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Neuropharmacology Mar 2021Antagonism of peripheral opioid receptors by methylnaltrexone (MNTX) was recently proposed as a potential mechanism to attenuate the development of opioid analgesic...
BACKGROUND
Antagonism of peripheral opioid receptors by methylnaltrexone (MNTX) was recently proposed as a potential mechanism to attenuate the development of opioid analgesic tolerance based on experiments conducted in mice. However, reports indicate that MNTX is demethylated to naltrexone (NTX) in mice, and NTX may subsequently cross the blood-brain barrier to antagonize centrally-mediated opioid effects. The goal of this study was to determine whether MNTX alters centrally-mediated behaviors elicited by the opioid analgesics, morphine and oxycodone, and to quantify concentrations of MNTX and NTX in blood and brain following their administration in mice.
METHODS
Combinations of MNTX and morphine were tested under acute and chronic conditions in thermal nociceptive assays. Effects of MNTX and NTX pretreatment were assessed in an oxycodone discrimination operant procedure. Blood and brain concentrations of these antagonists were quantified after their administration using liquid chromatography-mass spectrometry.
RESULTS
MNTX dose-dependently attenuated acute and chronic morphine antinociception. MNTX and NTX dose-dependently antagonized the discriminative stimulus effects of oxycodone. MNTX and NTX were detected in both blood and brain after administration of MNTX, confirming its demethylation and demonstrating that MNTX itself can cross the blood-brain barrier.
CONCLUSIONS
These results provide converging behavioral and analytical evidence that MNTX administration in mice attenuates centrally-mediated effects produced by opioid analgesics and results in functional concentrations of MNTX and NTX in blood and brain. Collectively, these findings indicate that MNTX cannot be administered systemically in mice for making inferences that its effects are peripherally restricted.
Topics: Analgesics, Opioid; Animals; Blood-Brain Barrier; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Morphine; Naltrexone; Narcotic Antagonists; Oxycodone; Pain Measurement; Quaternary Ammonium Compounds
PubMed: 33316279
DOI: 10.1016/j.neuropharm.2020.108437 -
Harm Reduction Journal Oct 2023Due to concerns over potential interactions between some hepatitis C direct-acting antivirals (DAAs) and opioids, we describe adverse event (AE) reports of concomitant...
INTRODUCTION
Due to concerns over potential interactions between some hepatitis C direct-acting antivirals (DAAs) and opioids, we describe adverse event (AE) reports of concomitant use of opioids and DAAs.
METHODS
AEs reported (July 28, 2017-December 31, 2021) with the administration of the DAAs glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir/voxilaprevir, and elbasvir/grazoprevir as suspect products were downloaded from the US Food and Drug Administration AE Reporting System Public Dashboard. The number of AE reports containing opioids (fentanyl, hydrocodone, oxycodone) as co-suspect products/concomitant products were counted and summarized by severity, reporting country and whether an outcome of death was reported. Overdose AEs were counted irrespective of opioid use, and changes over time were assessed.
RESULTS
In total, 40 AEs were reported for DAAs and concomitant fentanyl use, 25 (62.5%) were in the USA, 35 (87.5%) were considered serious, and 14 (35.0%) resulted in death; and 626 were reported with concomitant oxycodone/hydrocodone use, 596 (95.2%) were in the USA, 296 (47.3%) were considered serious, and 28 (4.5%) resulted in death. There were 196 overdose AEs (32 [16%] deaths) declining from 2018 (N = 56) to 2021 (N = 29).
CONCLUSIONS
Treating people with hepatitis C virus (HCV) infection who use drugs is key to achieving HCV elimination. Low numbers of DAA AE reports with opioids may provide reassurance to prioritize HCV treatment in this population. These data contribute to evidence supporting the continued scale-up of DAA treatment among people who use drugs to achieve HCV elimination goals.
Topics: Humans; Sofosbuvir; Antiviral Agents; Hepacivirus; Analgesics, Opioid; Hepatitis C, Chronic; Oxycodone; Hydrocodone; Hepatitis C; Fentanyl
PubMed: 37779203
DOI: 10.1186/s12954-023-00874-y -
Neuropharmacology Mar 2021Opioid use disorder is a leading cause of morbidity and mortality in the United States. Increasing pre-clinical and clinical evidence demonstrates sex differences in...
Opioid use disorder is a leading cause of morbidity and mortality in the United States. Increasing pre-clinical and clinical evidence demonstrates sex differences in opioid use and dependence. However, the underlying molecular mechanisms contributing to these effects, including neuroinflammation, are still obscure. Therefore, in this study, we investigated the effect of oxycodone exposure and withdrawal on sex- and region-specific neuroimmune response. Real-time PCR and multiplex cytokine array analysis demonstrated elevated neuroinflammation with increased pro-inflammatory cytokine levels, and aberrant oligodendroglial response in reward neurocircuitry, following withdrawal from chronic oxycodone treatment. Chronic oxycodone and withdrawal treated male mice had lower mRNA expression of TMEM119 along with elevated protein levels of pro-inflammatory cytokines/chemokines and growth factors (IL-1β, IL-2, IL-7, IL-9, IL-12, IL-15, IL17, M-CSF, VEGF) in the prefrontal cortex (PFC) as compared to their female counterparts. In contrast, reduced levels of pro-inflammatory cytokines/chemokines (IL-1β, IL-6, IL-9, IL-12, CCL11) was observed in the nucleus accumbens (NAc) of oxycodone and withdrawal-treated males as compared to female mice. No treatment specific effects were observed on the mRNA expression of putative microglial activation markers (Iba1, CD68), but an overall sex specific decrease in the mRNA expression of Iba1 and CD68 was found in the PFC and NAc of male mice as compared to females. Moreover, a sex and region-specific increase in the mRNA levels of oligodendrocyte lineage markers (NG2, Sox10) was also observed in oxycodone and withdrawal treated animals. These findings may open a new avenue for the development of sex-specific precision therapeutics for opioid dependence by targeting region-specific neuroimmune signaling.
Topics: Analgesics, Opioid; Animals; Female; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Neuroimmunomodulation; Oxycodone; Prefrontal Cortex; Sex Characteristics; Substance Withdrawal Syndrome
PubMed: 33485944
DOI: 10.1016/j.neuropharm.2021.108469 -
PloS One 2022This study aims to evaluate the efficacy and safety of oxycodone hydrochloride (OxyContin) rectal administration in cancer pain patients. This is geared towards... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
This study aims to evaluate the efficacy and safety of oxycodone hydrochloride (OxyContin) rectal administration in cancer pain patients. This is geared towards providing the research evidence for a novel route of OxyContin administration.
METHODS
Relevant randomized controlled trials (RCTs) were searched in electronic databases, including PubMed, Cochrane Library, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP database), Wanfang Data Knowledge Service Platform, and Chinese Biomedical Literature Database (CBM). Moreover, unpublished academic data were obtained by contacting the colleague, professor, or Institute of Traditional Chinese Medicine. The RCTs of transrectal Oxycodone administration of sustained-release tablets for moderate and severe pain patients were searched in the databases from inception to December 2020.
RESULTS
According to the inclusion criteria, a total of 8 RCTs were included, with a total of 648 patients. Meta analysis results showed that there was no statistically significant difference in the efficacy of moderate to severe pain control between the rectal administration group and the oral administration group (RR = 1.04, 95%CI: 0.99-1.10, p = 0.13>0.05). At the same time, the incidence of adverse reactions in the rectal administration group was low. In terms of constipation, the rectal administration group was less than the oral administration group, with a statistically significant difference (RR = 0.43, 95%CI: 0.31-0.58, p< 0.00001). In terms of nausea and vomiting, the rectal administration group was less than the oral administration group, and the difference was statistically significant(RR = 0.30, 95%CI: 0.21-0.42, p<0.00001). In terms of sleepiness, there was no significant difference between the two groups(RR = 0.54, 95%CI: 0.26-1.15, p = 0.11>0.05). In terms of dizziness, there was no statistically significant difference between the two groups (RR = 0.43, 95%CI:0.27-0.68, p = 0.31>0.05). In terms of dyuria, there was no statistically significant difference between the two groups (RR = 0.37, 95%CI: 0.02-7.02, p = 0.51>0.05). In terms of KPS scores there was no significant difference was noted between the rectal and oral administration groups (RR = 1.04, 95%CI: 0.89-1.21, p = 0.63>0.05).
CONCLUSION
In summary, we found no significant differences in efficacy between rectal administration of OxyContin and oral administration. Thus, rectal administration should be considered in managing cancer pain among patients with difficulty in oral OxyContin administration.
PROSPERO REGISTRATION NUMBER
CRD42021209660.
Topics: Administration, Rectal; Cancer Pain; Delayed-Action Preparations; Humans; Oxycodone; Pain
PubMed: 35759471
DOI: 10.1371/journal.pone.0266754 -
BioRxiv : the Preprint Server For... Dec 2023Oxycodone is commonly prescribed for moderate to severe pain disorders. While efficacious, long-term use can result in tolerance, physical dependence, and the...
Oxycodone is commonly prescribed for moderate to severe pain disorders. While efficacious, long-term use can result in tolerance, physical dependence, and the development of opioid use disorder. Cannabis and its derivatives such as Δ-Tetrahydrocannabinol (Δ-THC) have been reported to enhance oxycodone analgesia in animal models and in humans. However, it remains unclear if Δ-THC may facilitate unwanted aspects of oxycodone intake, such as tolerance, dependence, and reward at analgesic doses. This study sought to evaluate the impact of co-administration of Δ-THC and oxycodone across behavioral measures related to antinociception, dependence, circadian activity, and reward in both male and female mice. Oxycodone and Δ-THC produced dose-dependent antinociceptive effects in the hotplate assay that were similar between sexes. Repeated treatment (twice daily for 5 days) resulted in antinociceptive tolerance. Combination treatment of oxycodone and Δ-THC produced a greater antinociceptive effect than either administered alone, and delayed the development of antinociceptive tolerance. Repeated treatment with oxycodone produced physical dependence and alterations in circadian activity, neither of which were exacerbated by co-treatment with Δ-THC. Combination treatment of oxycodone and Δ-THC produced CPP when co-administered at doses that did not produce preference when administered alone. These data indicate that Δ-THC may facilitate oxycodone-induced antinociception without augmenting certain unwanted features of opioid intake (e.g. dependence, circadian rhythm alterations). However, our findings also indicate that Δ-THC may facilitate rewarding properties of oxycodone at therapeutically relevant doses which warrant consideration when evaluating this combination for its potential therapeutic utility.
PubMed: 38105953
DOI: 10.1101/2023.12.04.569809 -
Metabolites Jan 2022Postmortem metabolomics has recently been suggested as a potential tool for discovering new biological markers able to assist in death investigations. Interpretation of...
Postmortem metabolomics has recently been suggested as a potential tool for discovering new biological markers able to assist in death investigations. Interpretation of oxycodone concentrations in postmortem cases is complicated, as oxycodone tolerance leads to overlapping concentrations for oxycodone intoxications versus non-intoxications. The primary aim of this study was to use postmortem metabolomics to identify potential endogenous biomarkers that discriminate between oxycodone-related intoxications and non-intoxications. Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry data from 934 postmortem femoral blood samples, including oxycodone intoxications and controls positive and negative for oxycodone, were used in this study. Data were processed and evaluated with XCMS and SIMCA. A clear trend in group separation was observed between intoxications and controls, with a model sensitivity and specificity of 80% and 76%. Approximately halved levels of short-, medium-, and long-chain acylcarnitines were observed for oxycodone intoxications in comparison with controls ( < 0.001). These biochemical changes seem to relate to the toxicological effects of oxycodone and potentially acylcarnitines constituting a biologically relevant biomarker for opioid poisonings. More studies are needed in order to elucidate the potential of acylcarnitines as biomarker for oxycodone toxicity and their relation to CNS-depressant effects.
PubMed: 35208184
DOI: 10.3390/metabo12020109 -
BMC Geriatrics Apr 2024Tramadol is increasingly used to treat acute postoperative pain among older adults following total hip and knee arthroplasty (THA/TKA). However, tramadol has a complex...
BACKGROUND
Tramadol is increasingly used to treat acute postoperative pain among older adults following total hip and knee arthroplasty (THA/TKA). However, tramadol has a complex pharmacology and may be no safer than full opioid agonists. We compared the safety of tramadol, oxycodone, and hydrocodone among opioid-naïve older adults following elective THA/TKA.
METHODS
This retrospective cohort included Medicare Fee-for-Service beneficiaries ≥ 65 years with elective THA/TKA between January 1, 2010 and September 30, 2015, 12 months of continuous Parts A and B enrollment, 6 months of continuous Part D enrollment, and no opioid use in the 6 months prior to THA/TKA. Participants initiated single-opioid therapy with tramadol, oxycodone, or hydrocodone within 7 days of discharge from THA/TKA hospitalization, regardless of concurrently administered nonopioid analgesics. Outcomes of interest included all-cause hospitalizations or emergency department visits (serious adverse events (SAEs)) and a composite of 10 surgical- and opioid-related SAEs within 90-days of THA/TKA. The intention-to-treat (ITT) and per-protocol (PP) hazard ratios (HRs) for tramadol versus other opioids were estimated using inverse-probability-of-treatment-weighted pooled logistic regression models.
RESULTS
The study population included 2,697 tramadol, 11,407 oxycodone, and 14,665 hydrocodone initiators. Compared to oxycodone, tramadol increased the rate of all-cause SAEs in ITT analyses only (ITT HR 1.19, 95%CLs, 1.02, 1.41; PP HR 1.05, 95%CLs, 0.86, 1.29). Rates of composite SAEs were not significant across comparisons. Compared to hydrocodone, tramadol increased the rate of all-cause SAEs in the ITT and PP analyses (ITT HR 1.40, 95%CLs, 1.10, 1.76; PP HR 1.34, 95%CLs, 1.03, 1.75), but rates of composite SAEs were not significant across comparisons.
CONCLUSIONS
Postoperative tramadol was associated with increased rates of all-cause SAEs, but not composite SAEs, compared to oxycodone and hydrocodone. Tramadol does not appear to have a superior safety profile and should not be preferentially prescribed to opioid-naïve older adults following THA/TKA.
Topics: Humans; Aged; United States; Analgesics, Opioid; Tramadol; Oxycodone; Arthroplasty, Replacement, Knee; Hydrocodone; Retrospective Studies; Arthroplasty, Replacement, Hip; Medicare
PubMed: 38580920
DOI: 10.1186/s12877-024-04933-2 -
Journal of Healthcare Engineering 2021To analyze the effect of combined application of oxycodone hydrochloride injection and dexmedetomidine in anesthesia for laparoscopic cholecystectomy (LC) for patients...
OBJECTIVE
To analyze the effect of combined application of oxycodone hydrochloride injection and dexmedetomidine in anesthesia for laparoscopic cholecystectomy (LC) for patients with gallbladder lesions.
METHOD
93 patients with gallbladder lesions in our hospital were divided into 2 groups by the random number table method. 46 patients in the control group applied oxycodone hydrochloride injection in anesthesia, and 47 patients in the observation group applied oxycodone hydrochloride injection combined with dexmedetomidine in anesthesia.
RESULT
The T1 and T2 MAP levels in the observation group were lower than those in the control group ( < 0.05), and the difference between T3 and the control group was not significantly significant ( > 0.05). The T1 to T3 HR level in the observation group were lower than those in the control group ( < 0.05). The rate of excessive sedation (10.64%) and sedation inefficiency (12.77%) in the observation group was lower than that in the control group (28.26% and 30.43%), and the rate of satisfactory sedation (76.60%) was higher than that in the control group (41.30%) ( < 0.05). The postoperative awakening, tracheal tube removal, and first anal venting time were shorter in the observation group than in the control group ( < 0.05). The WHO scores of incisional pain at 6, 12, 24, and 48 hours after the operation were lower in the observation group than in the control group ( < 0.05). The T2 SOD level in the observation group was higher than that in the control group, and the ROS and MDA levels were lower than those in the control group ( < 0.05). The incidence of side effects of anesthetic in the observation group was 17.02%, which was not statistically different from the control group of 13.04% ( > 0.05).
CONCLUSION
The combined application of oxycodone hydrochloride injection and dexmedetomidine in anesthesia for LC for patients with gallbladder lesions can achieve better sedation and analgesia effect, accelerate postoperative awakening and recovery, and control oxidative stress and fluctuations in signs, without increasing anesthesia-related side effects.
Topics: Anesthesia; Cholecystectomy, Laparoscopic; Dexmedetomidine; Gallbladder; Humans; Oxycodone
PubMed: 34512931
DOI: 10.1155/2021/1290650 -
Journal of Palliative Medicine Nov 2022Equianalgesic tools are commonly utilized to guide dose of analgesic therapy, but there is no national consensus on equianalgesic calculations in the United States. To...
Equianalgesic tools are commonly utilized to guide dose of analgesic therapy, but there is no national consensus on equianalgesic calculations in the United States. To propose a summary of current opioid equianalgesic data that include variations and trends among national institutions. Opioid equianalgesic tools were obtained between May and September 2021. For meperidine, tramadol, codeine, hydrocodone, morphine, oxycodone, oxymorphone, hydromorphone, levorphanol, fentanyl, and tapentadol, details of adjustment for incomplete tolerance, opioid equianalgesic ratios, and formulation types were collected and analyzed. Baseline opioid pharmaco kinetic data were obtained through manufacturer labels on FDA databases, including half-life (), volume of distribution (), clearance (Cl), area under the curve (AUC), max concentration (), and time to max concentration (). Thirty-two institutions' equianalgesic tools were included with each study opioid appearing on an average of 23 institutions' tools. Few tools contained guidance on levorphanol or tapentadol; or included minimum and maximum recommended doses. All tools included guidance on fentanyl, hydromorphone, oxycodone, morphine, and hydrocodone. A minority of tools included guidance on cross-tolerance considerations ( = 12, 37.5%). Oral-tramadol-to-oral-morphine and oral-hydromorphone-to-intravenous (IV)-hydromorphone had the largest variances across equianalgesic tools (6.7 ± 2.8 and 4.06 ± 1.2 mg, respectively). Opioid equianalgesia tools from across the United States demonstrated significant variation in their inclusion of guidance on adjustment for incomplete cross-tolerance, oral-to-IV, and oral-to-oral opioid equianalgesic ratios, and which opioids and formulations were listed. Tramadol and hydromorphone had the most variation in their equianalgesic guidance among the opioids.
Topics: Humans; Analgesics, Opioid; Hydromorphone; Oxycodone; Tapentadol; Tramadol; Levorphanol; Hydrocodone; Administration, Oral; Fentanyl; Morphine
PubMed: 35559657
DOI: 10.1089/jpm.2021.0678 -
Neuropharmacology Apr 2023Recent evidence suggests that inhibition of the M muscarinic acetylcholine receptor (mAChR) may provide a novel non-opioid mechanism for the treatment of opioid use...
Recent evidence suggests that inhibition of the M muscarinic acetylcholine receptor (mAChR) may provide a novel non-opioid mechanism for the treatment of opioid use disorder (OUD). Previous studies from our group and others have demonstrated that acute administration of the long-acting M negative allosteric modulator (NAM) ML375 attenuates established self-administration of cocaine, ethanol, oxycodone, and remifentanil in rats. In the present study, we characterized the effects of acute and repeated administration of the novel, short-acting M NAM VU6008667 on the reinforcing effects of oxycodone and reinstatement of oxycodone-seeking behaviors in male Sprague-Dawley rats, as well as on physiological withdrawal from oxycodone. Acute VU6008667 decreased oxycodone self-administration under both fixed ratio 3 (FR3) and progressive ratio (PR) schedules of reinforcement and attenuated cue-induced reinstatement of lever pressing following extinction from oxycodone self-administration, a commonly used relapse model. When administered daily to opioid-naïve rats, VU6008667 prevented acquisition of oxycodone self-administration behavior. VU6008667 had minimal effects on naloxone-precipitated withdrawal. After acute administration, VU6008667 did not inhibit sucrose self-administration and, when given chronically, delayed but did not prevent acquisition of sucrose maintained self-administration. VU6008667 also did not impact oxycodone induced anti-nociception or motor coordination, but mildly decreased novelty exploration. Finally, acute or daily VU6008667 administration did not impair cued fear conditioning. Overall, these results suggest that inhibition of the M mAChR may provide a novel, non-opioid based treatment for distinct aspects of OUD by inhibiting opioid intake in established OUD, reducing relapse during abstinence, and by reducing the risk of developing OUD.
Topics: Animals; Male; Rats; Analgesics, Opioid; Opioid-Related Disorders; Oxycodone; Rats, Sprague-Dawley; Receptors, Muscarinic; Self Administration; Sucrose
PubMed: 36720403
DOI: 10.1016/j.neuropharm.2023.109424