Arner S, Rawal N, Gustafsson LL: Clinical experience of long-term treatment with epidural and intrathecal opioids—A nationwide survey
ABSTRACT Long-term use of spinal opioids to treat chronic severe pain is widely established. However, the indications, shortcomings and complications of the method have not been completely described. Experience with spinal opioids was analysed for the period 1979-1984 in a nationwide Swedish survey. Out of 93 anaesthesia departments, 69 used the method. Approximately 750 patients were treated with epidural morphine for an average duration of 124 days (3-450). Eighteen patients were treated with intrathecal morphine for an average period for 47 days (3-90). The intrathecal approach was used in all clinics because of failure of the epidural route. In only one department was the intrathecal approach used as the primary route of therapy, depending on the mechanism of pain. The highest daily morphine dose was 480 mg and 50 mg for epidural and intrathecal routes, respectively. The patients given the highest dosages were not necessarily those subjected to the longest treatment. The need for increased dosage seems to be related not only to changes in receptor sensitivity but also to changes in pain mechanisms. No case of threatening ventilatory depression was reported. Thirty-two departments had treated a few patients with chronic non-cancer pain conditions. Initial results were considered "excellent" in 11 departments, but at follow-up results were excellent in only one department. In addition to dislocation, occlusion of the catheters or leakage, injection pain was an obstacle to successful treatment. Pruritus urinary retention, and local infections were not reported as significant problems, but one case of meningitis was reported.
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- "Long-term opioid treatment frequently leads to an increased sensitivity to painful (hyperalgesia) and normally innocuous (allodynia) stimuli in humans (Arner et al., 1988; Wanigasekera et al., 2011) and in experimental animals (Vanderah et al., 2001b). It was suggested that long-term opioid-mediated paradoxical pain sensitization may play a role in apparent antinociceptive tolerance (Vanderah et al., 2001a, Ossipov et al., 2005). "
ABSTRACT: Spinal glial activation has been implicated in sustained morphine-mediated paradoxical pain sensitization. Since activation of glial CB2 cannabinoid receptors attenuates spinal glial activation in neuropathies, we hypothesized that CB2 agonists may also attenuate sustained morphine-mediated spinal glial activation and pain sensitization. Our data indicate that co-administration of a CB2-selective agonist (AM 1241) attenuates morphine (intraperitoneal; twice daily; 6 days)-mediated thermal hyperalgesia and tactile allodynia in rats. A CB2 (AM 630) but not a CB1 (AM 251) antagonist mitigated this effect. AM 1241 co-treatment also attenuated spinal astrocyte and microglial marker and pro-inflammatory mediator (IL-1β, TNFα) immunoreactivities in morphine-treated rats, suggesting that CB2 agonists may be useful to prevent the neuroinflammatory consequences of sustained morphine treatment.Journal of neuroimmunology 03/2012; 244(1-2):23-31. DOI:10.1016/j.jneuroim.2011.12.021 · 2.47 Impact Factor
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- "OIH has been observed both clinically ( Angst et al . , 2003 ; Arner et al . , 1988 ; Singla et al . , 2007 ) and experimentally ( Laulin et al . , 1999 ; Woolf , 1981 ) ."
ABSTRACT: Opioids currently represent the best treatment option for severe and chronic pain conditions. Opioids while effective at controlling pain states also come with a number of side effects such as respiratory depression, urinary retention, dependence, tolerance, and opioid-induced hypernociception (OIH). OIH is a phenomenon in which opioids induce pain and this pain is often experienced at a site separate from the site of injury. Much research has been conducted investigating the mechanism of OIH, but the mechanism remains unsolved. One potential mechanism that has yet to be adequately explored is chemokines. Chemokines role in OIH is warranted given recent studies demonstrating the interaction between opioids and chemokines. Chemokines were originally thought to solely function in the immune system, but have recently been found to play a major role in the nervous system, as well as being implicated in a number of different pain models. Therefore, the purpose of these studies was to investigate a possible interaction between opioids and chemokines in the peripheral nervous system and the role this interaction plays in the development and maintenance of OIH. To do this, I tested for changes in expression of SDF1 and CXCR4 signaling in the dorsal root ganglion following repeated morphine administration. Secondly, I investigated if opioid or non-opioid signaling was involved in the development of OIH and which of these receptor signaling cascades was responsible for changes in SDF1/CXCR4 signaling in the dorsal root ganglion. These studies employed the use of a number of different methods including animal behavior, in situ hybridization, immunocytochemistry, and calcium imaging. It was found that SDF1/CXCR4 signaling was indeed increased in OIH and that these changes in SDF1/CXCR4 signaling occur following activation of the mu opioid receptor. Additionally, OIH appears to be induced by both opioid and non-opioid receptor signaling. These results suggest that opioids are inducing a neuroinflammatory process that can be detrimental at anatomical sites separate from an injury. Therefore, to improve the analgesic effectiveness of opioids these off target effects must be considered and new treatments that can bypass these effects should be explored.
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- "Adaptive modifications in cellular responsiveness have been proposed as contributing to tolerance (Taylor and Fleming, 2001). An alternative hypothesis with in vivo evidence in animals (Mao et al., 1995) and in humans (Arner et al., 1988) is that chronic opioid receptor stimulation triggers the activation of anti-opioid systems that reduce sensory thresholds, thereby resulting in hypersensitivity to tactile and noxious thermal stimulation (Simonnet and Rivat, 2003). As a corollary to this hypothesis, such opioid-induced hypersensitivity paradoxically diminishes the net analgesic effect of the opioid agonist (Ossipov et al., 2003; Simonnet and Rivat, 2003). "
ABSTRACT: The clinical efficacy of opiates for pain control is severely limited by analgesic tolerance and hyperalgesia. Herein we show that chronic morphine upregulates both the sphingolipid ceramide in spinal astrocytes and microglia, but not neurons, and spinal sphingosine-1-phosphate (S1P), the end-product of ceramide metabolism. Coadministering morphine with intrathecal administration of pharmacological inhibitors of ceramide and S1P blocked formation of spinal S1P and development of hyperalgesia and tolerance in rats. Our results show that spinally formed S1P signals at least in part by (1) modulating glial function because inhibiting S1P formation blocked increased formation of glial-related proinflammatory cytokines, in particular tumor necrosis factor-α, interleukin-1βα, and interleukin-6, which are known modulators of neuronal excitability, and (2) peroxynitrite-mediated posttranslational nitration and inactivation of glial-related enzymes (glutamine synthetase and the glutamate transporter) known to play critical roles in glutamate neurotransmission. Inhibitors of the ceramide metabolic pathway may have therapeutic potential as adjuncts to opiates in relieving suffering from chronic pain.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2010; 30(46):15400-8. DOI:10.1523/JNEUROSCI.2391-10.2010 · 6.34 Impact Factor