Who receives naloxone from emergency medical services? Characteristics of calls and recent trends

Abstract

Background: With the rapid rise in opioid overdose-related deaths, state policy makers have expanded policies to increase the use of naloxone by emergency medical services (EMS). However, little is known about changes in EMS naloxone administration in the context of continued worsening of the opioid crisis and efforts to increase use of naloxone. This study examines trends in patient demographics and EMS response characteristics over time and by county urbanicity. Methods: We used data from the 2013–2016 National EMS Information System to examine trends in patient demographics and EMS response characteristics for 911-initiated incidents that resulted in EMS naloxone administration. We also assessed temporal, regional, and urban–rural variation in per capita rates of EMS naloxone administrations compared with per capita rates of opioid-related overdose deaths. Results: From 2013 to 2016, naloxone administrations increasingly involved young adults and occurred in public settings. Particularly in urban counties, there were modest but significant increases in the percentage of individuals who refused subsequent treatment, were treated and released, and received multiple administrations of naloxone before and after arrival of EMS personnel. Over the 4-year period, EMS naloxone administrations per capita increased at a faster rate than opioid-related overdose deaths across urban, suburban, and rural counties. Although national rates of naloxone administration were consistently higher in suburban counties, these trends varied across U.S. Census Regions, with the highest rates of suburban administration occurring in the South. Conclusions: Naloxone administration rates increased more quickly than opioid deaths across all levels of county urbanicity, but increases in the percentage of individuals requiring multiple doses and refusing subsequent care require further attention.     

Pharmacokinetics,pharmacodynamics and pharmacogenetics associated with nonsteroidal anti-inflammatory drugs and opioids in pediatric cancer patients

Introduction: Advancing appropriate and adequate analgesic pharmacotherapy in pediatric patients with cancer is an area of clinical need. Few studies have been performed to evaluate the selection of an analgesic and appropriate dosing corresponding to analgesic effect among pediatric cancer patients. This review describes information related to pharmacokinetic, pharmacodynamic, and pharmacogenomic (when applicable) considerations for analgesics that are commonly used to manage pain experienced by pediatric patients with cancer.

Areas covered: Analgesics commonly used to treat pediatric patients with malignancy patterned after the World Health Organization’s ‘analgesic ladder’ for cancer pain management.

Expert opinion: Addressing pain management safely and effectively in pediatric patients with cancer will require advances in both drug development, to increase the armament of analgesics available for children, and our pharmacologic understanding of those analgesics in current use. However, performing the necessary types of studies to develop new analgesics, or gain knowledge of existing therapy, within a population that is relatively small, diverse, and who experience pain originating from a variety of sources, is a tremendous challenge.     

Non-neuraxial analgesia in labour

Pain in labour is often described as one of the most severe pains experienced. Neuraxial techniques provide the most effective form of labour analgesia. However, not all women wish to have this or indeed want complete pain relief in labour. There are also subgroups of women in whom neuraxial techniques are contraindicated or attempted placement is unsuccessful. Therefore delivery units must be able to offer a range of non-neuraxial analgesia options for labour.     

When words are painful: unraveling the mechanisms of the nocebo effect

The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patient's distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinson's disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.     

Effect of mu and kappa opioids on injury-induced microglial accumulation in leech CNS: involvement of the nitric oxide pathway

Damage to the leech or mammalian CNS increases nitric oxide (NO) production and causes accumulation of phagocytic microglial cells at the injury site. Opioids have been postulated to modulate various parameters of the immune response. Morphine and leech morphine-like substance are shown to release NO and suppress microglial activation. Regarding the known immuno-modulatory effects of selective mu and kappa ligands, we have assessed the effect of these agents on accumulation of microglia at the site of injury in leech CNS. Leech nerve cords were dissected, crushed with fine forceps and maintained in different concentrations of opiates in culture medium for 3 h and then fixed and double stained with Hoechst 33258 and monoclonal antibody to endothelial nitric oxide synthase (NOS). Morphine and naloxone (> or =10(-3) M) but not selective mu agonist, DAMGO [d-Ala2, N-Me-Phe-Gly5(ol)-enkephalin] and antagonist, CTAP [D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2] inhibited the microglial accumulation. The effect of morphine was abrogated by pre-treatment with naloxone and also non-selective NOS inhibitor, l-NAME [N(omega)-nitro-l-arginine-methyl-ester; 10(-3) M] implying an NO-dependent and mu-mediated mechanism. These results are similar to properties of recently found mu-3 receptor in leech, which is sensitive to alkaloids but not peptides. Both selective kappa agonist, U50,488 [3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)cyclohexyl)-benzeneacetamide; > or =10(-3) M], and antagonist, nor-binaltorphimine (nor-BNI; > or =10(-3) M), inhibited the accumulation. The effect of nor-BNI was reversed by l-NAME. Immunohistochemistry showed decreased endothelial NOS expression in naloxone and U50,488-treated cords. Since, NO production at the injury site is hypothesized to act as a stop signal for microglias, opioid agents may exert their effect via changing of NO gradient along the cord resulting in disruption of accumulation. These results suggest an immuno-modulatory role for mu and kappa opioid receptors on injury-induced microglial accumulation which may be mediated via NO.     

A Conformationally Gated Model of Methadone and Loperamide Transport by P-Glycoprotein

P-glycoprotein (Pgp) is a multidrug resistance transporter that limits the penetration of a wide range of neurotherapeutics into the brain including opioids. The diphenylpropylamine opioids methadone and loperamide are structurally similar, but loperamide has about a 4-fold higher Pgp-mediated transport rate. In addition to these differences, they showed significant differences in their effects on Pgp-mediated adenosine triphosphate (ATP) hydrolysis. The activation of Pgp-mediated ATP hydrolysis by methadone was monophasic, whereas loperamide activation of ATP hydrolysis was biphasic implying methadone has a single binding site and loperamide has 2 binding sites on Pgp. Quenching of tryptophan fluorescence with these drugs and digoxin showed competition between the opioids and that loperamide does not compete for the digoxin-binding site. Acrylamide quenching of tryptophan fluorescence to probe Pgp conformational changes revealed that methadone- and loperamide-induced conformational changes were distinct. These results were used to develop a model for Pgp-mediated transport of methadone and loperamide where opioid binding and conformational changes are used to explain the differences in the opioid transport rates between methadone and loperamide.     

The prevalence of constipation at admission and after 1 week of palliative care: a multi-center study

Aim: To assess the prevalence and intensity of constipation in advanced-cancer patients referred to palliative care, and to assess changes after 1 week of specialist palliative care.

Methods: This was a prospective multi-center study in advanced patients for a period of 1 year. At admission (T0), age, gender, primary tumor, concomitant diseases, Karnofsky status, Palliative prognostic score (PaP), Edmonton Symptom Assessment scale (ESAS), Memorial Delirium Assessment Scale (MDAS), and bowel function index (BFI) were collected. In BFI, high values represent severe constipation. The use of medication was also recorded, as well as possible causes of constipation. The same parameters were recorded 1 week after admission for palliative care (T7).

Results: A total of 246 patients were screened for constipation. The mean BFI at T0 was 42.4 (SD?=?26.92). One hundred and sixty-three patients (66.3%) had a BFI >28. The mean BFI at T7 was 35.7 (SD?=?28.8), with a significant decrease from T0 to T7 (p?=?.000). A significant decrease of BFI in patients with a BFI >28 was reported (p?=?.000). In patients with a BFI ≤28 there was a significant worsening of constipation (p?=?.000). In patients with a BFI >28 at T0 there was a significant increase in the use of laxatives at T7 in comparison with patients having a BFI ≤28 (p?=?.002). In patients with a BFI ≤28 at T0, who had a significant worsening of BFI (Δ?>?12), the use of laxatives was significantly lower in comparison to patients who had a BFI >28 (p?=?.000). In the multivariate analysis, dehydration and the use of benzodiazepines were independently associated with higher BFI scores.

Conclusion: Constipation is present in approximately two-thirds of patients, and is principally associated with dehydration and the use of benzodiazepines. Patients with normal bowel function at initial assessment may see a worsening in their condition a week later due to lack of prevention or subsequent under-treatment.