Investigation of in vitro transdermal absorption of fentanyl from patches placed on skin samples obtained from various anatomic regions of dogs

Objective-To investigate in vitro transdermal absorption of fentanyl from patches through skin samples obtained from various anatomic regions of dogs. Sample Population-Skin samples from 5 Greyhounds. Procedure-Skin samples from the dogs' thoracic, neck, and groin regions were collected postmortem and frozen. After samples were thawed, circular sections were cut and placed in Franz-type diffusion cells in a water bath (32degreesC). A commercial fentanyl patch, attached to an acetate strip with a circular hole, was applied to each skin sample. Cellulose strips were used as control membranes. Samples of receptor fluid in the diffusion cells were collected at intervals for 48 hours, and fentanyl concentrations were analyzed by use of high-performance liquid chromatography. Results-Mean +/- SD release rate of fentanyl from the patch, defined by its absorption rate through the non-rate-limiting cellulose membrane, was linear during the first 8 hours (2.01 +/- 0.05 pg/cm(2) of cellulose membrane/h) and then decreased. Fentanyl passed through skin from the groin region at a faster rate and with a significantly shorter lag time, compared with findings in neck or thoracic skin samples. Conclusions and Clinical Relevance-In vitro, fentanyl from a patch was absorbed more quickly and to a greater extent through skin collected from the groin region of dogs, compared with skin samples from the thoracic and neck regions. Placement of fentanyl patches in the groin region of dogs may decrease the lag time to achieve analgesia perioperatively; however, in vivo studies are necessary to confirm these findings.

Comparison of the pharmacokinetics of oxycodone and noroxycodone in male dark agouti and Sprague-Dawley rats: Influence of streptozotocin-induced diabetes

Purpose. The aims of this study are to evaluate whether cytochrome P450 (CYP)2D1/2D2-deficient dark agouti (DA) rats and/or CYP2D1/2D2-replete Sprague-Dawley (SD) rats are suitable preclinical models of the human, with respect to mirroring the very low plasma concentrations of metabolically derived oxymorphone seen in humans following oxycodone administration, and to examine the effects of streptozotocin-induced diabetes on the pharmacokinetics of oxycodone and its metabolites, noroxycodone and oxymorphone, in both rodent strains. Methods. High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry was used to quantify the serum concentrations of oxycodone, noroxycodone, and oxymorphone following subcutaneous administration of bolus doses of oxycodone (2 mg/kg) to groups of nondiabetic and diabetic rats. Results. The mean (+/- SEM) areas under the serum concentration vs. time curves for oxycodone and noroxycodone were significantly higher in DA relative to SD rats (diabetic, p < 0.05; nondiabetic, p < 0.005). Serum concentrations of oxymorphone were very low (< 6.9 nM). Conclusions. Both DA and SD rats are suitable rodent models to study oxycodone's pharmacology, as their systemic exposure to metabolically derived oxymorphone (potent mu-opioid agonist) is very low, mirroring that seen in humans following oxycodone administration. Systemic exposure to oxycodone and noroxycodone was consistently higher for DA than for SD rats showing that strain differences predominated over diabetes status.

Postoperative analgesic requirements - total laparoscopic hysterectomy versus vaginal hysterectomy

Background: There is limited information available on the requirement for postoperative analgesic drugs in patients submitted to total laparoscopic hysterectomy (TLH) compared with patients undergoing vaginal hysterectomy (VH). Aim: To compare the postoperative analgesic requirements in patients who underwent a TLH with patients who had a VH. Methods: Chart review of 53 patients who had TLH and 47 who had VH and were seen postoperatively by an acute pain management service in order to assess postoperative analgesic requirements. Patient controlled analgesia (PCA) was part of the standard protocol for postoperative pain management. Analgesic requirement was recorded as the mean doses of morphine and number of days that patients used non-steroidal anti-inflammatory drugs (NSAIDs), oxycodone and tramadol. Results: The requirement for total morphine was approximately half the dose in patients who had a TLH (10.8 +/- 12.6 mg) compared with patients who had a VH (19.4 +/- 21.9 mg) (P 0.017). The length of use of NSAIDs was significantly reduced in patients who had undergone a TLH (2.0 +/- 0.95 days) as compared with patients who had a VH (2.85 +/- 1.1 days) (P < 0.0001). Conclusions: Patients submitted to TLH require less postoperative analgesic drugs when compared with patients who had VH. Prospective randomised trials are warranted to compare analgesic requirements between patients submitted to TLH and VH.

Ventilatory responses of healthy subjects to intravenous combinations of morphine and oxycodone under imposed hypercapnic and hypoxaemic conditions

Aims Previous isobolographic analysis revealed that coadministration of morphine and oxycodone produces synergistic antinociception in laboratory rodents. As both opioids can produce ventilatory depression, this study was designed to determine whether their ventilatory effects were synergistic when coadministered to healthy human subjects. Methods A placebo-controlled, randomized, crossover study was performed in 12 male volunteers. Ventilatory responses to hypoxaemia and hypercapnia were determined from 1-h intravenous infusions of saline ('placebo'), 15 mg morphine sulphate (M), 15 mg oxycodone hydrochloride (O), and their combination in the dose ratios of 1 : 2, 1 : 1, 2 : 1. Drug and metabolite concentrations in serial peripheral venous blood samples were measured by high-performance liquid chromatography-MS/MS. Results 'Placebo' treatment was without significant ventilatory effects. There were no systematic differences between active drug treatments on either the slopes or intercepts of the hypoxaemic and hypercapnia ventilation responses. During drug treatment, the mean minute ventilation at PETCO2 = 55 mmHg (V-E55) decreased to 74% of the subjects' before treatment values (95% confidence interval 62, 87), 68% (57, 80), 69% (59, 79), 68% (63, 73), and 61% (52, 69) for M15, M10/O5, M7.5/O7.5, M5/O10 and O15, respectively. Recovery was more prolonged with increasing oxycodone doses, corresponding to its greater potency and lower clearance compared with morphine. Conclusions Although adverse ventilatory effects of these drugs were found as expected, no unexpected or disproportionate effects of any of the morphine and oxycodone treatments were found that might impede their use in combination for pain management.

Will the new CB1 cannabinoid receptor antagonist SR-147778 have advantages over rimonabant?

Obesity and alcoholism are two common modern-day diseases. The cannabinoid CB, receptor antagonist rimonabant is in Phase III clinical trial for the treatment of obesity with preliminary results showing that it decreases appetite and body weight. Animal studies have shown that rimonabant is effective in the treatment of alcoholism. SR-147778 is a new potent and selective CB1 receptor antagonist. In animals, SR-147778 has been shown to inhibit CB1 receptor-mediated hypothermia, analgesia and slowing of gastrointestinal transit. In rats trained to drink sucrose, the oral administration of SR-147778 3 mg/kg, before the presentation of sucrose, decreased the consumption of sucrose. SR-147778 3 mg/kg also reduced spontaneous feeding in rats deprived of food and also in non-deprived rats. In Sardinian alcohol-preferring (sP) rats, in the alcohol-naive state, SR-147778 slowed the development of a preference for alcohol. in alcohol-experienced sP rats SR-147778 (2.5, 5 and 10 mg/kg p.o.) reduced the alcohol intake. When alcohol-experienced sP rats are deprived of alcohol for 15 days, there is a large intake of alcohol on reintroduction of alcohol, and this response was almost abolished by treatment with SR-147778. From the preclinical studies published to date, there is no obvious major point of difference between rimonabant and SR-147778, and both are promising agents for the treatment of obesity and alcoholism.

Prostanoids as friends, not foes: Further evidence from the interference by cycloxygenase-inhibitory drugs when inducing tolerance to experimental arthritigens in rats

Pharmacologists have generally been prejudiced against prostanoids, uncritically accepting their suppression as desirable therapy, especially for ‘quick-fix’ analgesia. This myopic perception for a long time ignored (a) the essentiality of prostanoid precursors in nutrition, (b) the physiological protective functions of natural prostaglandins (PGs) (vasculature, stomach, kidney), (c) resolution of inflammation after the expression of COX-2 and (d) increasing therapeutic use of either synthetic PGs (for erectile dysfunction, opthalmic disorders, inducing parturition, etc) or their natural precursors, e.g., ω3-rich polyunsaturated oils, to treat arthritis. Experimental studies in rats have indicated that prostaglandins (E series) are (i) useful, perhaps auto-regulators of established immunoreactivity and (ii) able to amplify (or even induce) anti-inflammatory activity with other agents. Furthermore, anti-prostanoid therapy (APT) can be arthritigenic!!, interfering with the acquisition of tolerance to some arthritigens. For patients with rheumatoid arthritis this additional side-effect of APT, barely recognised to date, may actually perpetuate their arthritis by impairing prostanoid-mediated remission processes. Hopefully, recent adverse publicity about COX-2 inhibitory drugs might stimulate serious re-assessment of some traditional anti-inflammatory therapies with low APT activity for the management of both acute pain (non-addictive cannabinoids, celery seed, etc.) and chronic inflammation, e.g., Lyprinol® (a mussel lipid extract).

After hours medical ward duties in a teaching hospital

In many Australian hospitals a medical officer is available for urgent review of in-patients outside normal working hours. Current practice in nurse-initiated requests for medical officer involvement out of hours may adversely affect patient outcome as well as medical and nursing resource use at these times. Of 10 523 nurse-initiated requests for out-of-hours review recorded by medical officers at our hospital in 2002-2003, the most frequent reasons for the requests were medication review, IV fluid orders, IV resite, venesection and pathology review, none of which are related to acute changes in clinical condition. Requests for routine review of medication and fluid orders were found to be rarely essential and often inappropriate. Medical officer activity was highest before midnight and least after midnight, suggesting most requests are fulfilled in the evening. Several strategies to reduce inappropriate out-of-hours requests were identified. Routine tasks could be completed by primary treating unit staff before going off-duty. IV cannulation and venesection may be performed by appropriately trained phlebotomists or skilled advanced practice nursing staff. Meticulous ordering of 'as required' analgesia and night sedation would reduce unnecessary requests. Clinical protocols for nurse-initiated adjustment of drugs with variable dosing may also decrease inefficiencies. This would leave the ward cover medical officers more available for their primary function of urgent patient review.

The effect of an algorithm-based sedation guideline on the duration of mechanical ventilation in an Australian intensive care unit

To examine the effect of an algorithm-based sedation guideline developed in a North American intensive care unit (ICU) on the duration of mechanical ventilation of patients in an Australian ICU. The intervention was tested in a pre-intervention, post-intervention comparative investigation in a 14-bed adult intensive care unit. Adult mechanically ventilated patients were selected consecutively (n =322) The pre-intervention and post-intervention groups were similar except for a higher number of patients with a neurological diagnosis in the pre-intervention group. An algorithm-based sedation guideline including a sedation scale was introduced using a multifaceted implementation strategy. The median duration of ventilation was 5.6 days in the post-intervention group, compared with 4.8 days for the pre-intervention group (P = 0.99). The length of stay was 8.2 days in the post-intervention group versus 7.1 days in the pre-intervention group (P = 0.04). There were no statistically significant differences for the other secondary outcomes, including the score on the Experience of Treatment in ICU 7 item questionnaire, number of tracheostomies and number of self-extubations. Records of compliance to recording the sedation score during both phases revealed that patients were slightly more deeply sedated when the guideline was used. The use of the algorithm-based sedation guideline did not reduce duration of mechanical ventilation in the setting of this study.

Analysis of the acute postoperative pain experience following oral surgery: identification of 'unaffected', 'disabled' and 'depressed, anxious and disabled' patient clusters

Background: Pain is defined as both a sensory and an emotional experience. Acute postoperative tooth extraction pain is assessed and treated as a physiological (sensory) pain while chronic pain is a biopsychosocial problem. The purpose of this study was to assess whether psychological and social changes Occur in the acute pain state. Methods: A biopsychosocial pain questionnaire was completed by 438 subjects (165 males, 273 females) with acute postoperative pain at 24 hours following the surgical extraction of teeth and compared with 273 subjects (78 males, 195 females) with chronic orofacial pain. Statistical methods used a k-means cluster analysis. Results: Three clusters were identified in the acute pain group: 'unaffected', 'disabled' and 'depressed, anxious and disabled'. Psychosocial effects showed 24.8 per cent feeling 'distress/suffering' and 15.1 per cent 'sad and depressed'. Females reported higher pain intensity and more distress, depression and inadequate medication for pain relief (p

Glycine receptors: A new therapeutic target in pain pathways

Although glycine receptor Cl- channels (GlyRs) have long been known to mediate inhibitory neurotransmission onto spinal nociceptive neurons, their therapeutic potential for peripheral analgesia has received little attention. However, it has been shown that alpha 3-subunit-containing GlyRs are concentrated into regions of the spinal cord dorsal horn where nociceptive afferents terminate. Furthermore, inflammatory mediators specifically inhibit alpha 3-containing GlyRs, and deletion of the murine alpha 3 gene confers insensitivity to chronic inflammatory pain. This strongly implicates GlyRs in the inflammation-mediated disinhibition of centrally projecting nociceptive neurons. Future therapies aimed at specifically increasing current flux through alpha 3-containing GlyRs may prove effective in providing analgesia.

Pain relief for neonates in Australian hospitals: A need to improve evidence-based practice

Objective: To ascertain the extent to which neonatal analgesia was used in Australia for minor invasive procedures as an indicator of evidence-based practice in neonatology. Methods: A cross-sectional telephone survey of hospitals in all Australian states and territories with more than 200 deliveries per year was carried out. Questions were asked regarding awareness of the benefits and the use of analgesia for minor invasive procedures in term and near term neonates. Analysis was undertaken according to state and territory, annual birth numbers and the level of neonatal nursery care available. Results: Data were available from 212 of 214 eligible hospitals. Of the total respondents, 51% and 70% respectively were aware of the benefits of sucrose and breast-feeding for neonatal analgesia. Eleven per cent of units administered sucrose before venepuncture and 25% of units used breast-feeding. Ten per cent of units used sucrose before heel prick with 49% utilizing breast-feeding. Expressed breast milk was used in 10% of units. Analgesia was given less frequently before intravenous cannulation compared to venepuncture and heel prick. Awareness and implementation of neonatal analgesia varied widely in the states and territories. There was a trend for hospitals providing a higher level of neonatal care to have a greater awareness of sucrose as an analgesic (P < 0.0001) and the use of sucrose for venepuncture (P = 0.029), heel prick (P = 0.025) and intravenous catheter insertion (P = 0.013). Similar trends were found on analysis according to birth number of the maternity units. Smaller units had a greater usage of breast-feeding as an analgesic for heel prick (P = 0.017). Conclusion: Despite good evidence for the administration of sucrose and breast milk in providing effective analgesia for newborn infants, it is not widely used in Australia. It is imperative that the gap between research findings and clinical practice with regard to neonatal analgesia be addressed.

Opioids and NMDA receptors: Neuro-excitation and abnormal pain behaviours

In the clinical setting, chronic administration of high doses of systemic morphine may result in neuro-excitatory behaviours such as myoclonus and allodynia in some patients. Additionally, high doses of m-opioid agonists such as morphine administered chronically by the intrathecal route in both rats and humans, as well as DAMGO in rats, have been reported to produce neuro-excitatory behaviours. However, more recently, it has begun to be appreciated that even at normal analgesic doses, opioids such as morphine are capable not only of activating pain inhibitory systems (analgesia/antinociception), but they also activate pain facilitatory systems such that post-opioid allodynia/hyperalgesia may be evident after cessation of opioid treatment. Whilst it is well documented that opioid receptors mediate the inhibitory effects of opioid analgesics, the excitatory and pro-nociceptive effects of opioids appear to involve indirect activation of N-methyl-D-aspartate (NMDA) receptors, such that the extent of pain relief produced may be the net effect of these two opposing actions. Apart from the NMDA-nitric oxide (NO) pro-nociceptive signaling cascade, considerable evidence also implicates dynorphin A as well as the endogenous anti-opioid peptides cholecystokinin (CCK), neuropeptide FF (NPFF) and orphanin FQ/nociceptin, in mediating opioid-induced neuro-excitation and abnormal pain behaviours. Apart from the neuro-excitatory effects that may be produced by the parent opioid, systemic administration of some opioid analgesics such as morphine and hydromorphone in rats and humans results in their rapid conversion to 3-glucuronide metabolites that also contribute significantly to the neuro-excitatory and abnormal pain behaviours produced