Antinociceptive Effects Of Oxycodone Research Articles

Effect of prenatal and early post-natal oxycodone exposure on the reinforcing and antinociceptive effects of oxycodone in adult C57BL/6J mice.

We examined how prenatal, and early-post natal oxycodone exposure affected opioid addiction behaviors. Adult male and female C57BL/CJ mice housed separately were first injected with ascending doses of oxycodone 1 time/day (1mg/kg × 10days, 1.5mg/kg × 10days, 2mg/kg × 10days, s.c.) whereas control mice were injected with saline. Newly formed parental dyads were then housed together and continued to receive ascending doses of oxycodone (3mg/kg × 10days, 4mg/kg × 10days, 5mg/kg × 10days, 6mg/kg × 10days or saline, s.c.) or saline during mating and gestation until the birth of the litter. The dams continued to receive oxycodone or saline through lactation, until F1 offspring were weaned. Upon reaching adulthood (12weeks of age), male and female F1 offspring were examined in intravenous self-administration (IVSA) of oxycodone, on oxycodone-induced conditioned place preference (CPP) and oxycodone-induced antinociception. Adult F1 male and female offspring of parental dyads exposed to oxycodone self-administered more oxycodone, compared to offspring of control parental dyads. Ventral and dorsal striatal mRNA levels of genes such as Fkbp5 and Oprm1 were altered following oxycodone self-administration. Prenatal and early post-natal oxycodone exposure enhanced oxycodone self-administration during adulthood in the C57BL/6J mice.

Quantitative sensory tests fairly reflect immediate effects of oxycodone in chronic low-back pain

IntroductionQuantitative sensory tests (QST) can be used for profiling anti-nociceptive effects of analgesics. However, anti-nociceptive effects detected by QST are not necessarily associated with analgesic effects in pain patients. As part of a large investigation on low back pain, this paper describes the immediate analgesic and anti-nociceptive effects of oxycodone in chronic low-back pain and ranks different QST according to their ability to reflect this effect. The results are expected to support the selection of QST for future studies on potential novel opioid agonists in human pain. MethodsIn this randomized, placebo-controlled and double-blinded cross-over study, 50 patients with chronic low-back pain received a single oral dose of oxycodone 15mg or active placebo, and underwent multiple QST testing. The intensity of low-back pain was recorded during 2h. The areas under the ROC curves and 95% confidence intervals were determined, whereby responder status (≥30% pain reduction) was set as reference variable and changes in QST from baseline were set as classifiers. ResultsSignificant analgesic effect on low-back pain as well as anti-nociceptive effects for almost all QST parameters were observed. The QST with the highest area under the curve were heat pain detection threshold (0.65, 95%-CI 0.46 to 0.83), single-stimulus electrical pain threshold (0.64, 95%-CI 0.47 to 0.80) and pressure pain detection threshold (0.63, 95%-CI 0.48 to 0.79). ConclusionsThe results suggest that anti-nociceptive effects assessed by QST fairly reflect clinical efficacy of oxycodone on low-back pain. Pressure pain detection threshold, heat pain detection threshold and single-stimulus electrical pain threshold may be more suitable to sort out potential non-responders rather than identifying potential responders to opioid medication. Future pre-clinical human research may consider these results when investigating the analgesic effect of opioid agonists by means of QST.

Effects of Cannabinoid Receptor Agonists on the Antinociceptive Effects of Oxycodone in Squirrel Monkeys

Opioids remain the most commonly prescribed drug class for the management of moderate to severe pain and, often, high doses that have unwanted behavioral effects are required for effective analgesia. One strategy that has been proposed to avoid prescribing high doses of opioids is co‐administration of a cannabinoid such as Δ9‐tetrahydrocannabinol (THC) that, by providing its own analgesic effects, will reduce opioid dosage. Studies using the warm water tail withdrawal assay, which remains the most commonly used method for assessing antinociception across species, have provided encouraging data in support of this approach. Here, we further study the potential clinical advantage of this approach by determining how different cannabinoid agonists modify the effects of oxycodone on tail withdrawal latency and food‐maintained behavior (reinforcement density, response rate) in squirrel monkeys. Daily sessions were comprised of four 5‐min response components, each preceded by a long timeout during which cumulative doses of drugs (10‐min for oxycodone and 30‐min for THC or the nabilone derivative AM 7444) could be administered. During each component, the completion of a 10‐response fixed‐ratio in the presence of stimulus lights initiated food delivery and a 30‐sec short timeout during which stimulus lights were off and tail withdrawal latency was measured.Results show that all three drugs produced dose related decreases on both measures of food‐maintained behavior but only oxycodone (0.032–0.56 mg/kg) and AM 7444 (0.0032–0.032 mg/kg) produced dose dependent increases in tail withdrawal latency. These antinociceptive effects were produced by doses of both drugs that did not greatly reduce reinforcement density and were more pronounced for oxycodone than the cannabinoid. Pretreatment with the highest dose of THC that did not eliminate responding (0.32 mg/kg) shifted the dose‐effect function for oxycodone's antinociceptive effects upward and leftward and its effects on food‐maintained behavior downward and leftward. Pretreatment with 0.0032 or 0.0056 mg/kg of AM7444 did not appreciably alter the antinociceptive effects of oxycodone whereas pretreatment with the higher dose (0.0056 mg/kg) markedly accentuated the effects of oxycodone on food‐maintained behavior.These data support previous findings that cannabinoid pretreatment can heighten the antinociceptive effects of morphine‐like opioids but indicate also that cannabinoid pretreatment may exacerbate their behaviorally disruptive effects. Thus, this approach to pain management, while effective, may not be appropriate for all therapeutic settings.

Adolescent oxycodone self administration alters subsequent antinociceptive effect of oxycodone in C57BL/6J mice in adulthood

methods usedwere BBT (1/32 articles) and transvaginal ultrasound (1/32 articles). Conclusions: There is a lack of consistency in methodology used to determine menstrual phase. We recommend combining several methods to improve accuracy of phase identification, minimize costs and burden, and reduce selection bias and confounding. The adoption of these recommendations will yield a decrease in misclassification bias and facilitate cross-study comparisons. Financial support: P50-DA033942, P50-DA016511, P50DA033945, K24DA038240, and K12HD055887.

G protein‐gated inwardly rectifying potassium (KIR3) channels play a primary role in the antinociceptive effect of oxycodone, but not morphine, at supraspinal sites

Oxycodone and morphine are μ-opioid receptor agonists prescribed to control moderate-to-severe pain. Previous studies suggested that these opioids exhibit different analgesic profiles. We hypothesized that distinct mechanisms mediate the differential effects of these two opioids and investigated the role of G protein-gated inwardly rectifying potassium (K(IR)3 also known as GIRK) channels in their antinociceptive effects. Opioid-induced antinociceptive effects were assessed in mice, using the tail-flick test, by i.c.v. and intrathecal (i.t.) administration of morphine and oxycodone, alone and following inhibition of K(IR)3.1 channels with tertiapin-Q (30 pmol per mouse, i.c.v. and i.t.) and K(IR)3.1-specific siRNA. The antinociceptive effects of oxycodone and morphine were also examined after tertiapin-Q administration in the mouse femur bone cancer and neuropathic pain models. The antinociceptive effects of oxycodone, after both i.c.v. and i.t. administrations, were markedly attenuated by K(IR)3.1 channel inhibition. In contrast, the antinociceptive effects of i.c.v. morphine were unaffected, whereas those induced by i.t. morphine were attenuated, by K(IR)3.1 channel inhibition. In the two chronic pain models, the antinociceptive effects of s.c. oxycodone, but not morphine, were inhibited by supraspinal administration of tertiapin-Q. These results demonstrate that K(IR)3.1 channels play a primary role in the antinociceptive effects of oxycodone, but not those of morphine, at supraspinal sites and suggest that supraspinal K(IR)3.1 channels are responsible for the unique analgesic profile of oxycodone.

Behavioral effects of oxycodone following traumatic brain injury in rats

Epidemiological data indicate that drug abuse rates increase following traumatic brain injury (TBI), but the underlying reasons remain unclear. There is overlap in reward pathways and regions commonly damaged in TBI suggesting that TBI could alter risk for drug abuse. Adult male Sprague Dawley rats underwent sham (control) or lateral fluid percussion injury of moderate severity followed by assesment of tolerance development and intravenous self ‐administration behavior. The antinociceptive effects of oxycodone were evaluated using hot plate‐induced paw withdrawal and warm water tail withdrawal models both acutely and following chronic administration of oxycodone. The reinforcing effects of oxycodone were examined using acquisition of oxycodone self‐administration behavior. No consistent differences have been detected in the antinociceptive effects of oxycodone between TBI subjects and sham injured subjects. However the data suggest that the high (0.03 mg/kg/infusion) and intermediate (0.01 mg/kg/infusion) doses of oxycodone resulted in a faster rate and a higher total percentage of TBI subjects acquiring self‐administration. Additionally, the TBI subjects appeared to be less sensitive to oxycodone's effects, self‐administering the highest number of infusions at the 0.03 mg/kg/infusion dose as compared to sham injured subjects. Research supported by DoD grant W81XWH‐11–1‐0374.

The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes

The aim of this study was to search for a possible association between the variant allele of the single nucleotide polymorphisms A118G in the OPRM1 gene and C3435T and G2677T/A in the ABCB1 gene and altered antinociceptive effect and adverse drug reactions of oxycodone. Thirty-three healthy subjects exposed to experimental pain including electrical stimulation and the cold pressor test were included. A118G: We found that the variant G allele was associated with reduced antinociceptive effect as measured by pain tolerance thresholds to single electrical nerve stimulation (8% increase vs. 25% for the wild-type carriers, P = 0.007). C3435T: The carriers of the variant T allele generally had less adverse drug reactions on oxycodone than the carriers of the wild-type genotype. G2677T/A: The carriers of the variant T allele had a better antinociceptive effect of oxycodone than the carriers of the wild-type genotype in the cold pressor test (25% reduction vs. 15%, P = 0.015 in the discomfort rating and 25% reduction vs. 12%, P = 0.007 in the pain time AUC) and less adverse drug reactions. The combined wild-type genotype 3435CC-2677GG was associated with less antinociceptive effect of oxycodone in the discomfort rating of the cold pressor test (13% reduction vs. 23%, P = 0.019) and more severe adverse drug reactions than the carriers of the variant alleles. We found a moderate association between less antinociceptive effect of oxycodone and the variant allele of A118G. There was strong association between less adverse drug reactions of oxycodone and the variant alleles of C3435T and G2677T/A.

Drug–drug interaction between oxycodone and adjuvant analgesics in blood–brain barrier transport and antinociceptive effect

To examine possible blood–brain barrier (BBB) transport interactions between oxycodone and adjuvant analgesics, we firstly screened various candidates in vitro using [3H]pyrilamine, a substrate of the oxycodone transporter, as a probe drug. The uptake of [3H]pyrilamine by conditionally immortalized rat brain capillary endothelial cells (TR-BBB13) was inhibited by antidepressants (amitriptyline, imipramine, clomipramine, amoxapine, and fluvoxamine), antiarrhythmics (mexiletine, lidocaine, and flecainide), and ketamine. On the other hand, antiepileptics (carbamazepine, phenytoin, and clonazepam) and corticosteroids (dexamethasone and prednisolone) did not inhibit [3H]pyrilamine uptake, with the exception of sodium valproate. The uptake of oxycodone was significantly inhibited in a concentration-dependent manner by amitriptyline, fluvoxamine and mexiletine with Ki values of 13, 65, and 44 µM, respectively. These Ki values are 5–300 times greater than the human therapeutic plasma concentrations. Finally, we evaluated in vivo interaction between oxycodone and amitriptyline in mice. Antinociceptive effects of oxycodone were increased by coadministration of amitriptyline. The oxycodone concentrations in plasma and brain were not changed by coadministration of amitriptyline. Overall, the results suggest that several adjuvant analgesics may interact with the BBB transport of oxycodone at relatively high concentrations. However, it is unlikely that there would be any significant interaction at therapeutically or pharmacologically relevant concentrations. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:467–474, 2010

Oxycodone’s Mechanism of Action and Potency Differences after Spinal and Systemic Routes of Administration

Thank you for the opportunity to comment on the letter by Smith et al. and to clarify some recurring misconceptions regarding the pharmacology of oxycodone.Oxycodone is a potent opioid, comparable to morphine, when given systemically. However, as Smith et al. also write, oxycodone has a significantly lower affinity for the μ-opioid receptor compared with morphine. This has been shown in several studies.1,2Indeed, the results of our own recent study3further support the findings that oxycodone has a significantly lower potency compared with morphine when administrated directly to the central nervous system in rats.4,5Smith et al. challenge our study and those by many others by arguing that the antinociceptive effect of oxycodone is mediated trough the κ-opioid receptor. The previous in vivo studies clearly demonstrate that oxycodone is a μ-opioid receptor agonist.1,2,6,7In these studies, the affinity of oxycodone for the κ-opioid receptor is remarkably lower than for the μ-opioid receptor.2,6To the best of our knowledge, not a single in vitro study (binding- or G-protein activation) showing κ-opioid receptor agonism of oxycodone has been published.Beardsley et al. 8studied the pharmacology of oxycodone in mice, rats, and rhesus monkeys. In an excellent article, they reported that oxycodone had potent antinociceptive effects in the mouse paraphenylquinone writhing, hot-plate, and tail-flick assays acting as a μ-opioid receptor agonist. The selective opioid receptor antagonists were studied in the mice tail-flick test. The antinociceptive effect of oxycodone (subcutaneous administration) was only blocked by the selective μ-opioid receptor antagonist β-funaltrexamine (intracerebroventricular administration). The selective κ- and δ-opioid receptor antagonists nor-binaltorphimine (administered subcutaneously 2 h before the agonist) and naltrindole (subcutaneous administration) were not able to block the antinociceptive effect of oxycodone.8Beardsley et al. wrote, “The results have shown that oxycodone is a robust antinociceptive agent, with an abuse liability profile consistent with full μ-opioid receptor agonists.”8Oxycodone completely suppressed signs of withdrawal in morphine-dependent rhesus monkeys. In the previous studies, the selective κ-opioid receptor agonists did not suppress signs of morphine withdrawal.9,10Beardsley et al. 8also demonstrated that even very high doses of oxycodone did not induce behavior (salivation or diuresis) indicative of κ-opioid like activity. Therefore, high-quality classic pharmacology experiments clearly show that oxycodone is a μ-opioid receptor agonist, not a κ-opioid receptor agonist.Smith et al. agree that oxymorphone is a potent μ-opioid receptor agonist.11In our recent study,3nor-binaltorphimine (administered 30 min before study drugs) was not able to antagonize the antinociceptive effect of oxymorphone or oxycodone. Should nor-binaltorphimine behave as a μ-opioid receptor antagonist when given 30 min before the study drugs, as suggested by Smith et al. , the antinociceptive effect of oxymorphone should have been significantly attenuated. The antinociceptive effect of oxymorphone, like that of oxycodone, was prevented only by naloxone, not by nor-binaltorphimine.In our recent study,3oxycodone showed weaker activation of the spinal μ-opioid receptors compared with morphine. The mechanisms behind this difference are interesting and will be studied further. In the brain, oxycodone activated the μ-opioid receptors, albeit to a lesser extent than morphine. The reason why oxycodone produces more potent antinociception compared with morphine after systemic administration remains to be clarified. Smith et al. argue that we are suggesting that the analgesic effects of systemic oxycodone are due to oxymorphone. This is not what we concluded. We suggested that the metabolites may have a role in oxycodone-induced analgesia. We agree that the circulating concentrations of oxymorphone after systemic administration of oxycodone are low, as we12–14and others15have shown. Because systemic oxycodone causes potent μ-opioid receptor agonist effects while being a weak μ-opioid receptor agonist with insignificant binding to other opioid receptors, pharmacokinetic explanations must be considered. One possibility is that the access of either oxycodone itself and/or some of its active metabolites to the central nervous system are more effective compared with that of morphine. There are a number of oxycodone metabolites produced in oxidative and reductive reactions that have not been studied in vivo . Oxymorphone, on the other hand, is an interesting spinal analgesic, and it has recently been launched as an oral analgesic, too.Oxycodone binds to the μ-opioid receptor and activates the μ-opioid receptor, whereas it does not bind to the κ-opioid receptor and does not activate the κ-opioid receptor. Importantly, in human beings, oxycodone behaves as a μ-opioid receptor agonist producing analgesia, euphoria, dependence, and other typical μ-opioid effects. Oxycodone does not cause psychotomimetic effects, dysphoria, diuresis, or other effects typical for a κ-opioid agonist. Several aspects of oxycodone pharmacology still need to be studied. However, it is obvious that oxycodone is a μ-opioid receptor agonist, not a κ-opioid receptor agonist.*University of Helsinki, Helsinki, Finland. kim.lemberg@helsinki.fi

Involvement of μ 1-opioid receptor on oxycodone-induced antinociception in diabetic mice

The effect of naloxonazine, a selective μ 1-opioid receptor antagonist, on oxycodone-induced antinociception was examined in streptozotocin-induced diabetic mice. Oxycodone (5 mg/kg, s.c.) induced significant antinociception in both non-diabetic and diabetic mice. This antinociceptive effect of oxycodone was completely antagonized by pretreatment with naloxonazine (35 mg/kg, s.c.) in both non-diabetic and diabetic mice. The selective κ-opioid receptor antagonist nor-binaltorphimine (20 mg/kg, s.c.) also antagonized oxycodone-induced antinociception in diabetic mice, but only had a partial effect in non-diabetic mice. These results suggest that although primarily interacts with μ 1-opioid receptor, κ-opioid receptors are also strongly involved in oxycodone-induced antinociception.

Characterization of the antinociceptive effects of oxycodone in diabetic mice

We investigated the antinociceptive efficacy of systemic and centrally injected oxycodone on thermal hyperalgesia in streptozotocin-induced diabetic mice. The antinociceptive response was assessed by recording the latency in the tail-flick test using the radiant heat from a 50-W projection bulb on the tail. The tail-flick latency in diabetic mice was significantly shorter than that in non-diabetic mice. Oral (p.o.) and i.t., but not i.c.v., administration of oxycodone prolonged the tail-flick latency in diabetic mice to a level that was considerably longer than the baseline latency in non-diabetic mice. However, morphine did not significantly inhibit the tail-flick response in diabetic mice. The antinociceptive effect of either p.o. or i.t. oxycodone in non-diabetic mice, but not in diabetic mice, was antagonized by pretreatment with a selective μ-opioid receptor antagonist, β-funaltrexamine. In non-diabetic mice, pretreatment with a selective κ-opioid receptor antagonist, nor-binaltorphimine, had no effect on the peak antinociceptive effect of either p.o. or i.t. oxycodone at 30 min after administration, however, it slightly but significantly reduced oxycodone-induced antinociception at 60 and 90 min after administration. On the other hand, pretreatment with nor-binaltorphimine practically abolished the antinociceptive effects of both p.o.- and i.t.-administered oxycodone in diabetic mice. Naltrindole, a selective δ-opioid receptor antagonist, had no effects on the antinociceptive effect of oxycodone in either non-diabetic or diabetic mice. These results suggest that the antinociceptive effects of oxycodone may be mediated by spinal κ-opioid receptors in diabetic mice, whereas it may interact primarily with supraspinal and spinal μ-opioid receptors in non-diabetic mice.

Antinociceptive effect of oxycodone in diabetic mice

The effect of oxycodone on thermal hyperalgesia in streptozotocin-induced diabetic mice was examined. The antinociceptive response was assessed by recording the latency in the tail-flick test using the radiant heat from a 50-W projection bulb on the tail. The tail-flick latency in diabetic mice was significantly shorter than that in non-diabetic mice. When diabetic mice were treated with oxycodone (5 mg/kg, s.c.), the tail-flick latency in diabetic mice was prolonged to the level considerably longer than the baseline latencies of non-diabetic mice. However, s.c. administration of morphine (5 mg/kg) did not produce a significant inhibition of the tail-flick response in diabetic mice. Oxycodone, at doses of 1.25–5.0 mg/kg administered s.c., produced a dose-dependent increase in the tail-flick latencies in both diabetic and non-diabetic mice. The antinociceptive effect of oxycodone was antagonized by pretreatment with a selective δ-opioid receptor antagonist, β-funaltrexamine (20 mg/kg, s.c.), in both non-diabetic and diabetic mice. In non-diabetic mice, pretreatment with a selective κ-opioid receptor antagonist, nor-binaltorphimine (20 mg/kg, s.c.) had no effect on the peak antinociceptive effect of oxycodone observed 30 min after administration, however, it slightly but significantly reduced oxycodone-induced antinociception observed 60 and 90 min after administration. On the other hand, pretreatment with nor-binaltorphimine practically abolished the peak (30 min) and persistent (60 and 90 min) antinociceptive effects of oxycodone in diabetic mice. Naltrindole (35 mg/kg, s.c.), a selective δ-opioid receptor antagonist, had no effects on the antinociceptive effect of oxycodone in both non-diabetic and diabetic mice. These results suggest that the antinociceptive effects of oxycodone may be mediated by μ- and κ-opioid receptors in diabetic mice, whereas it may interact primarily with μ-opioid receptors in non-diabetic mice.

The antinociceptive potencies of oxycodone, noroxycodone and morphine after intracerebroventricular administration to rats

The antinociceptive activity of noroxycodone (NOR) was determined and its potency compared with that of oxycodone (OXY) and morphine (MOR) after intracerebroventricular (icv) administration to Sprague-Dawley rats. The antinociceptive potencies of OXY and NOR relative to MOR were 0.44 and 0.17, respectively. Administration of naloxone (55 nmol icv) abolished the antinociceptive response produced by the subsequent administration of OXY (227 nmol icv), indicating that the antinociceptive effects of OXY are mediated by opioid receptors. In addition, the same dose of naloxone (55 nmol icv) markedly reduced the antinociceptive effects of NOR (332 nmol icv) and MOR (93 nmol icv) indicating the involvement of opioid receptors in the antinociceptive activities of NOR and MOR. NOR, administered by the icv route, also produced excitatory effects throughout the antinociceptive dose range, the severity of which was reduced but not abolished by prior administration of naloxone (55 nmol icv). As excitatory effects have not been observed in patients receiving OXY, it is unlikely that NOR contributes to the analgesic activity of OXY administered systematically to humans.