JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (26) Citing Articles via Google Scholar Google Scholar Articles by McMillan, M. R. Articles by Nugent, W. Search for Related Content PubMed PubMed Citation Articles by McMillan, M. R. Articles by Nugent, W. Related Collections Equipment Pain

---

PAIN MEDICINE

Catheter-Associated Masses in Patients Receiving Intrathecal Analgesic Therapy

Foothills Regional Pain Center and Mountainview Medical Imaging, Seneca, South Carolina

Address correspondence and reprint requests to Marion R. McMillan, MD, Foothills Regional Pain Center, 457 Sandifer Blvd., Seneca, SC 29678. Address e-mail to marionmc{at}worldnet.att.net

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
A cohort of seven patients receiving intrathecal analgesic drug therapy for chronic intractable pain underwent radiocontrast myelography and computed tomography (CT) scanning to screen for catheter-associated intrathecal masses. Three of seven patients examined had intraspinal masses associated with the tip of the drug infusion catheter after a total of 118 mo of therapy. The index case presented with exacerbation of neuropathic pain and paralysis of the left lower extremity. The two additional cases detected by CT myelography were asymptomatic at the time the catheter-associated mass was assessed. The mean duration of therapy before diagnosis of the catheter-associated mass was 19.6 mo, with a range of 16–25 mo. An intergroup comparison of demographic and treatment variables between patients, with and without catheter-associated masses, demonstrated that patients with masses were younger and were receiving a larger morphine dose than patients without masses. The differences were statistically significant (P = 0.05). In one patient with an asymptomatic catheter-associated intrathecal mass, regression of the mass was observed after cessation of therapy. In a second asymptomatic patient, the mass remained stable over 1 yr of continued treatment after substitution of hydromorphone for morphine without interruption of therapy. Neither asymptomatic patient has subsequently developed additional neurologic findings or injury after detection of occult catheter-associated intrathecal masses and clinical intervention. We suggest that all patients receiving long-term intrathecal analgesia should undergo periodic radiographic surveillance to further define their risk of developing occult catheter-associated masses and to allow intervention before neurologic injury can develop.

IMPLICATIONS: Catheter-associated intrathecal masses were detected in three of seven patients receiving long-term intrathecal analgesia. In the two asymptomatic patients, timely clinical intervention was associated with the avoidance of subsequent neurologic injury and spontaneous resolution of one of the occult masses.

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
The efficacy of intraspinal drug infusion for the treatment of a variety of chronic painful conditions is now well established (1–4). Initial enthusiasm for the broad application of this therapy has been dampened by the risk of neurologic injury caused by the development of catheter-associated intraspinal masses associated with the tips of spinal infusion catheters in some patients (5–10). Cases reported in the literature have occurred in patients receiving commercially prepared preservative-free morphine sulfate alone, as well as formulations of hydromorphone and morphine sulfate alone or in combinations with other analgesics and local anesthetics prepared by compounding pharmacies. An increasing number of analgesic substances have been used in individual patients with varying degrees of success (11–13). The situation is further complicated by the fact that commercially prepared preservative-free morphine sulfate is the only drug currently approved by the Food and Drug Administration (FDA) for long-term analgesia via implanted intrathecal drug delivery systems.

The exact incidence and prevalence of this complication is unknown but is estimated to range from approximately one intrathecal mass per 1000 patients (14) to as many as three intrathecal masses of a cohort of 60 patients screened for the presence of inflammatory mass by Blount et al (7). We report our recent experience with a cohort of seven patients receiving long-term intrathecal analgesic therapy with preservative-free morphine sulfate and fentanyl citrate, with and without the addition of preservative-free bupivacaine, complicated by the discovery of a symptomatic catheter-associated intrathecal mass in one patient and the subsequent discovery of occult catheter-associated masses in two additional asymptomatic patients identified by radiographic surveillance with computed tomography (CT) myelography. We also report the regression of a catheter-associated mass after complete cessation of intrathecal infusion without catheter removal, as well as stability of a second catheter-associated mass during continued intrathecal drug therapy after opioid substitution without the development of neurologic injury. Pertinent literature and recommendations for management of patients being treated with implanted analgesic drug delivery systems are discussed.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
The first occurrence of a catheter-associated intrathecal mass in our practice was documented in March 2001. All patients then receiving intrathecal drug therapy were being treated with reconstituted crystalline preservative-free morphine sulfate or fentanyl citrate in saline, with (n = 5) or without (n = 2) the addition of preservative-free bupivacaine. All patients were treated with programmable Medtronic Synchro-Med^® intrathecal pumps (Medtronic, Minneapolis, MN) and In-Dura^® one- or two-piece intrathecal catheters. Morphine and fentanyl solutions were compounded by an independent pharmacy in varying concentrations to allow the effective analgesic dose to be delivered with the maximum time between pump refills, which are recommended not to exceed 3 mo by the pump manufacturer. The range of concentrations and composition of the infusions as well as the clinical and demographic characteristics of the patients are listed in Table 1.

Statistical analyses were conducted using the Mann-Whitney U-statistic for intergroup differences in age, duration of therapy (at the time of radiographic surveillance), drug dose, and concentration among patients with and without catheter-associated masses. P values less than or equal to 0.05 were considered significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Table 1 shows the demographic and treatment characteristics of all seven patients in the study group, including those without (Group A) and with (Group B) catheter-associated masses. Table 2 shows intergroup comparisons with regard to treatment variables between patients with and without catheter-associated intrathecal masses.

The patients with catheter-associated masses had variable clinical presentations. Patient 5 had been previously treated with a spinal cord stimulator that had become ineffective and left in place before the start of intrathecal therapy. She was completely asymptomatic and receiving excellent analgesia at the time of diagnosis of the mass. She elected to continue intrathecal therapy with a different opioid and was treated with a continuous infusion of hydromorphone in bupivacaine without any interruption of therapy. Patient 6 required emergency decompression laminectomy for symptoms of spinal cord compression and has suffered permanent functional left lower-extremity paresis. Cultures of her pump contents and pathology specimens were sterile. Patient 7 was asymptomatic at the time of detection of the mass. She elected to discontinue intrathecal therapy with removal of the intrathecal pump, leaving the intrathecal catheter in place.

Repeat CT-myelograms at 6 mo in Patient 7 and at 6 and 12 mo in Patient 5 have documented spontaneous regression of the catheter-associated mass in Patient 7 and no progression of the size of the mass in Patient 5. Neither patient has developed additional treatment-related complications or neurologic impairment.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Our data confirm the development of catheter-associated masses in patients receiving long-term intrathecal analgesic drug therapy reported in the literature (5–10). Despite the unexpected finding of occult and symptomatic masses in three of seven patients after only 118 total months of therapy, the small size of our study precludes extrapolation of the risk of catheter-associated masses in a larger population of similar patients receiving intrathecal analgesic therapy. No reported series have documented the actual prevalence or incidence of catheter-associated masses in a cohort of patients at risk. Such estimates would require that sufficient numbers of patients receiving intrathecal analgesic therapy be evaluated by screening tests with appropriate sensitivity and specificity to detect these lesions. In our study, the mean duration of therapy when catheter-associated masses were detected was 19.6 months, with a range of 16–25 months. Given the limitations of our study design, these lesions may have been present earlier than they were detected. We have confirmed that clinical evaluation based solely on the development of neurologic symptoms or decreasing analgesic efficacy alone in the absence of specific imaging studies lacks sufficient sensitivity to exclude the presence of catheter-associated masses. These lesions may present with acute spinal cord compression and be associated with permanent neurologic sequelae, as documented previously, or be completely asymptomatic. Patients developing catheter-associated masses were younger and received a larger daily dose of morphine than patients without these masses. Likewise, the delivered concentration of morphine tended to be larger in patients developing intrathecal masses, and either may be causally related to the development of a catheter-associated mass (9,10). Although morphine concentration was not found to be significantly larger in our patients developing catheter-associated masses, the small sample size of our study lacks sufficient statistical power to exclude such an association.

The morphine concentrations were chosen to maximize the time between pump refills to approach the three-month limit allowed by the pump manufacturer. In our series, catheter-associated intraspinal masses were shown by serial CT myelograms to be reversible or nonprogressive and unassociated with subsequent neurologic injury in two patients after clinical interventions that left the intrathecal catheters intact. In this regard, our observations are similar to those of Cabbell et al. (9) who documented recurrence of a catheter-associated mass on morphine re-challenge in one patient followed by spontaneous regression during substitution of saline for morphine infusion for a period of 2 months. Patient 5 was able to continue effective intrathecal therapy after substitution of hydromorphone for morphine during continued use of bupivacaine. This provides additional evidence for a direct effect of the infused analgesic solution and argues further against a causative role for the intrathecal catheter (5,9) in the development of these lesions. We did not routinely obtain bacterial cultures of pump contents in any of our patients developing catheter-associated masses, with the exception of Patient 6 whose cultures demonstrated no bacterial growth. The possibility of occult infections cannot be excluded, but documented stability of a catheter-associated mass with continued intrathecal therapy in the absence of antibiotics in Patient 5 argues against this possibility.

The reasons for the development of catheter-associated masses in patients receiving long-term intrathecal analgesic therapy are unclear, and many potential causes have been considered in the literature. These have included previous anatomic damage to neural tissues possibly predisposing to analgesic toxicity, catheter tip configuration (5), characteristics of the drug itself, including dose and/or concentration (5,9), infection and/or hypersensitivity reactions (5,7), previous or simultaneous exposure to other intraspinal devices such as spinal cord stimulators (6), and regional cerebrospinal fluid flow dynamics (10). Catheter-associated masses previously reported in the literature have occurred in patients receiving morphine sulfate as well as hydromorphone alone or in various combinations with local anesthetics and other substances at the time of discovery of the mass. Coffey and Burchiel (10) recently analyzed a series of 41 such patients reported in the literature and to the FDA as of November 30, 2000 with catheter-associated masses. Within the limitations of voluntary case reporting, some useful associations were found. Thirty-nine of 41 patients with catheter-associated masses were receiving morphine and hydromorphone alone or in various combinations. They noted a median duration of therapy at the time of detection of the mass of 24 months, similar to the mean duration of therapy of 19.6 months found in our patients. They further implicate drug concentration and dose as potential causative factors in the formation of catheter-associated masses, which is similar to our data demonstrating a statistically significant larger morphine dose and younger age in patients developing these lesions. Despite the association of larger morphine doses with the formation of catheter-associated masses, Coffey and Burchiel (10) also found that fully 33% of the 18 patients receiving morphine for which dose information was available were receiving <10 mg/d, and 36% of 11 patients for which concentration data were available were receiving a concentration <25 mg/mL. The potentially devastating consequences of neurologic injury caused by these lesions are demonstrated by Patient 6, as well as by these investigators, in that 73% of patients with catheter-associated masses underwent surgery to remove or alleviate the effects of the mass, and 27% were nonambulatory at last follow-up.

The fact that catheter-associated mass lesions reported in the literature (5–9) as well as in our patients have been universally located at the catheter tip, rather than along its length, the absence of similar reports in patients receiving intrathecal baclofen and confirmation of mass regression or stability associated with discontinuation of morphine infusion leaving the intraspinal catheter intact in Patient 7, as well as substitution of saline (9) or another opioid for morphine in Patient 5, again suggest a causative role for the infused substances themselves in the pathogenesis of these lesions. Currently, baclofen and commercially prepared preservative-free morphine sulfate are the only two drugs recommended by the pump manufacturer or approved by the FDA for long-term use in implanted intrathecal drug delivery systems. The relentless development of tolerance and dosage escalation and the eventual diminution of analgesic effectiveness will result in exposure of increasing numbers of patients to ever larger analgesic concentrations and dosages. On the basis of our findings and those of others, we believe that other opioid and non-opioid analgesics, specifically including hydromorphone, local anesthetics, and clonidine, as well as the various congeners of fentanyl, should be evaluated and approved for long-term intrathecal use as an alternative to currently approved drugs (13).

The number of catheter-associated masses in our series of patients seems larger than that suggested by the pump manufacturer (14) and reported by previous authors (7,9,15), and the reasons for this discrepancy are currently unclear. In their report, Blount et al. (7) describe three patients receiving intrathecal morphine therapy that developed catheter-associated masses and subsequently performed screening magnetic resonance imaging (MRI) examinations on a cohort of 60 other patients receiving intrathecal therapy, finding no additional mass lesions. The details of drug concentration and dosage regimens were not specified. Reporting bias based on the requirement of new neurologic symptoms or decreasing analgesic efficacy to trigger diagnostic radiographic studies may result in systematic underreporting of this complication in other series. Alternatively, analgesic composition used in our patients including concomitant use of bupivacaine, morphine dose and/or concentration, patient-related factors, or other yet unknown factors may also be responsible. Two of the three patients in our series who developed catheter-associated masses underwent implantation because of complications of postlaminectomy syndrome with intractable back and leg pain similar to those of the other series referenced above. It is also possible that a systemic problem relating to the solutions prepared by our independent compounding pharmacy may explain the clustering of cases that we observed in our patients.

We have confirmed that CT myelography is an effective tool for the early detection of catheter-associated masses to allow time for the institution of protective countermeasures before the development of serious neurologic injury. Radiographic screening using MRI has been suggested by others (9) but is not yet widely practiced for many reasons, including cost. CT myelography was chosen by our group because of local availability and decreased cost compared with MRI and served us well. Until further comparative data are available, we believe that either is appropriate for patient evaluation. Despite the currently unknown risk of catheter-associated masses, we believe that the potentially devastating neurologic consequences of this complication and the ability to prevent progression of these masses and neurologic injury by early recognition and noninvasive intervention support the recommendation that all patients receiving intrathecal analgesic therapy should receive annual screening by CT myelography or MRI until further definitive data are available. We further suggest that additional analgesic drugs and combinations be evaluated and developed to manage tolerance and loss of efficacy in individual patients. On the basis of limited observations in our patients and by others, we believe it is safe to continue effective intrathecal opioid therapy without interruption in patients developing asymptomatic or minimally symptomatic catheter-associated intrathecal masses by changing to a different opioid drug. Alternatively, we suggest that intrathecal therapy may be safely discontinued without catheter explanation or surgery by substitution of saline infusion, or discontinuation of infusion altogether, with close neurologic monitoring. In patients with catheter-associated masses who elect to continue therapy, we consider regular clinical evaluation combined with screening CT myelography or MRI every six months for one year and annually thereafter to be a prudent, cost-effective option for continuing patient management.

	Acknowledgments

 
We gratefully acknowledge the cooperation of our patients and their families, as well as the technical assistance of our friends and colleagues at Mountainview Medical Imaging, Seneca, SC, without whose help and support this manuscript would not have been possible.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Coombs DW, Saunders RL, Gaylor MS, et al. Relief of continuous chronic pain by intraspinal narcotics infusion via an implanted reservoir. JAMA 1983; 250: 2336–9.[Abstract/Free Full Text]
2. Onofrio BM, Yaksh TL. Long-term pain relief produced by intrathecal morphine infusion in 53 patients. J Neurosurg 1990; 72: 200–9.[Web of Science][Medline]
3. Van Dongen RTM, Crul BJP, De Bock M. Long-term intrathecal infusion of morphine and morphine/bupivacaine mixtures in the treatment of cancer pain: a retrospective analysis of 51 cases. Pain 1993; 55: 119–23.[Web of Science][Medline]
4. Hassenbusch SJ, Stanton-Hicks M, Covington EC, et al. Long-term intraspinal infusions of opioids in the treatment of neuropathic pain. J Pain Symptom Manage 1995; 10: 527–43.[Web of Science][Medline]
5. North RB, Cutchis PT, Epstein JA, Long DM. Spinal cord compression complicating subarachnoid infusion of morphine: case report and laboratory experience. Neurosurgery 1991; 29: 778–84.[Web of Science][Medline]
6. Aldrete JA, Vascello LA, Ghaly R, Tomlin D. Paraplegia in a patient with an intrathecal catheter and a spinal cord stimulator. Anesthesiology 1994; 81: 1542–5.[Web of Science][Medline]
7. Blount JP, Remley KB, Yue SK, Erickson DL. Intrathecal granuloma complicating chronic spinal infusion of morphine: report of three cases. J Neurosurg 1996; 84: 272–6.[Web of Science][Medline]
8. Bejjani GK, Karim NO, Tzortzidis F. Intrathecal granuloma after implantation of a morphine pump: case report and review of the literature. Surg Neurol 1997; 48: 288–91.[Web of Science][Medline]
9. Cabbell KL, Taren JA, Sagher O. Spinal cord compression by catheter granulomas in high-dose intrathecal morphine therapy: case report. Neurosurgery 1998; 42: 1176–81.[Web of Science][Medline]
10. Coffey RJ, Burchiel K. Inflammatory mass lesions associated with intrathecal drug infusion catheters: report and observations on 41 patients. Neurosurgery 2002; 50: 78–87.[Web of Science][Medline]
11. Winkelmuller M, Winkelmuller W. Long-term effects of continuous intrathecal opioid treatment in chronic pain of non-malignant etiology. J Neurosurg 1996; 85: 458–67.[Medline]
12. Siddall PJ, Molloy AR, Walker S, et al. Efficacy of intrathecal morphine and clonidine in the treatment of pain following spinal cord injury. Anesth Analg 2000; 91: 1493–8.[Abstract/Free Full Text]
13. Cousins MJ, Walker SM, Goudas LC, Carr DB. Spinal opioid and non-opioid drugs. IARS 2002 Review Course Lectures (Supplement to Anesth Analg), March 2002:38–44.
14. Medtronic Corporation [manufacturer’s bulletin]. Implanting physician advisory: Important message regarding the occurrence of inflammatory masses at the tip of intraspinal catheters. January 19, 2001.
15. Schuchard M, Lanning R, North RB, et al. Neurologic sequelae of intraspinal drug delivery systems: results of a survey of American implanters of implantable drug delivery systems. Neuromodulation 1998; 1: 137–48.

This article has been cited by other articles:

				P. K. Singh, R. Jain, S. Mishra, S. Kumar, S. Bhatnagar, and S. Deo Management of Pericatheter Cerebrospinal Fluid Leak After Intrathecal Implantation of a Drug Delivery System American Journal of Hospice and Palliative Medicine, June 1, 2008; 25(3): 237 - 239. [Abstract] [PDF]

				V. L. Ghafoor, M. Epshteyn, G. H. Carlson, D. M. Terhaar, O. Charry, and P. K. Phelps Intrathecal drug therapy for long-term pain management Am. J. Health Syst. Pharm., December 1, 2007; 64(23): 2447 - 2461. [Abstract] [Full Text] [PDF]

				J. A. Phillips, E. J. Escott, J. J. Moossy, and H. C. Kellermier Imaging Appearance of Intrathecal Catheter Tip Granulomas: Report of Three Cases and Review of the Literature Am. J. Roentgenol., December 1, 2007; 189(6): W375 - W381. [Abstract] [Full Text] [PDF]

				G. Meta, A. Ghaleb, W. B. Gentry, and J. Firnhaber Intrathecal therapy-associated masses. Anesth. Analg., July 1, 2006; 103(1): 260 - 261. [Full Text] [PDF]

				P. M. Murphy, D. E. Skouvaklis, R. J.J. Amadeo, C. Haberman, D. H. Brazier, and M. J. Cousins Intrathecal catheter granuloma associated with isolated baclofen infusion. Anesth. Analg., March 1, 2006; 102(3): 848 - 852. [Abstract] [Full Text] [PDF]

				I. Ikushima, T. Hirai, Y. Korogi, M. Norio, M. Koganemaru, R. Suga, S. Morishita, and Y. Yamashita Spinal MR Findings in Continuous Epidural Analgesia without Infection AJNR Am. J. Neuroradiol., May 1, 2005; 26(5): 991 - 995. [Abstract] [Full Text] [PDF]

				L. Baker, M. Lee, C. Regnard, L. Crack, and S. Callin Evolving spinal analgesia practice in palliative care Palliative Medicine, September 1, 2004; 18(6): 507 - 515. [Abstract] [PDF]

				A. P. Gulve, S. Eldabe, J. Richardson, I. Rice, and M. Y. K Wee Obstetric epidural and chronic adhesive arachnoiditis Br. J. Anaesth., May 1, 2004; 92(5): 765 - 767. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (26) Citing Articles via Google Scholar Google Scholar Articles by McMillan, M. R. Articles by Nugent, W. Search for Related Content PubMed PubMed Citation Articles by McMillan, M. R. Articles by Nugent, W. Related Collections Equipment Pain

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999