Kim K. Lemberg

Antinociception by spinal and systemic oxycodone: why does the route make a difference? In vitro and in vivo studies in rats.

Background: The pharmacology of oxycodone is poorly understood despite its growing clinical use. The discrepancy between its good clinical effectiveness after systemic administration and the loss of potency after spinal administration led the authors to study the pharmacodynamic effects of oxycodone and its metabolites using in vivo and in vitro models in rats. Methods: Male Sprague-Dawley rats were used in hot-plate, tail-flick, and paw-pressure tests to study the antinociceptive properties of morphine, oxycodone, and its metabolites oxymorphone and noroxycodone. &mgr;-Opioid receptor agonist–stimulated GTP&ggr;[35S] autoradiography was used to study G-protein activation induced by morphine, oxycodone, and oxymorphone in the rat brain and spinal cord. Spontaneous locomotor activity was measured to assess possible sedation or motor dysfunction. Naloxone and the selective &kgr;-opioid receptor antagonist nor-binaltorphimine were used to study the opioid receptor selectivity of the drugs. Results: Oxycodone showed lower efficacy and potency to stimulate GTP&ggr;[35S] binding in the spinal cord and periaqueductal gray compared with morphine and oxymorphone. This could relate to the fact that oxycodone produced only weak naloxone-reversible antinociception after intrathecal administration. It also suggests that the metabolites may have a role in oxycodone-induced analgesia in rats. Intrathecal oxymorphone produced strong long-lasting antinociception, whereas noroxycodone produced antinociception with very high doses only. Subcutaneous administration of oxycodone and oxymorphone produced thermal and mechanical antinociception that was reversed by naloxone but not by nor-binaltorphimine. Oxymorphone was more potent than oxycodone, particularly in the hot-plate and paw-pressure tests. Conclusions: The low intrathecal potency of oxycodone in rats seems be related to its low efficacy and potency to stimulate &mgr;-opioid receptor activation in the spinal cord.

Morphine, oxycodone, methadone and its enantiomers in different models of nociception in the rat.

We studied the effects of the commonly used &mgr;-opioid receptor agonists morphine, oxycodone, methadone and the enantiomers of methadone in thermal and mechanical models of acute pain and in the spinal nerve ligation model of neuropathic pain in rats. Subcutaneous administration of morphine, oxycodone, and methadone produced a dose-dependent antinociceptive effect in the tail flick, hotplate, and paw pressure tests. l-methadone, racemic methadone, and oxycodone had a similar dose-dependent antinociceptive effect, whereas the dose-response curve of morphine was shallower. In the spinal nerve ligation model of neuropathic pain, subcutaneous administration of morphine, oxycodone, methadone and l-methadone had antiallodynic effects in tests of mechanical and cold allodynia. l-methadone showed the strongest antiallodynic effect of the tested drugs. d-methadone was inactive in all tests. Morphine 5.0 mg/kg, oxycodone 2.5 mg/kg, and l-methadone 1.25 mg/kg decreased spontaneous locomotion 30 min after drug administration. In conclusion, in acute nociception all &mgr;-opioid receptor agonists produced antinociception, with morphine showing the weakest effect. In nerve injury pain, l-methadone showed the greatest antiallodynic potency in both mechanical and cold allodynia compared with the other opioids. Opioids seem to have different profiles in different pain models. l-methadone should be studied for neuropathic pain in humans.

Pharmacological characterization of noroxymorphone as a new opioid for spinal analgesia.

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 &mgr;g/10 &mgr;L) induced a significantly longer lasting antinociceptive effect compared with oxycodone (200 &mgr;g/10 &mgr;L) and morphine (1 and 5 &mgr;g/10 &mgr;L). 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 &mgr;-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.

Is dental treatment of an infected tooth a risk factor for locally invasive spread of infection

PURPOSE To determine the impact of antecedent dental procedures and dental health on the course of odontogenic maxillofacial infections requiring hospital care. PATIENTS AND METHODS In this retrospective cohort study in a referral center, we evaluated medical records and panoramic radiographs of all patients admitted because of odontogenic maxillofacial infection (n = 84). The predictor variables were preceding dental treatment, antimicrobial therapy, and dental health. The outcome variables comprised infection parameters, length of stay, need for intensive care, and management during hospitalization. RESULTS The mean age of the patients was 43.2 ± 16.5 years and 60% were men. Dental procedure preceded the spread of the infection in 49 cases (58%): endodontic treatment (n = 22), tooth extraction (n = 19), and minor first aid (n = 8). Twenty-seven patients had not received any dental or antimicrobial treatment in the recent past. Antimicrobial treatment alone had been given to 8 patients. Patients without preceding treatment had the highest C-reactive protein levels on admission and at maximum (P = .020 and P = .011) and the highest white blood cell counts on admission (P = .011). Their length of stay was also longer, and they needed intensive care more often than the other patients. Maximum C-reactive protein levels and white blood cell counts between treatment groups did not significantly differ from each other. CONCLUSIONS The systemic response to the infection was strongest and the course of the infection most severe in the absence of preceding dental treatment and in patients with poor dental health. All types of dental treatment contributed to a less severe course of infection.

Stress‐Induced Analgesia and Morphine Responses Are Changed in Catechol‐O‐methyltransferase‐Deficient Male Mice

Catechol-O-methyltransferase (COMT) polymorphisms modulate pain and opioid analgesia in human beings. It is not clear how the effects of COMT are mediated and only few relevant animal studies have been performed. Here, we used old male Comt gene knock-out mice as an animal model to study the effects of COMT deficiency on nociception that was assessed by the hot plate and tail flick tests. Stress-induced analgesia was achieved by forced swim. Morphine antinociception was measured after 10 mg/kg of morphine subcutaneously. Morphine tolerance was produced with subcutaneous morphine pellets and withdrawal provoked with subcutaneous naloxone. In the hot plate test, morphine-induced antinociception was significantly greater in the COMT knock-out mice, compared to the wild-type mice. This may be due to increased availability of opioid receptors as suggested by previous human studies. In the tail flick test, opioid-mediated stress-induced analgesia was absent and morphine-induced analgesia was decreased in COMT knock-out mice. In the hot plate test, stress-induced analgesia developed to all mice regardless of the COMT genotype. There were no differences between the genotypes in the baseline nociceptive thresholds, morphine tolerance and withdrawal. Our findings show, for the first time, the importance of COMT activity in stress- and morphine-induced analgesia in mice. COMT activity seems to take part in the modulation of nociception not only in the brain, as suggested earlier, but also at the spinal/peripheral level.

Does co-administration of paroxetine change oxycodone analgesia: An interaction study in chronic pain patients

Abstract Oxycodone is a strong opioid and it is increasingly used in the management of acute and chronic pain. The pharmacodynamic effects of oxycodone are mainly mediated by the μ-opioid receptor. However, its affinity for the μ-opioid receptor is significantly lower compared with that of morphine and it has been suggested that active metabolites may play a role in oxycodone analgesia. Oxycodone is mainly metabolized by hepatic cytochrome (CYP) enzymes 2D6 and 3A4. Oxycodone is metabolized to oxymorphone, a potent μ-opioid receptor agonist by CYP2D6. However, CYP3A4 is quantitatively a more important metabolic pathway. Chronic pain patients often use multiple medications. Therefore it is important to understand how blocking or inducing these metabolic pathways may affect oxycodone induced analgesia. The aim of this study was to find out whether blocking CYP2D6 would decrease oxycodone induced analgesia in chronic pain patients. The effects of the antidepressant paroxetine, a potent inhibitor of CYP2D6, on the analgesic effects and pharmacokinetics of oral oxycodone were studied in 20 chronic pain patients using a randomized, double-blind, placebo-controlled cross-over study design. Pain intensity and rescue analgesics were recorded daily, and the pharmacokinetics and pharmacodynamics of oxycodone were studied on the 7th day of concomitant paroxetine (20 mg/day) or placebo administration. The patients were genotyped for CYP2D6, 3A4, 3A5 and ABCB1. Paroxetine had significant effects on the metabolism of oxycodone but it had no statistically significant effect on oxycodone analgesia or use of morphine for rescue analgesia. Paroxetine increased the dose-adjusted mean AUC0–12h of oxycodone by 19% (−23 to 113%; P = 0.003), and that of noroxycodone by 100% (5–280%; P < 0.0001) but decreased the AUC0–12 h of oxymorphone by 67% (−100 to −22%; P < 0.0001) and that of noroxymorphone by 68% (−100 to −16%; P < 0.0001). Adverse effects were also recorded in a pain diary for both 7-day periods (placebo/paroxetine). The most common adverse effects were drowsiness and nausea/vomiting. One patient out of four reported dizziness and headache during paroxetine co-administration, whereas no patient reported these during placebo administration (P = 0.0471) indicating that these adverse effects were due to paroxetine. No statistically significant associations of the CYP2D6 or CYP3A4/5 genotype of the patients and the pharmacokinetics of oxycodone or its metabolites, extent of paroxetine–oxycodone interaction, or analgesic effects were observed probably due to the limited number of patients studied. The results of this study strongly suggest that CYP2D6 inhibition does not significantly change oxycodone analgesia in chronic pain patients and that the analgesic activity of oxycodone is mainly due to the parent compound and that metabolites, e.g. oxymorphone, play an insignificant role. The clinical implication of these results is that induction of the metabolism of oxycodone may lead to inadequate analgesia while increased drug effects can be expected after addition of potent CYP3A4/5 inhibitors particularly if combined with CYP2D6 inhibitors or when administered to poor metabolizers of CYP2D6.

Pharmacology of oxycodone: does it explain why oxycodone has become a bestselling strong opioid?

Abstract As morphine, oxycodone is a m-opioid receptor agonist with a significantly different pharmacokinetic profile compared with morphine. It seems that oxycodone is able to compensate its lower binding affinity for the m-opioid receptor compared with that of morphine by active transport to the central nervous system. Although the analgesic properties of oxycodone are mainly due to its own activity, cytochrome (CYP) inhibitors and inductors may change oxycodone-induced analgesia as a result of higher or lower, respectively, oxycodone concentrations.