Opioid analgesic overdose mortality continues to rise in the United States, driven by increases in prescribing for chronic pain. Because chronic pain is a major indication for medical cannabis, laws that establish access to medical cannabis may change overdose mortality related to opioid analgesics in states that have enacted them.
It is well-known that genotypic differences can account for the subject-specific responses to opiate administration. In this regard, the basal activity of the endogenous system (either at the receptor or at the ligand level) can modulate the effects of exogenous agonists as morphine, and vice versa. The μ opioid receptor from zebrafish, dre-oprm1, binds endogenous peptides and morphine with similar affinities. Morphine administration during development altered the expression of the endogenous opioid propeptides proenkephalins and proopiomelanocortin. Treatment with opioid peptides (Met-ENK, MEGY and β-END) modulated dre-oprm1 expression during development. Knocking-down dre-oprm1 gene significantly modified the mRNA expression of the penk and pomc genes, thus indicating that oprm1 is involved in shaping penk and pomc expression. Besides, the absence of a functional oprm1 clearly disrupted the embryonic development, as proliferation was disorganized in the central nervous system of oprm1-morphant embryos: mitotic cells were found widespread through the optic tectum, and not restricted to the proliferative areas of the mid- and hindbrain. TUNEL staining revealed that the number of apoptotic cells in the Central Nervous System (CNS) of morphants was clearly increased at 24 hpf. These findings will help to understand the role of the endogenous opioid system in the CNS development. Our results will also contribute to unravel the complex feedback loops which modulate opioid activity, and which may be involved in establishing a coordinated expression of both receptors and endogenous ligands. Further knowledge of the complex interactions between the opioid system and analgesic drugs will provide insights that may be relevant for analgesic therapy.
- The Journal of pharmacology and experimental therapeutics
- Published over 2 years ago
The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADF) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS) while analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics.
Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids-which include fatal respiratory depression-are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21-a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.
On March 28, 2016, two patients were evaluated at the Contra Costa Regional Medical Center emergency department (ED) in Contra Costa County, California, for nausea, vomiting, central nervous system depression, and respiratory depression, 30 minutes after ingesting what appeared to be Norco, a prescription opioid pain medication that contains acetaminophen and hydrocodone. The patients purchased the drug from a friend a few days earlier. The two cases of drug intoxication were reported to a Contra Costa County Health Department public health official who subsequently notified the California State Health Department.
Prescription opioid analgesics play an important role in the treatment of postoperative pain; however, unused opioids may be diverted for nonmedical use and contribute to opioid-related injuries and deaths.
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology
- Published about 4 years ago
The WHO guidelines on cancer pain management recommend a sequential three-step analgesic ladder. However, conclusive data are lacking as to whether moderate pain should be treated with either step II weak opioids or low-dose step III strong opioids.
Codeine has been prescribed to pediatric patients for many decades as both an analgesic and an antitussive agent. Codeine is a prodrug with little inherent pharmacologic activity and must be metabolized in the liver into morphine, which is responsible for codeine’s analgesic effects. However, there is substantial genetic variability in the activity of the responsible hepatic enzyme, CYP2D6, and, as a consequence, individual patient response to codeine varies from no effect to high sensitivity. Drug surveillance has documented the occurrence of unanticipated respiratory depression and death after receiving codeine in children, many of whom have been shown to be ultrarapid metabolizers. Patients with documented or suspected obstructive sleep apnea appear to be at particular risk because of opioid sensitivity, compounding the danger among rapid metabolizers in this group. Recently, various organizations and regulatory bodies, including the World Health Organization, the US Food and Drug Administration, and the European Medicines Agency, have promulgated stern warnings regarding the occurrence of adverse effects of codeine in children. These and other groups have or are considering a declaration of a contraindication for the use of codeine for children as either an analgesic or an antitussive. Additional clinical research must extend the understanding of the risks and benefits of both opioid and nonopioid alternatives for orally administered, effective agents for acute and chronic pain.
An improved synthesis of a haptenic heroin surrogate 1 (6-AmHap) is reported. The intermediate needed for the preparation of 1 was described in the route in the synthesis of 2 (DiAmHap). A scalable procedure was developed to install the C-3 amido group. Using the Boc protectng group in 18 allowed preparation of 1 in an overall yield of 53% from 4 and eliminated the necessity of preparing the diamide 13. Hapten 1 was conjugated to tetanus toxoid and mixed with liposomes containing monophosphoryl lipid A as an adjuvant. The 1 vaccine induced high anti-1 IgG levels that reduced heroin-induced antinociception and locomotive behavioral changes following repeated subcutaneous and intravenous heroin challenges in mice and rats. Vaccinated mice had reduced heroin-induced hyperlocomotion following a 50 mg/kg heroin challenge. The 1 vaccine-induced antibodies bound to heroin and other abused opioids, including hydrocodone, oxycodone, hydromorphone, oxymorphone and codeine.
Many observers were surprised when Indiana Governor Mike Pence issued an executive order on March 26, 2015, declaring a public health emergency after a rapidly escalating outbreak of human immunodeficiency virus (HIV) was identified in Scott County, a rural region on the Kentucky border.(1) Others, however, had seen it coming. Over the years, a growing number of young people in Scott County - like those in surrounding counties and states - had begun abusing opiates such as oxymorphone, an opioid analgesic prescribed by local medical providers, until a more tamper-resistant formulation and policy reform began limiting its abuse. Facing the . . .