Study DesignRetrospective Cohort Study.ObjectivesTo determine whether cytochrome P450 2D6 (CYP2D6) metabolizer phenotype is associated with new persistent opioid use after cervical, thoracic, or lumbar spine surgery among opioid-naive adults.MethodsAdults with whole-genome sequencing data who underwent cervical, thoracic, or lumbar fusion or decompression between May 2018 and January 1, 2025, were identified in the All of Us Research Program. Participants had 365 days of baseline observation, 180 days of postoperative follow-up, and no opioid fills from 365 to 30 days before surgery. CYP2D6 phenotype was categorized as poor, intermediate, normal, or ultrarapid metabolizer. New persistent opioid use required a perioperative opioid fill and another fill 90 to 180 days postoperatively. Associations were estimated using Firth-penalized logistic regression adjusted for ancestry principal components and clinical covariates.ResultsAmong 3,820 participants, 460 (12.0%) developed new persistent opioid use. The overall association across CYP2D6 phenotypes was significant (χ[2] = 15.30; P = .002). Compared with normal metabolizers, adjusted odds ratios were 1.48 (95% CI, 1.00-2.18) for poor, 1.05 (95% CI, 0.85-1.30) for intermediate, and 1.50 (95% CI, 0.89-2.54) for ultrarapid metabolizers. Poor metabolizers receiving hydrocodone had higher odds of persistent use (OR, 2.15; 95% CI, 1.07-4.32).ConclusionsCYP2D6 phenotype was associated with new persistent opioid use after spine surgery, with higher risk estimates at the metabolic extremes. Extreme-phenotype estimates were reportable only in European-ancestry participants, so risk in other ancestry groups remains unknown. Medication-specific replication in larger, ancestry-diverse cohorts is needed before clinical implementation.

Opioids are commonly prescribed as standards of care for various types of pain. Multiple pathways can impact pain response, and understanding medication metabolism is imperative to achieving optimal analgesic response. Pharmacogenomics (PGx) can assist with understanding interindividual variability and aid in safe medication prescribing. Genetic variants in pharmacokinetic and pharmacodynamic genes have been evaluated, and literature generally favors use of pharmacokinetic associations in clinical practice. Tramadol and codeine have the most literature to support integration of PGx into routine prescribing practices. Hydrocodone and oxycodone have theoretical implications; however, data have been inconsistent. Clinical decision support has been the mainstay of integration of PGx results into routine clinical practice. Future research should focus on additional pathways implicated in opioid metabolism and response to further guide effective pain management with opioids.

For a long time, pain management has relied on relatively old opioids and broad-spectrum non-opioids, which display efficacy gaps and non-negligible safety risks. This review explores why voltage-gated sodium channels, particularly NaV1.7 and NaV1.8, emerged as prime targets for pain relief, and why early development efforts failed. NaV1.7 was initially considered a promising target due to its role in nociception and genetic evidence linking it to pain disorders. However, clinical trials of selective NaV1.7 inhibitors have repeatedly failed. We explore the reasons for these failures and discuss the clinical shortcomings of non-selective blockers and early NaV1.7 inhibitors. In contrast, NaV1.8 has emerged as a much stronger drug target, because it is mostly limited to peripheral nerves, directly drives continuous pain signaling, and shows less apparent functional redundancy in specific nociceptive axonal compartments. Nevertheless, compensatory mechanisms involving NaV1.7, NaV1.9, and other conductances remain context-, tissue-, and disease-dependent. Suzetrigine, a highly selective inhibitor of this channel, recently gained regulatory approval for acute pain, marking a major breakthrough in non-opioid options, even though its Phase 3 efficacy was comparable to hydrocodone/acetaminophen rather than superior to it. Its clinical success is built on high selectivity, excellent pharmacokinetics, and a smart trial design that focused specifically on standardized postoperative pain models. While suzetrigine shows that NaV1.8 can be successfully targeted, it represents a regulatory and mechanistic victory rather than a complete replacement for opioids in daily practice. Progress in this field will ultimately require precise targeting, better pharmacology, and trials that better match patient phenotypes.

Chronic exposure and overdose of opioid cause neurotoxicity through alterations of several neurotransmitters, including glutamate. Upregulating glutamate transporter 1 (GLT-1) has been shown to attenuate the behavioral and neurochemical effects of chronic exposure to drugs of abuse. This study investigated the effects of GLT-1 enhancers-MC-100093 and ceftriaxone-on locomotor activity, respiratory exchange, and glutamate transporters (GLT-1, cystine/glutamate transporter, xCT), brain derived neurotrophic factor (BDNF), and neuroinflammatory biomarkers (TNF-α and HMGB1) in nucleus accumbens (NAc) and amygdala (AMY) of C57BL/6 mice exposed to escalated doses of hydrocodone involving high dose. Male C57BL/6 mice were intraperitoneally (i.p.) injected with hydrocodone (20 mg/kg, i.p.) every other day for 13 days and then received a higher dose of hydrocodone (40 mg /kg, i.p.) on day 15. Control group received i.p. injection of saline every other day, and mice in treatment groups received MC-100093 (50 mg/kg, i.p.) or ceftriaxone (200 mg/kg, i.p.) during the last five days. This study used comprehensive laboratory animal monitoring system (CLAMS) to measure mice's respiratory frequency, locomotor activity, oxygen consumption (VO2), and carbon dioxide production (VCO2). The high-dose hydrocodone challenge significantly increased VO2 and VCO2 while reducing the respiratory exchange ratio (RER). MC-100093 and ceftriaxone attenuated hydrocodone-induced increases in VO2 and VCO2; however, restoration of RER occurred exclusively in MC-100093-treated mice. Furthermore, high-dose of hydrocodone downregulated GLT-1, xCT and BDNF expression, while upregulating TNF- α and HMGB1 in both the NAc and AMY. Notably, treatment with either MC-100093 or ceftriaxone significantly mitigated these molecular alterations. These findings suggest that the novel β -lactam compound, MC-100093, holds therapeutic potential in preventing or mitigating opioid-induced neurotoxicity and overdose effects.

Several studies have supported Dr Gideon Koren’s 1993 landmark article, “Medications Which Can Kill a Toddler with One Tablet or Teaspoonful.” Although each study has its own merits, most focus solely on pediatric overdoses, and few provide an exhaustive reference list for real-time evaluation of ingestions in children and adults. The following xenobiotics warrant special attention because of their potential to cause serious outcomes, even after exposure to small volumes. This list does not imply that all pediatric exposures to these agents result in fatality, and the absence of a xenobiotic from this list does not indicate that it is necessarily safe. α1-Adrenergic agonists and imidazoline receptor agonists: Clonidine, guanfacine, naphazoline, oxymetazoline, tetrahydrozoline, xylazine (veterinary). Sulfonylureas: Chlorpropamide, glyburide, glipizide, glimepiride. Calcium channel blockers: Verapamil, diltiazem, nifedipine, amlodipine, nicardipine, nimodipine; β-Blockers: Metoprolol, labetalol, propranolol, sotalol. Tricyclic antidepressants: Imipramine, desipramine, amitriptyline, nortriptyline. Opioids: Codeine, hydrocodone, methadone, morphine, heroin. Antidiarrheals: Diphenoxylate plus atropine, loperamide. Salicylates and methyl salicylate: Oil of wintergreen, bismuth subsalicylate, mentholated balms, paramao or lawang root oil . Antipsychotics: Loxapine, thioridazine, chlorpromazine. Antimalarials: Chloroquine, hydroxychloroquine, quinine, primaquine. Antiarrhythmics: Quinidine, disopyramide, procainamide, flecainide, amiodarone. Camphor: A terpenoid used as an analgesic, antipruritic agent, and component of cooling gels, ointments, balms, mothballs, household fragrances, and essential oils. Oral camphor use occurs in some regions for religious ceremonies, traditional remedies, aphrodisiacs, or lactation suppression. Nonalkaloid toxic lignan: Podophyllin, podofilox. Unique plant toxins: Colchicine. Oral acetylcholinesterase inhibitors: Rivastigmine, donepezil, galantamine, carbamate pesticides. Methylxanthines: Theophylline, 1,3-dimethylxanthine, caffeine. Other opioids: Buprenorphine, fentanyl. Toxic alcohols: Methanol, ethylene glycol, diethylene glycol. Caustics and other household products: Acidic or alkaline household products, hydrofluoric acid, selenious acid, acetonitrile, methylene chloride. Accidental overdoses continue to occur regularly despite the implementation of various safety measures, including widespread public education, the use of childproof containers, and easy access to poison control centers. In the US, poison control centers receive more than 2.4 million calls annually, with more than 50% involving children younger than 6 years. Most pediatric accidental ingestions involve household cleaning products and analgesics, followed by cosmetics, foreign objects, and dietary supplements. Adult overdoses may be unintentional but often involve larger total doses or high-risk medications, including opioids and sedative-hypnotics. America's Poison Centers identify the 5 most common substance classes as analgesics, household cleaners, antidepressants, cosmetic or personal care items, and cardiovascular drugs. The number of ingestions involving cleaning products increased sharply during the COVID-19 pandemic but has since declined.

Chronic exposure to opioid reduced the expression of astrocytic glutamate transporter 1 (GLT-1) and cystine/glutamate antiporter (xCT) in the mesocorticolimbic brain region and ceftriaxone, a beta-lactam antibiotic, attenuated this effect. Importantly, a novel synthetic non-antibiotic beta-lactam, MC-100093, was found effective in attenuating fentanyl and morphine overdose-induced reduction in GLT-1 expression in the nucleus accumbens (NAc) as well as attenuated fentanyl-induced liver inflammation and disruption of liver metabolites. In the present study, two novel synthetic non-antibiotic beta-lactams, MC-100093 and MC-290401, and one novel synthetic non-beta-lactam bicyclic, MC-290013, were tested in a mouse model of chronic exposure to hydrocodone with focus on GLT-1 expression as well as the transcriptional regulation of GLT-1. This study reports that MC-100093, MC-290401, and MC-290013 treatment attenuated hydrocodone-induced downregulation of GLT-1 in the NAc. MC-100093, MC-290401, and MC-290013 treatments normalized GLT-1 and xCT expression in the NAc, and this effect was associated with upregulation of NFκB in the nuclear fraction and downregulation of the expression of mTOR and IKB-α in the cytoplasmic fraction as well as upregulation of pAkt expression in the NAc. Furthermore, histological and statistical analyses revealed that MC-100093, MC-290401, and MC-290013 treatments attenuated chronic hydrocodone-induced liver inflammation (TNF-α, IL-1β, and IL-6). Finally, these GLT-1 modulators attenuated hydrocodone-induced upregulation of hepatic xCT and GLT-1. These findings suggest that these novel synthetic GLT-1 modulators may be considered as potential agents to attenuate hydrocodone-induced alterations in glutamate transporters and associated target proteins in the brain and liver.

Supercritical fluid extraction coupled on-line with supercritical fluid chromatography creates a powerful multidimensional analysis platform, but its adoption is limited by the resource-heavy process of method development. This research presents a surrogate optimization approach as a better alternative to traditional design of experiments and response surface methodology. Unlike fixed experimental designs, the surrogate model iteratively updates the response surface after each run, facilitating effective global optimization through continuous exploration and exploitation. The study adjusts both SFE- and SFC-specific variables-such as back-pressure regulation and split flow-to reduce peak FWHM and enhance extraction efficiency. Analytes, specifically reserpine, vigabatrin, hydromorphone, and hydrocodone, covering diverse physicochemical profiles, were optimized sequentially, guided by a molecular similarity metric, to broaden the design space. The surrogate model identified critical factors, including modifier concentration, chromatography pressure, dynamic extraction time, and flow rate, with adjusted coefficient of determination (R[2]) values reaching 0.97 as more data was collected and the model was refined. Response surface and parallel coordinate analyses showed that hydrocodone, hydromorphone, and vigabatrin favored high modifier concentrations, while reserpine had a distinct optimum more sensitive to static extraction time. Sensitivity analysis over 62.5-1000 ng mL[-1] yielded detection limits/quantification limits of 6.9/23.0 and 2.4/8.1 ng mL[-1] for hydrocodone and reserpine, respectively. Sequential optimization enhanced sensitivity by 15%, demonstrating the scalability and transferability of the surrogate optimization framework for developing SFE-SFC methods.

Background: Emergency department (ED) use for cancer-related pain is common, particularly among patients with metastatic disease who frequently require opioid analgesia. In October 2014, the U.S. Drug Enforcement Administration rescheduled hydrocodone combination products from Schedule III to Schedule II, introducing stricter prescribing and dispensing requirements. We evaluated whether hydrocodone rescheduling was associated with pain-related ED visits and hospitalizations among older adults with metastatic lung cancer. Methods: We conducted a retrospective SEER-Medicare cohort study of beneficiaries aged 66 years or older diagnosed with metastatic lung cancer. Diagnoses from January 2011 through September 2014 were classified as pre-policy, October 2014 was excluded as a transition month, and November 2014 through December 2018 constituted the post-policy period. Monthly 365-day cumulative incidences were estimated using the Aalen-Johansen estimator with death treated as a competing event. Segmented interrupted time-series models estimated immediate level and slope changes. Adjusted cause-specific Cox models evaluated time to first event. Results: The cohort included 52,371 beneficiaries. For narrowly defined neoplasm-related pain ED visits, the policy was associated with an immediate increase of 0.834 percentage points (95% CI, 0.330-1.338) and a post-policy slope increase of 0.030 percentage points per month (95% CI, 0.011-0.049). Pain-related hospitalizations increased immediately by 0.946 percentage points (95% CI, 0.336-1.556), with a slope increase of 0.024 percentage points per month (95% CI, 0.005-0.042). At 12 months, fitted cumulative incidences exceeded no-policy projections by 1.193 percentage points for ED visits and 1.228 percentage points for hospitalizations. Adjusted cause-specific hazard ratios were 1.14 for pain-related ED visits (95% CI, 1.00-1.30; p = 0.054) and 1.14 for hospitalizations (95% CI, 1.00-1.29; p = 0.049). Conclusions: Hydrocodone rescheduling was temporally associated with modest increases in acute-care encounters explicitly coded for neoplasm-related pain. The findings underscore the importance of preserving timely analgesic access for patients with advanced cancer.

Tramadol is frequently co-prescribed with oxycodone or hydrocodone after surgery under the assumption that its dual mechanism of action provides an opioid-sparing benefit. However, evidence supporting this practice is limited and inconsistent. We conducted a secondary analysis of the multicenter IGNITE ADOPT-PGx pragmatic trial of patients undergoing elective surgery who were prescribed oxycodone alone (n = 317) versus tramadol + oxycodone (n = 96), or hydrocodone alone (n = 563) versus tramadol + hydrocodone (n = 42). Co-primary outcomes of this study were cumulative morphine milligram equivalents (MME) consumed during the 10 days following surgery and composite pain scores at day 10 defined as the sum of current pain and average and worst pain in the past 7 days (score ranges from 3 to 15). Inverse probability of treatment weighting (IPTW) was used to adjust for demographic characteristics, comorbidities, and concomitant analgesics. Sensitivity analyses restricted to CYP2D6 normal metabolizers and sites prescribing both monotherapy and combination therapy and subgroup analysis including total knee arthroplasty patients were conducted. Compared to oxycodone alone, the combination of oxycodone and tramadol was associated with higher MME (adjusted mean 205.2 vs 122.5; P < 0.0001) and lower mobility, without meaningful differences in pain scores (adjusted mean 9.6 vs 9.4; P = 0.41). Similar findings were observed for hydrocodone-only vs hydrocodone + tramadol groups. Results were consistent in sensitivity and subgroup analyses. Co-administration of tramadol with oxycodone or hydrocodone was associated with substantially higher total MME and reduced mobility without any demonstrable improvement in pain control.