Secondary Logo

Share this article on:

Pharmacological Characterization of Noroxymorphone as a New Opioid for Spinal Analgesia

Lemberg, Kim K. DDS*†; Siiskonen, Antti O. MSc; Kontinen, Vesa K. MD, PhD; Yli-Kauhaluoma, Jari T. PhD; Kalso, Eija A. MD, PhD

doi: 10.1213/ane.0b013e3181605a15
Anesthetic Pharmacology: Research Report

BACKGROUND: Noroxymorphone is one of the major metabolites of oxycodone. Although oxycodone is commonly used in the treatment of acute and chronic pain, little is known about the antinociceptive effects of noroxymorphone. We present an in vivo pharmacological characterization of noroxymorphone in rats.

METHODS: The antinociceptive properties of noroxymorphone were studied with thermal and mechanical models of nociception in rats.

RESULTS: Intrathecal noroxymorphone (1 and 5 μg/10 μL) induced a significantly longer lasting antinociceptive effect compared with oxycodone (200 μg/10 μL) and morphine (1 and 5 μg/10 μL). Pretreatment with subcutaneous naloxone (1 mg/kg) 15 min before intrathecal drug administration significantly decreased the antinociceptive effect of both noroxymorphone and morphine, indicating an opioid receptor-mediated antinociceptive effect. In the hotplate, paw pressure, and tail flick tests, subcutaneous noroxymorphone was inactive in doses of 5, 10, and 25 mg/kg. Also, no effect on motor function was observed in the rotarod test with doses studied. No antihyperalgesic effect was observed in the carrageenan model for inflammation in rats with subcutaneous noroxymorphone 25 mg/kg.

CONCLUSIONS: The results of this study indicate that noroxymorphone is a potent μ-opioid receptor agonist when administered intrathecally. The lack of systemic efficacy may indicate reduced ability of noroxymorphone to penetrate the blood–brain barrier due to its low calculated logD value (log octanol/water partition coefficient). Thus, noroxymorphone should have a negligible role in analgesia after systemic administration of oxycodone. Because of its spinal efficacy and long duration of effect, noroxymorphone is an interesting opioid for spinal analgesia with a low potential for abuse. Its safety for spinal administration should be assessed before clinical use.

IMPLICATIONS: Noroxymorphone is a promising opioid for spinal analgesia with a significantly longer lasting antinociceptive effect compared with oxycodone and morphine after intrathecal administration in rats. Its safety for spinal administration should be assessed before clinical use.

From the *Institute of Biomedicine, Pharmacology, †Department of Oral Radiology, Institute of Dentistry, ‡Faculty of Pharmacy, Division of Pharmaceutical Chemistry, University of Helsinki, and §Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland.

This article has supplementary material on the Web site: www.anesthesia-analgesia.org.

Accepted for publication October 11, 2007.

Supported by funds from the University of Helsinki and a grant from the Finnish Association for the Study of Pain.

The authors do not have any conflicts of interest. Eija Kalso has received an unrestricted grant for clinical research from Mundifarma Oy Vantaa, Finland and she has received honoraria from Mundipharma Oy, Vantaa, Finland; Janssen-Cilag Oy Espoo, Finland; Pfizer Oy, Helsinki, Finland, and Astra Zeneca Oy, Espoo, Finland. Vesa Kontinen has received honoraria from Janssen-Cilag Oy, Espoo, Finland.

Address correspondence and reprint requests to Kim Lemberg, DDS, Institute of Biomedicine/Pharmacology, P. O. Box 63, FI-00014 University of Helsinki, Finland. Address e-mail to kim.lemberg@helsinki.fi.

Oxycodone (14-dihydrohydroxycodeinone) is a semisynthetic opioid and a derivative of thebaine. The pharmacokinetics of oxycodone are still poorly known, even though it has been widely used in the management of acute and chronic pain for more than 90 yr. The role of its several metabolites in its analgesic activity is still not fully understood. Oxycodone is extensively metabolized in humans mainly by hepatic cytochrome P450 (CYP) isoenzymes, including O-demethylation (mainly catalyzed by CYP2D6) to oxymorphone and N-demethylation (mainly catalyzed by CYP3A4) to noroxycodone, conjugation to α-d-glucuronic acid and conversion to 6-oxycodol.1–6 Only 10% of oxycodone is excreted in unchanged form in urine.7,8

Noroxymorphone is one of the major metabolites in humans after oral administration of oxycodone.9 Noroxymorphone is a secondary metabolite of oxycodone. It is formed mainly after O-demethylation of noroxycodone (mainly catalyzed by CYP2D6) and also at a lower rate after N-demethylation of oxymorphone (mainly catalyzed by CYP3A4 and 2D6).6 The metabolic formation of noroxymorphone is shown in Figure 1.

Figure 1

Figure 1

Noroxymorphone has shown relatively high affinity for the μ-opioid receptor (≈3 times higher than oxycodone) in transfected Chinese hamster ovary cells (CHO-cells).9 In the same study, the affinity of noroxymorphone for the μ-opioid receptor compared with that of morphine was reported to be almost 1.8 times lower. In G-protein activation studies, the EC50 of noroxymorphone has been shown to be 2.1 (in CHO-cells) and 7.3 (in rat thalamic membranes) times lower than that of oxycodone with an almost similar E max.9,10 In the above-mentioned studies of G-protein activation, noroxymorphone had a similar EC50 value as morphine when studied in rat thalamic membranes (1.2 times lower E max) and 1.8 times higher when studied in CHO-cells. The antinociceptive properties of intrathecally administered noroxymorphone have been reported by Yaksh and Harty in the hotplate and tail flick tests in a single time-point study.11

The aim of this study was to characterize the antinociceptive properties of noroxymorphone in rats and to evaluate its possible role in oxycodone-induced antinociception.

Back to Top | Article Outline

METHODS

Animals

The research was performed according to the guidelines of local authorities and the International Association for the Study of Pain.12 The institutional animal investigation committee and the provincial government of southern Finland approved the protocol of the study (Uudenmaan lääninhallitus, Helsinki, Finland).

Opioid-naïve male Sprague-Dawley rats (Harlan, Netherlands) weighing 200–250 g were used (n = 6–8 per protocol). The animals were housed in clear plastic cages with a 12 h artificial light–dark cycle. Water and lab chow were available ad libitum. Before the tests, the animals were habituated to the testing environment for 30 min/d for 3 days. After the tests, the animals were killed by decapitation under CO2 anesthesia.

Back to Top | Article Outline

Drugs

Oxycodone hydrochloride and morphine hydrochloride were purchased from the University Pharmacy, Helsinki, Finland, and naloxone hydrochloride from RBI (Natick, MA). Noroxymorphone hydrochloride was synthesized from naloxone hydrochloride dihydrate, obtained from Sigma-Aldrich Finland Oy (Helsinki, Finland) (online supplement available at www.anesthesia-analgesia.org). All drugs were dissolved in saline and administered subcutaneously or intrathecally. Saline served as control. The volume of the intrathecally administered drug solutions was 10 μL, followed by a 10 μL flush of saline. Naloxone (or saline as a control) was administered subcutaneously 15 min before intrathecal administration of the study drugs.

Back to Top | Article Outline

Nociceptive Tests

For the paw pressure test, performed with a paw pressure apparatus (Ugo Basile, Milan, Italy), the rats were gently wrapped in a towel. The left hindpaw of the rat was placed under the weight of the apparatus, and the test was started. A brisk foot withdrawal of the hindlimb after constantly increasing pressure terminated the measurement, and the pressure was recorded. To avoid tissue damage, 45 g was set as the cut-off.

Hotplate latencies were tested with a Harvard Apparatus Ltd. hotplate (Edenbridge, Kent, UK). In the test, the rats were kept inside a transparent plastic cage on a hotplate (52°C ± 0.3°C). Licking or shaking the hindpaw or jumping was considered as signs of thermal nociception. To avoid tissue damage, 60 s was set as the cut-off time.

Tail flick latencies were tested with a Ugo Basile (Comerio, Italy) apparatus. In the test, the rats were placed in transparent hard plastic tubes. The tests were repeated three times (with a 15 s-interval) at every time point. The intensity of the light beam was adjusted to produce a baseline latency of 3 s and the cut-off was set at 8 s to avoid tissue damage.

The results of the nociceptive tests where a cut-off value was used (paw pressure, hotplate, and tail flick tests) are reported as mean of the maximum percentage effect (MPE%), calculated as: [(postvalue − prevalue)/(cut off − prevalue)] * 100%.

Back to Top | Article Outline

Carrageenan Inflammation

Enflurane (Abbot Scandinavia AB., Solna, Sweden) was used to anesthetize the rats, and 0.2 mg λ-carrageenan (Sigma, St. Louis, MO) in 0.1 mL of saline was injected subcutaneously into the left hindpaw. The studied drugs were administered subcutaneously 90 min after carrageenan injection and the test for mechanical hyperalgesia was started 30 min after the injection of the study drugs. Saline served as a control. Drug testing was performed 30 min before the carrageenan injection. Thresholds for mechanical hyperalgesia were tested with a digital force gauge (Imada DPS-1, Imada CO, Northbrook, IL) with a custom made metal tip (φ = 0.5 mm). Both ipsi- and contralateral paws were tested. The rats were kept on a metal mesh covered with a transparent plastic cover. The ventral surface of the inflamed paw was touched with a tip of the gauge until a paw withdrawal (a brisk foot withdrawal, shaking, or licking of the paw) was observed and the force was recorded. A force of 90 g was able to lift a noninflamed paw and it was considered as a cut-off value.

Back to Top | Article Outline

Rotarod Test

To study possible changes in motor function or sedative effects of the drugs the rats were tested with a rotarod test apparatus (Palmer electric recording drum, UK; diameter 80 mm, speed 10 RPM). Rats were placed on the rotating rod and the time the rat stayed on the rotating rod was calculated. Animals that stayed at least 120 s on the rotating rod before drug administration (prevalue) were included to the test and 120 s was set as the cut-off time in the actual test.

Back to Top | Article Outline

Intrathecal Cannulation

Intrathecal cannulation was performed during anesthesia with subcutaneous injection of midazolam 5.0 mg/kg (Midazolam Alpharma, Alpharma, Oslo, Norway) and Hypnorm® 1.0 mL/kg (fentanyl 0.2 mg/mL and fluanisone 10 mg/mL, Janssen Pharmaceutica, Beerse, Belgium). A thin polyethene cannula (Portex Ltd., Hythe, Kent, UK) (original ID = 0.28 mm and OD = 0.61 mm, stretched to double its original length in hot water according to Yaksh and Rudy13) was inserted through the cisterna magna to the lumbar subarachnoid space with the tip of the cannula at 8 cm from the insertion. The cannula was fixed with a suture to the paravertebral muscles.13 The condition of the animals was checked after surgery and the animals were housed individually in clear plastic cages. Animals with any neurologic disturbances were immediately killed. Proper placement of the polyethene cannula was verified with an intrathecal injection of 10 μL of 10 mg/mL lidocaine (Lidocain®, Orion, Espoo, Finland) 5 days after cannulation. Only rats with reversible symmetrical paralysis of both hindlimbs after injection were used in the experiments, which started 10 days after the cannulation.

Back to Top | Article Outline

Statistical Analysis

Nonparametric analyses of variance with Bonferroni and Tukey tests implemented in Prism 4.0 (GraphPad Software Inc., San Diego, CA) were used for statistical analysis.

Back to Top | Article Outline

RESULTS

Subcutaneous Administration of Noroxymorphone

Subcutaneously administered noroxymorphone failed to induce antinociception in the models of thermal (Figs. 2a and b) and mechanical nociception (Fig. 2c) at the doses used (5, 10, and 25 mg/kg). A 100% MPE in the tail flick test, an 80.4% MPE in the hotplate test, and an 84.3% MPE in the paw pressure test were achieved with oxycodone 2.5 mg/kg 30 min after drug administration (significantly different from the saline group). In the carrageenan inflammation model (Fig. 3), no signs of hyperalgesia were observed before the carrageenan injection. In the control group, subcutaneous administration of saline 30 min before testing had no antihyperalgesic effects and a statistically significant decrease (from a mean of 79–32 g) in the thresholds compared with the pretreatment thresholds was observed in the inflamed paws. There were no changes in the thresholds in the contralateral paws (data not shown). Subcutaneous administration of 25 mg/kg of noroxymorphone 30 min before testing had no antihyperalgesic effects in this test. Subcutaneous administration of oxycodone 2.5 mg/kg abolished all hyperalgesic behavior and no statistically significant difference compared with the pretreatment thresholds was found.

Figure 2

Figure 2

Figure 3

Figure 3

In the rotarod test, no change in motor function or sedation was observed after subcutaneous administration of noroxymorphone with the studied doses (5, 10, and 25 mg/kg) 30 min after drug administration (Fig. 4). A 100% latency on the rotating rod was also achieved after administration of oxycodone 2.5 mg/kg. A statistically significant decrease in the rotarod latencies (65% compared with the predrug latencies) compared with the saline group was observed after oxycodone 5 mg/kg, 30 min after drug administration.

Figure 4

Figure 4

Back to Top | Article Outline

Intrathecal Administration of Noroxymorphone

Intrathecally administered noroxymorphone induced statistically significant potent and long-lasting antinociception (Fig. 5a). With 5 μg/10 μL of noroxymorphone, a MPE of 96% was achieved 15 min after the drug was administered and a MPE of 81% was still observed 12 h after the administration. A MPE of 17% was observed 24 h after the drug administration. Intrathecally administered morphine induced a potent antinociceptive effect with a shorter duration. A peak antinociceptive effect (MPE 95%) was reached 30 min after intrathecal morphine administration (5 μg/10 μL) and a MPE of 13% was observed 4 h after morphine administration (Fig. 5b). Pretreatment with subcutaneous naloxone (1 mg/kg) 15 min before intrathecal opioid administration significantly decreased the antinociceptive effect of both noroxymorphone and morphine compared with the saline pretreatment group (Fig. 6). A relatively short effect of subcutaneously administered naloxone was observed with the dose of 1 mg/kg. An antinociceptive effect of intrathecal morphine and noroxymorphone could be observed after the antagonist effect of naloxone had worn off (Figs. 7a and b). Intrathecal oxycodone showed weak antinociceptive potency (Fig. 8). A MPE of 100% was achieved 15 min after the administration of a large dose of oxycodone 200 μg/10 μL. The effect was short, and a MPE of 55% was observed 90 min after drug administration. Saline had no effects on the tail flick latencies in this test.

Figure 5

Figure 5

Figure 6

Figure 6

Figure 7

Figure 7

Figure 8

Figure 8

Back to Top | Article Outline

DISCUSSION

Subcutaneously administered noroxymorphone was found to be inactive in all models of nociception (Figs. 2a–c) and inflammation (Fig. 3) studied, whereas a potent antinociceptive effect was observed after subcutaneous administration of oxycodone 2.5 mg/kg. No change in motor function or any signs of sedation were seen after subcutaneous administration of noroxymorphone at doses of 5, 10, and 25 mg/kg (Fig. 4). A moderate, but statistically significant, decrease in survival on the rotating rod compared with the saline group was observed after subcutaneous administration of 5 mg/kg oxycodone, as a sign of sedation and reduced motor performance. No changes in the rotarod latencies were observed with 2.5 mg/kg oxycodone (Fig. 4). Plasma concentrations of noroxymorphone have been reported to be relatively high after oral administration of oxycodone in humans and after intragastric administration in rats.9 In the same study, Lalovic et al. also found that the brain-to-plasma distribution ratio of noroxymorphone (≈0.008) is extremely low, possibly due to its markedly lower calculated logD (pH, 7–8) compared with that of oxycodone (≈2.07). This is in agreement with the present results, as noroxymorphone was found to be inactive after subcutaneous administration.

To test the possibility that noroxymorphone could activate peripheral μ-opioid receptors in inflammation, subcutaneous noroxymorphone was studied in the carrageenan model.14 However, no antihyperalgesic effect was seen. This may have been due to the relatively acute character of the carrageenan model. Carrageenan-induced inflammation has been reported to up-regulate levels of μ-opioid receptor protein in dorsal root ganglions.15 Marked up-regulation takes place after 1–3 days of carrageenan injection. A rapid induction of μ-opioid receptor protein in the dorsal root ganglions has also been reported after injection of complete Freunds’ adjuvant.16 The early phase of hyperalgesia takes place after 1–2 h of injection and the late phase after 4 days. This indicates that different models of inflammation are able to induce different kinds of changes in gene regulation in dorsal root ganglions. In the present study, for ethical reasons, the animals were tested only after 120 min of carrageenan injection. Previously, loperamide, another μ-opioid receptor agonist that does not cross the blood–brain barrier, has been shown to have antihyperalgesic effects in thermal injury17 and in arthritic rats.18 Noroxymorphone should be tested in these models at different doses to explore its possible peripheral antinociceptive effects.

Opioids are administered intrathecally to achieve segmental spinal analgesia and to avoid adverse effects mediated by supraspinal opioid-receptor activation. After intrathecal administration, the antinociceptive potencies of opioids cannot be fully predicted by the receptor binding affinity, because the pharmacological activity is modulated by complicated pharmacokinetics. Intrathecally administered opioids can spread through various routes, which are controlled mainly by their lipophilicity. Sufentanil and fentanyl have superior binding affinity for μ-opioid receptors compared with morphine.19 Both sufentanil and fentanyl are more hydrophobic (higher logD-values) compared with morphine and other opioids used in this study (Table 1). After systemic administration, sufentanil and fentanyl are more potent compared with morphine in rodents,20,21 but after intrathecal administration, the relative potencies of sufentanil and fentanyl are decreased compared with morphine.20 Buerkle and Yaksh reported that remifentanil (which is more hydrophobic compared with morphine) was 60 times more potent compared with morphine after intraperitoneal administration but only 17 times more potent compared with morphine after intrathecal administration in rats.22 These observations can be understood by the results of Ummenhofer et al. who demonstrated that after intrathecal administration of morphine a higher spinal cord exposure (peak concentration and duration) was observed compared with intrathecally administered sufentanil and fentanyl in pigs.23 Also, morphine produces longer-lasting antinociception compared with more hydrophobic opioids after intrathecal administration,24 due to slower distribution of morphine to lipid-rich tissues and vasculature compared with hydrophobic opioids. More hydrophobic molecules (high logD values) undergo rapid penetration to the lipid-rich tissues surrounding the intrathecal space.23 This can be observed as a fast onset of the analgesic effect of hydrophobic opioids (e.g., sufentanil and fentanyl) after intrathecal administration, followed by rapid vascular absorption, leading to shorter duration of analgesia compared with the more hydrophilic opioids.24 Thus, the physicochemical properties of opioids, particularly the logD, can change the relative intrathecal/systemic potencies of the drugs and, more importantly, the duration of spinal analgesia.

Table 1

Table 1

After intrathecal administration, drugs do not need to penetrate the lipid-rich blood–brain barrier. This enables opioids that have low logD values (better distribution in aqueous phase/higher polarity/more water soluble) to induce analgesia after intrathecal administration (Table 1). In the present study, noroxymorphone (1 and 5 μg/10 μL) induced a potent and longer-lasting antinociceptive effect compared with morphine (1 and 5 μg/10 μL) and oxycodone (200 μg/10 μL) after intrathecal administration in rats (Figs. 5a and b, and 8). McQuay et al. have postulated that the antinociceptive potencies of intrathecally administered μ-opioid receptor agonists are inversely related to their lipophilicity.25 The longer duration of the analgesic effect induced by intrathecal administration of noroxymorphone compared with oxycodone may thus be related to its lower logD value (more water soluble), because of the low vascular absorption of high-polarity drugs (like noroxymorphone) from the spinal fluid.26 The poor intrathecal potency of oxycodone compared with noroxymorphone and morphine can partly be explained by the lower μ-opioid receptor affinity of oxycodone compared with the other study drugs. The ability of oxycodone to activate μ-opioid receptor-mediated G proteins at the spinal level has been shown to be significantly weaker compared with morphine.27 Oxycodone had the highest logD value of the study drugs, indicating highest lipophilicity of the drugs studied (Table 1). According to Poyhia et al. the physicochemical properties, liposolubility, and protein-binding of oxycodone resemble those of morphine.28 The longer duration of antinociception of noroxymorphone compared with morphine seems to be related to both its chemical properties as a very hydrophilic compound with a low ClogD value (more water soluble) and its relatively high affinity to the μ-opioid receptor.9 As ED50 values were not determined, it is possible that noroxymorphone was also somewhat more potent compared with morphine in the doses used. We used similar intrathecal doses of morphine and noroxymorphone that produced similar MPE% values. However, the MPE% values were close to the maximum, even with the lower dose of 1 mg/10 mL. Compared with the study drugs, sufentanil and fentanyl have higher ClogD values (more hydrophobic drugs) (Table 1).29 When hydrophilic drugs are administered intrathecally they can spread to supraspinal parts of the central nervous system and cause sedation and respiratory depression. No respiratory depression was observed after intrathecal administration of noroxymorphone in the doses that were used in this study.

The good systemic potency of oxycodone compared with the low potency after epidural administration in humans30,31 and intrathecal administration in rats32,33 has led to the suggestion that active metabolites may be important. Lalovic et al. postulated that the analgesic activity of oxycodone can be explained by activity of its own.9 According to the results of the present study, noroxymorphone cannot explain the pharmacokinetic/ pharmacodynamic discrepancy between the good systemic effectiveness of oxycodone compared with its relatively low binding affinity to the μ-opioid receptor in vitro,9,34,35 because noroxymorphone is not pharmacologically active after subcutaneous administration in doses comparable to those produced by metabolism of oxycodone.

Mechanisms that may influence the pharmacokinetics of intrathecally administered opioids include cell membrane-bound proteins that may act as influx or eflux transporters for opioids. A recent study reported that oxycodone has a three-times higher unbound concentration in the brain than in the blood, indicating an active influx across the blood–brain barrier with an unidentified carrier protein in rats.36 P-glycoprotein plays an important role as an eflux transporter located in the blood–brain barrier.37 P-glycoprotein can limit the entry of drugs from plasma to the central nervous system. Some opioids, such as morphine and methadone, have been identified to act as substrates for P-glycoprotein.38 Conflicting results have been reported regarding the interaction of oxycodone with P-glycoprotein in rats.39,40 High concentrations of free oxycodone in the central nervous system after systemic administration may explain the high potency of systemic oxycodone.36

In rats and mice, intrathecally administered large doses of morphine may cause hyperalgesia, allodynia, and agitation.11,41–43 This behavior is not reversed by opioid receptor antagonists,11,41,43 whereas it is abolished by neurokinin 143 and N-methyl-d-aspartate antagonists,44 indicating involvement of non-opioid neuronal mechanisms. Like morphine, large doses of noroxymorphone have been reported to induce spontaneous and touch-evoked agitation in rats.11 In that study, the ED40 of noroxymorphone to produce spontaneous or touch-evoked agitation was 161 and 92 μg, respectively. In the present study, no such behavior was observed with the doses studied (1 and 5 μg).

Because of the relatively invasive nature of spinal administration of opioids, an ideal molecule for spinal analgesia should have strong potency and efficacy and a long duration of the analgesic effect, and it should not be neurotoxic. In the present study, noroxymorphone was shown to be as efficient and potent as morphine, and with a significantly longer duration of analgesic effect. Noroxymorphone may be a useful new spinal analgesic for both perioperative and long-term spinal analgesia. However, a safety assessment of noroxymorphone, focusing on neurotoxicity, should be performed before the clinical effectiveness of noroxymorphone is studied.

Back to Top | Article Outline

CONCLUSIONS

Noroxymorphone is a promising opioid for spinal analgesia and it should be further studied.

Back to Top | Article Outline

ACKNOWLEDGMENTS

These studies were supported by a grant of the Finnish Association for the Study of Pain and The Graduate School in Pharmaceutical Research.

Back to Top | Article Outline

REFERENCES

1. Ishida T, Oguri K, Yoshimura H. Isolation and identification of urinary metabolites of oxycodone in rabbits. Drug Metab Dispos 1979;7:162–5
2. Weinstein SH, Gaylord JC. Determination of oxycodone in plasma and identification of a major metabolite. J Pharm Sci 1979;68:527–8
3. Ishida T, Oguri K, Yoshimura H. A novel metabolite of oxycodone in the urine of rabbits. J Pharmacobio Dyn 1982;5:134–6
4. Cone EJ, Darwin WD, Buchwald WF, Gorodetzky CW. Oxymorphone metabolism and urinary excretion in human, rat, guinea pig, rabbit, and dog. Drug Metab Dispos 1983;11:446–50
5. Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM. Inhibition by fluoxetine of cytochrome P450 2D6 activity. Clin Pharmacol Ther 1993;53:401–9
6. Lalovic B, Phillips B, Risler LL, Howald W, Shen DD. Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos 2004;32:447–54
7. Poyhia R, Seppala T, Olkkola KT, Kalso E. The pharmacokinetics and metabolism of oxycodone after intramuscular and oral administration to healthy subjects. Br J Clin Pharmacol 1992;33:617–21
8. Kirvela M, Lindgren L, Seppala T, Olkkola KT. The pharmacokinetics of oxycodone in uremic patients undergoing renal transplantation. J Clin Anesth 1996;8:13–8
9. Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen DD. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 2006;79:461–79
10. Thompson CM, Wojno H, Greiner E, May EL, Rice KC, Selley DE. Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O- and N-demethylated metabolites at mu- and delta-opioid receptors. J Pharmacol Exp Ther 2004;308:547–54
11. Yaksh TL, Harty GJ. Pharmacology of the allodynia in rats evoked by high dose intrathecal morphine. J Pharmacol Exp Ther 1988;244:501–7
12. Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983;16:109–10
13. Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarachnoid space. Physiol Behav 1976;17:1031–6
14. Winter CA, Risley EA, Nuss GW. Carrageenan-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc Soc Exp Biol Med 1962;111:544–7
15. Ji RR, Zhang Q, Law PY, Low HH, Elde R, Hokfelt T. Expression of mu-, delta-, and kappa-opioid receptor-like immunoreactivities in rat dorsal root ganglia after carrageenan-induced inflammation. J Neurosci 1995;15:8156–66
16. Puehler W, Zollner C, Brack A, Shaqura MA, Krause H, Schafer M, Stein C. Rapid upregulation of mu opioid receptor mRNA in dorsal root ganglia in response to peripheral inflammation depends on neuronal conduction. Neuroscience 2004;129:473–9
17. Nozaki-Taguchi N, Yaksh TL. Characterization of the antihyperalgesic action of a novel peripheral mu-opioid receptor agonist–loperamide. Anesthesiology 1999;90:225–34
18. Cook CD, Nickerson MD. Nociceptive sensitivity and opioid antinociception and antihyperalgesia in Freund’s adjuvant-induced arthritic male and female rats. J Pharmacol Exp Ther 2005;313:449–59
19. Emmerson PJ, Liu MR, Woods JH, Medzihradsky F. Binding affinity and selectivity of opioids at mu, delta and kappa receptors in monkey brain membranes. J Pharmacol Exp Ther 1994;271:1630–7
20. Abram SE, Mampilly GA, Milosavljevic D. Assessment of the potency and intrinsic activity of systemic versus intrathecal opioids in rats. Anesthesiology 1997;87:127–34
21. Meert TF, Vermeirsch HA. A preclinical comparison between different opioids: antinociceptive versus adverse effects. Pharmacol Biochem Behav 2005;80:309–26
22. Buerkle H, Yaksh TL. Comparison of the spinal actions of the mu-opioid remifentanil with alfentanil and morphine in the rat. Anesthesiology 1996;84:94–102
23. Ummenhofer WC, Arends RH, Shen DD, Bernards CM. Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil. Anesthesiology 2000;92:739–53
24. Yaksh TL, Noueihed RY, Durant PA. Studies of the pharmacology and pathology of intrathecally administered 4-anilinopiperidine analogues and morphine in the rat and cat. Anesthesiology 1986;64:54–66
25. McQuay HJ, Sullivan AF, Smallman K, Dickenson AH. Intrathecal opioids, potency and lipophilicity. Pain 1989;36:111–5
26. Dickenson AH, Sullivan AF, McQuay HJ. Intrathecal etorphine, fentanyl and buprenorphine on spinal nociceptive neurones in the rat. Pain 1990;42:227–34
27. Lemberg KK, Kontinen VK, Siiskonen AO, Viljakka KM, Yli-Kauhaluoma JT, Korpi ER, Kalso EA. Antinociception by spinal and systemic oxycodone: why does the route make a difference?: in vitro and in vivo studies in rats. Anesthesiology 2006;105:801–12
28. Poyhia R, Seppala T. Liposolubility and protein binding of oxycodone in vitro. Pharmacol Toxicol 1994;74:23–7
29. Skold C, Winiwarter S, Wernevik J, Bergstrom F, Englstrom L, Allen R, Box K, Comer J, Mole J, Hallberg A, Lennernas H, Lundtedt T, Ungell AL, Karlen A. Presentation of a structurally diverse and commercially available drug data set for correlation and benchmarking studies. J Med Chem 2006;49:6660–71
30. Backlund M, Lindgren L, Kajimoto Y, Rosenberg PH. Comparison of epidural morphine and oxycodone for pain after abdominal surgery. J Clin Anesth 1997;9:30–5
31. Yanagidate F, Dohi S. Epidural oxycodone or morphine following gynaecological surgery. Br J Anaesth 2004;93:362–7
32. Plummer JL, Cmielewski PL, Reynolds GD, Gourlay GK, Cherry DA. Influence of polarity on dose-response relationships of intrathecal opioids in rats. Pain 1990;40:339–47
33. Poyhia R, Kalso EA. Antinociceptive effects and central nervous system depression caused by oxycodone and morphine in rats. Pharmacol Toxicol 1992;70:125–30
34. Monory K, Greiner E, Sartania N, Sallai L, Pouille Y, Schmidhammer H, Hanoune J, Borsodi A. Opioid binding profiles of new hydrazone, oxime, carbazone and semicarbazone derivatives of 14-alkoxymorphinans. Life Sci 1999;64:2011–20
35. Chen ZR, Irvine RJ, Somogyi AA, Bochner F. Mu receptor binding of some commonly used opioids and their metabolites. Life Sci 1991;48:2165–71
36. Bostrom E, Simonsson US, Hammarlund-Udenaes M. In vivo blood-brain barrier transport of oxycodone in the rat-indications for active influx and implications for PK/PD. Drug Metab Dispos 2006;34:1624–31
37. Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 1989;86:695–8
38. Thompson SJ, Koszdin K, Bernards CM. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 2000;92:1392–9
39. Bostrom E, Simonsson USH, Hammarlund-Udenaes M. Oxycodone pharmacokinetics and pharmacodynamics in the rat in the presence of the P-glycoprotein inhibitor PSC833. J Pharm Sci 2005;94:1060–6
40. Hassan HE, Myers AL, Lee IJ, Coop A, Eddington ND. Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel’s tissue distribution in Sprague-Dawley rats. J Pharm Sci 2007;96:2494–506
41. Yaksh TL, Harty GJ, Onofrio BM. High dose of spinal morphine produce a nonopiate receptor-mediated hyperesthesia: clinical and theoretic implications. Anesthesiology 1986;64:590–7
42. Woolf CJ. Intrathecal high dose morphine produces hyperalgesia in the rat. Brain Res 1981;209:491–5
43. Sakurada T, Wako K, Sakurada C, Manome Y, Tan-No K, Sakurada S, Kisara K. Spinally-mediated behavioural responses evoked by intrathecal high-dose morphine: possible involvement of substance P in the mouse spinal cord. Brain Res 1996;724:213–21
44. Sakurada T, Watanabe C, Okuda K, Sugiyama A, Moriyama T, Sakurada C, Tan-No K, Sakurada S. Intrathecal high-dose morphine induces spinally-mediated behavioral responses through NMDA receptors. Brain Res Mol Brain Res 2002;98:111–8
© 2008 International Anesthesia Research Society