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Journal of Clinical Medicine Dec 2023Opioids are used in pharmacotherapy for chronic pain. The phenomenon of their influence on the oxidative-antioxidant balance is poorly understood. Additionally, little...
BACKGROUND
Opioids are used in pharmacotherapy for chronic pain. The phenomenon of their influence on the oxidative-antioxidant balance is poorly understood. Additionally, little is known about the oxidative status in patients receiving chronic opioid noncancer pain therapy.
METHODS
The primary goal was to explore oxidative status using the total oxidative capacity (TOC) and total antioxidative capacity (TAC) in patients with chronic lower back pain (LBP) treated with opioids. The secondary task was to present the risk factors connected with the duration of therapy or anthropometric parameters. Plasma TOC and TAC were analyzed in the study group (n = 28), i.e., patients with chronic LBP treated with opioids, and in the control group (n = 11), i.e., healthy volunteers.
RESULTS
The TAC was significantly lower in the study group compared to the control group ( < 0.05), while the TOC did not differ significantly. A statistically lower TOC for buprenorphine compared to oxycodone ( = 0.019) and tramadol ( = 0.036) was observed. The TOC did not differ between tramadol and oxycodone. The highest TAC was described for oxycodone, while the TAC for buprenorphine and tramadol was significantly lower in comparison with oxycodone ( = 0.007 and = 0.016). The TOC/TAC ratio was higher in patients with nicotinism in both groups.
CONCLUSIONS
Patients receiving chronic opioid therapy presented a lower antioxidative capacity. There were differences in opioid-induced oxidative imbalance, which is very important clinically. Nicotinism increases the oxidative-antioxidative imbalance. The least oxidative capacity was associated with buprenorphine, while oxycodone showed the greatest antioxidant activity. The most favorable TOC/TAC ratio was observed for buprenorphine. It is suggested that buprenorphine or oxycodone has the best profile, and there is no correlation with the duration of opioid therapy or the opioid dose. However, all opioid substances can potentially enhance the oxidative-antioxidative status.
PubMed: 38202088
DOI: 10.3390/jcm13010082 -
BioRxiv : the Preprint Server For... Apr 2024Opioid use disorder is heritable, yet its genetic etiology is largely unknown. Analysis of addiction model traits in rodents (e.g., opioid behavioral sensitivity and...
Opioid use disorder is heritable, yet its genetic etiology is largely unknown. Analysis of addiction model traits in rodents (e.g., opioid behavioral sensitivity and withdrawal) can facilitate genetic and mechanistic discovery. C57BL/6J and C57BL/6NJ substrains have extremely limited genetic diversity, yet can show reliable phenotypic diversity which together, can facilitate gene discovery. The C57BL/6NJ substrain was less sensitive to oxycodone (OXY)-induced locomotor activity compared to the C57BL/6J substrain. Quantitative trait locus (QTL) mapping in an F2 cross identified a distal chromosome 1 QTL explaining 7-12% of the variance in OXY locomotor sensitivity and anxiety-like withdrawal in the elevated plus maze. We identified a second QTL for withdrawal on chromosome 5 near the candidate gene Gabra2 (alpha-2 subunit of GABA-A receptor) explaining 9% of the variance. Next, we generated recombinant lines from an F2 founder spanning the distal chromosome 1 locus (163-181 Mb), captured the QTL for OXY sensitivity and withdrawal, and fine-mapped a 2.45-Mb region (170.16-172.61 Mb). There were five striatal cis-eQTL transcripts in this region (Pcp4l1, Ncstn, Atp1a2, Kcnj9, Igsf9), two of which were confirmed at the protein level (KCNJ9, ATP1A2). Kcnj9, a.k.a., GIRK3, codes for a potassium channel that is a major effector of mu opioid receptor signaling. Atp1a2 codes for a subunit of a Na+/K+ ATPase enzyme that regulates neuronal excitability and shows adaptations following chronic opioid administration. To summarize, we identified genetic sources of opioid behavioral differences in C57BL/6 substrains, two of the most widely and often interchangeably used substrains in opioid addiction research.
PubMed: 38798314
DOI: 10.1101/2024.04.16.589731 -
Frontiers in Pharmacology 2024The effect of oxycodone as an opioid receptor agonist on immune function is still controversial. In this study, we investigated the possible effects of oxycodone on...
BACKGROUND
The effect of oxycodone as an opioid receptor agonist on immune function is still controversial. In this study, we investigated the possible effects of oxycodone on immune function in mice and its possible mechanisms of action.
METHODS
By repeated intraperitoneal injections of 25 mg/kg morphine and 5 mg/kg, 20 mg/kg, and 60 mg/kg oxycodone, we assessed possible changes in the number of splenic lymphocytes and inflammatory cytokines in the serum of mice. CD4 T cells and CD8 T cells were sorted from the spleen to observe whether the expression levels of opioid receptors and downstream signals were altered.
RESULTS
Repeated administration of oxycodone at a dose above 20 mg/kg resulted in significant weight loss. Repeated administration of oxycodone exhibits significant dose-dependent reduction in CD4 T cells, with little effect on CD8 T cells and little effect on inflammatory cytokine levels. Low- and intermediate-dose oxycodone increased the mRNA expression level of MOR, KOR, and DOR to varying degrees. Moreover, oxycodone increases the mRNA expression levels of the TLR4 signaling pathway to varying degrees.
CONCLUSION
Repeated intraperitoneal injection of oxycodone induces immunosuppression in mice.
PubMed: 38953110
DOI: 10.3389/fphar.2024.1370663 -
Plastic and Reconstructive Surgery.... Aug 2023This trial aimed to compare the efficacy of a multimodal analgesic regimen with gabapentin to a multimodal nonsteroidal anti-inflammatory drug (NSAID) regimen following...
UNLABELLED
This trial aimed to compare the efficacy of a multimodal analgesic regimen with gabapentin to a multimodal nonsteroidal anti-inflammatory drug (NSAID) regimen following cosmetic surgery. This was a prospective randomized study of 106 patients undergoing elective outpatient cosmetic surgery.
METHODS
Patients were randomly assigned to a multimodal regimen of postoperative acetaminophen, gabapentin, and oxycodone with an acetaminophen and gabapentin preload or postoperative ibuprofen and oxycodone-acetaminophen protocol without a preload. Data on compliance, number of narcotic pills consumed, duration of analgesic use, pain levels, patient satisfaction, time from incision close to postanesthesia care unit (PACU) admission, and incidence of bleeding-related complications were collected and analyzed.
RESULTS
Patients from both regimens reported equivalent postoperative pain control with the exception of pain in PACU. NSAID patients exhibited a 9.3% higher rate of compliance ( = 0.01), a 6.0% higher rate of satisfaction with pain control ( = 0.04), a 25.2% shorter interval between closure and PACU (=0.01), and an 8.2% lower rate of bleeding-related complications, all of which were statistically significant ( < 0.05).
CONCLUSIONS
Both regimens are viable tools in combating opioid overprescription as they both effectively reduce postoperative pain. However, the NSAID protocol resulted in greater satisfaction related to pain management and was more cost-effective by reducing emergence time from anesthesia. As there were no hematomas associated with the use of NSAIDs and a significantly higher rate of compliance, the use of NSAIDs in enhanced recovery after surgery protocols is supported.
PubMed: 37577251
DOI: 10.1097/GOX.0000000000005181 -
Psychopharmacology Jul 2024Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is...
RATIONALE
Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain.
OBJECTIVE
Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays.
METHODS
Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability.
RESULTS
In vitro, ITI-333 is a potent 5-HT receptor antagonist (K = 8 nM) and a biased, partial agonist at μ-opioid (MOP) receptors (K = 11 nM; lacking β-arrestin agonism) with lesser antagonist activity at adrenergic α (K = 28 nM) and dopamine D (K = 50 nM) receptors. In vivo, ITI-333 blocks 5-HT receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys.
CONCLUSIONS
ITI-333 acts as a potent 5-HT receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal/reinstatement, supporting its potential utility as a treatment for OUD.
Topics: Animals; Mice; Male; Substance Withdrawal Syndrome; Rats; Humans; Rats, Sprague-Dawley; Receptors, Opioid, mu; Serotonin 5-HT2 Receptor Antagonists; Substance-Related Disorders; Opioid-Related Disorders; Dose-Response Relationship, Drug; Oxycodone; Analgesics, Opioid; Self Administration; Cricetulus; CHO Cells
PubMed: 38710856
DOI: 10.1007/s00213-024-06578-w -
Multimodal Pain Management After Outpatient Orthopedic Hand Surgery: A Prospective Randomized Trial.Journal of Hand Surgery Global Online Jan 2024Opioid stewardship ensures effective pain management while avoiding overprescribing of opioids after surgery. This prospective randomized study investigates the efficacy...
PURPOSE
Opioid stewardship ensures effective pain management while avoiding overprescribing of opioids after surgery. This prospective randomized study investigates the efficacy of a multimodal postoperative pain regimen compared to a traditional opioid-only pain regimen following elective outpatient orthopedic hand surgery. We hypothesized that patients receiving multimodal pain management would consume fewer opioids and report greater satisfaction than patients receiving only opioids.
METHODS
Consecutive patients undergoing outpatient hand and upper extremity surgery performed by two board-certified fellowship-trained orthopedic hand surgeons at one institution were recruited and randomized into either a study or control group. The study group received a standing multimodal postoperative regimen consisting of scheduled oral acetaminophen and naproxen as well as oxycodone to be taken as needed. The control group received only oxycodone to be taken as needed. Postoperatively, daily pain levels, medication usage, refills, satisfaction, and adverse events were recorded. Descriptive statistics were performed.
RESULTS
Of the 112 patients enrolled, 54 were randomized to the control group, and 58 were randomized to the study group. Study and control group patients did not differ significantly based on daily average pain scores or daily worst pain scores. However, study group patients reported fewer average daily oxycodone intake and total oxycodone pill count (7.0 vs 2.4 total pills, <.005). In addition, the study group patients were more likely to report satisfaction with their postoperative pain control than control regimen patient's and were more likely to use the same pain regimen again if required.
CONCLUSION
A multimodal postoperative pain regimen reduces opioid usage and has higher patient satisfaction rates in comparison to traditional opioid-only regimens. Use of multimodal pain regimens that use nonopioids, such as acetaminophen and naproxen, over an opioid should be considered for postoperative pain after orthopedic hand surgery.
LEVEL OF EVIDENCE
Therapeutic II.
PubMed: 38313605
DOI: 10.1016/j.jhsg.2023.07.021 -
Cureus Sep 2023Ehlers-Danlos syndrome (EDS) is a rare disorder affecting the connective tissue, resulting in joint hypermobility, elastic skin, and often chronic pain, especially in...
Ehlers-Danlos syndrome (EDS) is a rare disorder affecting the connective tissue, resulting in joint hypermobility, elastic skin, and often chronic pain, especially in the hypermobility variant. Although opioids are commonly prescribed for pain, they can lead to opioid use disorder (OUD) and overdose. A 67-year-old female with Ehlers-Danlos syndrome hypermobility type (EDS-HT), osteoarthritis (OA), and anxiety received opioid-based pain management for a decade before changing her primary care physician. Her medications included oxycodone and morphine sulfate extended-release (ER) at different dosages. To lower overdose risk, her morphine milligram equivalents (MME) were tracked, and a step-by-step opioid tapering process was started. Diagnosing EDS is difficult due to symptom overlap with other connective tissue disorders. Chronic pain in EDS involves both nociceptive and neuropathic pain, necessitating a comprehensive pain management approach. The essential components of pain management include non-opioid medications, physical therapy, and psychological support. Opioids should be used cautiously in EDS patients because of connective tissue vulnerabilities and potential side effects. Personalized plans for opioid tapering may be appropriate for those on long-term opioid therapy. Managing EDS-related chronic pain requires a tailored, multidisciplinary approach. Early and accurate diagnosis and specialized healthcare providers familiar with EDS are crucial for effective pain management. Ongoing research and evidence-based pain management approaches are vital to address the unique needs of EDS patients, promoting better pain relief and overall well-being. Through meticulous evaluation and personalized treatment plans, healthcare professionals can better support EDS patients in managing chronic pain and reducing opioid dependence and misuse risks. A comprehensive approach, incorporating non-opioid medications, physical therapy, and psychological support, can offer effective pain relief and improve the quality of life for those living with EDS.
PubMed: 37745744
DOI: 10.7759/cureus.45713 -
Biomedicine & Pharmacotherapy =... Jul 2024The association between polymorphisms of the human ATP binding cassette subfamily B member 1 (ABCB1) gene and opioid response has attracted intense attention recently....
The association between polymorphisms of the human ATP binding cassette subfamily B member 1 (ABCB1) gene and opioid response has attracted intense attention recently. As the ABCB1 gene encodes for the transporter P-glycoprotein in the brain and intestine involved in the pharmacokinetics of opioids, we investigated the effects of ABCB1 genetic polymorphisms on doses of opioids for pain relief and determined which pharmacokinetic process was affected in cancer pain patients. Sixty-eight cancer pain patients admitted for intrathecal therapy (ITT) were included. The association between ABCB1 genetic polymorphisms (C3435T, C1236T, G2677T/A and A61G) and systemic doses of opioids before ITT were investigated. Concentrations of oxycodone in plasma and cerebrospinal fluid (CSF) were determined by HPLC-MS/MS in 17 patients treated with oral oxycodone before ITT, and the influences of ABCB1 genetic polymorphisms on plasma-concentration to oral-dose ratios and CSF-concentration to plasma-concentration ratios of oral oxycodone were further analyzed. ABCB1 C3435T and G2677T/A polymorphisms were significantly associated with systemic doses of opioids before ITT, which coincided with the influences of ABCB1 C3435T and G2677T/A polymorphisms on the ratios of plasma-concentration to oral-dose. However, no significant difference was found in ratios of CSF-concentration to plasma-concentration among ABCB1 SNP genotypes. The present study provided the first evidence that ABCB1 C3435T and G2677T/A polymorphisms affect opioid requirement in cancer pain patients via altering transportation function of P-glycoprotein in the intestine, which will further expand our knowledge about pharmacokinetics of opioids and could contribute to the individualization of opioids use.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B; Male; Female; Analgesics, Opioid; Middle Aged; Polymorphism, Single Nucleotide; Aged; Oxycodone; Cancer Pain; Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Intestinal Mucosa; Genotype
PubMed: 38850645
DOI: 10.1016/j.biopha.2024.116897 -
BioRxiv : the Preprint Server For... Aug 2023Opioids such as Morphine, Codeine, Hydrocodone, and Oxycodone target the μ-opioid receptor, a G-protein-coupled receptor (GPCR), blocking the transmission of...
Opioids such as Morphine, Codeine, Hydrocodone, and Oxycodone target the μ-opioid receptor, a G-protein-coupled receptor (GPCR), blocking the transmission of nociceptive signals. In this study, four opioids were analyzed for ADMET properties and molecular interactions with a GPCR crystal structure (PDB ID: 8EF6). This aided in the computational design of two novel drug candidates with improved docking scores and ADMET properties when compared to Hydrocodone. Homology analysis indicated that a (house mouse) animal model could be used in the preclinical studies of these drug candidates in the development of safer and more effective opioid drugs for pain management with reduced side effects.
PubMed: 37662242
DOI: 10.1101/2023.08.25.554876 -
Frontiers in Surgery 2024We aimed to compare the anesthesia induction effects of oxycodone and sufentanil on postoperative pain in patients undergoing laparoscopic gallbladder-preserving...
Comparison of the analgesic effects of oxycodone vs. sufentanil on postoperative pain after laparoscopic gallbladder-preserving cholecystolithotomy: a prospective randomized controlled trial.
BACKGROUND
We aimed to compare the anesthesia induction effects of oxycodone and sufentanil on postoperative pain in patients undergoing laparoscopic gallbladder-preserving cholecystolithotomy, as well as changes in serum levels of inflammatory factors (TNF-α, IL-6, and IL-10) in the perioperative period.
METHODS
Sixty patients who underwent laparoscopic gallbladder-preserving cholecystolithotomy were evenly divided into oxycodone (O) and sufentanil (S) groups. In groups O and S, oxycodone (0.3 mg/kg) and sufentanil (0.3 ug/kg) were administered, respectively, followed by propofol (2 mg/kg) and rocuronium (0.6 mg/kg). In both groups, the intraoperative electroencephalography double-frequency index was used to guide the use of sedative and analgesic drugs, assessing the follow-up analgesic effect (VAS), degree of sedation (Ramsey), and postoperative complications at seven different time points (0, 0.5, 2, 4, 6, 8, and 24 h postoperatively).
RESULTS
Compared with the S group, patients in the O group exhibited lower VAS scores within 24 h postoperatively ( < 0.001), but there was no statistical difference between wound and shoulder pain scores (> 0.05). Regarding postoperative awakening and extubation duration, O group patients experienced shorter times and better remedial analgesia ( < 0.05). In terms of the degree of sedation, the Ramsay score decreased at 0 h postoperatively compared with the S group ( < 0.001).
CONCLUSION
Compared with sufentanil, oxycodone anesthesia induced better postoperative analgesia and less inflammatory responses in patients undergoing laparoscopic gallbladder-preserving cholecystolithotomy.
CLINICAL TRIAL REGISTRATION
This study has been approved by the Ethics Committee of Peking University Shougang Hospital, with ethical approval (No. IRBK-2020-009), and has completed registration in the Chinese Clinical Trials Register (http://www.chictr.org.cn/) (ChiCTR2000031230).
PubMed: 38721023
DOI: 10.3389/fsurg.2024.1382759