Continuous intrathecal morphine infusion is used in the control of chronic pain. By histopathology and MRI, we demonstrated that chronic intrathecal infusion of high concentrations of morphine in a well characterized canine model had no effect upon the spinal parenchyma, but led to the concentration and time dependent development of an aseptic granuloma (neutrophils and macrophages) proximal to the catheter tip, arising from the dura-arachnoid layer. Our studies show that granulomas are induced by morphine, hydromorphone, methadone and DAMGO, but not fentanyl. Based on ex vivo and in vivo work, we believe that the granuloma arises from extravasation of inflammatory cells from the meningeal vasculature. Preliminary work suggests that SQ infusion of two different mast cell (MC) stabilizers reduces the incidence of granuloma formation. This work leads to the following hypotheses and proposed work. Hypothesis 1. Meningeal MC degranulation mediates the granuloma produced by intrathecal morphine. We will assess effects on morphine-evoked-granuloma of SQ infusions of agents that block MC degranulation and opiate receptor activation (naloxone). Hypothesis 2. Intrathecal morphine induced MC degranulation leads to a local increase in CSF-MC products and an increased dural influx of vascular cells. We will measure products of MC degranulation in lumbar CSF and influx into dura and CSF of monocytes labeled with 111-Indium using gamma camera scintigraphy under control conditions and with intrathecal morphine. Hypothesis 3. As fentanyl does not produce granulomas or degranulation, other less lipid soluble opiates in this structural series will behave similarly. We will examine effects of alfentanil on ex vivo dural MC degranulation and histamine release and granuloma formation after 28 days of infusion. Hypothesis 4. Clonidine (alpha2 agonist) and midazolam (benzodiazepine) suppress MC activation and this will diminish granuloma formation. We will examine co-delivery of clonidine or midazolam on intrathecal morphine evoked granuloma formation. Hypothesis 5. Granuloma formation requires a minimum morphine concentration for a minimum period of time. Lower concentrations for more extended periods will not lead to granuloma formation. We will use serial MRIs to determine whether a 3-month exposure to a morphine dose having minimum 28-day liability increases the risk of granuloma formation. These studies provide 1) a novel mechanistic explanation for the pathology produced by chronic intrathecal opiates. 2) Measurement of inflammatory products in CSF may provide a differential predictor of granuloma formation. 3) The differential effects of the fentanyl like drugs points to several potential therapies for dealing with this problem. PROJECT NARRATIVE: Continuous spinal infusion of morphine is a powerful tool for controlling chronic pain. However, patients receiving this therapy are at risk for development of a spinal mass (a granuloma), which can compress the spinal cord. The present studies aim to define the mechanisms of granuloma formation and point to specific methods to prevent granuloma formation, which will increase the utility and reduce the risks of this important pain therapy.
Showing the most recent 10 out of 21 publications
