosyl transferase” or “COMT” or “catechol o amine methyltransferase”. Last, we searched for terms relating to the predefined opioids: “opioid” or “opiate” or “fentanyl” or “tramadol” or “codeine” or “morphine” or “oxycodone” or “tapentadol” or “methadone.”Each of the groups of search terms was searched simultaneously with the “AND” Boolean operator to identify original research articles, reviews, and metanalyses published up to February 2020. The search was limited to articles published in the English language with human subjects. Other relevant articles were retrieved from the available papers.Opioids are mainly metabolized by the cytochrome P450 (CYP) system or by UDP-glucuronosyl-transferase (UGT) in the liver, which where therefore mainly investigated in the setting of opioids’ PK . Some opioids see  are desiCYP2D6 gene is characterized by extreme variability [The cytochrome P450 2D6 isoenzyme (CYP2D6) is primarily responsible for activation of opioid pro-drugs and deactivation of substrate opioid drugs . The CYPiability  that traiability .CYP2D6 variability is classified in 4 phenotype groups: ultra-rapid metabolizer (UM), extensive  metabolizer (NM), intermediate metabolizer (IM), and poor metabolizer (PM [izer (PM ). CYP2D6 may help in predicting the extent of analgesia in clinical patients. Some case reports have described severe and even unexpected lethal adverse events in patients with CYP2D6 variants  when treated with codeine and tramadol ,12,13,14CYP2D6 deals with postoperative analgesia: available data suggest that genetic testing may be a valuable tool to improve opioid prescription in different surgical settings and for different molecules [CYP2D6 polymorphism was significantly (p = 0.018) associated with treatment outcome: reduced (CYP2D6*6) or absent (CYP2D6*9) CYP2D6 activity was correlated with lack of therapeutic effect, and ultra-rapid metabolizers showed an increased risk of side effects [The wider part of the literature on olecules . Less daolecules ; as wellolecules . Further effects . CYP2D6 variability has been proposed for clinician treating chronic pain, to improve safety and efficacy [n = 375) and scheduled to receive tramadol/codeine were assigned to standard care  or to a CYP2D6-guided prescription. In the latter group, CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing according to this phenotype. IM/PMs had greater improvement in the CYP2D6-guided versus usual care arm (p = 0.016); furthermore, clinically meaningful reduction in pain was more often observed (24% versus 0%) when patients were prescribed according to CYP2D6 phenotype rather than usually done. On the other hand, NM didn’t show any difference when genetic-guided approach was pursued instead of usual (p = 0.54). This trial demonstrated successful implementation of CYP2D6-guided opioid prescription and improved pain control in patients theoretically more prone to benefit of this pharmacogenetic approach (IM/PMs prescribed with tramadol or codeine) [Recently, personalized opioid dosing algorithm based on efficacy ,19. Thiscodeine) .CYP2D6 genotype impacts on plasma concentrations of tramadol and its demethylated metabolites, as well as drug tolerability [CYP2D6 genotypes had clear effects on the pharmacokinetics of opioids (namely oxycodone), no difference was found between the class of metabolizers in pain intensities, nausea, tiredness, and cognitive function [Surprisingly, very few studies deal with chronic cancer pain. With not much data available, the evidence of genetics on clinical outcomes is controversial. A recent study in cancer patients shows that rability . On the function . This lack of clinical association may be linked to several factors, cachexia being one of the major ones. Cachexia is associated with abnormalities in a body’s homeostasis that reflect a chronic inflammatory status, and has been demonstrated to impact on oxycodone metabolism in different studies ,24. FurtCYP2D6 profoundly impacts opioids metabolism, but differences between opioids may exist. As well, differences in clinical effects should consider other factors  that may influence opioid metabolism. These motivations strongly recommend new studies in this specific population, where indications drained by postsurgical setting and benign pain may apply differently and may justify discrepancies in clinical efficacy/safety. Further data from dedicated studies, focusing on specific opioids and analyzing cancer-specific variables may better guide CYP-related opioid prescription.Taken together, these data suggest that CYP3A4 and CYP3A5) [CYP2D6 [CYP3A4 and CYP3A5 encode for decreased enzymatic activity [CYP2D6 these variables might be considered in the future, since their relationship to efficacy and adverse effects may aid in improving the safety and efficacy of opioids [Other relevant genes for opioids are cytochrome P450 family 3 subfamily A members 4 and 5 ( CYP3A5) . They ar CYP3A5)  , while drugs that are deactivated by CYP2D6 may be dangerous in the first. On the contrary, UMs should avoid pro-drugs because of the documented possibility of lethal side effects, while inactivated drugs may be ineffective. CYP3A4/5 may also impact on opioid response. Relative influence may vary according to the type of opioid and (most relevant) to other features  peculiar for the clinical scenario of cancer patients. UDP-glucuronosyl-transferase (UGT) 2B7 is the cornerstone for morphine metabolism: morphine is glucuronated to morphine 6-glucuronide (M6G) and morphine 3-glucuronide (M3G) . M6G hasUGT2B7 in both the other coding and regulatory region were studied in different cohorts on long-term morphine therapy [As for Cytochrome P-450, genetic polymorphisms may ideally translate into a variable activity of the enzyme and of morphine PK. However, studies highlighted their minor clinical significance. Polymorphisms in  therapy . Even wh therapy . These sUGT2B7 polymorphisms were not significantly (p > 0.5) associated with responders or non-responders [UGT1A1/UGT1A8 showing weak associations with lower morphine glucuronide to morphine ratios after oral administration of morphine [A further study in cancer patient established that the genotypes or allelic frequencies of various sponders , with nosponders . Recentlmorphine .UGT2B7 have been significantly associated with morphine-induced adverse effects in a study on Japanese cancer patients under oral controlled-release morphine: the frequency of nausea was significantly associated with the UGT2B7*2 (p = 0.023), which appears to have a protective effect [Surprisingly, polymorphisms in e effect . HoweverUGTB7 variability seems not to determine clinical variations in patient’s response to morphine. Some effect may be exerted on side effects, but very few data are available. However, molecules with UGT-based metabolism  may be a valuable choice for patients with CYP variants or concomitant medications that contraindicate the use of other opioids.To summarize, The μ opioid receptor (OPRM) is the main target of both endogenous- and clinically-used opioids primarily involved in drug dependence and opioid-induced respiratory depression .OPRM1) codes for this receptor. A functionally important variant is the mostly studied  is associated with lower pain threshold, and higher opioid consumption in post-operative patients as well . Thus, tpendence ,58. Somependence ,59,60. TOPRM1 may be more complicated: we need to elucidate the magnitude of its effect on opioid response in combination with other genetic variants  [However, results on chronic cancer and non-cancer patients are conflicting : some stor ESR1)  and the COMT) gene is one of the most frequently analyzed genes in the pain scenario. This gene codes for COMT enzyme, which is involved in numerous physiological functions (including pain perception) [Catechol-O-methyltransferase (ception) ,63,64,65ception) ,67. Three functional haplotypes have been defined, i.e., low pain sensitivity (LPS = Met/Met), average pain sensitivity (APS), and high pain sensitivity  . More reCOMT variations and opioid requirements in perioperative pain. They have been recently pooled in a metanalysis, which failed to detect any association with postoperative pain and opioid requirements in the perioperative setting [OPRM1, COMT, and ESR1 genes better explain variability in morphine consumption than single genetic variants after major abdominal surgery [Different studies have been conducted to investigate the correlation between  setting . Reasons surgery . Rapid d surgery .COMT variability has been associated with morphine requirements in different studies, including the pediatric population [COMT) and opioid requirements [COMT variability. In the context of chronic cancer pain, pulation . Howeverpulation . Since mpulation ,78, whilpulation . As a mairements . Thus, fCOMT may influence opioid response with other-than Val158Met variability. Rakvag et al showed that a specific haplotype including 11 COMT SNPs (that is mostly represented in the Caucasian population) was associated with less morphine consumption than non-carriers did [iers did . This apiers did .OPRM1 and COMT gene variations are involved in both pain sensitivity and opioid response. Cancer patients with at least one A allele (OPRM – A118G variant) and a Met allele  seem to experience less pain and more analgesia, with less side effect. Other genes involved in drug transport and metabolism are likely to have an effect on clinical response, alone or in combination. In summary, Pain is a main concern for most of patients with cancer: pain is limiting for their quality of life and also has a huge impact on their outcome . OpioidsOne of the major contributors in determining pharmacologic response (including opioids) is the genetic background, which is different among patients and can influence several aspects of drug response (pharmacokinetics) and sensitivity (pharmacodynamics). Theoretically, mapping the inter-individual variability in genes involved in opioid response is the “Holy Grail” for pain physicians. Knowing how a patient may react to a specific drug may actually be the main step towards a more effective “personalized” therapy. Pharmacogenetics has the specific endpoint of understanding those genetic variations, in order to tailor specific treatments to each and every patient. This is even more important in cancer patients: they are usually multi-pharmacologic, more prone to drug–drug interactions and potential adverse events. The “trial-and-error” approach is ineffective, dangerous, costly, and causes delays in effective care: pharmacogenetics and personalized medicine may help in overcoming this obsolete approach, using genetic tests to assess each patient’s risk for adverse events and the likelihood to positively respond to a given drug, thereby allowing an “informed” drug selection. In such a scenario, different genetic variants have been investigated for many aspects of opioids, including both PK and PD features. In a clinical purpose, it is even more important for prescribers to understand how genetic variants affect efficacy and safety, i.e., how each variant and their combinations affect pain relief and the development of side effects. Testing a patient for this purpose may help changing prescriptions to improve therapeutic profile, determining the most effective drug at the safest dose. In the field of PK  the main actor is the cytochrome P 450 family, which is involved in liver metabolism of many drugs (including opioids). Different isoforms are active in opioid metabolism, but CYP2D6, 3A4, and 3A5 are the main (or at least those who have been mostly investigated).CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers [Testing CYP2D6 in the clinical setting provided interesting data; although less of them come from the specific scenario of cancer pain management, they suggest that CYP family testing may help better opioid prescribing. It’s probably too early to tell if we can screen patients to specifically identify those who will respond better and with lower doses, although studies to genotype patients and guide oxycodone prescribing are in place , and a rbolizers . In any bolizers . CYP2D6 gene . With this approach, patients with dysfunctional alleles should be treated with caution: CYP2D6 substrate drugs (including opioids) should probably be avoided since they may result in poor efficacy and/or increased adverse events . Literature provides less evidence for other opioids; caution should especially be taken with the use of tramadol, oxycodone, and hydrocodone.A recent paper has even proposed an alternative to classic nomenclature that is more practical for clinician . This syents see . Specifigenotype . Both CYThe Dutch Pharmacogenetics Working Group (DPWG) has produced other relevant guidelines . Even thCYP2D6 status is also important when other medications affecting the same/other pharmacokinetic pathways are concomitantly administered. Several drugs have common metabolic pathways and combining them can alter drug kinetics and lead to lethal consequences in patients with existing comorbidities or a pre-existing UM status.Further, since CYP450 family affects many drugs and their metabolism, whenever patients display abnormal reactions to these drugs, a genetic contribution should be always considered. Once investigated, such a contribution may unravel an unexpected abnormal response to opioids.UGT genetic variability failed to demonstrate any important association with opioid response [OPRM1, KCNJ6, and COMT gene variants [In these cases, or whenever drug–drug interaction may be suspected, molecules with different metabolic pathways may be a better choice. Since the available data on response , morphinresponse , as wellresponse ; this mavariants .OPRM1 and COMT genes. Many open issues remain that need to be fixed in the future, but it is honest to affirm that identifying patients with some specific variants of these two genes may help in better opioid prescription. Pharmacogenetics is a major tool for clinicians when approaching to PD of opioids. In this context, more data are available than for PK, especially for OPRM1 A/A genotype and patients with COMT Met/Met genotype have been invariably associated with a more favorable phenotype, also in specific cancer patients’ populations: less pain sensitivity, better response to opioids with lower consumption, less side effects [Patients with  effects ,36,39,66Further, since opioids are immunosuppressive and affect the endocrine system , they miCYP2D6) for clinical management of patients with OPRM1 variants based on 3 allelic variants: Normal, sub-functional, dysfunctional [OPRM1 is subnormal or dysfunctional, the patient is less likely to benefit from opioids, and more likely to experience side effects and dependence [OPRM1 status. Relying on non-opioid drugs or alternative therapies may be better, in this case. As for CYP testing, pharmacogenetics may help screening patients prone to ineffective pain relief and adverse events. The same authors proposed a simple classification  with pain relief. However, rs12948783 of the RHBDF2 gene showed the best statistical association [Since different genes regulate pain and analgesia, approaching pharmacogenetics with a multiple SNPs approach may be promising . To the RGMA, associated with opioid dependence (p = 1.3 × 10−8) [RGMA encodes repulsive guidance molecule A, which is a central nervous system axon guidance protein. GWAS (Genome—Wide Association Studies) unraveled new lead into our understanding of pain pathophysiology [A recent analysis on 4 different populations with thousands of patients identified a variant on chromosome 15, rs12442183, near  × 10−8) . RGMA enysiology , confutiysiology , also beBetter prescribing and better patients’ management may also have a pharmaco-economic impact. For example, 70% of cardiac drugs showed a different response or a different risk of adverse effects based on genetics, supporting the idea that having this information before prescribing is warranted . The samOn the other hand, costs for obtaining and interpreting samples, as well as counseling patients should be accounted. However, broader data and more knowledge, combined with refined and cheaper testing, may help overcoming the obsolete “trial-and-test” philosophy, improving patients’ outcome and impacting on healthcare costs . Some prThe same concept may be applied to pharmacologic development in industries , which mIn the meantime, when a genomic-oriented medical approach is pursued, ethical concerns rise (as well as with any “omics” approach), especially in the field of pain medicine. Genomics (and other “omics”) technologies produced not only a deep change in biomedical research, but the potential to discover large amounts of possibly important incidental information is an issue, as well as physicians’ obligations arising from this type of the research, protection of the included individuals and personal data, and communication of such research to patients and the community .In the specific context of opioids, pharmacogenetics may exacerbate inequalities in the delivery of healthcare . GeneticThis information may lead to different treatments covered by health insurance companies, since patients more prone to have “poor profile of response” would be unraveled before treatment . Hence pharmacogenetics could raise the following questions: who decides to perform the test: patients? Care providers? Insurance company? Once a genetic-driven prescription is pursued, how the needs of insurance companies will fit with the variability of the clinical scenario?Finally, pharmacogenetics information can vary according to racial or ethnic origin. Discovering a genetic variant that influences a medicine’s response in a particular ethnic group, may lead to the design of medications for a specific ethnic group or for an ethnic group most likely to be able to afford the medications . This woOnce the concept of pharmacogenetics becomes mainstream and knowledge will increase in patients as in care physicians, one may lie or forge his profile to obtain specific drugs (and abuse of them) . This woOf course, these are potential scenarios that may configure or not, but they should be kept in mind when evaluating the potential implications of genetic profiling for opioid prescriptions, especially in cancer patients, in which ethical concerns are strictly related to life expectations.Pharmacogenetics to guide opioid prescription is not a myth, but likely to become a reality. Even though many concerns remain in the complex scenario of genetic variability in the PK and PD of opioids, some candidates have been identified to have a specific role. Of course, the impact of their role should be better defined, but it is straightforward to think that some genetic variants may already be used to select groups of patients with different clinical response. Initial studies on the pharmacogenomics-guided approach to opioid prescription are promising: they already led to higher efficacy and reduced side effects, and may apply to all opioids.Limiting factors still exist to the widespread introduction of genetic testing in opioid prescription dealing with costs, selection of patients, and ethical concerns. However, as far as our knowledge will increase and new data will confirm the validity of genetic profiling, these limits may be overcome. The complexity of mechanism involved in opioid response may not be fully elucidated in the near future, but even refined knowledge on a few genes may be the cornerstone for the diffusion of genomic-guided opioid prescription to improve a patient’s outcome.


Existing studies on cognitive impairments in chronic pain do not investigate peripheral neuropathic pain (PNP) or compare pain conditions in a satisfactory manner. Here we aimed to compare executive dysfunctions in PNP patients with fibromyalgia (FM) and healthy controls (HC). Patients who self-reported cognitive impairments were assessed according to criteria for PNP or FM. Seventy-three patients met criteria and completed testing on executive functioning and IQ measures. We also included twenty matched healthy controls. Regression models controlling for age, sex and IQ, tested associations between group category  and outcomes. If a substantial association was detected, we followed up with head-to-head comparisons between PNP and FM. Multivariate regression models then tested associations between executive functioning and pain type, controlling for significant confounders. Results from head-to-head comparison between pain conditions showed significant differences on years lived with pain (FM > PNP), the use of anticonvulsants (PNP > FM) and use of analgesics (PNP > FM). When controlled for all significant differences, PNP patients had significantly lower scores on an attention-demanding cued-recall task compared to FM. Poor performance on attention-demanding cued-recall task was associated with PNP, which translate into problems with retaining fast-pace or advanced information. Impairments of these functions are prevalent in chronic pain patients2, cited no rigorous comparison of executive functioning between pain types, even though clinical experience argues for substantial contrasts in cognitive difficulties between pain conditions. As an example of this, pain clinicians often claim that fibromyalgia (FM) patients present more problems with executive functioning than those with neuropathic pain (NP)6.Current knowledge does not allow for describing differences in executive dysfunction between pain types, as most studies only include heterogeneous, poorly defined pain conditions. A recent review7, but so do patients with NP9. However, NP patients reporting cognitive dysfunction receive little attention. As an example, available computerized cognitive training (CCT) programs are based solely on results from patients with musculoskeletal disorders11, even though potential differences in executive dysfunction between pain conditions is highlighted in these studies.Indeed, FM patients do rate cognitive decline and its consequences as one of the most significant limitations to their everyday life12, any executive dysfunction in chronic pain would be the result of the interplay between the attention paid to peripheral input and the goal-directed activity of the brain. NP arises as a direct consequence of a localized lesion or disease affecting the somatosensory system, while FM on the other hand is a centrally driven pain condition13. As such, the Neurocognitive Model hypothesizes that there would be differences in executive functioning driven by different inputs to and from the brain12, a notion which is yet to be tested in a rigorously classified sample of chronic patients2.According to the Neurocognitive Model of Attention to Pain14, which over time could drive differences in executive functioning from sustained cognitive activation12.Comparing FM and NP patients on executive functioning is also argued from the insight that the former is a pain condition of unknown origin. As such, it lends itself less well to a pathophysiological understanding, potentially driving extended thinking about “why” a FM patient experiences pain. Such extended thinking taxes attentional resources15, two building blocks of cognitive-behavioral therapy (CBT). Illuminating differences in executive functioning could help evolve a more targeted CBT for chronic pain, potentially improving its therapeutic effects17. Moreover, as trials of CCT has shown some promise in alleviating impairments11, but lack so-called “far transfer” of effects, tailoring condition-specific cognitive training would be a pre-requisite for achieving effect in NP patients18.Any such difference between pain types would be important as executive functioning is crucial when performing goal-directed behavior and problem-solving3. The FM group showed a significant impairment in a composite of executive functioning coined updating, while the heterogeneous non-FM group showed impairments in the executive function composites of response inhibition and cognitive flexibility3. While underlining the paucity of studies investigating well-defined pain conditions, these results could be viewed as an indication of differences in executive functioning existing between pain conditions.One meta-analysis has attempted to compare executive functions in pain conditions, indicating significant differences between pain conditions when broadly defining them as FM versus “non-FM” pain19, where it is not clear to what extent the dysregulation of insulin and co-morbidities are driving executive dysfunctions20. Others mix NP with radicular pain21, or report only on a handful of participants with PNP24.Peripheral neuropathic pain (PNP) without concomitant systemic disease would provide a good model when attempting to investigate potential contrasts between etiologically different pain conditions. However, there is a considerable gap in knowledge on how PNP affects cognition. Available studies describe diabetic polyneuropathy26. Moreover, only one study controls for the impact of sleep deficiency26, though the impact of poor sleep on cognition is well known27. A single comparison of cognitive impairments in neuropathic pain (NP) and generalized pain (including FM) exits, using neuropsychological tests of verbal memory and inhibition28. However, this study mixed central and peripheral NP, had a small sample size (n = 14), and no healthy control group. Nevertheless, a higher percentage of FM patients than NP patients performed below cut-off for normal performance on the interference and switching conditions of the Stroop test. Conversely, more NP patients compared to FM patients performed below cut-off on the California Verbal Learning Test28. This result aligns with a review claiming that NP could specifically impact the most attention-demanding cognitive processes, such as holding information in working memory for long-term encoding and retrieval2.Only two studies have an adequate sample of PNP patients and these studies use a superficial screening of cognition29.As both a review, clinical experience, and a single experimental study, indicates differences in executive functioning between pain conditions, the aim of the current investigation was to provide a detailed description of executive functioning in PNP and compare this to FM. As a vantage point for our comparison we chose the Unity and Diversity Model (UDM) of executive functioning, which indicates three core components of executive function that are functionally separable31. Results from twin studies show that the correlations among the three components are substantial, but far from perfect (~ 0.5)32. Since both a previous study28 and a recent review2 suggested that patients with NP could have a specific impairment of executive functioning when processing more attention-demanding recall tasks, an appropriate test should be added when testing these chronic pain patients.These components are inhibition (inhibitory control and interference control), updating or working memory (the ability to maintain accurate representations of information which changes over time) and cognitive flexibility 33, and both patients with FM34 and NP35 report higher levels of insomnia severity when compared to other pain conditions. In addition, both depression and pain medication can influence executive dysfunction and need to be controlled for3.Moreover, in studies of heterogeneous chronic pain conditions, insomnia worsens working memory performance29, and the fourth tested attention-demanding cued recall. Our specific hypotheses were that (1) FM patients would demonstrate executive dysfunctions beyond HC and patients with PNP on the three executive functions of inhibition, updating and flexibility; (2) that PNP patients would perform significantly worse on an attention-demanding cued-recall task compared to FM patients and HC.We here aimed to evaluate whether there were differences between FM, PNP or healthy controls (HC) on four tests of executive functioning. Three of the tests reflect the core components in the UDM of executive functioningFrom July 2016 until March 2018, we recruited potential candidates, prospectively and retrospectively, from the patient population at the Department of Pain Management and Research, Oslo University Hospital. This is a tertiary multidisciplinary pain clinic and all pain conditions would have lasted more than 3 months when referred to the clinic.In addition, we circulated information leaflets to all relevant pain clinics and patient organizations asking general practitioners to refer patients to the study. Potential patients had to indicate that they experienced problems with memory and/or ability to concentrate. Finally, twenty HC were recruited through a hospital network of potential volunteers after the inclusion of patients was completed, in order to match HC with patients on age and sex.We examined 225 patients, and 79 patients met the criteria for inclusion in the study. Of these patients, 73 initiated and completed neuropsychological testing and were available for the current analyses Fig. . In addi36. We then performed IQ testing and neuropsychological testing within 30 min of finishing the online survey. The complete testing regime lasted a total of 2.5 h per patient.Patients completed several questionnaires upon arrival at the clinic using a tablet connected to an online registry system (OPR)We alternated the sequence of neuropsychological tests several times during the data collection period to ensure that no sequential effects were confounding the results. Before the initiation of testing, participants filled out visual analogue scales (VAS) indicating level of anxiety and if they had a desire to leave the situation. The VAS was presented as a straight horizontal line of fixed length (100 mm) across a continuum from none to an extreme amount of anxiety or avoidance orientated from the left (none) to the right (extreme). Sleep parameters were recorded immediately and for seven consecutive days at home after collecting baseline data.www.dam.no (grant number: 2016/FO78689). In the protocol and in ClinicalTrials.gov it was registered as study 1 in a larger randomized controlled trial . We here confirm that the study complied with good clinical practice, including the most recent version of the declaration of Helsinki, as well as all relevant rules and regulations in Norway. Participation was based upon signed informed consent, and thorough information was provided orally as well as in writing.The Regional Committee for Medical Health and Research Ethics in South-Eastern Norway approved this study  and the protocol was published on The patients’ pain conditions should have lasted longer than 3 months, i.e., regarded as chronic, when referred to the pain clinic. At the clinic, the patients filled out a standardized questionnaire before a multidisciplinary pain team  evaluated them.peripheral neuropathic pain: First, the participant had to (1) present pain with a distinct, neuroanatomically plausible distribution, and (2) a history suggestive of a relevant lesion or disease affecting the peripheral somatosensory nervous system. Then, during examination the participant had to (3) demonstrate a distinct neuroanatomically plausible distribution of somatosensory disturbances and (4) harbor a relevant lesion or disease by at least one confirmatory test 37.In cases of suspected PNP or FM, the patients were referred within the clinic to a specialist, either a neurologist  or one specific specialist in physical medicine and rehabilitation (FM), who then performed a structured assessment of the disorder. The following two independent levels of criteria were needed to arrive diagnostically at definite fibromyalgia: The participants had to present: (1) pain in the left side of the body, pain in the right side of the body, pain above the waist, and pain below the waist. In addition, axial skeletal pain  had to be present. In this definition, shoulder and buttock pain is considered as pain for each involved side. (2) Participants’ had to describe pain in 11 of 18 tender point sites on palpation during a clinical examination . A confirmed condition of either at least probable peripheral neuropathic pain37 or fibromyalgia was necessary in order to be included in the study.The following criteria needed to be met to arrive at a diagnosis of Exclusion criteria were reviewed after the aforementioned examinations had been completed. A diagnosis or suspicion of ongoing mania, psychosis or suicidal ideation with previous suicidal attempts was considered a cause for exclusion. Participants were also excluded if suicide attempts or plans of suicide were reported during the project period.It was also an exclusion criterion if participants could not speak fluent Norwegian, were pregnant or unable to use the touch screen used for neuropsychological testing.Finally, participants were excluded if they had a combination of PNP and FM, or if they had any disorder or diagnosis that could otherwise explain any potential cognitive impairment, such as an unrelated stroke or diabetes. Chronic pain participants often use medications, so we allowed for stable analgesic medication throughout the test period.39). The tests were presented on touchscreen Windows 7 tablet PC running CANTAB-eclipse software. The order of the tests was alternated three times during the study period.All participants completed four tests from Cambridge Automated Neuropsychological Test Battery (CANTAB). CANTAB is based on self-administrated neuropsychological tests, and is a widely used cognitive assessment tool . The SST is a response inhibition test that measures a subject’s ability to inhibit a pre-potent response. The outcome variable used in the study was an estimate of the stop signal reaction time (SSRT) in milliseconds (lower results indicate higher performance). This outcome provides a measure of the speed of the inhibitory process40.The executive component of updating was measured through the Spatial Working Memory (SWM) task. This task assesses spatial working memory by measuring a subject’s ability to retain spatial information and to manipulate remembered items in working memory. The pre-selected outcome was a component score reflecting the strategy participants´ used to avoid unnecessary errors.The executive component of flexibility was measured using the Intra-Extra Dimensional Shift (IED) task. The IED is a computerized analog of the widely used Wisconsin Card Sorting Test and is a test of cognitive flexibility. The pre-selected outcome was IED total errors, a composite of the number of completed stages and the number of errors made.Attention-demanding cued recall was measured using the Paired Associates Learning (PAL) task. The PAL task is a cued recall test that assesses memory and new learning. The pre-selected outcome was performance on the hardest stage, total errors 8 shapes adjusted, which report the numbers of errors made on the last, most difficult stage of the PAL test.Participants reported daily medication usage upon inclusion and this was controlled with the list of medications provided by the general practitioner and any information given during the interview by the pain specialist.sleep efficiency and average total sleep time.Each participant wore the Philips Respironics Actiwatch Spectrum or Spectrum Pro on the wrist for 7.5 days following the visit to the department. In addition, patients filled out a sleep diary for the same time-period yielding a comparable sleep entry should the actigraph data for some reason not reflect a valid sleep pattern. The Actiwatch and sleep diary were used in combination to create the variables 41 measures intelligence in adults. It consists of four index scores attempting to measure four major components of intelligence. As two of the components are strongly correlated with CANTAB tests, namely working memory and processing speed, we chose to use the two components that would add the most to the examination of intelligence in addition to our tests of executive functioning. These were the indexes of verbal comprehension and perceptual reasoning. In the current study, we chose to use the subtests of similarities and matrix reasoning to measure the corresponding indexes41.The Wechsler Adult Intelligence Scale (WAIS) IVdepression we used the GP referral where a depression was indicated by an ICPC-2 diagnosis as well as a self-report measure of mental distress included in the OPR.Patients admitted in the study had been diagnosed by their general practitioner with a musculoskeletal (L), mental (P), or general/unspecific diagnosis, e.g., fatigue, burnout (A),  (2nd edition). To determine the presence or absence of 36. Here we give a brief account of selected variables included in the analyses for this study: Usual pain intensity (0–10); Pain bothersomeness ;36; Insomnia Severity Index (ISI).A complete list of the measures in this study has been published previously through a detailed description of the online registry (OPR)Demographics and patient characteristics were analyzed as either number and percent, or mean and standard deviation (SD). We performed bivariate correlations to check for substantial correlations between the chosen executive functioning measures and potential covariates before moving on to regression models.The regression analyses in the current study were performed in two stages. In the first stage, we wanted to detect significant differences in the four executive function outcomes between categories FM, PNP and healthy controls, while controlling for age, sex and IQ.We therefore performed four hierarchical linear regression models, where the variables were entered in steps, using the four selected outcomes as dependent variables in the four models. In all regression models, we entered age and sex in the first step to control for any inherit differences as both age and sex could affect executive functioning (1), in the second step (2) we entered verbal and performance IQ to control for any differences in intellectual ability. Then in the third and final step (3), we entered the categorical group variable using controls as the reference value .If the subsequent regression output showed a significant difference between categories  controlled for age, sex and IQ in this initial stage, we aimed to move on to the second stage of regressions.t tests or chi square statistics were used to test for group differences between FM and PNP on self-reported registry variables, sleep deficiency and medication. Significance level to detect substantial differences was set at p < 0.05.Through hierarchical linear regression, we wanted to evaluate and test for substantial differences between the two categories of pain, now excluding healthy controls. Because we aimed to evaluate differences between pain categories, this next stage of regressions was to be performed while controlling for all other significant differences between the two pain types, while keeping age, sex and IQ in the model. Given the interval or categorical nature of the variables investigated, independent Again, we used a hierarchical linear regression where we entered age and sex in the first step (1) and in the second step (2) we entered verbal and performance IQ. In the third step (3) we entered years lived with pain. In the fourth step (4), we entered the categorical use of analgesics yes (reference category) or no. In the fifth step (5) we entered use of anticonvulsants yes (reference category) or no, before the sixth (6) and final step where pain condition (FM vs PNP) was entered using FM as the reference category. This stepwise approach allowed for investigating changes in explained variance when introducing the diagnostic category, while controlling for other significant differences.All statistical analyses were performed using SPSS version 25.The participating pain patients in this study were predominantly females (73%), married (44%), with high school education (49%), who were currently out of work (59%). The healthy controls were matched on age and sex. None of the participants reported anxiety for the test being administrated, or a wish to avoid the neuropsychological testing as indicated on VAS before administering the test.Table On the working memory task, the FM group showed a higher score on the use of working memory strategy than both the PNP group and healthy controls. The PNP group on the other hand had more errors on the cued recall task when this task reached the hardest level. The results show that the participants with PNP made more mistakes when asked to remember shapes hidden in eight different boxes (see Table p = 0.04), when controlled for these covariates  on performance on neuropsychological tests while controlling for age, sex and IQ. Only the outcome from the PAL test showed a significant difference between categories . None of the other categorical variables showed substantial differences between the two groups.To evaluate substantial differences between the two pain categories on PAL 8 shapes, we then excluded healthy controls from the analysis and looked for significant differences between pain types. When tested with a chi-square statistic for categorical variables, the two groups had significant differences in sex, medication usage and use of anticonvulsants . Otherwise, the T tests showed no significant differences between the FM and PNP groups on pain intensity or bothersomeness, IQ measures, mental distress, quality of life, fatigue or sleep parameters.p = 0.02). Adding pain category in the final step resulted in an r2 change, which explained 9% of the variance on the dependent variable.To test the association of pain category we then added the significant differences between pain types as covariates in the final model. A hierarchical linear regression models showed that when controlling for age, sex, IQ, years lived with pain, taking any analgesic, and taking anticonvulsants, having peripheral neuropathic pain remained significantly associated with the number of errors made on the hardest stage of the PAL test  of the hierarchical regression analysis is depicted in Table The main aim of this study was to compare patients with PNP to FM patients using four objective neuropsychological tests measuring executive functioning. In accordance with our first hypothesis, FM patients scored worse on measures of inhibitory control compared to PNP and healthy controls. However, this difference was not significant when controlled for age, sex and IQ.In accordance with our second hypothesis, we found that patients with PNP had more errors than FM patients and healthy controls on the attention-demanding cued-recall task. When tested in a regression model, being in the PNP category remained significantly associated with worse cued recall (i.e. more mistakes) also when controlling for age, sex and IQ.In the next step of analysis, the patients with PNP were compared head-to-head with FM patients, controlling for any other significant differences between the two pain categories. The association between the PNP group and cued recall remained significant even when controlling for years lived with pain, medication usage, as well as age, sex and IQ.This indicates that the impairment was associated with the PNP category beyond any other significant differences between groups.44. The observed reduction in performance could therefore be tied to working memory function in PNP, as any diminishing of attention would disrupt the patients’ ability to maintain information in working memory45.We see this result as complimentary to experimental data showing that pain only disrupts attentional and perceptual performance when interacting with a high load or demanding cognitive tasks2. A popular theory is that this bias is due to a hypervigilance caused by living with pain. Hypervigilance referring to the idea that pain patients do not have a reduced attention, but rather a biased attention towards pain-related information driven by aversive conditioning and anxiety23. Differences in pain patients’ attentional bias and subsequent cued-recall, could be linked to differences in pain intensity46, or anxiety symptoms47, however, none of these proved to be significant in our analyses.Our results could also stem from an attentional bias. A recent review showed that pain patients are better at recalling self-relevant material than neutral information, suggesting an attentional bias affecting recollectionWe would instead suggest a specific attentional deficiency or bias tied to persistent activation of peripheral nociceptors, as is the case in PNP. This is supported by pre-clinical data.48. The attentional disruption found in this study was tied to how demanding the task was for the subject studied.All though we are hesitant to the direct translation of results from animal models to humans, a recent rodent model of presumed PNP showed that repeated stimulation of peripheral nociceptive afferents greatly increased the disruptive effect from injury to the spinal nerve (L5) on visual attention49. This ties on to our results on the PAL test as a functional MRI study of participants performing the PAL test it was shown that the encoding phase of the task activated the hippocampus, and that extra-hippocampal areas show increased blood-oxygen-levels during PAL performance50. A specific impairment of attention in PNP patients affecting attention-demanding cued recall would then fit with the findings from pre-clinical data, suggesting hippocampus function as a potential mediator. As the PAL test has not been administered in previous studies of PNP, the current results could be the first indication of a specific disruption in PNP patients complaining about cognitive impairments.In addition to this recent finding, impaired short-term plasticity or decreased neurogenesis in the hippocampus have previously been reported in animal models of presumed neuropathic painOur ability to remember shapes and patterns is tied to the process of re-activating the same brain regions during two phases of memory, namely encoding and retrieval.51. The retrieval of this memory then relies on the hippocampus re-activating the neuronal network previously active in encoding. Speculating in a specific impairment of the hippocampus in PNP would fit with the current finding and the difference between groups may be tied to hippocampal function.A neuroanatomical model has been proposed where the hippocampus binds neuronal changes in creating a bridge from encoding into memoryAt the clinical level, this impairment corresponds to forgetfulness, the forgetfulness getting worse when the task is demanding and a delay separates the learning from the recall.A practical consequence of our findings could be that PNP patients struggle with accurately remembering information given during complex presentations and meetings. The type of paired-associate learning tested in this study is required whenever you want to remember which objects you previously saw, along with the location where they were seen. It enables you to remember where you parked your car, but also impacts more complex pairing such as which password to use when you are entering a specific website or what budget post the speaker is referring to on his/her previous slide.52. The choice of using cued recall with patterns in this study was primarily because the test is not affected by previous learning. The presented stimuli are novel and changes for each administration, so the patient cannot learn from test to test. However, our results could have consequences for CBT and other psychological treatments of pain. Presuming that more data confirms our current finding, CBT could potentially be tailored to fit the specific impairment presented by PNP patients in this study. Should the PNP patient report cognitive impairments one could teach evidence-based strategies for improving encoding through attention training53.Newer studies have shown that if instructed, stroke patients with damage to a memory path can recruit alternative brain regions through top down learned strategies, improving memory performanceFuture investigations should include studying whether CBT or other psychological treatments are mediated by paired associative learning performance or whether specific executive impairments in different chronic pain conditions are improved by targeted cognitive training programs. It should also be an aim to investigate if a tailored attention training before receiving CBT could benefit patients with PNP, or even if attention training alone may be of benefit.The participants in this study were selected from a large sample of patients attending a tertiary multi-disciplinary pain clinic, and represent a selection bias. Many patients will not experience cognitive impairments when living with pain, the current sample did, and the sample selected for this study should not be generalized to all patients with PNP or FM. However, the strict pain type identification procedure serving as the foundation of the study necessitated a large pool of participants to select from as both included pain conditions are not infrequently mislabeled by referring general practitioners.Patients with PNP appear to have a specific impairment when it comes to resource-demanding cued recall. This is the first study to show condition-specific impairment in this pain type using adequate and objective measures of executive function. The results demand further investigation and the rigorous methods applied should inform future research into specific impairments found in our sample.Supplementary Information.


To evaluate the efficacy of submucosal injection of triamcinolone acetonide for the treatment of type II/III interstitial cystitis/bladder pain syndrome.A retrospective analysis of the clinical data of type II/III interstitial cystitis/bladder pain syndrome patients treated in our department from April 2016 to August 2018 was conducted, and changes in International Prostate Symptom Scores and the Pelvic Pain and Urgency/Frequency symptom scale after surgery were evaluated to explore factors that may affect patient outcomes.p = 0.015), high pain scores (p = 0.040), and higher International Prostate Symptom Scores (p = 0.037) and Pelvic Pain and Urgency/Frequency symptom scale scores (p = 0.020) were more likely to benefit from submucosal injection of triamcinolone acetonide. Gender, disease duration, and the presence of Hunner’s lesions had no predictive value for treatment outcomes.A total of 27 female patients and 8 male patients were enrolled, with type II patients accounting for 62.9% of the sample, and the median follow-up duration was 31 months (range: 12–40 months). Twenty-two patients (74.3%) had significantly improved questionnaire scores at 4 weeks postoperatively. Treatment efficacy was sustained for at least 1 year in 15 patients, and persistent effectiveness was noted in 10 (28.6%) patients. Patients with an advanced age (Submucosal injection of triamcinolone acetonide can improve the clinical symptoms and quality of life in both men and women with type II/III interstitial cystitis/bladder pain syndrome. Patients with an advanced age and more severe interstitial cystitis/bladder pain syndrome related symptoms may benefit more from triamcinolone acetonide injection. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a clinical syndrome with an unclear cause. It mainly manifests as pain in the suprapubic area or discomfort with bladder filling, which can be alleviated with urination. IC/BPS is often accompanied by frequent urination, urgency, and nocturia and is more common in middle-aged women. IC/BPS seriously affects the quality of life of patients . The etiThe European Society for the Study of Interstitial Cystitis (ESSIC) divided IC/BPS into the following three major types based on changes in the bladder mucosa after cystoscopy and/or bladder hydrodistention in IC/BPS patients: type I: normal bladder mucosa; type II: glomerulations in the bladder mucosa; and type III: visible Hunner’s lesions in the bladder mucosa with or without glomerulations. Type II and type III account for 30 ~ 60% of all IC/BPS cases .The AmerCox and other researchers have reported treating female patients with type III IC/BPS with submucosal TA injection . WhetherThe medical records of type II/III IC/BPS patients treated with submucosal TA injection in our hospital from April 2016 to August 2018 were retrospectively analyzed. IC/BPS was diagnosed using the “exclusive diagnosis” method and according to the AUA IC/BPS Guideline  and the 2O for 5 min under cystoscopy. After venting, the bladder was filled again, and lesions in the bladder wall were observed and recorded in detail. For patients who did not show obvious abnormalities under cystoscopy, surgery was concluded. For type II/III IC/BPS patients, TA solution was injected into the submucosa at the bladder hemorrhage site and/or into the center of Hunner’s lesions . After ensuring the absence of active bleeding in the bladder, a 16 Fr double-lumen catheter was inserted. The catheter was removed the next day after surgery.Endoscopic diagnosis and treatment were performed by an experienced specialist. After successful spinal anesthesia, bladder hydrodistention was performed with the patient in the lithotomy position at the pressure of 60 cm HThe patients were assessed with the International Prostate Symptom Score (IPSS) and the Pelvic Pain and Urgency/Frequency (PUF) symptom scale before surgery, and 4 weeks, 6, 12, and 18 months after surgery. If a patient’s symptoms recurred, then he or she returned to the hospital for a timely follow-up.p values of 0.05 or less was considered statistically significant. A Kaplan-Meier curve was plotted to depict the sustained efficacy duration after the first treatment; Patients for whom no repeat procedure occurred and exhibited persistent effectiveness at the last follow-up were censored. All of the statistical analyses were performed using the Statistical Package for Social Sciences, version 19, for Windows .The results are presented as the means ± standard deviation (SD). Comparisons were performed using the Wilcoxon rank-sum test to analyze scores before and after treatment The Mann-Whitney test was used to analyze factors influencing the treatment effect. Data with A total of 35 patients were included in the study, with 8 males (22.9%) and 27 females (77.1%). The patients’ ages ranged from 33 to 80 years, with an average age of 51.7 ± 12.0 years. The average disease duration was 5.2 ± 4.6 years. Twenty-two patients (62.9%) had type II IC/BPS, and 13 patients (37.1%) had type III IC/BPS. All patients were followed up for at least 1 year after the first submucosal injection, with a median follow-up duration of 31 months (range: 12–40 months).p < 0.0001), IPSS decreased by 17.2 points (p < 0.0001), PUF symptom scores decreased by 8.9 points (p < 0.0001), and PUF bother scores decreased by 4.5 points (p < 0.0001).IPSS and PUF scores at 4 weeks after surgery are shown in Table p = 0.015), high pain scores (p = 0.040), and high IPSS (p = 0.037) and PUF scores (p = 0.020) were more likely to benefit from submucosal injection of TA. No difference in the response to treatment was noted for patients with Hunner’s lesions (p = 0.644), and male patients had similar treatment response rates to those of female patients (p = 0.959). Disease duration had no significant predictive value for treatment efficacy (p = 0.516).We further analyzed the clinical characteristics of the patients with a positive therapeutic effect and nonresponsive patients Table . Patientp = 0.46, PUF symptom score: p = 0.16, and PUF bother score: p = 0.60).At the last follow-up, 10 (28.6%) patients had no significant worsening of symptoms. We further analyzed the factors that may have influenced the treatment efficacy for at least 1 year. No clinical parameters that clearly affected patients’ treatment effect duration was found  patients were satisfied with symptom control at 1 year after surgery. Their 1-year postoperative scores increased slightly compared with those at 4 weeks after surgery, but no significant difference was found  in the past and the therapeutic effect aimed at CP/CPPS with antibiotics, alpha-blockers and other phytotherapeutic agents was poor. For one patient with the symptom of dysuria, concomitant bladder-outlet obstruction was also considered. The maximum flow rate was 11 ml/s with urinary volume 95 ml and the obstruction was ruled out by pressure-flow study with normal result. These male patients complained with pelvic region pain during the urine storage period which could be relieved after urination. The pain is different from CP/CPPS pain, which is usually located in the perineum, penis, testicles or suprapubic region, and often worsens by urination or ejaculation. They were diagnosed with IC/BPS finally. Because the symptoms also could not be relieved by oral taken of amitriptyline. They were enrolled in the study. This study is the first to include male patients with type II IC/BPS, to demonstrate the efficacy of this therapy for Hunner’s lesion-subtype IC/BPS and to explore the efficacy of this treatment in males and type II IC/BPS patients. The IPSS is mainly used to evaluate urinary symptoms, is easy to understand and manage, and can easily and intuitively reflect the negative impact of urinary symptoms on quality of life. By comparing the preoperative and postoperative IPSS and PUF scores, nearly 3/4 of the patients were found to have significant pain relief and reduced urinary tract symptoms at 4 weeks after surgery, and their quality of life improved significantly. No perioperative and long-term complications were noted, and the treatment efficacy was comparable to that reported by researchers such as Cox [The current study shows that the duration of the treatment effect of simple bladder hydrodistention for IC/BPS is generally less than 6 months, and the duration of the treatment effect of submucosal injection of TA for IC/BPS is not clear. The longest follow-up time in the current study was only 3 months . We perfThe main limitations of our study include the retrospective analysis, small sample size, and lack of a control group. Although the time of symptom relief we reported was obviously longer than simple bladder hydrodistention, the efficacy of hydrodistension can’t be ignored. We are aiming at performing a prospective, randomized control study with the groups who will receive saline injections or only bladder hydrodistention at present. The study will reveal more information on the therapeutic effect of submucosal injection of TA for IC/BPS in the future. In addition, The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Network findings , 16 indiSubmucosal injection of TA has demonstrated an acceptable safety profile for treating IC/BPS. TA may be effective in controlling symptoms in type II as well as type III IC/BPS, and can improved symptoms and the quality of life of male IC/BPS patients. Patients with an advanced age and more severe IC/BPS-related symptoms may have greater benefits. Further investigation of submucosal injection of TA for the treatment of IC/BPS is warranted with a larger, longer, randomized and controlled trial.Additional file 1: Table S1. Patient demographics stratified by the length of time (less than 1 year vs at least 1 year) of symptom relief with analysis of risk factors associated with clinical effect.


To identify prognostic factors for the effectiveness of needle aspiration of calcific deposits (NACD) for rotator cuff calcific tendinitis (RCCT)t tests or Mann-Whitney U tests depending on the distribution of data) were performed to build a multivariable linear regression model. Stepwise regression analysis through backward elimination was performed to evaluate the effect of predefined prognostic factors on the outcome.One hundred forty-nine patients with symptomatic RCCT were included in a prospective cohort study. Pain (VAS), shoulder function (SST and DASH), and quality of life (EQ-5D) were assessed at baseline and at 3, 6, and 12 months post-NACD. Univariate analyses (independent p < 0.01). Furthermore, a larger reduction in VAS pain scores at 3 months post-NACD was associated with a larger reduction in VAS pain scores at 12 months (p < 0.01). More improvement of SST and DASH scores at 3 months was associated with better SST, DASH, and EQ-5D scores at 12 months (p < 0.01). Smaller-size calcific deposits were associated with less improvement of DASH (p = 0.03) and EQ-5D scores (p = 0.01). A longer duration of symptoms prior to NACD was associated with less improvement of EQ-5D scores (p = 0.01).Patients who underwent multiple NACD procedures had less reduction of pain  contains supplementary material, which is available to authorized users. Rotator cuff calcific tendinitis (RCCT) is a frequently diagnosed shoulder disease, which is found in up to 54% of patients with shoulder complaints . It is sA prospective cohort study was conducted at the departments of orthopedic surgery and radiology. All consecutive patients referred to the department of radiology between October 2014 and August 2016 for the treatment of symptomatic RCCT were included. Inclusion criteria were clinical signs of calcific tendinitis defined as pain in the deltoid region worsening by elevation of the arm above the shoulder level and/or at night and the presence of calcific deposits on radiographs and/or ultrasound examination. Exclusion criteria were age < 18 years, being unable to read and write the Dutch language, previous NACD treatment or surgery of the affected shoulder, and the presence of other causes for shoulder complaints . Only the treatment of the first shoulder was analyzed in patients who underwent bilateral treatment.Since it was a prospective cohort study evaluating current treatment and follow-up standards of our department, the study was declared free from subject to the medical research involving human subjects act and the IRB approved the local study execution.After the participating patients signed informed consent forms, baseline data, including demographics and data related to the medical history and previous treatments, were collected.Prior to the NACD procedure, baseline scores were completed by all patients: visual analogue scale for pain (VAS 0–100 mm where 0 mm represents “no pain” and 100 mm “the worst pain ever possible”), the Simple Shoulder Test  to 12 (best score)), the Disabilities of the Arm, Shoulder and Hand questionnaire  to 100 (most severe disability)), and the EQ-5D (0 (worst score) to 1 (best score)).Every 2 weeks during the first 10 weeks following the NACD procedure, patients reported a VAS pain score, whether they had physiotherapy and whether they had used analgesic medication (type and dose).At 3 months, 6 months, and 1 year after the NACD procedure, patients reported the VAS pain score, SST, DASH, and EQ-5D questionnaires. Furthermore, the number of NACD procedures patients underwent was noted. The indication to perform a repeated NACD procedure was persisting clinical symptoms of calcific tendinitis with calcific deposits on ultrasound examination in the absence of another cause for shoulder complaints . A minimum period of 6 weeks between the first and second NACD procedure or the second and third NACD procedure was applied.The primary endpoints were as follows: reduction of pain at 12 months post-NACD (∆VAS baseline-12 months); improvement of shoulder function at 12 months post-NACD (∆SST baseline-12 months and ∆DASH baseline-12 months); improvement of quality of life (QoL) at 12 months post-NACD (∆EQ-5D baseline-12 months). Minimal clinically important differences . Calcific deposits were categorized into three different types using the classification described by Gärtner and Heyer : type I Ultrasound was performed using a standardized protocol by experienced musculoskeletal radiologists. The size, the number of calcific deposits, and the affected tendon(s) were recorded. Furthermore, the presence of subacromial bursitis, partial rotator cuff tears, and subacromial impingement was assessed prior to the NACD procedure.During the NACD procedure, the consistency of the calcific deposits was assessed as either soft (toothpaste like) or hard. Furthermore, the possibility to aspirate the calcific deposit was reported.Ultrasound-guided NACD was performed using a single-needle technique with 20- or 21-gauge needle. After maneuvering the needle into the calcific deposit, the deposits were infiltrated with lidocaine 1%, fragmented in case of a hard calcific deposit, and removed by aspiration. After completing the aspiration, the subacromial bursa was infiltrated with 4 ml bupivacaine  and 1 ml kenacort . No specific rehabilitation program was prescribed.t tests in case of normally distributed data and the Mann-Whitney U tests in case the data was not normally distributed) were performed to build a multivariable linear regression model. Factors that approached a significant correlation (p < 0.10) were included for multivariable linear regression analysis.Univariate analyses  was deleted. This process was continued until all factors in the equation had a significance level of p < 0.05.Stepwise regression analysis through backward elimination was performed to determine factors associated with better reduction of pain, better improvement of shoulder function, and better improvement of QoL. All the previously selected factors were entered into the equation after which the factor that contributed the least .One hundred forty-nine consecutive patients were included of which 39 patients were lost to follow-up as these patients did not complete the 12-month follow-up questionnaires , none of the other demographic or baseline values differed significantly between these groups.Except for age  and these 10 patients had less pain relief at 3 months post-NACD compared to the non-failed group . None of the other prognostic factors studied in this study differed significantly between patients that required surgery and those who did not.During the course of the study, 10 patients failed NACD treatment and had arthroscopic surgery due to persisting symptoms  of patients.At 12 months follow-up, 83% (91/110) of patients had lower pain scores compared to their preintervention baseline score and 70% (77/110) of patient reached MCID. The average decrease of VAS scores was 31 mm (SD 24.3).With regard to function, respectively 74% (81/110) and 78% (86/110) of patients showed improved SST and DASH scores (average improvement SST 3.6 (SD 3.5); average improvement DASH 17.5 (SD 15.9)) and respectively 65% (72/110) and 64% (70/110) of patients reached MCID. QoL improved in 56% (62/110) of the patients and remained the same in 24% (26/110); 46% (51/110) of patients showed a clinical important improvement. The average improvement in EQ-5D was 0.12 (SD 0.26).The largest decrease of pain, improvement of function, and QoL was seen at 3 months following the NACD procedure after which the level of pain, shoulder function, and QoL scores remained within the MCID interval Fig. .Fig. 2CoA summary of the results of the univariate analyses for factors related to decrease of pain, improvement of shoulder function, and QoL is presented in Table With regard to reduction of pain, multiple NACD procedures were associated with more pain 12 months after the intervention. A greater reduction of pain at 3 months after NACD was associated with more pain relief at 12 months  1 year after NACD. A good initial response after NACD was associated with a better outcome at 12 months, whereas patients who required multiple procedures and patients with a longer duration of symptoms prior to the NACD procedure showed less favorable results. Furthermore, smaller-size calcific deposits were associated with worse shoulder function outcome and less improvement of QoL.In our study, 70% of patients had a clinical relevant decrease of VAS pain scores. Furthermore, 64 to 65% of patients showed clinically important improvement of shoulder function, respectively measured by the SST and DASH. In 46% of the patients, QoL scores were clinically relevant improved at 1 year after NACD. The largest decrease in pain and improvement of shoulder function and QoL was seen at 3 months post-intervention after which the improvement seemed to stabilize Fig. . A similPrognostic factors for negative outcomes of NACD found in this study were multiple NACD procedures, smaller-size calcific deposits, and a longer duration of symptoms prior to NACD. The latter is a well-known negative prognostic factor which is supported by multiple studies , 7.Regarding the effects of multiple procedures on the outcome of NACD doubt could exist about if this variable represents a cause of bad prognosis or simply represents the consequence of attempting the same procedure in non-responding patients. Studies on the effect of multiple procedure on the outcome of NACD are scarce and inconclusive. Farin et al, for example, found that the outcomes of second and third procedures were inferior to the outcome of the primary NACD procedure . On the r = − 0.35, p = 0.738; SST: r = − 0.149, p = 0.153; DASH: r = 0.099, p = 0.345). It seems therefore unlikely that patients with smaller-size calcific deposits have less complaints compared to patients with larger-size calcific deposits which makes it more likely that the shoulder complaints in patients with smaller-size calcific deposits have another cause, such as a more complex inflammatory pathology.With regard to the size of calcific deposits, larger-size calcific deposits have been associated with worse outcomes in the conservative treatment of RCCT and after ESWT , 18. In Calcific tendinitis is not always symptomatic as it is found in up to 35% of adults without shoulder complaints . HoweverEarlier studies on prognostic factors for the effectiveness of NACD, which were all retrospective, found that smoking, female gender, dominant arm involvement, bilateral disease, longer duration of symptoms, and multiple calcifications all were associated with less favorable outcomes , 9, 10. Twenty-eight possible prognostic factors for the outcome after NACD were evaluated of which only the size of the calcific deposit and the duration of symptoms prior to the intervention were associated with the outcome. Additionally, it is important to acknowledge that NACD is often performed after other therapies have failed. Even more important, little is known on the effect of these previous (failed) therapies on the perceived outcome of NACD. Results of this study demonstrate that previous unsuccessful treatments, in particular ESWT and subacromial injections with corticosteroids, did not affect the outcome of NACD. NACD is therefore also indicated after failure of other therapies for RCCT. Furthermore, other radiological findings such as AC arthrosis and partial thickness rotator cuff tears are often present in RCCT . In the , this study has several limitations. First, a relatively large number of patients  was lost to follow-up at 12 months. However, a certain drop-out rate could be expected as others reported drop-out rates of 30% for web-based surveys [This is the first prospective study evaluating prognostic factors for the effectiveness of NACD. Nevertheless surveys . Secondl surveys , 17, 24,In conclusion, NACD provides early pain relief and improvement of shoulder function and quality of life. A good initial response to NACD is associated with a better outcome whereas a longer duration of symptoms prior to NACD, multiple NACD procedures, and smaller-size calcific deposits are associated with inferior outcomes.ESM 1(DOCX 31 kb)


An anal fissure is one of the most common anorectal diseases resulting from a longitudinal tear in anoderm under the dentate line. It causes severe pain during defecation, and the resulting emotional stress leads to a reduction in the overall quality of life of a person. There are several medical and surgical treatment procedures that are employed to treat anal fissures. In the present retrospective study, we aimed to evaluate the safety and efficacy of lateral internal sphincterotomy (LIS) surgical procedure for the treatment of chronic anal fissure. Additionally, we also analyzed the complications arising after the surgery and the factors affecting the complications.The present study is a retrospective study that included 691 patients treated for chronic anal fissure in a private sector setting, by a single Saudi female surgeon, starting from April 2004 to April 2020.Out of the 691 patients included in the study, all the patients were female, with an average age of 45.77 years (ranging from 17 to 82 years). Major complaints of the patients were as follows: pain, bleeding, constipation, pruritus, perianal discharge. Recurrence was reported in 2 patients (0.3%) while, 3 patients (0.4%) developed gas incontinence.The complaints of all patients with gas incontinence regressed over a period of time.This study reports that lateral internal sphincterotomy (LIS) is a safe surgical treatment for chronic anal fissure, leading to a reduction in recurrence, incontinence rate and substantially improves symptoms, especially pain. •In patients with chronic anal fissures, the majority of the patients had a posterior anal fissure.•Lateral internal anal sphincterotomy (LIS) is a safe and effective surgical treatment for chronic anal fissure.•LIS procedure results in high patient satisfaction rates and improvement in the quality of life.•Incontinence and recurrence rate are very low in our study. It is a painful longitudinal tear in the anoderm distal to the dentate line . The patConservative methods of medical management are used first to heal an anal fissure. Medical therapies, such as the application of local anaesthetic, fiber diet, and topical nitroglycerin aid in the early healing of fissure . SimilarSince the last 3-4 decades, lateral internal sphincterotomy (LIS) has been the preferred method for treating chronic anal fissures . With a The primary objective of this study is to understand the safety and effectiveness of the lateral internal anal sphincterotomy (LIS) for the treatment of chronic anal fissure in a cohort of patients. Preoperative complaints of the patients were recorded and were further analyzed for subsequent weeks, postoperatively, for the relief in the pain due to anal fissure. Further, we also analyzed the early and late complications arising from the LIS; recurrence of anal fissures and incontinence in the patients were among the major complications we studied. Finally, patient satisfaction, as a measure of improvement in the overall health quality, was recorded post LIS. Overall, this study enhances our knowledge about the importance of LIS, as a procedure, in treating chronic anal fissures.22.1There were minimal ethical implications and issues since it is a retrospective study. Patient identity and confidentiality were protected by assigning each patient with a specific serial number. Prior approval was obtained from the Institutional Review Board at the Bakhsh Hospital; Ethical Approval number- 29102019. Since it is a retrospective study, the consent of the patient was not required for the study. The work has been reported in line with the STROCSS criteria [2.2The present study is a retrospective study, where 691 female patients were included who underwent surgery for the treatment of chronic anal fissure. Lateral internal sphincterotomy (LIC) procedure was performed on the patients by the open method in the private sector Bakhsh Hospital in Jeddah, Saudi Arabia, from April 2004 to April 2020. All patients in the study were operated upon by the author previously. Before the surgery, medical management for all the patients was done, which included the prescription of a combination of stool softener, laxative, high fiber diet, and a warm sitz bath.Inclusion criteria for the patients included in the present study were as follows: a female patient suffering from anal fissure for more than six weeks, exposed internal anal sphincter fibers, the appearance of sentinel piles, and hypertrophied anal papilla. Patients who were suffering from an anal abscess, anal fistulae, hemorrhoid disease, and inflammatory bowel disease were excluded from the study. Most patients had a history of normal delivery, and no patient had any history of anal or rectal cancer.Lateral internal sphincterotomy (LIS) surgical procedures were performed with the open method in a lithotomy position. The procedures were performed as a daycare procedure under general or regional anesthesia. Prophylactic antibiotics and rectal enemas were not used. The anal canal was visualized with the help of an anoscope. A longitudinal incision of about 1 cm was made, at 3 o clock, in the intersphincter groove and an artery was used to separate the muscle from the mucosa. The distal half of the internal anal sphincter, below dentate line, was divided under direct vision followed by application of pressure for 3 min, and then wound was closed using vicryl 3-0 suture and a small dressing was applied at end of procedure. Marcaine (0.25% 10 cc) was injected locally to relieve postoperative pain, while Voltarene Suppositories (100 mg) was administered into the rectum to decrease the postoperative pain.2.3Wound dressing  was removed after 6 h of the surgery. Paracetamol (1 g) intravenous every 6 h, and a narcotic (Pethidine 50 mg IM q6h) if needed. Oral metronidazole was administered, 500 mg twice daily, for one week postoperative. NSAID  (Voltarene 50 mg p.o. q8h), stool softeners , local xylocaine gel 2% every 6h, and mebo ointment applied locally to the wound (q6h), were also prescribed to the patient at the time of hospital discharge.Anorectal examination of the patients was performed in every follow-up clinic visit, and the fissure healing was monitored; the postoperative follow-up visits were scheduled after 1 week, then after 2 weeks, 4 weeks, and 8 weeks, respectively. Pain relief was assessed using a visual analog scale representing the severity of pain from 0 (no pain) to 10 (worst imaginable pain).The medical records of the patients were analyzed retrospectively. The parameters that were analyzed included patient's age, medical history, symptoms and findings, and response to the treatment . Subsequently, the side effects of the treatment and incidences of the disease's recurrence were also recorded and analyzed.3The patients were evaluated for the relief in pain after the first, second, fourth, and eighth week following surgery. The patients’ response towards the treatment and the status of their complaints was assessed . In the The median duration of the disease was 27 months (ranging from 1 to 34 months). In the long term follow up, recurrence of anal fissure occurred in 2 patients (0.3%), and 3 patients (0.4%) developed incontinence for gas, which improved with time, and regressed in the fourth postoperative month . The patPatient satisfaction was found to be high (93.0%), and the healing was nearly complete (98.0%) at the end of the eight weeks.4An anal fissure is a common disease of the anal canal, which leads to a vicious cycle of pain, sphincter spasm, and inflammation . Our stuThere are different strategies to manage and treat chronic anal fissure. In the initial phase, some studies recommend conservative and medical treatment strategies as they are non-invasive and avoid the risk of anal sphincter injury ,21. An eOur study group included 691 female patients , who suffered from chronic anal fissures. During the initial investigations, it was found that a large number of patients (98.0%) had a history of constipation . The patNext, pain relief in the patients was measured postoperatively. The number of patients whose pain got relieved improved consistently from the first week of the surgery (63.1%) to the second week (77.2%), fourth week (87.0%), and at the end of the eighth week, most patients (92.0%) experienced pain relief . These rAlthough LIS procedure is highly successful, there are instances of different complications during the early stages as well as the late stages post-surgery. The early complications that were in the present study were rectal bleeding (0.7%), perianal abscess (0.3%), and perianal hematoma (0.2%) . SimilarOther complications arising from LIS are anal incontinence, which is a major disadvantage of LIS . It is eWhile success rates of the LIS procedure remain high, as judged by the successful healing of the anal fissure, there is a risk of recurrence in 1.3%–25% of the cases ,31. Lian5This study reports that lateral internal sphincterotomy (LIS) is a safe and effective surgical treatment for chronic anal fissure, and leads to a reduction in recurrence and substantially improves the pain symptoms. The present study supports the surgical intervention by LIS procedure because of the high percentage of fissure healing and patient satisfaction. Although gas incontinence was observed in a few patients, high-risk patients must be closely monitored by measuring sphincter pressure. Additionally, supportive Botox treatment can be considered for high-risk patients to reduce the chances of incontinence further.Not commissioned, externally peer reviewed.The work was not supported or funded by any drug company.There were minimal ethical implications and issues since it is a retrospective study. Patient identity and confidentiality were protected by assigning each patient with a specific serial number.Prior approval was obtained from the Institutional Review Board at the Bakhsh Hospital; Ethical Approval number- 29102019.Since it is a retrospective study, the consent of the patient was not required for the study.1.Name of the registry: Research Registry2.Unique Identifying number or registration ID: researchregistry57953.https://www.researchregistry.com/browse-the-registry#home/Hyperlink to your specific registration (must be publicly accessible and will be checked): Fatma Al-thoubaity.The author declares no competing financial interest. Furthermore, the work was not supported or funded by any drug company.Study concept or design - Fatma Al-thoubaityData collection- Fatma Al-thoubaityData analysis or interpretation- Fatma Al-thoubaityWriting the paper- Fatma Al-thoubaityThe author declares no competing financial interest.


One of the major impacts following a neck of femur fracture is pain. Most patients  undergo an operation. This usually includes the frailest terminal patients and deemed a palliative procedure to reduce ongoing pain. The operation comes with risks and can reduce life expectancy in these patients and result in prolonged hospital admission, delirium, and postoperative complications. This case highlights a novel approach to managing the frailest end-of-life patients that does not require them to undergo a conventional operation. The case resulted in a quick discharge from hospital and for the patient and family to maximise the time out of hospital, with a reduced analgesic burden and a peaceful passing away. We feel that this could be an alternative, more humane option for such patients. Today, the vast majority of patients are managed following a hip fracture with an operation; this stems from the greater mortality in those patients not operated, including the frailest cohort , 2 . In An 89-year-old gentleman was admitted to a district general hospital with right groin and thigh pain. He was known to suffer from Alzheimer's dementia, osteoarthritis, previous proximal femoral fracture with dynamic hip screw (DHS), and severe aortic stenosis. He was living in the local area in a nursing home, requiring care with all activities of daily living, spending the vast majority of the day in bed. He was able to transfer with assistance of two into the chair but unable to walk prior to admission.On admission, he was found to have an externally rotated right hip and pain on movement of the hip. His abbreviated mental test score (AMTS) on admission was zero, and that was felt to be his baseline. On auscultation of the precordium, a very quiet second heart sound was heard with an additional ejection systolic murmur present.Basic blood tests showed a haemoglobin of 115, white cell count of 11.9, C-reactive protein of 130, sodium of 137, potassium of 3.8, urea of 8.3, and creatinine of 113.2 and a gradient of 71 mmHg.Pelvic X-ray was reported to identify generalised osteopenia, left DHS, and displaced surgical neck fracture of the right femur. An urgent echocardiogram identified an ejection fracture of 60% and a severely stenosed aortic valve with an area of 0.8 cmBased on his cardiac, cognitive, and functional status, the decision was made that his outcome was extremely poor and he was deemed not to be a surgical candidate.As a result of him not undergoing a conventional operation and him being managed conservatively, we felt that consideration for a phenol nerve block would aid pain relief and assist in being able to discharge him into the community for end-of-life care. As the patient lacked capacity to consent for a proposed intrathecal phenol injection for intractable hip pain, secondary to the fracture, it was deemed in his best interest to proceed. The plan was discussed and agreed with the next of kin and multidisciplinary team.The procedure was performed in the anaesthetic room in aseptic conditions . The patient was attached to full monitoring with supplemental oxygen given. Intravenous sedation was given in preparation for the block in the form of 1 milligram of midazolam with 5 milligrams of ketamine.The patient was placed in a right lateral position (bad side down). 0.5% chlorhexidine was applied to the skin. The L4 level and spinous process were palpated using Tuffier's line. A 25G needle was inserted 2 cm right lateral to the spinous process infiltrating 4 millilitres of 1% lidocaine at a 45′ angle aiming for a lumbar interlaminar space via a paramedian approach.A 20G Quincke spinal needle was passed until cerebrospinal fluid (CSF) was observed. 1 millitre of 0.5% heavy bupivacaine was injected; then, the patient was observed for 5 minutes for any cardiovascular instability. Following this, 1 millilitre of 5% phenol in glycerol was injected via the Quincke needle. The spinal needle was flushed with 0.5 millilitres of 1% lidocaine, and CSF was observed.Dressing was applied, and the patient was placed in the recovery unit and remained in a right lateral position for 30 minutes.Following the procedure, the patient was not complaining of any pain in his hip  and we were able to rotate the hip without any tenderness. He was discharged back to his nursing home with the community palliative care team. He remained pain free and required limited medication for symptom control and passed away four weeks after the neck of femur fracture.We report the successful use of targeted phenol neurolysis in an end-of-life patient with a conservatively managed hip fracture. This intervention left him pain free, with a short admission to hospital without high-risk surgery or the prolonged use of opioids.Early operative repair is the standard management for hip fractures in almost all cases. NICE guidance recommends “if a hip fracture complicated or precipitates terminal illness, the MDT should still consider the role of surgery as part of a palliative care approach” . Of the These patients have poor outcomes. One meta-analysis reported an unadjusted odds ratio of 3.95 for 30-day mortality in patients managed nonoperatively compared to the operated group [Without surgical fixation, achieving adequate pain control presents a significant challenge. Nonoperative management is currently dependent on opiate analgesics, which are likely needed for a prolonged period of time. This is in an already frail population at higher risk of side effects such as sedation, acute delirium, worsening cognitive impairment, respiratory depression, nausea, and constipation.Peripheral nerve catheters are widely used to good effect in the acute management of hip fractures. In nonoperatively managed NOFs, Rashidifard et al. (2019) demonstrated that continuous peripheral pain catheters decreased visual analogue scale (VAS) scores of an average of 4.45 points after 24 hours . 90% werNeurolysis involves the chemical or physical denervation of a nerve. Phenol induces Wallerian degeneration by causing separation of the myelin sheath from the axon and axonal oedema. Effects are produced in minutes and can last months to years depending on the target nerve. Phenol neurolysis was first described in a 1955 report by Maher, who administered phenol intrathecally for the relief of terminal cancer pain . It was The use of phenol as a neurolytic agent has declined in recent decades due to concerns related to its possible serious adverse effects, including dysesthesias, flaccid paralysis, tissue necrosis, and systemic complications. However, modern techniques allow highly accurate delivery of phenol to the target nerve and favourable safety profiles .Neurolysis for spasticity is aimed at preventing contractures, reducing pain, and improving overall functional status . It is uPhenol neurolysis has a good evidence base in some areas of palliative pain management; particularly patients with intractable pain refractory to high-dose opioids. Celiac plexus neurolysis (CPN) is well established in the treatment of visceral pain resulting from upper abdominal malignancy, mainly cases of pancreatic cancer. A Cochrane systematic review comparing CPN to conventional therapy found improvements in VAS, a significant decrease in opioid consumption, and fewer reported adverse side effects at four and eight weeks . They reThere is some evidence for the use of phenol neurolysis in the management of nonmalignant pain. Weksler et al. (2007) studied the efficacy and safety of phenol neurolysis in a heterogenous group of patients with intractable nonmalignant pain . ParticiPhenol is an effective and relatively safe neurolytic agent which already has a good evidence base for use in malignant pain and spasticity. There are a small number of promising studies which support expanding its use for non-malignant pain. This case report presents a new clinical application of a treatment modality that has been used for decades. This intervention could have a particular value in terminal NOF fracture patients with poor prognosis and deemed not fit for surgical fixation. It provides a novel means of pain palliation in neck of femur fractures. In this case, phenol neurolysis was effective at reducing pain, reduced opioid use, and gave an alternative to high-risk surgery in a very frail patient.