Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol ...and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87-95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%. Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours. The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O- and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites. The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated. Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids.
Here we report the isolation and characterization of three metagenome-derived clones that interfere with bacterial quorum sensing and degrade N-(3-oxooctanoyl)-L-homoserine lactone (3-oxo-C₈-HSL). By ...using a traI-lacZ gene fusion, the metagenome-derived clones were identified from a soil DNA library and analyzed. The open reading frames linked to the 3-oxo-C₈-HSL-degrading activities were designated bpiB01, bpiB04, and bpiB07. While the BpiB07 protein was similar to a known lactonase, no significant similarities were observed for the BpiB01 and BpiB04 proteins or the deduced amino acid sequences. High-performance liquid chromatography-mass spectrometry analyses confirmed that the identified genes encode novel lactone-hydrolyzing enzymes. The original metagenome-derived clones were expressed in Pseudomonas aeruginosa and employed in motility and biofilm assays. All clones were able to reproducibly inhibit motility in P. aeruginosa. Furthermore, these genes clearly inhibited biofilm formation in P. aeruginosa when expressed in P. aeruginosa PAO1. Thus, this is the first study in which metagenome-derived proteins have been expressed in P. aeruginosa to successfully inhibit biofilm formation.
Background
Atopic dermatitis (AD) is associated with an increased risk for viral infections including those caused by herpes simplex virus and varicella zoster virus.
Objectives
This study examined ...treatment‐emergent (TE) herpes simplex infection including eczema herpeticum (EH), and herpes zoster (HZ), in adult patients with AD receiving ≥1 dose of baricitinib (BARI), an oral selective inhibitor of Janus kinase 1/2.
Methods
We evaluated data from six double‐blinded, randomized, placebo‐controlled (PC) trials and two long‐term extension studies, within three analysis sets: PC, 2–4‐mg BARI extended and All‐BARI‐AD. Frequency, incidence rate (IR)/100 person‐years (PYs) and clinical characteristics of TE‐herpes simplex, EH and HZ were reported.
Results
In the All‐BARI‐AD dataset (n = 2531; 2247 PYs), herpes simplex was reported in 8.9% of patients (n = 224; IR = 10.3). Most herpes simplex events were rated as mild or moderate (93.3%), rarely led to permanent discontinuation (2.2%) and presented mostly as oral/perioral herpes simplex (51.3%). TE‐EH occurred at a low frequency (All‐BARI‐AD 1.7% n = 43; IR = 2.0) and were reported in 0.5%, 0.2% and 1.4% of patients receiving placebo, 2‐mg or 4‐mg BARI respectively. In the All‐BARI‐AD dataset, most events were investigator‐rated as mild/moderate (79.1%), affected ≤2% of the body surface area (74.2%) and occurred as single events (88.4%). Serious TE‐EH (n = 11) occurred exclusively in patients with poor disease control (vIGA‐AD™ score ≥3) at infection onset. TE‐HZ was reported in 2.1% of BARI patients (n = 53; IR = 2.3), without a dose relationship during the PC period (IR = 2.7 and IR = 0.0) or the extended dataset (IR = 3.7 and IR = 1.7) for 2‐ or 4‐mg BARI respectively.
Conclusions
TE‐herpes simplex was common, while occurrence of EH was uncommon. Most events of EH were localized with involvement of a small BSA and were linked to poor disease control. Events of HZ were rare in the PC dataset and without a dose dependent increase in frequency.
30-day hospital readmissions after head and neck cancer surgery continue to be a significant source of patient harm and healthcare expenditure. While there is substantial data in the literature ...assessing predictive factors for readmissions after head and neck cancer surgery, there are a paucity of studies which attempt to understand if such readmissions are preventable. The goal of this paper is to determine factors associated with 30-day hospital readmissions after head and neck cancer surgery and to understand if these readmissions were preventable.
Retrospective review from a single academic tertiary care center. Patients readmitted within 30 days after undergoing surgery for cancers of the head and neck between 2015 and 2018 were identified.
Over a 3-year period, 26 patients undergoing resection with or without reconstruction of head and neck cancers were readmitted to the hospital within 30 days of discharge. There were 15 (58%) men and 11 (42%) women with a mean age of 68 years (SD 14 years). Twenty-one (81%) patients had squamous cell carcinoma and 13 (50%) had a primary site in the oral cavity. Thirteen (50%) had undergone free or regional flap reconstruction. The indication for readmission was related to the surgical wound in 19 (73%) and to medical complications in 7 (27%). Each case was categorized as “possibly preventable” versus “uncertain if preventable” based on whether a reasonable and feasible change in management may have prevented readmission. Six (23%) readmissions were deemed possibly preventable. Four were related to the surgical wound where initial free or regional flaps may have prevented complication. Two were medical complications that may have benefited from longer inpatient observation.
For a subset of patients readmitted within 30 days of head and neck cancer surgery, a reasonable and feasible change in management may have prevented their hospital readmission. The significance of better understanding this patient population is underscored by the high mortality rate.
The fentanyl iontophoretic transdermal system (fentanyl ITS) enables needle-free, patient-controlled analgesia for postoperative pain management. This study compared the efficacy, safety, and ease of ...care of fentanyl ITS with patient-controlled, i.v. analgesia (PCIA) with morphine for postoperative pain management.
A prospective, randomized, multicentre trial enrolled patients in Europe after abdominal or orthopaedic surgery. Patients received fentanyl ITS (n = 325; 40.0 µg fentanyl over 10 min) or morphine PCIA n = 335; bolus doses (standard at each hospital) for ≤72 h. Supplemental i.v. morphine was available during the first 3 h. The primary efficacy measure was the patient global assessment (PGA) of the pain control method during the first 24 h.
PGA ratings of ‘good’ or ‘excellent’ were reported by 86.2 and 87.5% of patients using fentanyl ITS or morphine PCIA, respectively (95% CI, −6.5 to 3.9%). Mean (sd) last pain intensity scores (numerical rating scale, 0–10) were 1.8 (1.77) and 1.9 (1.86) in the fentanyl ITS and morphine PCIA groups, respectively (95% CI, −0.38 to 0.18). More patients reported a system-related problem for fentanyl ITS than morphine PCIA (51.1 vs 17.9%, respectively). However, fewer of these problems interrupted pain control (4.4 vs 41.3%, respectively). Patients, nurses, and physiotherapists reported more favourable overall ease-of-care ratings for fentanyl ITS than morphine PCIA. Study termination rates and opioid-related side-effects were similar between groups.
Fentanyl ITS and morphine PCIA were comparably effective and safe.
Most patients with advanced cancer develop diverse symptoms that can limit the efficacy of pain treatment and undermine their quality of life. The present study surveys symptom prevalence, etiology ...and severity in 593 cancer patients treated by a pain service. Non-opioid analgesics, opioids and adjuvants were administered following the WHO-guidelines for cancer pain relief. Other symptoms were systematically treated by appropriate adjuvant drugs. Pain and symptom severity was measured daily by patient self-assessment; the physicians of the pain service assessed symptom etiology and the severity of confusion, coma and gastrointestinal obstruction at each visit. The patients were treated for an average period of 51 days. Efficacy of pain treatment was good in 70%, satisfactory in 16% and inadequate in 14% of patients. The initial treatment caused a significant reduction in the average number of symptoms from four to three. Prevalence and severity of anorexia, impaired activity, confusion, mood changes, insomnia, constipation, dyspepsia, dyspnoea, coughing, dysphagia and urinary symptoms were significantly reduced, those of sedation, other neuropsychiatric symptoms and dry mouth were significantly increased and those of coma, vertigo, diarrhea, nausea, vomiting, intestinal obstruction, erythema, pruritus and sweating remained unchanged. The most frequent symptoms were impaired activity (74% of days), mood changes (22%), constipation (23%), nausea (23%) and dry mouth (20%). The highest severity scores were associated with impaired activity, sedation, coma, intestinal obstruction, dysphagia and urinary symptoms. Of all 23 symptoms, only constipation, erythema and dry mouth were assessed as being most frequently caused by the analgesic regimen. In conclusion, the high prevalence and severity of many symptoms in far advanced cancer can be reduced, if pain treatment is combined with systematic symptom control. Nevertheless, general, neuropsychiatric and gastrointestinal symptoms are experienced during a major part of treatment time and pain relief was inadequate in 14% of patients. Cancer pain management has to be embedded in a frame of palliative care, taking all the possibilities of symptom management into consideration.
The
N-acyl-homoserine lactones (
N-AHLs) play an important role in bacterial cell–cell signaling. Up to date, however, only a few different experimentally proven classes of
N-AHL ring-cleaving ...enzymes are known. Here we report on the isolation and biochemical characterization of a novel hydrolase derived from the soil metagenome and acting on
N-AHLs. The identified protein designated BpiB05 is weakly similar to hypothetical proteins from
Bacteroides fragilis, the draft genomes of two
Burkholderia species as well as a marine metagenomic ORF but is otherwise not similar to any known protein. BpiB05 was overexpressed in
Escherichia coli as a 10× His-tagged fusion protein. The recombinant protein revealed a molecular weight of about 70
kDa and was tested for its quorum quenching (QQ) activities using a
lacZ-bioassay. Additional HPLC–MS analyses confirmed the lactonolytic activity of the purified protein in the presence of Ca
2+. Further tests suggested that BpiB05 strongly reduces motility in
Pseudomonas aeruginosa, pyocyanin synthesis and biofilm formation in this microbe. Because BpiB05 is not distantly related to any of the currently known hydrolases it forms probably a novel group within the growing number of proteins acting on
N-AHLs.
This paper reports on the experience gained using World Health Organization Guidelines for cancer pain relief over a 10-year period in an anaesthesiology-based pain service associated with a ...palliative care programme. The course of treatment of 2118 patients was assessed prospectively over a period of 140,478 treatment days. Non-opioid analgesics (WHO step I) were used on 11%, weak opioids (WHO step II) on 31% and strong opioids (WHO step III) on 49% of treatment days. Administration was via the enteral route on 82% and parenterally on 9% of treatment days. On the remaining days, either spinally applied opioids (2%) or other treatments (6%) were utilised. Fifty-six percent of the patients were treated with morphine. Morphine dose escalation was observed in about one-half of the patients being cared for until death, whereas the other half had stable or decreasing doses over the course of treatment. Co-analgesics were administered on 37% of days, most often antidepressants (15%), anticonvulsants (13%) and corticosteroids (13%). Adjuvants to treat symptoms other than pain were prescribed on 79% of days, most commonly laxatives (42%), histamine-2-receptor antagonists (39%) and antiemetics (35%). In addition, palliative antineoplastic treatment was performed in 42%, nerve blocks in 8%, physiotherapy in 5%, psychotherapy in 3% and TENS in 3% of patients. A highly significant pain reduction was achieved within the 1st week of treatment (P < 0.001). Over the whole treatment period, good pain relief was reported in 76%, satisfactory efficacy in 12% and inadequate efficacy in 12% of patients. In the final days of life, 84% rated their pain as moderate or less, while 10% were unable to give a rating. Analgesics remained constantly effective in all 3 steps of the WHO ladder. Other clinical symptoms were likewise significantly reduced at 1 week after initial assessment, with the exception of neuropsychiatric symptoms. During the course of treatment, the latter were the major symptoms on 23% of days, followed by nausea (23%), constipation (23%) and anorexia (20%). Our results emphasise once again the marked efficacy and low rate of complications associated with oral and parenteral analgesic therapy as the mainstay of pain treatment in the palliative care of patients with advanced cancer. Wide dissemination of WHO guidelines among doctors and healthcare workers is thus necessary to effect a clear improvement in the treatment of the many patients suffering from cancer pain in the clinical and home setting.
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