Andreas Sandner-Kiesling

Long-term efficacy and safety of combined prolonged- release oxycodone and naloxone in the management of non-cancer chronic pain

Objective:  The aim of this study was to assess safety and efficacy of fixed combination oxycodone prolonged release (PR)/naloxone PR in terms of both analgesia and improving opioid‐induced bowel dysfunction (OIBD) and associated symptoms, such as opioid‐induced constipation (OIC), in adults with chronic non‐cancer pain.

Effects of acupuncture on the oxygenation of cerebral tissue

Monitoring of regional cerebral oxygen saturation (r. cereb. O2 satn.) was carried out continuously in 12 healthy subjects (mean age 35.2 +/- 4.4 years; range 26-41 years; 4 women, 8 men), prior to, during and following acupuncture. Measurements were obtained with the INVOS 3100 cerebral oximeter (Somanetics Corp., Troy, USA). In addition new robotic transcranial Doppler sonography (TCD) probes enabling three-dimensional imaging of the middle cerebral artery by the use of multi-scan techniques were used simultaneously. The results showed small increases in r. cereb. O2 satn. mean values (69.9% before, 70.3% during and 70.2% after acupuncture) and a significant (p < 0.01; ANOVA, Tukey test) increase in mean bloodflow velocity during acupuncture measured simultaneously at different depths within the right middle cerebral artery. There are reports in the literature about the effects of acupuncture on the oxygenation of cerebral tissue in a study with animals. An increase in the cerebral oxygen saturation could be registered with the help of microelectrodes in the cortex. This is parallel evidence to the present results with near infrared spectroscopy and transcranial Doppler sonography. Quantifiable changes in the physiological effects of acupuncture may contribute to improved acceptance of this unconventional complementary medical procedure.

Estrogen Reduces Efficacy of μ- but Not κ-Opioid Agonist Inhibition in Response to Uterine Cervical Distension

BackgroundAlthough the uterine cervix is a common source of acute and chronic visceral pain in women, there is practically no neurobiological investigation of nociception from this visceral organ. With use of a novel model of uterine cervical distension nociception in rats, the estrogen dependency o

Effect of kappa opioid agonists on visceral nociception induced by uterine cervical distension in rats

&NA; Although uterine distension in rats results in an escape reflex, there exists no model of uterine cervical distension (UCD), the pain stimulus during the first stage of labor. The aims of this study were to develop such a model in virgin rats and to test whether peripherally restricted kappa opioid receptor (KOR) agonists (ADL 10‐0101, ADL 10‐0102, ADL 10‐0116) inhibit responses to UCD. Under intravenous (i.v.) pentobarbital and alpha‐chloralose anesthesia, fine metal rods were inserted in both uterine cervical osses through a small midline laparotomy. UCD was performed by manual separation of the rods (25–100 g). Single‐unit afferent responses in hypogastric nerve or reflex rectus abdominis electromyographic (EMG) activity were determined before and after i.v. KOR agonists. UCD resulted in a stimulus‐dependent increase in single‐unit afferent activity. Units could be characterized as low threshold (mean threshold 6.6±2.7 g), or high threshold (mean threshold 55±8.8 g); all were C fibers, all responded to topical bradykinin. ADL 10‐0116 (10 mg/kg) reduced the afferent response to UCD. Reflex EMG response occurred over a distension force range of 25–100 g, unaffected by i.v. saline. All three KOR agonists produced a dose‐dependent, naloxone‐reversible inhibition of the EMG response with a potency relationship of ADL 10‐0102 (ED50 0.04 mg/kg)>ADL 10‐0101 (ED50 0.65 mg/kg)=ADL 10‐0116 (ED50 0.60 mg/kg). These data support the use of acute UCD as a noxious stimulus, inducing afferent and reflex activity. Like other visceral stimuli, UCD is sensitive to inhibition by KOR agonists.

Preoperative pregabalin administration significantly reduces postoperative opioid consumption and mechanical hyperalgesia after transperitoneal nephrectomy

BACKGROUND Preoperative administration of pregabalin is proposed as a promising way of enhancing postoperative pain control. Whereas a few studies have investigated the effect of pregabalin on postoperative opioid consumption, no study has focused on the influence on postoperative hyperalgesia. In this randomized, triple-blinded, placebo-controlled study, we aimed to demonstrate that a single, preoperative dose of pregabalin reduces postoperative opioid consumption, mechanical hyperalgesia, and pain sensitivity. METHODS Patients undergoing elective transperitoneal nephrectomy received 300 mg pregabalin or placebo 1 h before anaesthesia. After operation, patients received piritramide via a patient-controlled analgesia device. Pain levels and side-effects were documented. The area of hyperalgesia for punctuate mechanical stimuli around the incision was measured 48 h after the operation with a hand-held von Frey filament. Mechanical pain threshold was tested before and 48 h after surgery with von Frey filaments with increasing diameters. RESULTS In each group, 13 patients were recruited. Total piritramide consumption [77 (16) vs 52 (16) mg, P=0.0004] and the normalized area of hyperalgesia [143 (87) vs 84 (54) cm(2), P=0.0497] were significantly decreased in the pregabalin group. There were no significant differences in mechanical pain threshold levels [1.20 (0.56) log(g) vs 1.05 (0.58) log(g), P=0.6738]. No case of severe sedation was reported in both groups. No other side-effects were observed. CONCLUSIONS Our study has shown that preoperative administration of 300 mg pregabalin in patients undergoing transperitoneal nephrectomy reduces postoperative opioid consumption and decreases the area of mechanical hyperalgesia.

Implementation of a standardized pain management in a pediatric surgery unit.

Postoperative pain is still a major complication causing discomfort and significant suffering, especially for children. Therefore, every effort should be made to prevent pain and treat it effectively once it arises. Under-treatment of pediatric pain is often due to a lack of both knowledge about age-specific aspects of physiology and pharmacology and routine pain assessment. Factors for long term success require regularly assessing pain, as routinely as the other vital signs together with documentation of side effects. The fear of side effects mostly prevents the adequate usage of analgesics. Essential is selecting and establishing a simple concept for clinical routine involving a combination of non-pharmacological treatment strategies, non-opioid drugs, opioids and regional anesthesia.

Morphine-induced spinal release of adenosine is reduced in neuropathic rats

Background Spinally administered opioids show decreased potency and efficacy in the treatment of neuropathic pain. As reported previously, morphine stimulates spinal opioid receptors to effect adenosine release, which acts at adenosine receptors to produce analgesia. The authors hypothesized that morphine induces less adenosine release in neuropathic compared with normal rats, explaining its reduced potency and efficacy. Methods Sprague-Dawley rats (200–250 g) were divided into three groups: no surgery (n = 52), sham surgery (n = 20), or left L5 and L6 spinal nerve ligation (n = 64). Two weeks after surgery, mechanical hypersensitivity of the left hind paw was verified. For each experiment, a crude synaptosomal P2 suspension was prepared by homogenizing cervical and lumbar dorsal spinal cord halves from four rats, followed by differential centrifugation, and aliquots incubated with morphine sulfate from 10−8 to 10−4 m alone or in presence of 10−5 m dipyridamole. Extrasynaptosomal concentrations of adenosine were analyzed by high-pressure liquid chromatography. Results Synaptosomal release of adenosine in the absence of morphine was similar between groups. Morphine produced a concentration-dependent adenosine release, which was less in synaptosomes from dorsal lumbar spinal cord in spinal nerve ligation compared with normal or sham animals. This reduction was removed by adding dipyridamole. Conclusion Morphine normally stimulates spinal release of adenosine, a potent antihypersensitivity compound. Because this effect of morphine is diminished in spinal nerve ligation animals, one explanation for decreased efficacy and potency of opioids in the treatment of neuropathic pain may be a dipyridamole-sensitive disruption in the opioid–adenosine link in the spinal cord.

Pharmacology of Opioid Inhibition to Noxious Uterine Cervical Distension

Background Reflex abdominal muscle contraction elicited by colorectal distension in male rats is inhibited by &mgr;- and &kgr;-opioid receptor agonists and sites of action and receptor subtypes have been probed. The authors examined the pharmacology of opioid agonist inhibition in visceral pain related to the uterine cervix, the source of labor pain. Methods Ovariectomized female rats were anesthetized with halothane, and metal rods inserted in the uterine cervix through a small midline laparotomy. After a period of stabilization the cervix was distended by manual separation of the rods, using stimuli of 25–100 g, and reflex rectus abdominis electromyographic activity was recorded. After determining the stimulus response relationship, we tested inhibition of reflex activity by −U50,488 and morphine and their reversal with norbinaltorphimine, or with naltrexone and methyl-naltrexone, respectively. Results Cervical distension produced a stimulus-dependent increase in electromyographic activity, with a threshold of 25 g. Morphine and −U50,488 produced dose-dependent inhibition of the reflex activity. Log linear regression analysis demonstrated an ID50 of 0.03 for morphine, and of 0.05 mg/kg for −U50,488. These effects were reversed by naltrexone, but not by methylnaltrexone or norbinaltorphimine. Conclusions These data suggest that &mgr;- and &kgr;-opioid receptor agonists effectively inhibit responses to acute uterine cervical stimulation. Lack of reversal by norbinaltorphimine further supports evidence of a novel &kgr;-opioid receptor by visceral afferents. Lack of morphine reversal by methylnaltrexone suggests central (spinal or supraspinal) sites of action for inhibition of this visceral noxious stimulus.

Pressor and mesenteric arterial hyporesponsiveness to angiotensin II is an early event in haemorrhagic hypotension in anaesthetised rats

OBJECTIVE Vascular responsiveness to vasoconstrictors is known to be attenuated in haemorrhagic shock. In this study we assessed the temporal development and the underlying mechanisms of haemorrhage-induced vascular hyporeactivity to pressor agents. METHODS In phenobarbital-anaesthetised rats hypotension was induced by graded haemorrhage (8 ml blood total). Sham-manipulated rats served as controls. Blood flow (BF) was recorded with ultrasonic transit time flow probes. RESULTS Following haemorrhage mean arterial pressure (MAP) fell by 25-45 mm Hg and was accompanied by a reduction in mesenteric BF without any alteration of mesenteric vascular conductance (VC). While pressor responses to arginine vasopressin remained unaltered, hyporesponsiveness to phenylephrine (10 nmol kg-1) developed 120-180 min after hypotension had been induced. Pressor and mesenteric constrictor responses to angiotensin II (30 pmol kg-1) became significantly blunted as early as 60 min post haemorrhage. The hypotensive effect of an angiotensin1 receptor antagonist, telmisartan (1 mg kg-1), was likewise blunted 3 h after haemorrhage. Pretreatment with the cyclooxygenase inhibitor indomethacin (10 mg kg-1) exaggerated the hypotensive reaction to haemorrhage but did not prevent the development of angiotensin II hyporesponsiveness. In contrast, the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (10 mg kg-1), as investigated 3 h post haemorrhage, restored the systemic pressor responses to angiotensin II and phenylephrine as well as the mesenteric constrictor responses to phenylephrine to normal level and diminished the mesenteric hyporesponsiveness to angiotensin II. Glibenclamide (20 mg kg-1), an inhibitor of ATP-sensitive K- channels given 180 min post haemorrhage, partially reversed haemorrhage-induced hypotension but did not modify angiotensin II hyporesponsiveness. CONCLUSION Systemic pressor responsiveness and mesenteric arterial reactivity to endogenous and exogenous angiotensin II is selectively impaired at an early stage of haemorrhagic hypotension. This phenomenon partially involves NO and is not related to ATP-sensitive K+ channels.

Perioperative pain therapy in opioid abuse.

Opioid addiction represents an exaggerated organic and psychological comorbidity and should be regarded as a high-risk problem. Particular features seen perioperatively are tolerance, hyperalgesia and higher analgesic requirement together with physical and psychological withdrawal symptoms. Adequate pain management should have a high priority even for these patients. This review deals with the specific problems of addiction or opioid tolerance in this vulnerable patient group in the perioperative period. In this group are opioid-tolerant chronic pain patients on long-term therapy, addicts with long-term substitution therapy, those currently addicted and those with a previous history of addiction, mainly to heroin. This article intends to simplify the management of drug-dependent patients and offers strategies for perioperative analgesia that include stabilisation of physical dependency by substitution with methadone or &mgr;-agonists; avoidance of stress; use of regional techniques in combination with non-opioids or opioids with higher doses than those used in non-addicts; avoidance of inadequate analgesic dosing; effective use of the opioid-sparing effect of different co-analgesics; and psychological support wherever appropriate. Those caring for abstinent patients should note that an inadequate dosage of analgesics can potentially reactivate addiction. After successful withdrawal of opioids and prolonged abstinence, opioid therapy can result in an exaggerated response.