Iatrogenic Side Effects of Pain Therapies.

Pain regimens, particularly for chronic cancer and noncancer pain, must balance the important analgesic benefits against potential risks. Many effective and frequently used pain control regimens are associated with iatrogenic adverse events. Interventional procedures can be associated with nerve injuries, vascular injuries, trauma to the spinal cord, and epidural abscesses. Although rare, these adverse events are potentially catastrophic. Pharmacologic remedies for pain must also consider potential side effects that can occur even at therapeutic doses of over-the-counter remedies such as paracetamol (acetaminophen) or nonsteroidal anti-inflammatory drugs. Opioids are effective pain relievers but are associated with many side effects, some of which can be treatment limiting. A prevalent and distressing side effect of opioid therapy is constipation. Opioid-induced constipation is caused by binding to opioid receptors in the gastrointestinal system, making conventional laxatives ineffective. Peripherally acting mu-opioid receptor antagonists are a new drug class that offers the benefits of preserving opioid analgesia without side effects in the gastrointestinal system. An important safety concern, particularly among geriatric patients is the increasingly prevalent condition of polypharmacy. Many senior patients take five or more medications, including some that may be contraindicated in geriatric patients, duplicative of other drugs, have potential pharmacokinetic drug-drug interactions, or may not be the optimal choice for the patient's age and condition. Careful assessment of medications in the elderly, including possibly deprescribing with tapering of certain drugs, may be warranted but should be done systematically and under clinical supervision.

Current Approaches to Four Challenging Pain Syndromes.

During a conference of pain specialists, some of the experts addressed the potential management of four prevalent but difficult painful conditions, namely, chronic postsurgical pain (CPSP), knee osteoarthritis, chest trauma, and facet joint arthropathy. In all cases, the conditions posed challenges in accurate diagnoses as well as safe, effective treatments, especially using locoregional blocks. It is not clear why some surgical patients develop CPSP and others do not, although some risk factors have been identified. More importantly, the transitional phase of pain from acute to chronic deserves greater scrutiny. It appears as if more aggressive and more effective perioperative and postoperative analgesia could help mitigate or possibly prevent CPSP. Knee osteoarthritis is prevalent but is often managed pharmacologically and then with joint replacement; many patients simply live with the condition which can be viewed as a disease of the entire joint. New approaches with intra-articular injections of hyaluronic acid, platelet-rich plasma, and botulinum toxin may provide safe, effective, and durable pain control. Chest trauma can be extremely painful and a source of morbidity, but its management tends to rely on watchful waiting and drug therapy. New approaches to regional nerve blocks can be beneficial and may reduce troublesome symptoms such as the inability to cough or clear the lungs. Facet joint arthropathy is very prevalent among older people but is not completely clarified. It may be the source of intense pain with limited management strategies. The role of nerve blocks in facet joint arthropathy is an important new addition to the armamentarium of pain management, particularly for geriatric patients.

Is Fibromyalgia a Fashionable Diagnosis or a Medical Mystery?

Despite its prevalence, there is no clear-cut diagnostic path or treatment paradigm for fibromyalgia; this can lead to a multiplicity of symptoms and comorbid conditions that complicate care. "Overlapping symptoms" describe conditions that can occur concomitantly with fibromyalgia and include migraine, irritable bowel syndrome, obesity, and pelvic pain syndromes. A variety of pharmacologic and nonpharmacologic treatments are available for fibromyalgia, but treatment is best personalized for an individual and recognizes potential comorbidities. Opioids are not the recommended front-line treatment, cannabinoids hold promise but with limitations and nonpharmacologic options, such as aerobic or resistance exercise and cognitive behavior therapy, can play a very important but often underestimated role. Amitriptyline appears to be safe and effective in treating six of the main fibromyalgia domains: pain, disturbed sleep, fatigue, affective symptoms, functional limitations, and impaired cognition ("fibro fog"). Very low-dose naltrexone (2.5-4.5 mg) may offer analgesic and anti-inflammatory benefits to fibromyalgia patients, but further studies are needed. Fibromyalgia can be a devastating and debilitating condition for patients, and clinicians are challenged with its diagnosis and treatment as well. Further research as well as compassionate approaches to offering personalized care to those with fibromyalgia are required.

What's New in Neuropathy?

Neuropathic pain presents diagnostic and treatment challenges. Despite recent advances in our understanding of the diagnosis and treatment of neuropathy, much remains to be elucidated. Familiar with neuropathy is the paradox that aberrant nerve signaling causes both sensory loss and pain. Voltage-gated sodium channels play an important role in neuronal electrogenesis and communication among neurons, and their dysregulation leads to hyperexcitability and pain. While numerous validated diagnostic assessment tools are available for neuropathy, patients often experience a diagnostic delay about the cause of their neuropathy. New research is defining more specific types of neuropathy beyond peripheral and central forms. The prevalence of pain varies by type of neuropathy, with chronic idiopathic axonal polyneuropathy associated with the highest proportion of patients experiencing pain. In the majority of types, it exceeds 50%. Gluten neuropathy, a form of peripheral neuropathy, is a new diagnostic consideration. It may require electrochemical conductance testing of hands and feet to test for sudomotor dysfunction. Among those with serologically confirmed gluten sensitivity or celiac disease, gluten neuropathy is a common neurological manifestation and may be addressed at least partially by a gluten-free diet. In Greece, a new neuropathic pain registry was created in 2014 in order to help gather data from real-world neuropathic pain patients. While still in its earliest phase, this registry has already produced demographic and treatment data that suggest suboptimal prescribing and less than recommended use of interventional procedures. Awareness campaigns are underway to encourage more Greek pain clinics to participate in this important registry.

Expert consensus on difficult airway assessment.

Background: Identifying a potentially difficult airway is crucial both in anaesthesia in the operating room (OR) and non-operation room sites. There are no guidelines or expert consensus focused on the assessment of the difficult airway before, so this expert consensus is developed to provide guidance for airway assessment, making this process more standardized and accurate to reduce airway-related complications and improve safety. Methods: Seven members from the Airway Management Group of the Chinese Society of Anaesthesiology (CSA) met to discuss the first draft and then this was sent to 15 international experts for review, comment, and approval. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) is used to determine the level of evidence and grade the strength of recommendations. The recommendations were revised through a three-round Delphi survey from experts. Results: This expert consensus provides a comprehensive approach to airway assessment based on the medical history, physical examination, comprehensive scores, imaging, and new developments including transnasal endoscopy, virtual laryngoscopy, and 3D printing. In addition, this consensus also reviews some new technologies currently under development such as prediction from facial images and voice information with the aim of proposing new research directions for the assessment of difficult airway. Conclusions: This consensus applies to anesthesiologists, critical care, and emergency physicians refining the preoperative airway assessment and preparing an appropriate intubation strategy for patients with a potentially difficult airway.

The Diagnostic Odyssey of Patients with Chronic Neuropathic Pain-Expert Opinion of Greek Pain Specialists.

The diagnosis of chronic neuropathic pain requires a laborious process and can be a very long journey for the patients, one that can be characterized as an "odyssey." Our aim was to describe the "diagnostic odyssey" associated with chronic neuropathic pain in the Greek context. Specialized clinicians working at dedicated chronic pain and palliative care centers were asked to participate in a survey regarding the diagnostic process in Greece. In total, 44 respondents provided information on the organization of their centers, the diagnostic process, and the perceived obstacles involved in the diagnosis of chronic neuropathic pain. Most respondents reported that their centers were not fully or efficiently organized and believed that additional specialized healthcare personnel should be employed. Raising public awareness about the existence of such centers was also considered key. The two main obstacles in reaching a diagnosis were the difficulty non-experts had in recognizing chronic neuropathic pain and the lack of acknowledgement that chronic neuropathic pain is a condition that needs to be addressed. When considering these responses in light of the extended socioeconomic burden associated with chronic neuropathic pain, efforts should be made to limit the "diagnostic odyssey" of chronic neuropathic pain in Greece. The aim of this study is to explore the experience of patients with chronic neuropathic pain in Greece from the viewpoint of pain specialists. A better organization of pain and palliative care centers, facilitation of communication with previously treating clinicians, increased personnel, utilization of a chronic pain registry, and guidelines development can aid in this venture. Keypoints: The diagnosis of chronic neuropathic pain in Greece is a laborious and time-consuming process that needs to be refined; Greek clinicians believe that their centers were not fully or efficiently organized and think that additional specialized healthcare personnel should be employed; Patient comorbidities and retards in visiting a clinic at the onset of symptoms delay the diagnosis of neuropathic pain and may complicate subsequent care; The diagnostic delay has been reported as three years between the onset of symptoms and seeking general medical help and another nine years before a referral to a pain specialist; Neuropathic pain is associated with patient distress and socioeconomic burdens, and diagnostic delays prolong the condition, may allow it to worsen, and utilize valuable healthcare resources without providing effective solutions.

The efficacy of 5HT3-receptor antagonists in postoperative nausea and vomiting: the role of pharmacogenetics.

INTRODUCTION: Genetic variants may affect drug efficacy on postoperative nausea and vomiting (PONV). The understanding of these mechanisms will help to identify the surgical patients who might benefit from specific prophylactic and therapeutic antiemetic treatment. The aim of the present review was to investigate gene polymorphisms that influence 5-hydroxytryptamine (serotonin) type 3 receptor antagonists (5HT3RA) efficacy in PONV. EVIDENCE AQUISITION: We included articles published from 2005 to 2022, utilizing the electronic databases PUBMED, EMBASE, COHRANE Library and ScienceDirect. To explore the relationship between genetic variations and 5HT3 receptor antagonist efficacy in PONV we focused on three different gene polymorphisms: the cytochrome P450 mono-oxygenase system gene (CYP2D6), the adenosine triphosphate (ATP)-binding cassette subfamily B gene (ABCB1) as well as the 5HT3 receptor gene (5HT3R). We also explored the relationship between the above genetic variations and their impact on 5HT3RA efficacy in the context of chemotherapy induced nausea and vomiting. EVIDENCE SYNTHESIS: Our search retrieved a total of 70 articles; 29 of them were included in the present review. Regarding polymorphisms of the CYP2D6 gene and the efficacy of serotonin antagonists in PONV, the ultra-rapid metabolizer genotype was associated with reduced efficacy of ondansetron, dolasetron and tropisetron, with the latter presenting more pronounced failure in these patients, while granisetron's efficacy remained unaffected. Regarding variations in the ABCB1 gene, three polymorphisms ("2677G>T/A" in exon 21; "3435C>T" in exon 27; "C1236T" in exon 12) were associated with a better response to ondansetron and ramosetron, while they did not affect palonosetron's efficacy. Additionally, polymporphisms of the 5-HT3B receptor gene were associated with ondancetron's postoperative efficacy; the "100_-102AAG" deletion variant was associated with reduced efficacy, while the Y129S variant did not show any effect on the drug's antiemetic effect. CONCLUSIONS: This review highlights that inefficacy of a specific drug in managing PONV could be attributed to specific genetic profiles and patients would possibly benefit from a drug switch.

Pharmacological Management of Neuropathic Pain after Radiotherapy in Head and Neck Cancer Patients: A Systematic Review.

Background: Neuropathic pain (NP) in head and neck cancer (HNC) patients represents a treatment challenge. Most studies investigating drugs against NP are conducted in patients suffering with diabetic neuropathy or postherpetic neuralgia, while data are limited in cancer pain management. Additionally, regarding cancer therapy-related NP, most of the studies do not focus on HNC patients. The aim of this review is to identify the studies on systematically administered medication for NP management that included HNC patients under radiotherapy. Methods: A systematic literature search was performed, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, in PubMed, Cochrane Library, Web of Science and ClinicalTrials.gov on 30 October 2021. The medical subject heading (MeSH) terms were ("head and neck cancer" OR "tumor") AND "neuropathic pain" AND "medication" AND "radiotherapy." The Cochrane Collaboration tool was used for quality assessment. Results: The search identified 432 articles. Three more articles were identified after searching the reference lists of the retrieved articles. A total of 10 articles met the eligibility inclusion criteria and were included in this review; 6 on gabapentin, 1 on pregabalin, 1 on nortriptyline, 1 on methadone, and 1 on ketamine. Statistically significant results in pain reduction compared to placebo or standard pain medication were found in the studies on pregabalin (p = 0.003), methadone (p = 0.03), ketamine (p = 0.012), and in two out of six gabapentin studies (p < 0.004). Two of the studies (both concerning gabapentin) had no comparison arm. Conclusions: Treatments including pregabalin, methadone, ketamine, and gabapentin were found to provide pain relief against HNC NP. While there is a plethora of pharmacological treatments available for the management of NP, only a few studies have been conducted regarding the pharmacological management of therapy-related NP in HNC patients. More studies should be conducted regarding the pharmacological approaches in HNC therapy-related NP so that specific treatment algorithms can be developed.

Pain Management and COVID-19: A Latin American Perspective.

Vaccinations and therapeutics have been developed for COVID-19, but vaccine uptake varies markedly among countries. Public health responses have also varied, in particular, with lockdown efforts and school closing. All over the world, the pandemic exposed healthcare and economic weaknesses. COVID-19 exacerbated mental health issues by exposing the population to prolonged periods of fear, anxiety, financial stress, psychological uncertainties, and sometimes isolation from even family and friends. Chronic pain patients have been disproportionately affected. The pandemic-associated stresses may have exacerbated their already painful symptoms while at the same time interrupting their access to care. The ramifications of the COVID-19 post-viral syndrome ("long COVID-19") are not yet known. COVID-19 viral infection has been associated with neuropathic pain symptoms. Tele-triage and telehealth applications can help manage chronic pain patients in the COVID-19 era, but many interventional procedures, injections, or other treatments have been delayed. The role of palliative care for patients with terminal cases of infection must be re-examined. Palliative care is a relatively new medical specialty and allows terminally ill patients to die in as much comfort and peace as can be afforded to them. More training in palliative care for all clinicians is urgently needed. COVID-19 exposed much that is wrong or weak or inadequate in our healthcare systems, but it also allowed us to embrace new technologies and develop better systems to manage the challenge of a pandemic.

What Is New in the Clinical Management of Low Back Pain: A Narrative Review.

Low back pain (LBP) is a prevalent condition associated with disability. Treating patients with LBP becomes further complicated by the potential presence of underlying conditions, such as cancer or traumatic injury, or biopsychosocial aspects. LBP usually has a neuropathic component that must be assessed and treated appropriately. Pharmacological management of LBP requires a thorough knowledge of the available agents and the mechanisms of the LBP. Although there are effective pharmacological treatments for LBP, it is important to consider safety issues. Fixed-dose combination products may be helpful, as they can reduce opioid consumption without sacrificing analgesic benefits. Neuromodulation is an important and sometimes overlooked treatment option for LBP and may be appropriate for chronic LBP requiring long-term treatment. Imaging studies support neuroplastic changes in the brain as a result of neuromodulation. Interventional approaches to chronic LBP are numerous and must be appropriately selected based on the individual patient. Evidence in support of epidural injections for LBP is strong for short-term pain control but moderate to limited for long-term relief. Rehabilitation for LBP can be an important element of long-term care, and new forms of rehabilitation programs are being developed using telemedicine. A variety of new and established treatments are available for patients with LBP, and clinicians and patients may benefit from emerging new treatment modalities.

Perioperative Dexmedetomidine or Lidocaine Infusion for the Prevention of Chronic Postoperative and Neuropathic Pain After Gynecological Surgery: A Randomized, Placebo-Controlled, Double-Blind Study.

INTRODUCTION: The transition of acute to chronic postoperative pain (CPP) remains a significant burden to the rehabilitation of patients. The research for adjuvants to prevent CPP continues; among others, dexmedetomidine and lidocaine seem promising agents. METHODS: This is a long-term follow-up of a randomized, placebo-controlled, double-blind study on women who underwent open abdominal gynecological surgery and received dexmedetomidine or lidocaine or placebo infusion perioperatively (n = 81). The effect of these adjuvants on the development of CPP and neuropathic pain was assessed during a 12-month follow-up. Eighty-one (81) women ASA I-II, aged between 30 and 70 years, were randomly assigned to receive either dexmedetomidine (DEX group) or lidocaine (LIDO group) or placebo (CONTROL group) perioperatively. Before anesthesia induction, all patients received a loading intravenous dose of either 0.6 µg/kg dexmedetomidine or 1.5 mg/kg lidocaine or placebo, followed by 0.6 µg/kg/h dexmedetomidine or 1.5 mg/kg/h lidocaine or placebo until last suture. Patients were followed up to obtain the long-term outcomes at 3, 6, and 12 months. At these time-points, pain intensity was assessed with the Numerical Rating Scale, (NRS: 0-10) and the development of neuropathic elements with the Douleur Neuropathique 4 (DN4) score. Prognostic parameters that could affect chronic pain and its components were also identified. RESULTS: Data from 74 women were analyzed. Dexmedetomidine significantly reduced NRS scores comparing to placebo at 3 months (p = 0.018), while at 6 months, lidocaine was found superior to placebo (p = 0.02), but not to dexmedetomidine, in preventing neuropathic pain (DN4 < 4). Regarding secondary endpoints, higher NRS cough scores at 48 h were associated with statistically significant NRS and DN4 scores at 3, 6, and 12 months (p < 0.02). At 6 months, a statistically significant correlation was also found between higher NRS values and older age (p = 0.020). CONCLUSIONS: Dexmedetomidine was superior to placebo regarding the duration and severity of CPP, while lidocaine exhibited a protective effect against neuropathic elements of CPP. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03363425.

Updates on Palliative Medicine in the COVID-19 Era.

The advances in knowledge in the field of pain medicine in the last half century have recently been reported from both the scientific and the social points of view [...].

The Greek Neuropathic Pain Registry: The structure and objectives of the sole NPR in Greece.

OBJECTIVES: Neuropathic pain (NP) is a complex condition that impairs the patients' quality of life. Registries are useful tools, increasingly used as they provide high-quality data. This article aims to describe the Greek Neuropathic Pain Registry (Gr.NP.R.) design, the patients' baseline data, and real-world treatment outcomes. METHODS: The Gr.NP.R. collects electronically, stores, and shares real-world clinical data from Pain and Palliative Care centers in Greece. It is a web-based application, which ensures security, simplicity, and transparency. VAS, DN4, and Pain Detect were used for pain and NP assessment. RESULTS: From 2016 to 2020, 5980 patients with chronic pain, of cancer or non-cancer origin, were examined and 2334 fulfilled the NP inclusion criteria (VAS > 5, DN4 > 4, and Pain Detect ≥ 19). At the first visit, the mean age was 64.8 years, 65.5% were female patients, and 97.9% were Greek. The mean (SD) time from pain initiation to visiting the pain clinics was 1.5 (3.8) years. Most patients were undertreated. Following the patients' registration, the national guidelines were implemented. The majority of the prescribed medications were gabapentinoids (70.2%), especially pregabalin (62.6%), and opioids (tramadol, 55.3%). At visits 1 and 6, mean VAS was 7.1 and 5, and mean DN4 score was 5.6 and 3.5, respectively. CONCLUSIONS: The Gr.NP.R. provides information on the demographics, clinical progress, treatment history, treatment responses, and the drugs of choice for patients with cancer and non-cancer NP. The collected data may help physicians plan the management of their patients.

Constraint-Induced Movement Therapy Combined With Botulinum Toxin for Post-stroke Spasticity: A Systematic Review and Meta-Analysis.

Stroke is considered one of the main causes of adult disability and the second most serious cause of death worldwide. The combination of botulinum toxin type A (BTX) with rehabilitation techniques such as modified constraint-induced movement therapy (mCIMT) has emerged as a highly efficient intervention for stroke patients to start synchronized motor function along with spasticity reduction. The current systematic review and meta-analysis were conducted in order to evaluate the available literature about the safety and efficacy of constraint-induced movement therapy (CIMT) combined with BTX in stroke patients with upper limb spasticity. Searches were conducted on WoS (Web of Science), Ovid, EBSCO-ASC&BSC, and PubMed for identifying relevant literature published from 2000-2020. Randomized Controlled Trials (RCTs) and Quasi-experimental studies were considered for inclusion. Rayyan (systematic review tool) QCRI (Qatar Computing Research Institute) was used for independent screening of the studies by two reviewers. For risk of bias and study quality assessment, Cochrane risk of bias tool (RoB 2) and Physiotherapy Evidence Database (PEDro) scales were used. Cochrane review manager was used to carry out the meta-analyses of the included studies. The search resulted in a total of 13065 references, of which 4967 were duplicates. After the title, abstract and full-text screening, two RCTs were deemed eligible for inclusion. Both the RCTs scored 8 on PEDro and were level evidence. The studies were heterogeneous. The findings of this meta-analysis in all the three joints post-stroke spasticity assessed on modified Ashworth scale (MAS) at four weeks post-injection aren't statistically significant (elbow P-value 0.74, wrist P-value 0.57, fingers P-value 0.42), however, according to one of the included studies the therapeutic efficacy of the combination of BTX-mCIMT injection assessed at four weeks post-injection in wrist and finger flexors was promising.  The effectiveness of BTX-CIMT combination over conventional therapy (CT) for improving post-stroke spasticity still needs to be explored with long-term, multicenter rigorously designed RCTs having a good sample size. However, the BTX-CIMT combination is promising for enhancing motor function recovery and improving activities of daily living (ADLs).

Effects of Intravenous Dexmedetomidine Versus Lidocaine on Postoperative Pain, Analgesic Consumption and Functional Recovery After Abdominal Gynecological Surgery: A Randomized Placebo-controlled Double Blind Study.

BACKGROUND: The management of acute postoperative pain remains challenging, and the search for adjuvants to reduce opioid use continues. OBJECTIVES: We studied the effect of intravenous dexmedetomidine and lidocaine on postoperative pain, opioid consumption, and functional recovery. STUDY DESIGN: A randomized controlled trial was performed. SETTING: The trial was conducted at Aretaieio University Hospital, Athens, Greece. METHODS: In this double-blind study, 91 women, 30-70 years old, with an American Society of Anesthesiologists Physical Status of I or II, scheduled for abdominal hysterectomy or myomectomy, were randomized to receive either dexmedetomidine (DEX group), lidocaine (LIDO group), or placebo (CONTROL group). Before anesthesia induction, a loading intravenous dose of one of the aforementioned drugs was given to all patients (0.9mL/kg/h for 10 minutes), followed by 0.15mL/kg/h infusion until the last suture. Identical 50 mL syringes containing dexmedetomidine 4 mg/mL (bolus: 0.6 µg/kg, infusion: 0.6 µg/kg/h), or lidocaine 10 mg/mL (bolus: 1.5 mg/kg, infusion: 1.5 mg/kg/ h), or NaCl 0.9% were used. The main outcomes were cumulative morphine consumption and postoperative pain at rest and cough (Numeric Rating Scale, [NRS]: 0-10). Other measurements included anesthetic (sevoflurane) consumption, nausea/vomiting, postoperative sedation, time to first passage of flatus/stool, mobilization, sleep quality, satisfaction, discharge time, and drug side effects. Measurements were performed at Post-anesthesia Care Unit (PACU), 2 hours, 4 hours, 8 hours, 24 hours, and 48 hours. RESULTS: Data from 81 patients were analyzed (DEX group:26, LIDO group:29, CONTROL group:26). Cumulative morphine consumption (mg) was significantly lower in the LIDO group versus the CONTROL group in the PACU (LIDO group: 8.41 ± 1.45, CONTROL group: 10.4 ± 3.29, P = 0.017); at 24 hours (LIDO group: 16.86 ± 5.85, CONTROL group: 23.4 ± 9.54, P = 0.036); and 48 hours (LIDO group: 20.45 ± 6.58, CONTROL group: 28.87 ± 12.55, P = 0.022). The DEX group experienced significantly less nausea compared to the CONTROL group in the PACU (P = 0.041). Finally, the use of vasoconstrictors was higher in the treatment groups, especially in the DEX group compared to the CONTROL group (P = 0.012). The rest of the measurements regarding NRS scores, sevoflurane consumption, bowel function, and other recovery characteristics, satisfaction, discharge time, and drug side effects did not differ significantly among the groups. LIMITATIONS: Different doses of the studied medications were not assessed, drugs were administered only pre- and intraoperatively, and pain was not managed according to the World Health Organization (WHO) pain relief ladder. However, all patients were adequately covered with patient-controlled anesthesia morphine and acetaminophen; parecoxib (not approved for use in the United States) was preserved as a rescue analgesic. CONCLUSIONS: Dexmedetomidine and lidocaine could be useful adjuvants for analgesia after abdominal surgery. Lidocaine significantly reduced postoperative opioid consumption, while dexmedetomidine prevented early postoperative nausea. However, hypotension and the need for vasopressors was common with both agents, especially with dexmedetomidine.

Efficacy and Safety of Peripherally Acting µ-Opioid Receptor Antagonist (PAMORAs) for the Management of Patients With Opioid-Induced Constipation: A Systematic Review.

In treating chronic and acute pain, opioids are widely used. Although they do provide analgesia, their usage does come with adverse events (AEs). One of the most burdensome is opioid-induced bowel dysfunction, and more specifically opioid-induced constipation (OIC). The pathogenesis of these AEs is well known as the consequence of the action of opioids on m-receptors in the enteric nervous system. In recent years, medicines counteracting this specific action at the receptors have been registered for clinical use: the peripherally acting µ-opioid receptor antagonists (PAMORAs). The knowledge of their comparative efficacy and tolerability is very important for physicians and patients in opioid therapy. This systematic review of the existing literature on PAMORAs aimed to study the relative clinical advantages and disadvantages. The most important data banks, including "PubMed," "Embase," "CT.gov," "ICTRP" and "CINAHL" were used to find the published material on PAMORAs. The selected publications were examined to systematically analyze the efficacy and safety of the four existing PAMORAs. All of the medications are superior to placebo in reducing OIC. There are few published data on alvimopan used to treat OIC, and it is only indicated for the treatment of post-abdominal surgery ileus. Methylnaltrexone is studied mainly in its subcutaneous (SC) formulation. When used in its oral formulation, it seems more rapid than naloxegol and placebo in the reduction of OIC. Naldemedine is able to produce more spontaneous bowel movements (SBMs) when compared to alvimopan and naloxegol. Tolerability was found to be similar for all of them. In particular, they affect the gastrointestinal tract (GI), with flatulence and diarrhea, especially at high dosages. For some of them, nasopharyngitis and abdominal pain were observed as treatment adverse effects (TEAs). Several cardiovascular TEAs were reported after methylnaltrexone use, but it is not clear whether they were consequences of the drug or related to the general conditions of the patients. Considering the existing data, naloxegol and naldemedine seem to be the best choices, with a higher number of spontaneous bowel movements following naldemedine administration.

Factors for Timely Identification of Possible Occurrence of Delirium in Palliative Care: A Prospective Observational Study.

Delirium occurs in 50-80% of end-of-life patients but is often misdiagnosed. Identification of clinical factors potentially associated with delirium onset can lead to a correct early diagnosis. To this aim, we conducted a prospective cohort study on patients from an Italian palliative care unit (PCU) admitted in 2018-2019. We evaluated the presence of several clinical factors at patient admission and compared their presence in patients who developed delirium and in those who did not develop it during follow-up. Among 503 enrolled patients, after a median follow-up time of 16 days (interquartile range 6-40 days), 95 (18.9%) developed delirium. Hazard ratios (HR) and corresponding 95% confidence intervals were computed using Cox proportional hazard models. In univariate analyses, factors significantly more frequent in patients with delirium were care in hospice, compromised performance status, kidney disease, fever, renal failure, hypoxia, dehydration, drowsiness, poor well-being, breathlessness, and "around the clock" therapy with psychoactive drugs, particularly haloperidol. In multivariate analyses, setting of care (HR 2.28 for hospice versus home care, 95% CI 1.45-3.60; p < 0.001), presence of breathlessness (HR 1.71, 95% CI 1.03-2.83, p = 0.037), and administration of psychoactive drugs, particularly haloperidol (HR 2.17 for haloperidol, 95% CI 1.11-4.22 and 1.53 for other drugs, 95% CI 0.94-2.48; p = 0.048) were significantly associated with the risk of developing delirium. The study indicates that some clinical factors are associated with the probability of delirium onset. Their evaluation in PC patients could help healthcare professionals to identify the development of delirium in those patients in a timely manner.

Successful Spinal Cord Stimulation for Necrotizing Raynaud's Phenomenon in COVID-19 Affected Patient: The Nightmare Comes Back.

Necrotizing Raynaud's phenomenon is a vascular clinical syndrome characterized by vasospasm of distal resistance vessels, usually triggered by cold temperatures or by psychological conditions such as anxiety and stress. Pain is the first reported symptom, related to insufficient oxygen delivery to the extremities that leads to ischemia of the peripheral tissues. The initial treatment is conservative, but if the symptoms persist, necrosis and distal amputation can occur. In selected patients, neuromodulation with spinal cord stimulation (SCS) can be an effective treatment by reducing pain and amputation rate. Recent evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause endotheliopathy with microvascular and macrovascular thrombotic events and can present as a systemic inflammatory vascular disease. We present a case of a severe necrotizing Raynaud's phenomenon successfully treated and controlled with SCS that abruptly reappeared during SARS-CoV-2 infection. The report of this case is suggestive for potential treatment in case of peripheral ischemia consequent to COVID-19 vasculopathy. The interaction between SCS and SARS-CoV-2-related endotheliopathy is unknown and would deserve further studies.