Intrathecal Analgesia and Catheter-tip Inflammatory Masses (2003)

University of Iowa Hospitals and Clinics, Iowa City, Iowa. kenneth-follett@uiowa.eduThe advent of intrathecal analgesic therapy, which involves delivery of analgesic agents directly into the spinal fluid via implanted infusion pump, has revolutionized the treatment of chronic pain. Compared to other routes of drug delivery, intrathecal administration offers the relative advantages of greater efficacy and fewer adverse effects. Compared to most interventional, ablative approaches to pain management, this nondestructive, reversible, adjustable therapy is generally very safe. However, as occurs with the maturation of many innovations in medical care, growing experience has revealed that this therapy is not without complications. One of the most potentially serious complications is the formation of an inflammatory mass at the tip of the intrathecal catheter placed to deliver analgesic agents. This issue of Anesthesiology includes two articles authored by leaders in the field of intrathecal analgesia, who provide valuable insights into the formation of catheter tip inflammatory masses (“granulomas”). 1,2The phenomenon of intrathecal granuloma associated with intrathecal analgesic administration was first described in 1991 in a case report of a patient who presented with paralysis caused by an intrathecal mass that compressed and damaged the spinal cord. 3Since then, dozens of granulomas have been reported, and there is growing awareness of the causal relationship between intrathecal analgesic administration and the formation of inflammatory masses at the catheter tip. Despite growing recognition of the problem, we understand relatively little about the causes of granulomas; consequently, we do not know how best to treat or prevent these mass lesions.Why do we need to understand the pathophysiology of catheter-tip inflammatory masses? At the very least, granulomas can result in loss of pain relief for affected patients. More important, they may cause neurologic deficit, including myelopathy and paralysis, which may not improve despite aggressive treatment. Loss of pain relief, neurologic injury, and the need for medical and/or surgical treatment of the intrathecal mass result in personal and economic loss that compromise the utility of this pain therapy.Approximately 92 cases of catheter-tip inflammatory masses have been reported on a voluntary basis in the literature, to manufacturers of the infusion pumps, and to the U.S. Food and Drug Administration. 4On the basis of the number of pumps implanted, the incidence of granuloma formation is estimated to be 0.04% after 1 yr of therapy, increasing to 1.15% after 6 yr of therapy. 4These figures undoubtedly underestimate the true incidence, because voluntary reporting probably reveals only a small fraction of the total number of granulomas. The number of patients developing granulomas is almost certain to increase during the coming years. The annual rate of growth of number of pumps implanted each year for the treatment of chronic pain is approximately 12% (Robert Coffey, M.D., Medtronic, Inc., Minneapolis, Minnesota, verbal communication). In contrast to the early days of intrathecal analgesic therapy, when this modality was restricted generally to the treatment of pain in cancer patients with relatively short life expectancies, intrathecal analgesic therapy is currently used most often for the treatment of chronic noncancer pain in patients with relatively long life expectancies, and these individuals may receive intrathecal drugs for long periods of time. Thus, an ever-increasing number of patients will be exposed to intrathecal analgesics for increasingly greater lengths of time; the number of patients developing granulomas is expected to rise accordingly.In this issue, Gradert et al. 2and Yaksh et al. 1describe the formation of intrathecal granulomas in sheep and dog models, respectively. These two reports provide, for the first time, detailed information about the development of these lesions, the factors associated with their development, and a possible explanation of the pathophysiology of granulomas. The results described in these articles correspond to descriptions of granulomas in humans, with the exception of the more rapid time course of granuloma formation (within 4 weeks) in the animal models. Granulomas have been reported to occur in humans within several weeks after initiation of therapy but in general do not occur until months or years of therapy have elapsed. 4Despite this difference, the models described by Yaksh and Gradert provide a means for us to understand the etiology of these inflammatory masses, which will enable us to develop effective strategies to treat them and, ideally, minimize or eliminate their occurrence.As reported in these two articles, these intraspinal lesions are inflammatory masses that develop in response to the intrathecal administration of opioid agents, perhaps mediated via immune responses. Granulomas have not been reported to occur as a result of intrathecal infusion of nonopioid agents such as baclofen. Clinical data and the research reports within this volume of the journal indicate that granulomas occur at higher rather than lower doses and concentrations of opioid. Unfortunately, neither the articles presented here nor clinical data provide insight into whether opioid concentration or total dose is more (or equally) important in the genesis of granulomas. Particularly intriguing is the observation by Yaksh et al. that a nonopioid agent (clonidine) delivered concurrently with opioid might have a protective effect.The information provided by these two sets of authors has significant implications for the management of patients receiving intrathecal analgesics. The results support recommendations published recently in an effort to increase awareness of intrathecal granulomas and their treatment and prevention. 4,5In particular, the findings reported by Gradert et al. and Yaksh et al. support the consensus recommendations 4,5that the total daily dose and the concentration of intrathecal opioid should be kept as low as possible to reduce the likelihood of granuloma formation.What are the important messages associated with the articles published here? First, catheter-tip inflammatory masses are a potentially serious complication. Given the adverse impact of granuloma formation on the success of intrathecal analgesic therapy (including the potential for permanent neurologic injury), we must understand the pathophysiology of intrathecal granulomas and work toward eliminating them as a complication of therapy. We can accomplish this with good-quality basic science investigations, such as those published in this issue, combined with clinical observations. Second, granulomas may become more common as physicians who manage intrathecal analgesic infusions become more aggressive with the therapy, administering higher doses, which require higher concentrations, and for longer durations. Third, physicians who manage patients receiving intrathecal analgesics must be highly aware of the possible development of intrathecal granulomas and must perform regular surveillance of their patients to detect these masses early, before serious complications arise. Patients who are suspected of harboring intrathecal granulomas must be evaluated and treated promptly to minimize the possibility of permanent neurologic deficit.Intrathecal therapy has been a tremendous advancement in the field of pain management. Yaksh et al. and Gradert et al. are to be commended for their attention to the complication of intrathecal catheter-tip inflammatory masses. Their work, and future efforts directed toward determining the causes, treatment, and prevention of this disorder, will allow physicians to offer this therapy with greater confidence in its ability to provide safe and effective pain relief.