Purely ropivacaine-based TEA vs single TAP block in pain management after elective laparoscopic colon surgery within an upgraded institutional ERAS program.

BACKGROUND: The aim of this study was to compare thoracic epidural analgesia (TEA) with transversus abdominis plane (TAP) block in post-operative pain management after laparoscopic colon surgery. METHODS: One hundred thirty-six patients undergoing laparoscopic colon resection randomly received either TEA or TAP with ropivacaine only. The primary endpoint was opioid requirement up to 48 h postoperatively. Intensity of pain, time to onset of bowel function, time to mobilization, postoperative complications, length of hospital stay, and patients' satisfaction with pain management were also assessed. RESULTS: We observed a significant decrease in opioid consumption on the day of surgery with TEA compared with TAP block (30 mg vs 14 mg, p < 0.001). On the first two postoperative days (POD), the balance shifted to opioid consumption being smaller in the TAP group: on POD 1 (15.2 mg vs 10.6 mg; p = 0.086) and on POD 2 (9.2 mg vs 4.6 mg; p = 0.021). There were no differences in postoperative nausea/vomiting or time to first postoperative bowel movement between the groups. No direct blockade-related complications were observed and the length of stay was similar between TEA and TAP groups. CONCLUSION: TEA is more efficient for acute postoperative pain than TAP block on day of surgery, but not on the first two PODs. No differences in pain management-related complications were detected.

Analgesic Effect of Intraoperative Intravenous S-Ketamine in Opioid-Naïve Patients After Major Lumbar Fusion Surgery Is Temporary and Not Dose-Dependent: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Severe pain often accompanies major spine surgery. Opioids are the cornerstone of postoperative pain management but their use can be limited by numerous side effects. Several studies claim that adjuvant treatment with intravenous (IV) ketamine reduces opioid consumption and pain after back surgery. However, the exact role of ketamine for this indication is yet to be elucidated. We compared 2 different doses of S-ketamine with placebo on postoperative analgesic consumption, pain, and adverse events in adult, opioid-naïve patients after lumbar fusion surgery. METHODS: One hundred ninety-eight opioid-naïve patients undergoing lumbar spinal fusion surgery were recruited to this double-blind trial and randomly assigned into 3 study groups: Group C (placebo) received a preincisional IV bolus of saline (sodium chloride [NaCl] 0.9%) followed by an intraoperative IV infusion of NaCl 0.9%. Both groups K2 and K10 received a preincisional IV bolus of S-ketamine (0.5 mg/kg); in group K2, this was followed by an intraoperative IV infusion of S-ketamine (0.12 mg/kg/h), while in group K10, it was followed by an intraoperative IV infusion of S-ketamine (0.6 mg/kg/h). Postoperative analgesia was achieved by an IV patient-controlled analgesia (IV PCA) device delivering oxycodone. The primary end point was cumulative oxycodone consumption at 48 hours after surgery. The secondary end points included postoperative pain up to 2 years after surgery, adverse events, and level of sedation and confusion in the immediate postoperative period. RESULTS: The median [interquartile range (IQR)] cumulative oxycodone consumption at 48 hours was 154.5 [120] mg for group K2, 160 [109] mg for group K10, and 178.5 [176] mg for group C. The estimated difference was -24 mg between group K2 and group C (97.5% confidence interval [CI], -73.8 to 31.5; P = .170) and -18.5 mg between group K10 and C (97.5% CI, 78.5-29.5; P = .458). There were no significant differences between groups.Postoperative pain scores were significantly lower in both ketamine treatment groups at the fourth postoperative hour but not later during the 2-year study period.The higher ketamine dose was associated with more sedation. Otherwise, differences in the occurrence of adverse events between study groups were nonsignificant. CONCLUSIONS: Neither a 0.12 nor a 0.6 mg/kg/h infusion of intraoperative IV S-ketamine was superior to the placebo in reducing oxycodone consumption at 48 hours after lumbar fusion surgery in an opioid-naïve adult study population. Future studies should assess ketamine's feasibility in specific study populations who most benefit from reduced opioid consumption.

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 microg/10 microL) induced a significantly longer lasting antinociceptive effect compared with oxycodone (200 microg/10 microL) and morphine (1 and 5 microg/10 microL). 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 mu-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.

Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety.

BACKGROUND: Gabapentin and pregabalin have antiallodynic and antihyperalgesic properties useful for treating neuropathic pain. These properties may also be beneficial in acute postoperative pain. In this study we evaluated randomized, controlled trials examining the analgesic efficacy, adverse effects, and clinical value of gabapentinoids in postoperative pain. METHODS: A systematic search of Medline, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL) databases yielded 22 randomized, controlled trials on perioperative administration of gabapentinoids for postoperative pain relief. RESULTS: Pain relief was better in the gabapentin groups compared with the control groups. The opioid-sparing effect during the first 24 h after a single dose of gabapentin 300-1200 mg, administered 1-2 h preoperatively, ranged from 20% to 62%. The combined effect of a single dose of gabapentin was a reduction of opioid consumption equivalent to 30 +/- 4 mg of morphine (mean +/- 95% CI) during the first 24 h after surgery. Metaregression analysis suggested that the gabapentin-induced reduction in the 24-h opioid consumption was not significantly dependent on the gabapentin dose. Gabapentin reduced opioid-related adverse effects, such as nausea, vomiting, and urinary retention (number-needed-to-treat 25, 6, and 7, respectively). The most common adverse effects of the gabapentinoids were sedation and dizziness (number-needed-to-harm 35 and 12, respectively). CONCLUSIONS: Gabapentinoids effectively reduce postoperative pain, opioid consumption, and opioid-related adverse effects after surgery. Conclusions about the optimal dose and duration of the treatment cannot be made because of the heterogeneity of the trials. Studies are needed to determine the long-term benefits, if any, of perioperative gabapentinoids.

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

We studied the effects of the commonly used mu-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 mu-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.

New approach for treatment of prolonged postoperative pain: APS Out-Patient Clinic.

BACKGROUND AND AIMS: Persistent postoperative pain (PPP) is a significant clinical problem. Several patient-related risk factors for PPP have been identified, including a previous chronic pain problem, young age, female gender and psychological vulnerability. Intra- and postoperative risk factors include surgical complications such as infections, haematoma, nerve damage and repeated surgery. As the length of hospital stay has been shortened, some patients may be discharged despite ongoing pain and insufficient analgesic medication. The challenge is to identify patients at high risk of developing PPP and to create a targeted care pathway to ensure effective and safe pain treatment especially in the subacute postoperative phase at home. This observational study describes the first two years of the Acute Pain Service Out-Patient Clinic (APS-OPC) at the Helsinki University Hospital. METHODS: Patient characteristics, known risk factors, and details of treatment of PPP for the first 200 patients referred to our APS-OPC were retrospectively collected from the medical records. The APS-OPC clinic functions in close collaboration with the Multidisciplinary Pain Clinic (MPC), and the number of patients in need of physiotherapist, psychologist or psychiatrist counselling was recorded, as well as the number of patients referred to the MPC for further PPP management. RESULTS: Patients were referred to the APS-OPC from different surgical specialities, the two most common being thoracic and orthopaedic surgery. Seventy per cent of the patients (139/200) presented symptoms indicating neuropathic postsurgical pain. The patients had, on average, five risk factors for PPP. The median time from surgery to the first contact to the APS-OPC was two months, and the median duration of follow-up was 2.8 months (0-16 months). The median number of contacts with APS-OPC was 3 (range 1-14). Every fourth patient needed only one contact to the APS-OPC. Nineteen per cent of the patients had an appointment with the physiotherapist and 20% with a psychologist or psychiatrist. At discharge after surgery, 54% of the patients were using weak opioids, 32% strong opioids and 71% gabapentinoids; at discharge from the APS-OPC, these numbers were 20%, 6% and 43%, respectively. Twenty-two per cent of the patients were referred to the MPC for further pain management. CONCLUSIONS: The APS-OPC provides a fluent fast-track method of ensuring effective multimodal analgesia in the subacute recovery phase after surgery. Even strong opioids can be safely used after discharge and then tapered off in close supervision of the APS-OPC anaesthesiologist. As the APS-OPC was implemented in close collaboration with the MPC, the multidisciplinary resources are easily available during the course of the APS-OPC treatment. IMPLICATIONS: The first two years of the APS-OPC have shown that a significant number of surgical patients benefit from continuing active pain management after discharge from hospital. This fast-track service provides physician-supervised titration of analgesics to improve pain relief in the subacute phase. An important task of the APS-OPC is to ensure that strong opioids are not inappropriately continued after recovery. Another goal of the APS-OPC is to identify patients in need of multidisciplinary pain management services to prevent chronification.

Effects of midazolam in the spinal nerve ligation model of neuropathic pain in rats.

Potential changes in the spinal GABAergic activity after nerve injury were studied by comparing the effects of systemic administration of the benzodiazepine midazolam on the noxious evoked responses of dorsal horn in rats with spinal nerve ligation of neuropathy and control animals. The tight ligation of the L(5) and L6 spinal nerves was performed in adult male Sprague-Dawley rats and resulting mechanical and cold allodynia were assessed with von Frey hairs and the acetone drop test. Single unit extracellular recordings of dorsal horn neurones were performed 15-18 days after the surgery under halothane anaesthesia using transcutaneous electrical stimulation of the receptive field at three times the C-fibre threshold. The rats in the spinal nerve ligation group, but not in the sham-operated control group developed mechanical and cold allodynia. Subcutaneous administration of midazolam 0.1-3.0 mg/kg reduced the Adelta-fibre evoked activity in a dose-related manner in all study groups, but the C-fibre evoked activity was significantly reduced only in the spinal nerve ligation group. The inhibitory effects of s.c. midazolam were significantly reversed by i.t. administration of flumazenil, suggesting a spinal site of action. Midazolam reduced C-fibre evoked firing significantly more in the spinal nerve ligation model than in the non-operated or sham controls. These results indicate changes in the spinal GABAergic system in the neuropathic animals and could be of importance in the development of new treatments for neuropathic pain.

Weight bearing of the limb as a confounding factor in assessment of mechanical allodynia in the rat.

Effect of weight bearing of the hindlimbs on the assessment of mechanically-induced hindlimb withdrawal threshold was determined in intact rats and in rats with various pathophysiological conditions causing allodynia or hyperalgesia. Hindlimb withdrawal was elicited by applying a series of calibrated monofilaments to the plantar or the dorsal surface of the paw. During testing the rat was either in a restraint tube with hindlimbs hanging semi-extended without weight bearing or it was standing on a metal grid (bearing its own weight). In intact rats, the withdrawal thresholds were significantly lower when the stimulus site was the dorsal hairy skin rather than the plantar glabrous skin. Also, thresholds were significantly lower when the hindlimbs were not bearing weight. Following carrageenan-induced unilateral inflammation of the plantar paw or a tibial nerve cut there was a marked threshold decrease to test stimuli applied to plantar or dorsal paw, respectively, ipsilateral to the pathological condition in standing rats. However, when the hindlimbs were not weight bearing the unilateral threshold decrease was markedly attenuated (carrageenan-treated rats) or completely abolished (tibial cut). In contrast, in rats with a unilateral spinal nerve ligation the threshold decrease ipsilateral to the nerve lesion was highly significant independent of the weight bearing of the hindlimbs. The results indicate that weight bearing of hindlimbs is an important confounding factor in the assessment of tactile allodynia in rats.

Cutaneous vascular responses evoked by noxious stimulation in rats with the spinal nerve ligation-induced model of neuropathy.

Antidromic activation of nociceptive nerve fibres innervating the skin produces an axon reflex that involves extravasation and vasodilation of cutaneous blood vessels. We determined whether the axon reflex of the hindlimb skin is influenced by an experimental model of neuropathy induced by unilateral ligation of spinal nerves L(5) and L(6) in the rat. Ligation of spinal nerves induced symptoms mimicking tactile allodynia, as indicated by a marked decrease of the hindlimb withdrawal threshold to mechanical stimulation. The axon reflex induced by antidromic electrical stimulation of nociceptive fibres innervating the plantar skin ipsilateral to the ligation was attenuated according to determination of extravasation response and blood flow response. Lidocaine block or transection of the sciatic nerve of the neuropathic limb did not induce any change in basal blood flow of the plantar skin. The results indicate that ligation of spinal nerves induces an attenuation of the axon reflex. This attenuation reflects a decrease in the efferent function of primary afferent nociceptors innervating the hypersensitive skin of the hindpaw. The attenuation of antidromically-induced vascular responses was not caused by overriding sympathetic activity, as indicated by lack of blood flow effects by lidocaine blocks or a transection of the sciatic nerve.

Sleep and EEG patterns in the chronic constriction injury model of neuropathic pain.

Chronic neuropathic pain patients often report sleep disturbances such as reduced amount of sleep and excessive daytime tiredness. The aim of this study was to evaluate possible abnormalities in sleep patterns in a widely used animal model of neuropathic pain. Adult male Sprague-Dawley rats were chronically implanted with electrodes for electroencephalogram (EEG) and electromyogram (EMG) registrations to allow continuous 24-h polygraphic recording. Subsequently, a chronic constriction injury (CCI) was inflicted on eight rats in accordance with the CCI model of neuropathic pain and a sham operation was performed on another eight rats. The polygraphic recordings were repeated 13, 27, 55, and 146 days after surgery. Although the CCI animals developed significant mechanical and cold allodynia and heat hyperalgesia, there were no significant differences between the CCI rats and the sham-operated control animals in the spontaneous EEG/EMG in homecage-like conditions. It is concluded that in the chronic phase, this neuropathic pain model does not produce clear sleep disturbances. Such an absence of general suffering from sleep disturbances is advantageous to the CCI model as it makes use of the model more acceptable ethically. Nonetheless, this outcome appears to be in contrast with the clinical situation in neuropathic pain and therefore could also be seen as a disadvantage for the face validity of the CCI model.

Functional role of exogenous administration of substance P in chronic constriction injury model of neuropathic pain in gerbils.

Substance P (SP) acts as a transmitter of nociception in both the peripheral and the central nervous system. Because the NK-1 receptors in gerbils are comparable to those in humans, gerbil models could be used to study the role of SP in neuropathic pain. A modification of the rat chronic constriction injury (CCI) model of neuropathic pain was produced in male gerbils by placing four loose chromic catgut ligatures around the sciatic nerve. This procedure clearly resulted in mechanical hypersensitivity. Intraplantar injections of SP and the selective NK-1 receptor agonist, [Sar(9)-Met(O(2))(11)]-substance P (Sar-SP), to the paw ipsilateral to the nerve injury and intrathecal administration of these peptides produced paw-lifting behavior in the CCI gerbils in thermoneutral conditions. In sham-operated and nonoperated controls, no such effects were observed. Systemic administration of the NK-1 antagonist R116301 attenuated the SP and the Sar-SP-induced paw-lifting behavior in the CCI gerbils indicating the role of NK-1 receptors in these effects. Intraplantar injection of the highest dose of SP (200 ng) to the paw contralateral to the CCI produced lifting of the paw ipsilateral to the injury, indicative for spinal mechanisms especially since administration of SP to the ipsilateral front paw or even intracardially did not have any effect at all. The SP-induced responses were not antagonized by the NMDA antagonist MK801. These results indicate that the peripheral and spinal SP reveal an increased reactivity in a neuropathic pain model. This increased pain sensitivity seems to involve spinal NK-1 mechanisms.

Does the pharmacology of oxycodone justify its increasing use as an analgesic?

Oxycodone is a semisynthetic opioid analgesic that is increasingly used for the treatment of acute, cancer, and chronic non-malignant pain. Oxycodone was synthesized in 1917 but its pharmacological properties were not thoroughly studied until recently. Oxycodone is a fairly selective µ-opioid receptor agonist, but there is a striking discrepancy between the relatively low binding potential and G protein activation by oxycodone and its analgesic efficacy. It has been claimed that this is because of active metabolites and enhanced passage to the central nervous system by active transport. We critically review studies on the basic pharmacology of oxycodone and on its pharmacokinetics and pharmacodynamics in humans. In particular, the role of pharmacogenomics and population pharmacokinetics in understanding the properties of oxycodone is discussed in detail. We compare oxycodone with morphine, the standard opioid in clinical use.

Randomized clinical trial comparing ambulatory and inpatient care after inguinal hernia repair in patients aged 65 years or older.

BACKGROUND: There is a lack of evidence from randomized studies of the feasibility of ambulatory surgery in patients aged 65 years and older. METHODS: Medically stable patients scheduled for open inguinal hernia repair, with postoperative care available at home, were randomized to receive treatment either as outpatients or inpatients. Younger patients undergoing the same procedure served as a reference group. Outcome measures during the 2 weeks after surgery were complications, unplanned admissions, visits to the hospital, unplanned visits to primary health care, and patients' acceptance of the type of provided care. RESULTS: Of 151 patients, 89 were included. Main reasons for exclusion were lack of postoperative company (16%), unwillingness to participate (13%), and medical conditions (10%). All outpatients were discharged home as planned, and none of the study patients were readmitted to the hospital. Patient satisfaction was high with no differences between the groups. CONCLUSIONS: Ambulatory surgery was safe and well accepted by older, medically stable patients.

Nitecapone reduces development and symptoms of neuropathic pain after spinal nerve ligation in rats.

Neuropathic pain is caused by damage or malfunctioning of the nervous system. It is fairly common and more resistant to treatment than other types of pain. Since nitecapone, an inhibitor of catechol-O-methyl-transferase (COMT), has decreased neuropathic symptoms in diabetic rats, we studied its effects in another model of neuropathic pain, the spinal nerve ligation (SNL) model. Spinal nerves L5-6 were ligated in male Wistar rats under anaesthesia to produce the SNL model of neuropathic pain. Nitecapone (30 mg/kg, i.p.) or vehicle was administered once daily starting either 1h before or 2 days after surgery and continued for 14-19 days. Threshold for mechanical allodynia was measured with the digital von Frey test and responses to cold stimuli with the acetone test, before surgery and every other day after it 1h before drug administration. Mechanical and cold allodynia developed in all study groups. Both nitecapone treatments significantly reduced mechanical allodynia and withdrawal thresholds were 80-95% higher compared with the control group. In the acetone test, both nitecapone groups also showed less signs of cold allodynia than the control groups. In nitecapone-naïve animals a single dose of nitecapone also reduced mechanical allodynia on the 14th day after the surgery. Nitecapone reduced the symptoms of neuropathic pain after the SNL, which is in line with the earlier study. Our results suggest that nitecapone and other COMT inhibitors should be studied further in the treatment of neuropathic pain.

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.

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. Mu-opioid receptor agonist-stimulated GTPgamma[S] 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 kappa-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 GTPgamma[S] 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 mu-opioid receptor activation in the spinal cord.