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Anesthesiology Sep 2023Opioids are effective analgesics, but they can have harmful adverse effects, such as addiction and potentially fatal respiratory depression. Naloxone is currently the... (Review)
Review
Opioids are effective analgesics, but they can have harmful adverse effects, such as addiction and potentially fatal respiratory depression. Naloxone is currently the only available treatment for reversing the negative effects of opioids, including respiratory depression. However, the effectiveness of naloxone, particularly after an opioid overdose, varies depending on the pharmacokinetics and the pharmacodynamics of the opioid that was overdosed. Long-acting opioids, and those with a high affinity at the µ-opioid receptor and/or slow receptor dissociation kinetics, are particularly resistant to the effects of naloxone. In this review, the authors examine the pharmacology of naloxone and its safety and limitations in reversing opioid-induced respiratory depression under different circumstances, including its ability to prevent cardiac arrest.
Topics: Humans; Naloxone; Analgesics, Opioid; Narcotic Antagonists; Opiate Overdose; Respiratory Insufficiency; Drug Overdose; Heart Arrest
PubMed: 37402248
DOI: 10.1097/ALN.0000000000004622 -
JAMA Psychiatry Jul 2021Opioid use disorder (OUD) is a significant cause of morbidity and mortality in the US, yet many individuals with OUD do not receive treatment.
IMPORTANCE
Opioid use disorder (OUD) is a significant cause of morbidity and mortality in the US, yet many individuals with OUD do not receive treatment.
OBJECTIVE
To assess the cost-effectiveness of OUD treatments and association of these treatments with outcomes in the US.
DESIGN AND SETTING
This model-based cost-effectiveness analysis included a US population with OUD.
INTERVENTIONS
Medication-assisted treatment (MAT) with buprenorphine, methadone, or injectable extended-release naltrexone; psychotherapy (beyond standard counseling); overdose education and naloxone distribution (OEND); and contingency management (CM).
MAIN OUTCOMES AND MEASURES
Fatal and nonfatal overdoses and deaths throughout 5 years, discounted lifetime quality-adjusted life-years (QALYs), and costs.
RESULTS
In the base case, in the absence of treatment, 42 717 overdoses (4132 fatal, 38 585 nonfatal) and 12 660 deaths were estimated to occur in a cohort of 100 000 patients over 5 years, and 11.58 discounted lifetime QALYs were estimated to be experienced per person. An estimated reduction in overdoses was associated with MAT with methadone (10.7%), MAT with buprenorphine or naltrexone (22.0%), and when combined with CM and psychotherapy (range, 21.0%-31.4%). Estimated deceased deaths were associated with MAT with methadone (6%), MAT with buprenorphine or naltrexone (13.9%), and when combined with CM, OEND, and psychotherapy (16.9%). MAT yielded discounted gains of 1.02 to 1.07 QALYs per person. Including only health care sector costs, methadone cost $16 000/QALY gained compared with no treatment, followed by methadone with OEND ($22 000/QALY gained), then by buprenorphine with OEND and CM ($42 000/QALY gained), and then by buprenorphine with OEND, CM, and psychotherapy ($250 000/QALY gained). MAT with naltrexone was dominated by other treatment alternatives. When criminal justice costs were included, all forms of MAT (with buprenorphine, methadone, and naltrexone) were associated with cost savings compared with no treatment, yielding savings of $25 000 to $105 000 in lifetime costs per person. The largest cost savings were associated with methadone plus CM. Results were qualitatively unchanged over a wide range of sensitivity analyses. An analysis using demographic and cost data for Veterans Health Administration patients yielded similar findings.
CONCLUSIONS AND RELEVANCE
In this cost-effectiveness analysis, expanded access to MAT, combined with OEND and CM, was associated with cost-saving reductions in morbidity and mortality from OUD. Lack of widespread MAT availability limits access to a cost-saving medical intervention that reduces morbidity and mortality from OUD. Opioid overdoses in the US likely reached a record high in 2020 because of COVID-19 increasing substance use, exacerbating stress and social isolation, and interfering with opioid treatment. It is essential to understand the cost-effectiveness of alternative forms of MAT to treat OUD.
Topics: Adult; Buprenorphine; Combined Modality Therapy; Cost-Benefit Analysis; Delayed-Action Preparations; Female; Humans; Male; Methadone; Middle Aged; Naloxone; Opiate Overdose; Opiate Substitution Treatment; Opioid-Related Disorders; Psychotherapy; Treatment Outcome
PubMed: 33787832
DOI: 10.1001/jamapsychiatry.2021.0247 -
The Journal of Clinical Investigation Sep 2023The nucleus accumbens (NAc) is the most promising target for drug use disorder treatment. Deep brain stimulation (DBS) of NAc is effective for drug use disorder...
The nucleus accumbens (NAc) is the most promising target for drug use disorder treatment. Deep brain stimulation (DBS) of NAc is effective for drug use disorder treatment. However, the mechanisms by which DBS produces its therapeutic effects remain enigmatic. Here, we define a behavioral cutoff criterion to distinguish depressive-like behaviors and non-depressive-like behaviors in mice after morphine withdrawal. We identified a basolateral amygdala (BLA) to NAc D1 medium spiny neuron (MSN) pathway that controls depressive-like behaviors after morphine withdrawal. Furthermore, the paraventricular nucleus of thalamus (PVT) to NAc D2 MSN pathway controls naloxone-induced acute withdrawal symptoms. Optogenetically induced long-term potentiation with κ-opioid receptor (KOR) antagonism enhanced BLA to NAc D1 MSN signaling and also altered the excitation/inhibition balance of NAc D2 MSN signaling. We also verified that a new 50 Hz DBS protocol reversed morphine withdrawal-evoked abnormal plasticity in NAc. Importantly, this refined DBS treatment effectively alleviated naloxone-induced withdrawal symptoms and depressive-like behaviors and prevented stress-induced reinstatement. Taken together, the results demonstrated that input- and cell type-specific synaptic plasticity underlies morphine withdrawal, which may lead to novel targets for the treatment of opioid use disorder.
Topics: Mice; Animals; Analgesics, Opioid; Nucleus Accumbens; Receptors, Dopamine D2; Morphine; Naloxone; Substance Withdrawal Syndrome; Receptors, Dopamine D1; Mice, Inbred C57BL
PubMed: 37561576
DOI: 10.1172/JCI163266 -
The New England Journal of Medicine May 1990Studies in animals indicate that methylprednisolone and naloxone are both potentially beneficial in acute spinal-cord injury, but whether any treatment is clinically... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study.
Studies in animals indicate that methylprednisolone and naloxone are both potentially beneficial in acute spinal-cord injury, but whether any treatment is clinically effective remains uncertain. We evaluated the efficacy and safety of methylprednisolone and naloxone in a multicenter randomized, double-blind, placebo-controlled trial in patients with acute spinal-cord injury, 95 percent of whom were treated within 14 hours of injury. Methylprednisolone was given to 162 patients as a bolus of 30 mg per kilogram of body weight, followed by infusion at 5.4 mg per kilogram per hour for 23 hours. Naloxone was given to 154 patients as a bolus of 5.4 mg per kilogram, followed by infusion at 4.0 mg per kilogram per hour for 23 hours. Placebos were given to 171 patients by bolus and infusion. Motor and sensory functions were assessed by systematic neurological examination on admission and six weeks and six months after injury. After six months the patients who were treated with methylprednisolone within eight hours of their injury had significant improvement as compared with those given placebo in motor function (neurologic change scores of 16.0 and 11.2, respectively; P = 0.03) and sensation to pinprick (change scores of 11.4 and 6.6; P = 0.02) and touch (change scores, 8.9 and 4.3; P = 0.03). Benefit from methylprednisolone was seen in patients whose injuries were initially evaluated as neurologically complete, as well as in those believed to have incomplete lesions. The patients treated with naloxone, or with methylprednisolone more than eight hours after their injury, did not differ in their neurologic outcomes from those given placebo. Mortality and major morbidity were similar in all three groups. We conclude that in patients with acute spinal-cord injury, treatment with methylprednisolone in the dose used in this study improves neurologic recovery when the medication is given in the first eight hours. We also conclude that treatment with naloxone in the dose used in this study does not improve neurologic recovery after acute spinal-cord injury.
Topics: Acute Disease; Adolescent; Adult; Double-Blind Method; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Methylprednisolone; Middle Aged; Motor Activity; Multicenter Studies as Topic; Naloxone; Randomized Controlled Trials as Topic; Sensation; Spinal Cord Injuries; Time Factors
PubMed: 2278545
DOI: 10.1056/NEJM199005173222001 -
British Journal of Anaesthesia Oct 2019
Topics: Humans; Naloxone
PubMed: 31420087
DOI: 10.1016/j.bja.2019.07.007 -
Clinical Pharmacokinetics Apr 2024Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people... (Review)
Review
Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the μ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of the opioid agonist, such as dissociation rate from the MOR receptor and constitution of the victim. Aim of treatment is a balancing act between restoration of respiration (not consciousness) and avoidance of withdrawal, achieved by titration to response after initial doses of 0.4-2 mg. Naloxone is rapidly eliminated [half-life (t) 60-120 min] due to high clearance. Metabolites are inactive. Major routes for administration are intravenous, intramuscular, and intranasal, the latter primarily for take-home naloxone. Nasal bioavailability is about 50%. Nasal uptake [mean time to maximum concentration (T) 15-30 min] is likely slower than intramuscular, as reversal of respiration lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual and between-study variability in pharmacokinetics in volunteers are large. Variability in the target population is unknown. The duration of action of 1 mg intravenous (IV) is 2 h, possibly longer by intramuscular and intranasal administration. Initial parenteral doses of 0.4-0.8 mg are usually sufficient to restore breathing after heroin overdose. Fentanyl overdoses likely require higher doses of naloxone. Controlled clinical trials are feasible in opioid overdose but are absent in cohorts with synthetic opioids. Modeling studies provide valuable insight in pharmacotherapy but cannot replace clinical trials. Laypeople should always have access to at least two dose kits for their interim intervention.
Topics: Humans; Administration, Intranasal; Analgesics, Opioid; Drug Overdose; Half-Life; Naloxone; Narcotic Antagonists
PubMed: 38485851
DOI: 10.1007/s40262-024-01355-6 -
American Journal of Public Health Apr 2022
Topics: Drug Overdose; Humans; Naloxone; Narcotic Antagonists
PubMed: 35319955
DOI: 10.2105/AJPH.2021.306699 -
Child and Adolescent Psychiatric... Jul 2016Opioid use and addiction in adolescents and young adults is a health problem of epidemic proportions, with devastating consequences for youth and their families. Opioid... (Review)
Review
Opioid use and addiction in adolescents and young adults is a health problem of epidemic proportions, with devastating consequences for youth and their families. Opioid overdose is a life-threatening emergency that should be treated with naloxone, and respiratory support if necessary. Overdose should always be an opportunity to initiate addiction treatment. Detoxification is often a necessary, but never sufficient, component of treatment for OUDs. Treatment for OUDs is effective but treatment capacity is alarmingly limited and under-developed. Emerging consensus supports the incorporation of relapse prevention medications such as buprenorphine and extended release naltrexone into comprehensive psychosocial treatment including counseling and family involvement.
Topics: Adolescent; Analgesics, Opioid; Buprenorphine; Drug Overdose; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders
PubMed: 27338968
DOI: 10.1016/j.chc.2016.03.002 -
The International Journal on Drug Policy Dec 2019
Topics: Drug Overdose; Humans; Naloxone; Narcotic Antagonists; Opioid-Related Disorders
PubMed: 30527865
DOI: 10.1016/j.drugpo.2018.11.008 -
Clinical Toxicology (Philadelphia, Pa.) Apr 2022Older adults are less likely than younger adults to receive naloxone therapy. Given high rates of prescription opioid use/misuse and increasing illicit opioid use among...
CONTEXT
Older adults are less likely than younger adults to receive naloxone therapy. Given high rates of prescription opioid use/misuse and increasing illicit opioid use among older adults, factors associated with naloxone administration for older opioid poisoning cases need examination.
METHODS
We analyzed the 83,135 opioid-involved cases aged 50+ from the 2015-2020 National Poison Data System. Single-variable logistic regression was used to examine associations of naloxone administration with demographic factors, exposure site/reason, medical outcomes, management site/level of care, clinical effects, and other interventions. Multivariable logistic regression models were fit to examine associations of naloxone administration with different types of opioids.
RESULTS
Over the six years, the proportion of prescription opioid cases that received naloxone therapy increased steadily from 21.9% to 28.4%. The proportion of illicit opioid cases that received naloxone therapy was 51.9% in 2015 and 59.8% in 2020 with a high of 64.4% in 2019. In 2020, the death rate for illicit opioid cases without naloxone therapy was 31.4% compared to 2.3% for those with the therapy. Cases managed at healthcare facilities (HCF) had higher odds of receiving naloxone therapy. Among prescription opioid cases, naloxone therapy rates among older and female cases and those managed at non-HCF settings were especially low even for major medical outcomes. Cases involving oxycodone, morphine, methadone, prescription fentanyl, hydromorphone, oxymorphone, and other/unknown opioids had higher odds of naloxone administration.
DISCUSSION
Rates of naloxone therapy for older prescription opioid poisoning cases need improvement. While rates were higher among illicit opioid cases, the drop in 2020 and the sharp increase in deaths among illicit opioid cases without naloxone therapy confirm the importance of access to this life-saving intervention.
CONCLUSIONS
Increased naloxone co-prescribing and other means of facilitating access to naloxone are needed to prevent opioid poisoning deaths among older adults who use prescription opioids.
Topics: Aged; Analgesics, Opioid; Female; Humans; Middle Aged; Naloxone; Opioid-Related Disorders; Poisons; Prescriptions
PubMed: 34554013
DOI: 10.1080/15563650.2021.1981362