polyanalgesic consensus conference—2012: consensus on diagnosis, detection, and treatment of...

Polyanalgesic Consensus Conference—2012:Consensus on Diagnosis, Detection, andTreatment of Catheter-Tip Granulomas(Inflammatory Masses)Timothy R. Deer, MD1, Joshua Prager, MD2, Robert Levy, MD, PhD3,James Rathmell, MD4, Eric Buchser, MD5, Allen Burton, MD6,David Caraway, MD, PhD7, Michael Cousins, MD8, José De Andrés, MD, PhD9,Sudhir Diwan, MD10, Michael Erdek, MD11, Eric Grigsby, MD12,Marc Huntoon, MD, PhD13, Marilyn S. Jacobs, PhD2, Philip Kim, MD14,Krishna Kumar, MD15, Michael Leong, MD16, Liong Liem, MD17,Gladstone C. McDowell, II, MD18, Sunil Panchal, MD19, Richard Rauck, MD20,Michael Saulino, MD, PhD21, B. Todd Sitzman, MD, MPH22, Peter Staats, MD23,Michael Stanton-Hicks, MD, PhD24, Lisa Stearns, MD25, Mark Wallace, MD26,K. Dean Willis, MD27, William Witt, MD28, Tony Yaksh, PhD26,Nagy Mekhail, MD, PhD24

Address correspondence to: Timothy Deer, MD, Center for Pain Relief, 400 Court Street, Suite 100, Charleston, WV 25301, USA. Email: [email protected]

1Center for Pain Relief, Charleston, WV, USA;2University of California—Los Angeles, Los Angeles, CA, USA;3University of Florida, Jacksonville, FL, USA;4Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA;5Anaesthesia and Pain Management Department, EHC-Hospital, Morges & CHUV University Hospital, Lausanne, Switzerland;6Houston Pain Associates, LLC, Houston, TX, USA;7Center for Pain Relief, Tri-State, Huntington, WV, USA;8Kolling Institute of Medical Research at the Royal North Shore Hospital Sydney, NSW, Australia;9Valencia University School of Medicine and General University Hospital, Valencia, Spain;10SUNY Downstate Medical Center, Staten Island University Hospital, New York, NY, USA;11Departments of Anesthesiology, Critical Care Medicine and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;12Napa Pain Institute and Neurovations Clinical Research and Education, Napa, California, USA;13Vanderbilt University, Nashville, TN, USA;14Christiana Hospital, Newark, DE, USA and Bryn Mawr Hospital, Bryn Mawr, PA, USA;15University of Saskatchewan, Regina, Sask., Canada;16Stanford University, Palo Alto, CA, USA;17St. Antonius Hospital, Nieuwegein, The Netherlands;18Integrated Pain Solutions, Columbus, OH, USA;19National Institute of Pain, Lutz, FL, USA;20Carolinas Pain Institute and Wake Forest University Baptist Health, Winston-Salem, NC, USA;21MossRehab and Department of Rehabilitation Medicine, Jefferson Medical College, Philadelphia, PA, USA;22Advanced Pain Therapy, PLLC, Hattiesburg, MS, USA;23Premier Pain Centers, Shrewsbury, NJ, USA and Johns Hopkins University, Baltimore, MD, USA;24Department of Pain Management, Cleveland Clinic, Cleveland, OH, USA;25Center for Pain and Supportive Care, Phoenix, AZ, USA;26University of California San Diego, La Jolla, CA, USA;27Alabama Pain Center, Huntsville, AL, USA and University of Alabama School of Nursing, Birmingham, AL, USA; and28University of Kentucky—Lexington, KY, USA (Emeritus Professor)

<Correction added after online publication 11 April 2012: The original version of this article contained incomplete and inaccurate author affiliations. The complete,corrected list of author affiliations is presented here.>

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Neuromodulation: Technology at the Neural Interface

Received: December 9, 2011 Revised: February 11, 2012 Accepted: February 14, 2012

(onlinelibrary.wiley.com) DOI: 10.1111/j.1525-1403.2012.00449.x

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www.neuromodulationjournal.com Neuromodulation 2012; ••: ••–••© 2012 International Neuromodulation Society

Introduction: Continuous intrathecal infusion of drugs to treat chronic pain and spasticity has become a standard part of thealgorithm of care. The use of opioids has been associated with noninfectious inflammatory masses at the tip of the intrathecalcatheter, which can result in neurologic complications.

Methods: The Polyanalgesic Consensus Conference is a meeting of a group of well-published and experienced practitioners; thepurpose of the meeting is to update the standard of care for intrathecal therapies to reflect current knowledge gleaned fromliterature and clinical experience. An exhaustive literature search was performed, and information from this search was providedto panel members. Analysis of the published literature was coupled with the clinical experience of panel participants to formrecommendations regarding intrathecal inflammatory masses or granulomas.

Results: The panel has made recommendations for the prevention, diagnosis, and management of intrathecal granulomas.

Conclusion: The use of chronic infusions of intrathecal opioids is associated with the formation of inflammatory masses at theintrathecal catheter tip in a small minority of treated patients. Nonetheless, the appearance of these space-occupying lesions canlead to devastating neurologic sequelae. The prevention, early detection, and successful treatment of intraspinal granulomas areimportant considerations when offering intrathecal drug therapy to patients with chronic intractable pain.

Keywords: Chronic pain, consensus, granuloma, inflammatory mass, intrathecal

Conflicts of Interest: Timothy R. Deer, MD: consulting (Medtronic). Joshua Prager, MD: honoraria (Medtronic, Eli Lily, Qutenza).Robert Levy, MD, PhD: consulting (Medtronic and Codman & Shurtleff). Eric Buchser, MD: consulting (Medtronic). Allen Burton, MD:consulting (Medtronic, BSCIS, Stryker), speaking (Azur, Cadence, Cephalon, Neurogsx, Pricara, Pfizer), stockholder (Vapogenix).David Caraway, MD, PhD: consulting (Medtroinc, Spinal Modulation, MedSys, Codman). Michael Cousins, MD: nothing to disclose.José De Andrés, MD, PhD: nothing to disclose. Sudhir Diwan, MD: speaking (Neurotherm, BSCI). Michael Erdek, MD: nothing todisclose. Eric Grigsby, MD: clinical research (Alfred Mann Foundation, Medtronic, NeurogesX, Spinal Restoration), speaking (AzurPharma), consulting (Medtronic, St. Jude Medical, Spinal Modulation, Vertos, Xalud), stock options (Spinal Modulation, SpinalRestoration, Vertos, Xalud). Marc Huntoon, MD, PhD: nothing to disclose. Marilyn Jacobs, PhD: consulting (Medtronic). Philip Kim,MD: consulting (Medtronic, Biotronik, Stryker, Azur). Krishna Kumar, MD: consulting and research (Medtronic, Boston Scientific).Michael Leong, MD: advisor (Covidien). Liong Liem, MD: grant (Spinal Modulation). Gladstone McDowell, MD: speaking (Azur),consulting (Medtronic, Mysys). Nagy Mekhail, MD, PhD: speaking (Endo Pharmaceutical), research (Baylis, Inc., Vertos). Sunil J.Panchal, MD: nothing to disclose. Richard Rauck, MD: research (Medtronic, Medasys, Azur, Codman, Al Mann Foundation), con-sulting (Medtronic, Medasys, Azur), data and safety monitoring board membership (Medtronic, Al Mann Foundation). MichaelSaulino, MD, PhD: speaking (Medtronic, Azur), research (Medtronic). B. Todd Sitzman, MD: nothing to disclose. Peter Staats, MD:nothing to disclose. Michael Stanton-Hicks, MD: nothing to disclose. Lisa Stearns, MD: research (Medtronic, Insys Therapeutics,Vertos Medical), consulting (Medtronic). Mark Wallace, MD: research and consulting (Medtronic). K. Dean Willis, MD: speaking(Boston Scientific, Medtronic, St. Jude Medical), Implantable Systems Performance Registry participant (Medtronic), advisorycommittee (Boston Scientific). William Witt, MD: consulting (Medtronic), speaking (Cadence, Pfizer, Medtronic). Tony Yaksh, PhD:consulting (Vertex, Adynxx, Solace, Neuroadjuvants, Trevana), research (Adynxx, Johnson & Johnson, Xenome, Torrey Pines, ThirdRock Ventures, Advanced Targeting Systems, Nektar Pharma, Endo Pharmaceuticals, Sage Rx, Solstice, Epigen).

INTRODUCTION

Catheter-tip inflammatory masses (granulomas) have beenobserved after chronic intrathecal (IT) administration of a variety ofanalgesic agents. The first case of a catheter-tip granuloma associ-ated with IT morphine infusion for the treatment of chronic intrac-table pain was reported by North et al. in 1991 (1). Granulomas havebeen characterized in large animals (e.g., dogs, sheep) and humansas distinct, globular, or spheroid collections of macrophages,plasma cells, eosinophils, or lymphocytes (2–8). They are aseptic (7),as defined by staining or culture, and almost always arise from thearachnoid layer of the meninges and not from neuronal tissue ofthe spinal parenchyma (2,7). Granulomas characteristically occur atthe distal portion of the catheter (3).

Although granuloma formation is still thought to be an infre-quent event in patients who undergo IT drug administration,reports of inflammatory masses are increasing. This increase mayreflect the rising incidence of this potentially serious adverse event,as evidenced by postmarketing surveillance reports fromMedtronic, Inc. (9,10), and by the increasing number of case reportsand retrospective surveys of granuloma formation that haveappeared in the literature since this phenomenon was first

described (2,11–15). The seriousness of this adverse event is under-scored by the finding that, among clinicians who have treated atleast one patient with a granuloma, 66% reported having a patientwho experienced permanent or temporary neurologic injury asa result of granuloma formation (12). The purpose of this commu-nication is to further increase awareness on all of these clinicalfronts.

The Polyanalgesic Consensus Conference (PACC) is a series ofmeetings convened by an expert panel of clinicians experiencedwith the use of IT analgesics for chronic pain management. Thispanel has published a series of consensus statements proposingways to minimize the likelihood of granuloma formation. Accordingto the 2000 consensus statement on the management of ITcatheter-tip inflammatory masses (and an updated 2007 consensusstatement on this topic), catheter-tip granuloma formation wasassociated exclusively with the use of IT opioid medications, bothalone and in combination with nonopioid analgesics (5,16). Discon-tinuation of the offending IT medication in asymptomatic patientswas recommended, with the expectation (based on previous clinicalobservations) that granuloma resolution would follow within two tofive months (16). Indeed, results from magnetic resonance imaging(MRI) studies in canine models of IT morphine-evoked granulomas

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demonstrated a significant time-dependent reduction in the size ofthe IT mass after discontinuation of morphine infusion (8). Thus,support for the maintenance of a low daily dose and low concen-tration of IT opioid medication, including morphine sulfate, inpatients with no signs of granuloma was one key recommendationfrom the panel (16). The balance between avoiding granulomas andproviding acceptable pain relief is often challenging and remains asignificant problem in the successful management of this complexpatient group.

In the 2007 consensus statement on the management of ITcatheter-tip inflammatory masses (16), the PACC panel concludedthat granulomas were associated with high doses or concentrationsof opioid in the infusate, particularly when delivered over a longperiod; combinations of high drug concentration and slow cere-brospinal fluid (CSF) circulation rate; and intrathecally administeredopioids (e.g., morphine). Generally, patients seek medical help afternoticing new or worsening pain or the appearance of new focalneurologic abnormalities. Diagnosis can be difficult because mostpatients who experience these signs and symptoms do not have agranuloma; rather, they are experiencing progression of their under-lying disease or escalating drug tolerance. Given the complexity ofpatient management and the difficulties in recognizing granulomaformation, expert guidelines might help to improve care. Indeed,members of the previous PACC panel issued a consensus statementin which they made key recommendations for prevention, screen-ing, clinical assessment, and treatment relevant to IT granulomaformation in patients receiving IT drug therapy (16).

Granuloma occurrence in clinical practice has persisted, perhapseven increased, since the PACC last convened in 2007, and muchnew evidence related to the diagnosis and prevention of this con-dition has appeared in the scientific literature. Thus, the PACC recon-vened in 2011 to modify and update their earlier recommendationsregarding IT catheter-tip granuloma formation. The expert panelmembers reviewed previous PACC guidelines and recent reports ofcatheter-tip granulomas in the literature. The group also conducteda survey of physicians who routinely offer treatment with IT drugtherapy. Consensus recommendations on critical issues related to ITcatheter-tip granulomas were formulated.

MethodsThe present article is based on a review of previous PACC guidelinesfrom conferences convened in 2000, 2003, and 2007 and includesdata obtained from reports on IT catheter-tip granulomas thatappeared in the medical literature between January 15, 2007, andMarch 1, 2011. These reports focused on the use of IT therapy forchronic pain. Databases searched included MEDLINE®, BioMed Cen-tral®, Current Contents Connect®, EmbaseTM, International Pharma-ceutical Abstracts®, and Web of Science®. Search terms includedmorphine, fentanyl, sufentanil, methadone, adenosine, hydromor-phone, meperidine, gabapentin, baclofen, ketorolac, midazolam, neo-stigmine, octreotide, ziconotide, ropivacaine, dexmedetomidine,clonidine, bupivacaine, and lidocaine. These searches yielded 391articles, which were evaluated for relevance to granulomas in ITtherapy for chronic pain, yielding a total of 41 articles.

To find and evaluate data on MRI and IT granulomas, a separateliterature search of Google Scholar and PubMed was performedwith the use of the terms intrathecal drug delivery, catheter, granu-loma, and inflammatory mass. Google was searched for imagesunder the term catheter tip granuloma. Accessed internal bibliogra-phies were also searched for content and additional references.Google was also used to search for recent relevant information

regarding IT therapy for chronic pain, and additional literature con-sidered by panel members to be relevant to this new consensuspaper was reviewed. From these sources, 21 additional referenceswere identified, for a total of 62 articles.

The literature search was limited by the potential inability toacquire accurate numerators from other sources on non-publishedcases, and may underestimate the actual incidence of granuloma. Infuture searches, the authors will consider sources such as FDA Med-Watch and the MAUDE database to identify unpublished cases.

LITERATURE REVIEW: SUMMARY OF CLINICALAND PRECLINICAL DATAOverviewThere are no data from controlled trials that document factors gov-erning the formation of IT granulomas in patients receiving IT drugdelivery for treatment of chronic pain. A single rigorous retrospec-tive analysis was identified (13), as well as 12 case reports (2,17–26).Descriptive case reports are the primary sources of informationabout these granulomas.

EpidemiologyMore than 95,000 IT drug-delivery systems have been implantedworldwide since the 1980s, and the incidence of catheter-tip granu-loma has generally been estimated at <3%, although estimates inselect populations have been as high as 43% (27). Between 1990and 2000, 41 cases of granuloma were reported through postmar-keting surveillance to the US Food and Drug Administration (FDA)by Medtronic, Inc (9). Subsequently, from October 2000 throughSeptember 2007, Medtronic received reports of 448 granulomacases in patients who had been implanted with drug infusionsystems for treatment of pain (10). On the basis of the reportsreceived by Medtronic through September 2007, the incidence ofgranuloma was estimated at 0.49% for patients ever implanted witha drug infusion system for the treatment of pain (10). Becausepatients receiving IT therapy have not routinely undergone imagingstudies, the presence of a granuloma may be suspected only afterclinical signs appear. However, occult granulomas that do notproduce neurologic signs do occur (27); thus, the actual incidence ofgranuloma formation is likely higher than has been reported. Themost recent analysis conducted by the pump manufacturer(Medtronic) indicates that the incidence of granuloma developmentis approximately five times higher (0.49%) than that originallyreported in 2001 (0.1%), and the rate of detection of granulomas isexpected to continue to increase (10).

According to results from an online survey that was developed tocoincide with the 2007 PACC, 63.9% of physicians reported that atleast one of their patients had developed a granuloma (12,13). In aretrospective analysis of hospital medical records, at a mean postim-plantation follow-up time of 91 months (range, 9–209 months), 4cases of IT granuloma occurred among 56 patients who received ITopioids, an incidence of 7% (13). In a retrospective cohort study witha three-year follow-up, �3.5% of 57 patients who received IT opioidtherapy for chronic nonmalignant pain had a granuloma (11). Aslightly lower rate of granuloma occurrence (3.0%) was reported foranother cohort of patients (N = 131) receiving a continuous IT infu-sion of morphine (15).

Granuloma Results from Actions of Opiods on Inflammatoryor Mast-Cell Opiod ReceptorsResults from pharmacologic investigations have indicated that thedevelopment of IT opioid-induced granulomas is not dependent on

3CATHETER-TIP GRANULOMA CONSENSUS


opioid receptor activation (28). Instead, migration of inflammatorycells, most likely mast cells, from the local meningeal vasculatureappears to be an important component of granuloma formation(28). The stimulus for this migration appears to be drug related,rather than related to a nonspecific effect of the catheter itself or theprocess of infusion, but the physiologic mechanism that drives cellmigration remains unknown (7,23,28).

Etiology

Drug DoseIn current clinical practice, the dosage of opioid used for IT drugdelivery is often increased gradually over the course of treatmentbecause of tolerance, disease progression, or a new pain generator(2,19,20,23). It is common in clinical practice to increase the drugconcentration as the daily dose of opioid is increased. The opioidconcentrations needed often exceed the recommended limits(16,25,26). A correlation between opioid dose, yearly increase inopioid dose, and granuloma formation was demonstrated byDuarte et al. (13) in a rigorous retrospective analysis of 56 consecu-tive patients who received long-term IT drug therapy. In this study,a significant positive correlation was found between opioid (mor-phine or diamorphine) dose and granuloma formation (r = 0.275,p < 0.05). The mean � standard deviation (SD) opioid dose forpatients with a granuloma was 4.68 � 1.55 mg/d (range, 3.79–7.00);for those patients without a granuloma, it was 3.01 � 2.15 mg/d(range, 0.64–11.57; p < 0.05). There was a significant correlationbetween yearly increase of the morphine dose and granuloma for-mation (r = 0.433, p < 0.01); median opioid dose increase per yearwas 0.22 mg (p < 0.005) for patients with a granuloma. The mean �SD annual change in dose was 0.88 � 0.43 mg/d (range, 0.48–1.41)for patients with granuloma and 0.22 � 0.19 mg/d (range, -0.08 to0.97) for patients without granuloma (p < 0.01). It should be notedthat some granulomas have been reported even in the setting ofrelatively low opioid concentrations. Thus, granuloma formationappears more likely in patients who are receiving higher opioidconcentrations and in whom the rate of drug delivery is escalatedmore rapidly. This article is an example of an unusual presentationsince diacetyl morphine was used during this study and is availablein limited countries (UK).

Although a need for an increasing opioid dose may signal thedevelopment of a granuloma in some patients (13), there are casereports of opioids being titrated well beyond the recommendeddosage limits (16) without the development of a granuloma (29).According to one report, 60 patients in a physician’s practice hadreceived high doses of IT opioids that were well beyond the recom-mended limits without the occurrence of a single catheter-tipgranuloma (29). There appear to be some patient-specific character-istics that determine the propensity to develop these lesions, butsuch characteristics have yet to be identified.

Drug ConcentrationExtended tissue exposure to high concentrations of opioids such asmorphine (>25 mg/mL) is believed to be an important factor in thedevelopment of catheter-tip granulomas (30–32). Results from astudy in dogs showed that the morphine concentration of the infu-sate correlated with the local drug concentration near the cathetertip (8,28). Over a range of drug concentrations (i.e., 1.5–12.5 mg/mL) there was a strong correlation between the infusion drug con-centration and drug concentration in the CSF at the sampling sitewithin 2 to 3 cm of the infusion site. By assuming that the drugconcentration precisely at the catheter tip corresponds to the infu-sion concentration, the authors determined that the local drug con-centration (i.e., the steady-state drug concentration within the CSF)

decreased 250- to 300-fold within 3 cm of the infusion site and thatsimilar ratios were noted across a range of infusate drug concentra-tions. In this study, granulomas developed reliably with infusiondrug concentrations of 12.5 mg/mL infused at 40 mL/h; under theseconditions, the local drug concentration was 50 mg/mL. Granulo-mas were much less likely to develop at local drug concentrationsless than 50 mg/mL. Extrapolating these animal data to clinical prac-tice suggests that the use of an infusate with a lower drug (e.g.,morphine, other opioids) concentration may reduce the likelihoodof granuloma development in patients (20). It is interesting to notethat the daily bolus delivery of a similar concentration of morphinein the dog did not produce a granuloma. This observation suggeststhat an ongoing exposure of the local meninges to analgesics viacontinuous infusion may be required for the accumulation of amass of inflammatory cells. These findings raise the question ofwhether drug delivery by intermittent bolus may be safer than con-tinuous infusion. No studies yet exist to compare the relative safetyof these modes for drug delivery. In both human and caninestudies, termination of the infusion leads to regression of the mass(8,20).

CSF Flow Rate and Drug DistributionCurrent biochemical and radiologic data do not support the exist-ence of a consistent pattern of CSF flow to and from the cerebralventricles and the lumbar cistern, and the dynamics of this processare controversial. Results from biochemical studies demonstrate aconsistent and marked rostrocaudal concentration gradient forboth the small metabolites (33) and the large protein constituents(34) of normal CSF. Radiologic findings obtained by using gated MRIdemonstrate that CSF moves in a to-and-fro oscillation with respi-ration and the cardiac cycle (35), but there are conflicting data onthe existence of bulk flow (36,37).

Direct evidence that CSF does not circulate has been obtainedfrom preclinical studies in a porcine animal model (38). Limitedrostral spread of IT opioid medications results in diffusion of muchof the drug from the CSF to the epidural space, where it is absorbedinto the systemic circulation. Consequently, much of the opioiddose placed within the IT space never reaches its intended targetwithin the spinal cord. Results from these studies have demon-strated that drug distribution within the CSF and drug uptake (anddispersal) in the spinal cord (i.e., upon continuous IT injection atlow-flow rates) may be limited to the region within a few centime-ters of the catheter tip (39–41).

Mathematical modeling of fluid dynamics shows that, after IT dyeinjection, most dye is contained within the area directly adjacent tothe catheter tip (30). Additionally, results from a study of chronic ITmorphine delivery in a porcine model demonstrated a significantdrug concentration gradient within the spinal cord as a function ofdistance from the infusion catheter tip. The authors suggested thatthe tendency for granuloma to form at the catheter tip may berelated to a relatively high local drug concentration there (40).

The interpretation of the dye distribution analysis (30) and of theresults from preclinical studies (8,40) is consistent with findings froma case report in which a granulomatous mass grew around a leakthat had developed between an IT pump and the catheter (19). Thegranulomatous mass growing around the site of the leak provided asealed conduit through which drug flow between the pump and thecatheter had been reestablished. The authors suggested thatgrowth of the granuloma at the site of the leak rather than at thecatheter tip could be taken as evidence that the infused opioid hadbeen the cause of the granulomatous lesion (19).

Drug Flow RateThe 2007 consensus statement on the management of IT catheter-tip inflammatory masses (16) indicated that granuloma formation

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may be associated specifically with a high drug concentration andlow drug administration flow rate. Although no association of a slowdrug infusion rate and occurrence of granulomatous masses wasfound by Duarte et al. (13) in their retrospective study, the authorsacknowledged that flow rate was not fixed; dosage changes weremade by altering the flow rate of the infusate (i.e., with the use of aprogrammable pump), making it difficult to detect an effect of flowrate on granuloma formation (13). Further study of the impact offlow rate and the impact of localized CSF drug concentrationswill be helpful in the design of new devices and novel agents forinfusion.

Duration of InfusionCumulative risk for granuloma appears to be related to the length oftime that the pump has been implanted (10). In patients who hadpumps implanted for the treatment of pain, the incidence of granu-loma occurrence over time since pump implantation showed abiphasic increase, first rising to a plateau after 2 years, then increas-ing once more at approximately 12 years, and remaining stable atthat level at least for another 6 years (10). The reasons for this bipha-sic pattern are unknown.

Drug Classes Implicated in Granuloma FormationAnalysis of current data shows trends that can be used to educatephysicians who are involved in the implantation of IT pumps. Inaddition to the use of morphine, other opioids are used in an off-label fashion. The clinician should consider whether these drugsmay cause granuloma formation. In a review of the literature, we canevaluate the current data on the basis of FDA and manufacturer(Medtronic) reporting. The 2007 PACC panel provided specific guid-ance for doses and concentrations of IT opioids, including maximumconcentrations and daily dose recommendations (see table 3 inDeer et al. 2008) (16). Somewhat different dosing and concentrationguidelines have been provided in other review papers (42,43).

Granuloma formation has been consistently associated with theIT administration of opioids (e.g., morphine), either alone or in com-bination with other agents (13,17), as described in several casereports (Table 1) (2,17–26). In one case, a granuloma recurred twicein a single patient who had received IT morphine for approximatelysix years (23). After the first occurrence of a granuloma, IT morphinewas resumed through a new catheter, and a new catheter-tip granu-loma was identified five months later. Following surgical resectionof the second granuloma, IT morphine therapy was again resumed,and a third catheter-tip granuloma was discovered three years later(23). One other case, in which a granuloma recurred within ninemonths of the surgical resection of the first granuloma, has beenreported (17). These findings suggest the consideration of a conver-sion to an alternate opioid or nonopioid (e.g., ziconotide) in patientswho have developed a granuloma with morphine and in whom ITtherapy is still appropriate. If the clinician feels that the offendingagent is still the best choice for treatment when considering therisk-to-benefit ratio, careful follow-up and high clinical suspicion forgranuloma recurrence are recommended.

The development of a catheter-tip granuloma within the spinalcord parenchyma in a patient receiving long-term IT administrationof morphine has also been described (2). A 54-year-old woman pre-sented with an 18-year history of lower back pain, numbness fromthe waist down, and pain in her left leg, buttock, and groin. Thepatient had been receiving IT therapy for >9 years when progressivelower extremity weakness and urinary incontinence became mark-edly worse over the course of three weeks. An MRI study revealed aT2-weighted focal intramedullary enhancement of the left dorsal

aspect of the spinal cord that was located adjacent to the cathetertip positioned near the arachnoid membrane; a 5-mm mass sur-rounded by edema that extended cephalad to the mid-T8 level andcaudal to the level of T12-L1 was also noted. On surgical interven-tion, granulomatous material with scar tissue under the dura wasobserved, and a granuloma that had breached the pia materthrough the dorsal aspect of the cord was present. This case of agranuloma of parenchymal origin is highly unusual because granu-lomas are commonly held to be meningeal in origin, and thus theygenerally arise from the dural and arachnoid layers, rather than fromthe pia matter or spinal cord (2). There was no evidence in this casethat the mass had grown first and then penetrated into the spinalcord, since spinal tissue surrounding the small entry site was pre-served (2). There was nothing unusual in the patient’s medication orinfusion history to suggest that these factors might be responsiblefor the manner in which the granuloma formed. The authors sug-gested that the granuloma may have been forced to grow withinthe spinal cord parenchyma because of a combination of factors: athickened dura (which was not visible on MRI), the location of thecatheter tip, and the particular characteristics of CSF flow (2). Thetheories presented by the authors cannot be confirmed because oflingering questions regarding potential causes of dural thickening,CSF flow relationship to the catheter tip, and any variations in CSFflow that may have occurred.

Results from preclinical studies in the canine model have shownthat IT granulomas similar to those observed with morphine can beseen with other opioids, although some opioids are not associatedwith granulomas, even when used at relatively high concentrations/doses (28). In humans, catheter-tip granuloma formation has alsobeen reported in association with the use of IT opioids other thanmorphine (Table 2) (29,44,45). In one such case, the patient had aconfusing drug infusion history (44). She originally received ITopioid therapy but had inadequate pain reduction. The patient thenreceived IT ziconotide monotherapy for approximately four months(44), but she again had an inadequate response and was switched toIT baclofen monotherapy; then, two months later, therapy wasswitched twice more to two other IT opioid medications adminis-tered as monotherapy. The patient subsequently developed agranuloma. This case is a good example of the complexity of deter-mining the cause and effect of drug selection when analyzing thiscomplication. The cause of the mass in this case was uncertain, andalthough the author suspected that the granuloma was opioidinduced, no definite determination could be made (44). Additionalcases of the association of IT catheter-tip granulomas with opioidsother than morphine have been reported (14,45).

Several case reports associate hydromorphone use with IT granu-lomas (24,46). Coffey and Burchiel (46) described 41 patients withinflammatory masses who were identified from the literature(N = 16) or from Medtronic and FDA patient complaint databases(N = 25). All but two cases involved morphine (N = 29) or hydromor-phone (N = 10) therapy. With both opioids, the inflammatory massesoccurred over a wide variety of doses and concentrations. However,there is consensus that higher concentrations and doses increasethe risk for inflammatory masses (16).

No cases of IT inflammatory masses associated with fentanyl orsufentanil have been reported (16,47). Results from animal modelstudies demonstrate that opioids have differing effects on inflam-mation and neurotoxicity (47). These models provide insight intomechanisms underlying causes of granuloma formation and differ-ences in severity based on drug characteristics. Under experimentalconditions, IT morphine has been shown to be the most aggressiveinflammatory mass-causing agent, and these findings are consis-



Table 1. Recent Case Reports of the Occurrence of Intrathecal Catheter-Tip Granulomas With Morphine.

Authorsand year

Case description Cathetertipplacement

Time from pumpplacementto granulomadetection

Presentingsigns/symptoms

MRI/CT findings Surgical findings

Jourdain et al.,2009 (20)

41-year-old man; intractableneuropathic pain; traumaticspinal cord injury; ITmorphine for 3 months

T12-L1 5 weeks Persistent pain Mass visualized at catheter tip NA

Hoederathet al., 2010(17)

52-year-old woman; history ofchronic low back pain; ITmorphine initially; switchedto ziconotide andsubsequently to anotheropioid

NA 20 months (asecondgranulomadeveloped 9months aftersurgicalresection)

Increasing and persistent lowback pain; onset of diffusesensory deficits; hypoesthesiain the right lower extremityand in both feet

Intradural extra-medullary lesionat the level of T8-9; cordcompression and contrastenhancement; secondgranuloma at T10-11

Decompressive laminectomyrevealed a 1 ¥ 1 ¥ 3-cm massadherent to the spinal cordat the catheter tip

Jhas and Tuli,2008 (2)

54-year-old woman; 18-yearhistory of lower back pain,numbness from the waistdown and pain in her left leg,buttock, and groin; ITmorphine analgesicadmixture initially; switchedto another opioid

NA >9 years Progressive lower extremityweakness markedly worseover the previous 3 weeks;left leg weakness; urinaryincontinence

On MRI, a T2-weighted focalintramedullary enhancementof left dorsal aspect of cordadjacent to an arachnoidcatheter tip; a 5-mm masssurrounded by edemaextending cephalad to themid-T8 level and caudal tothe level of T12-L1

Granulomatous material withscar tissue under the dura;granuloma breached the piathrough the dorsal aspect ofthe cord

Leong et al.,2010 (22)

68-year-old woman; previouslumbar surgery; IT morphine

T9-T10 >7 years Persistent thoracic spine pain;progressive lower limbweakness with paraesthesia,ataxia, constipation, andmicturition difficulties

A 3.1 ¥ 1.6 ¥ 1.5-cm T1W andT2W isointense mass withmarginal enhancement atthe level of T9-T10;indentation of the thecal sac;moderate spinal cordcompression; catheter tipseen in the posterior epiduralspace at T9-T10

Decompressive laminectomy atthe T9-T10 level; the cathetertip had migrated epidurallyand was embedded in alarge extradural fibrous mass

Leong et al.,2010 (22)

39-year-old man; chronic painfrom lumbar injury; ITmorphine pump for 5 years

T12-L1 >5 years Progressive paraesthesia; lowerlimb weakness; foot drop;urinary incontinence; lowbladder sensation;hyperreflexia in both limbs

A 2.0-cm ¥ 1.0-cm T1W and T2Whypointense intradural mass;marginal cord compression atthe level of T8

Decompressive T8-T10laminectomy; intraduralcalcified mass encasing thecatheter tip

De Andréset al., 2010(23)

60-year-old woman; motorneurologic deficit in lowerlimbs; poliovirus infection inchildhood; IT morphine for16 years, then switched toziconotide

T9-T10 12 years, withrecurrences 5months laterand 3 yearsafter that

Progressive motor weakness;stabbing neuropathic pain inthe lower limbs; increasedlocal back pain, radicularpain, and hyperreflexia; lossof sensation

First intradural mass at T10;second and third masses atT11-T12

Surgical removal of a mass of 1¥ 1.4 cm and of a secondmass of 0.8 ¥ 0.5 cm

Webb et al.,2011 (19)

38-year-old woman on chronicIT morphine/analgesicadmixture; chronicgastrointestinal pain; Crohn’sdisease and diabeticgastroparesis

NA 4 years Decline in drug benefit 1 yearbefore presentation;increased pain

Hub fracture observedon x-ray

Granulomatous structure notedsurrounding the region ofthe pump nozzle

Abejón et al.,2009 (21)

Central neuropathic painfollowing removal of a tumor;long-term infusion ofmorphine

NA NA Gradual development ofneurologic signs andsymptoms suggestingradicular or spinal cordcompression; steady increasein morphine dose

MRI images obtained NA

Ramsey et al.,2008 (24)

52-year old man; history ofchronic lumbar pain; ITmorphine for 6 years, thenswitched to another opioid

NA 8 years Increasing back pain, gaitinstability; recent-onseturinary retention andweakness in the lowerextremities

Intradural-extramedullary lesionat the level of T8-T9 with cordcompression

Decompressive laminectomyrevealed a 1-cm massadherent to the spinal cordadjacent to the catheter tip

Vadera, 2007(25)

47-year-old man; 3-week historyof inability to ambulate ormove his legs; multiple failedback surgeries for pain; ITmorphine

T10-T11 >4 years Paralysis of both lowerextremities and suddenincrease in daily morphinerequirements

Cord-compressing massobserved at the catheter tip

Laminectomy performed fromT10-L1; a 1-cm intraduralgranuloma at T10 and T11and at the catheter tip wasnoted; the mass wasadherent to the spinal cordand involved thepia-arachnoid layer

Williams et al.,2011 (26)

38-year-old woman; chronicthoracic spine pain related toT4 and T5 vertebralhemangiomas

NA NA Need for a high concentrationand increased daily dose ofmorphine; decreasedanalgesia

Catheter-tip mass identified Granulomatous mass removed

Sloan andGrider,2010 (18)

51-year-old woman; metastaticbreast cancer to the spine; ITmorphine

NA <1 year Rapid increase in daily dose ofmorphine; inadequateanalgesia; severe, constantlow back pain

Granuloma surrounding thecatheter was apparentfrom a pump myelogram

NA

MRI, magnetic resonance imaging; CT, computed tomography; NA, not available; IT, intrathecal; T1W, T1-weighted; T2W, T2-weighted.

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DEER ET AL.


tent with clinical observations (8,16). Animal models with hydro-morphone as the IT agent in both the dog and sheep model haveshown the development of granuloma (48).

Two case reports of apparent granulomas associated with ITbaclofen use have been described (Table 3) (49). In one case, thecatheter tip was positioned at the T10-T11 interspace, and a space-occupying inflammatory mass was detected at the catheter tip viaMRI. In the other case, an oval lesion consistent with an inflamma-tory mass was identified by MRI (49). The initial clinical presentationin both cases was reduced response to baclofen and increasing doserequirements.

Reevaluation of the MRI findings in these cases showed that theylacked the distinct globular- or spheroid-shaped lesions on T1 MRIsequences with gadolinium contrast that are considered diagnosticfor histologically proven opioid-induced granulomas (50). Further-more, in one of the cases, the patient who had severe and intrac-table spasticity had received a pharmacy-compounded IT baclofenpreparation at a concentration of 4000 mg/mL, and the MRI scans inthis case were similar to those obtained in a case in which a chalk-like precipitate had been found at the catheter tip (50). Notably,results of laboratory studies suggest that a pharmacy-compounded

baclofen concentration of 4000 mg/mL is beyond the limit of drugsolubility at physiological CSF osmolality and pH (51). It was there-fore suggested that, in light of the preclinical and clinical findings,the reported data and images in these cases do not support a diag-nosis of granuloma (50,52). In canine studies, the administration ofbaclofen at concentrations of up to 2000 mg/mL/d was not associ-ated with the occurrence of any evident mass pathology (53). Sincethe mass in the patient who was receiving commercially availablebaclofen was equally problematic, the phenomenon cannot beattributed to compounding alone. Further analysis is needed shouldmore of these lesions arise in other clinical settings. Granulomaformation associated with IT baclofen infusion, regardless of etiol-ogy, appears to be infrequent.

Time for Development of GranulomaAccording to one report of a retrospective analysis, the mean � SDtime for the development of granuloma is 39.5 � 13.5 months(range, 22–52 months) (13). However, according to a variety of casereports, granulomas have been detected between 5 weeks (20) and12 years (23) after the initiation of IT therapy (Table 1). In addition to

Table 2. Case Reports of the Occurrence of Intrathecal Catheter-Tip Granulomas With Opioids Other Than Morphine.

Authorsand year

Case description Catheter tipplacement

Time frompumpplacement togranulomadetection

Presentingsigns/symptomsrelated togranuloma

MRI/CT findings Surgical findings

Gupta et al.,2010 (44)

86-year-old woman; failedback surgery syndrome;pain localized to the lowerlumbosacral spine;sequential IT ziconotide,baclofen, andnonmorphine opioid

T11 2 years Lower extremityweakness, sensorychanges, intractablelumbar pain

CT-myelogram confirmedthe presence of agranuloma; identified a4-mm epidural massindenting the left anterioraspect of the dural sacand pushing the spinalcord

Surgery notrecommended; ITmedicationreplaced withnormal saline

De Andréset al., 2010(45)

61-year-old woman; morbidobesity, hypertension, anddyslipidemia; history ofstroke without residualneurologic deficits; lowback pain, lumbar canalstenosis

NA 2.5 years Numbness on theoutside of the leftlower limb; severeparaesthesia in thelower limbs;significant reductionin walking ability

Extramedullary, intradural,round mass (5 ¥ 7 mm) atthe T9 level; stenosis in thespinal canal

Dorsal laminectomy atT9 and T10; removalof a mass localizedaround the catheter

MRI, magnetic resonance imaging; CT, computed tomography; IT, intrathecal; NA, not available.

Table 3. Case Reports of the Occurrence of Intrathecal Catheter-Tip Granuloma With Baclofen.

Authorsand year

Case description Catheter tipplacement

Time from pumpplacement togranulomadetection

Presentingsigns/symptomsrelated togranuloma

MRI/CT findings Surgicalfindings

Deer et al,2007 (49)

70-year-old man; right-sidedweakness, atrophy, secondaryspasticity of the upper andlower extremities secondary toa cerebrovascular accident

T10-T11 2.5 years Dose requirementsincreased

Catheter tip at the T10-T11interspace; space-occupyinginflammatory mass at thecatheter tip

NA

Deer et al,2007 (49)

39-year-old woman; progressivemultiple sclerosis; permanentprogrammable IT pump

NA 5 years Worseningspasticity

Oval lesion consistent with aninflammatory mass identified

NA

MRI, magnetic resonance imaging; CT, computed tomography; NA, not available; IT, intrathecal.



the case in which a granuloma was detected five weeks after initia-tion of IT therapy, other cases in which granulomas developedwithin one year have been reported (Table 1) (17,18,23). These casereports suggest that the formation of a granuloma is not strictly along-term phenomenon. The time course over which a granulomadevelops is likely to be underestimated because, in a clinical setting,the assessment of a granuloma depends on the appearance of neu-rologic signs, which may not be appreciated until well after thegranuloma has actually begun to form. Asymptomatic lesions mayexist for months or years before a clinical diagnosis is made orbefore symptoms and signs of clinical morbidity appear. Animaldata suggest that granulomas can begin to form in days to weeks(8); the clinical implications of this finding are uncertain but mayimply that, in some atypical patients, a course of early formation andpotential clinical signs could arise. The acute models of animalstudies have unknown implications for clinical practice.

Catheter PositionCatheter tips have been positioned at various thoracic levels, includ-ing T10, T11, and T12 (Tables 1 and 2) (20,22,23,25,44), as well as atcervical levels (20,22,23,25,44,54–57). No relationship betweengranuloma formation and catheter tip location has been identifiedto date. Support for previous theories that the low-flow state of CSFin the thoracic region may be responsible for an increase in granu-loma formation has not been scientifically validated. The previousrecommendations to keep the catheter below the conus do notappear to have any scientific support; no studies to date haveshown that this practice will prevent neurologic sequelae, and somehave theorized it may affect the efficacy of the therapy. Furtherstudy is needed to resolve these complex issues regarding catheterplacement. It currently appears equally reasonable to argue in favorof placing the catheter at the level of the pain generator or in thelower thoracic spine or to support a placement below the conus toreduce the potential impact of mass compression on neural struc-tures. Experts disagree, and no current consensus can be reached onthe basis of scientific data.

Clinical Signs and Symptoms of GranulomaThe most frequently reported symptoms that lead to the diagnosisof a granuloma are decreased therapeutic response, inadequatepain relief, and onset of pain with new characteristics (e.g., increasedlocal back pain, thoracic spine pain, gastrointestinal pain)(19,22,23,29). According to a report from Medtronic, Inc., decreasedtherapeutic response or inadequate pain relief and pain werereported in 33.5% of cases of IT therapy associated with a catheter-tip granuloma (10). Neurologic deficit or dysfunction accounted foranother 17.4% of such cases (10). Other symptoms that have led tothe diagnosis of granuloma include paralysis/paraplegia/paresis(15% of cases) and generalized weakness/muscle weakness (13.8%of cases) (2,22–24,29). Individual patient experiences that are con-sistent with the results of the aforementioned analysis are summa-rized in Table 1 (2,17,18,20,22,24).

Radiologic Differential DiagnosisBecause the number of patients with IT granulomas remains low inthe population undergoing MRI scans, identification of such lesionswith certainty may be difficult for radiologists, but any radiologistshould be easily able to identify the presence of a mass. The radio-graphic appearance of these masses is easily confused with abscess

or tumor. Thus, it is important that the radiology community includegranuloma in the differential diagnosis for patients who are receiv-ing IT therapy. In two case reports of patients who had symptoms ofprogressive spinal cord compression, features of catheter-tip granu-loma included a thoracic spinal mass, central-low to intermediateT1-weighted and T2-weighted signal, a hypointense rim on both T1-and T2-weighted images, and relatively prominent regular border ofenhancement on T1-weighted images taken after administration ofgadolinium (22). In these reports, which describe typical MRI find-ings, the differential diagnosis of IT catheter-associated granulomaincluded progressive primary neurologic spinal cord disease,metastasis or infection, hemorrhagic ependymoma or hemangio-blastoma with a secondary cord syrinx (because of cord hemor-rhage), and intramedullary cavernoma. Addition of computedtomography (CT) allows for correlation between the position of thecatheter tip and the location of the mass seen on MRI scan, therebyfacilitating a presumptive diagnosis of granuloma. The diagnosis ofcatheter-tip granulomatous mass is confirmed by surgical resectionin some cases, but more commonly the diagnosis remains uncon-firmed because of the lack of need to resect the lesion when remo-ving or replacing the catheter (19,22,24,25).

Screening and DetectionMRI with gadolinium contrast administration with thin slices at thecatheter tip is the most common method for determining the pres-ence of a catheter-related granuloma (16,29,58). According toresults from a survey of IT practices, 94.3% of practitioners had usedMRI to evaluate a suspected granuloma (12). MRI permits visualiza-tion of the soft tissue structures within the spinal canal (59) and canbe used to define the size and location of any granulomatous lesion.Indeed, results from systematic studies in canines demonstrated aclose covariance between size of the mass and the MRI image (8,28).In a letter to the editor of Anesthesia & Analgesia, Coffey and Allen(60) described catheter-tip inflammatory masses as usually “distinct,globular- or spheroid-shaped lesions best visualized on T1 MRimage sequences with gadolinium contrast” and suggested thatimaging diagnoses based on other criteria could be misleading. Theauthors included contrast-enhanced MRI scans of a catheter-tipinflammatory mass in a patient who was receiving morphine. Insome cases an MRI is not possible because of contraindications. CTmyelogram is an option in those cases and can be helpful in identi-fying lesions. Phillips et al. (61) presented three cases of IT catheter-tip granulomas and a report on imaging correlations between CTmyelography and MRI. They also reviewed the literature on imagingappearance of granulomas in humans and animals.

In a report of three patients who were receiving IT therapy forpain, Blount et al. (62) described infusion complications due togranuloma formation. Magnetic resonance images indicated that allthree lesions were relatively isointense with respect to the spinalcord on T1-weighted images and were hyperintense with ahypointense rim on T2-weighted images. The authors stated that ITcontrast is necessary to differentiate inflammatory masses from thespinal cord.

It is important to be aware that a paramagnetic or metallic sus-ceptibility artifact associated with MRI can distort the local tissueimage and make it difficult to distinguish between a small massaround the catheter tip and an artifact caused by the metallic cath-eter tip itself in catheters with this feature (59). Failure to distinguishbetween the two can lead to unwarranted changes in therapy orunnecessary surgery. The imaging artifact is characterized by acentral signal void appearing between two bright signals; the diam-

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DEER ET AL.


eter of the bright artifact is amplified 3.5-fold relative to the actualdiameter of the catheter tip (59). Magill et al. (59) conducted a studythat used three Medtronic catheter-tip models to characterizenormal MRI image distortion produced by metallic IT catheter tipsand differentiate that from catheter-tip granulomas. In an evalua-tion of patients with catheters in place, the authors provided imagesfrom MRI scans of those with and without granulomas and notedthat granulomas enhanced after contrast administration, an impor-tant finding that suggests contrast should be used when indicated.

CT with myelography, a different imaging technique from MRI,can sometimes be used adjunctively with MRI to show a cathetermore clearly than does MRI alone (22). This can be helpful ininstances where metal artifact is present. More commonly, CT isused for patients in whom an MRI is not possible. According toresults from a survey of IT practices, 43.4%, 7.5%, and 18.9% ofpractitioners had obtained a CT-myelogram, used CT, or performeda side-port study, respectively, to confirm granuloma formation (12).In using the side port to perform a CT-myelogram, care must betaken to aspirate CSF from the diagnostic port before administeringcontrast for myelography to avoid the potential for IT drug overdosecaused by administering a bolus of concentrated drug that lieswithin the catheter between the side port and the CSF (29). TypicalMRI and CT findings in patients with catheter-tip granulomas aredescribed in Tables 1 through 3.

Miele et al. (3) provided another review of literature on catheter-related IT granulomas, which included a discussion of imaging.

It is important that the radiologists familiarize themselves withthe subtle differences between artifact from metal catheter tips andgranulomas. It is not possible or appropriate to expect the implant-ing doctor to educate the radiologist in this area and the panelrecommends that radiologists who image patients in this popula-tion undergo proper training and continuing education.

Treatment/InterventionA variety of treatments and interventions for the management ofgranuloma have been proposed, many in the context of casereports. One option involves a nonsurgical approach in which drugdelivery is either discontinued or replaced with saline infusion,allowing the granuloma to regress spontaneously (17,20). Anotheroption is to replace the infusate with normal saline and leave theexisting catheter in place while a new catheter is inserted for sub-sequent resumption of IT drug delivery. Indeed, the catheter-tipgranulomatous mass often regresses spontaneously when theoffending agent is removed from the area of the mass (20). In manycases, the physician may choose to remove the catheter and replaceit with another catheter at a different IT level. This is often donewhen symptoms are bothersome, efficacy is not acceptable, or neu-rologic abnormalities are noted. Finally, fear of progressive neuro-logic injury may be a concern for cases in which spinal cordcompression has occurred because of the presence of a granuloma-tous mass. In such cases, performance of a decompressive laminec-tomy with possible mass resection may be necessary (17,22). Thecatheter can be either removed (22) or reinserted (17) after surgicalresection of the granuloma.

DISCUSSIONS OF THE CONSENSUS PANELOverviewThe consensus panel reviewed and discussed options for the pre-vention, detection/diagnosis, and treatment of granuloma inpatients receiving IT opioid therapy for pain. Discussions were

focused on the recent published literature, the 2007 consensusstatement on the management of IT catheter-tip granuloma, andthe experience of the panel members.

Patient Risk StratificationAlthough the development of IT granulomas is infrequent, patientsshould be informed of the risks associated with IT therapy. Certainpatients may be at greater risk of granuloma development. Thepanel noted that the following factors appear to place patients athigher risk for the development of granulomas: 1) administration ofIT opioids of relatively high concentrations for any time period,although risk appears to increase with time; 2) a steady increase inthe annual opioid dose, although this may be confounded by theconsideration that increasing doses often lead to use of higher con-centrations; 3) administration of high concentrations of IT drugs atlow drug administration flow rates; 4) a history of granuloma forma-tion; and 5) anatomic disease states that result in low flow of CSFaround the catheter tip, such as severe cervical stenosis or traumaticspinal cord injury. A high index of suspicion for the development ofgranuloma is warranted in such high-risk patients. Published casereports provide little evidence of factors that identify patients asbeing at low risk for granuloma development. Granuloma formationcan occur in patients who do not fit the high-risk profiles notedabove.

Prevention of GranulomaDrug dose, drug concentration, method of IT administration, andduration of treatment continue to be the focus in prevention ofgranulomas, use of the lowest effective drug dose and concentra-tion is recommended (10). Panel members indicated that bolusdosing as an adjunct to continuous infusion should be consideredfor IT drug administration as a way to limit the exposure of patientsto opioid analgesics. By administering four to five boluses per day,the overall IT drug dose and the basal dose may be reduced. Thetotal dose of opioid analgesics may also be reduced by the use ofadjuvant therapy with nonopioid analgesics, thus theoretically low-ering the patient’s risk of developing a granuloma. Granuloma for-mation in association with lipophilic opioids appears to be rare, if itoccurs at all; thus, the development of lipophilic drugs indicated forIT treatment of chronic pain may also lower the potential for theselesions.

Catheter PlacementPrevious recommendations to place the tip of the intraspinal cath-eter in the lumbar thecal sac below the conus medullaris (10), when-ever medically possible, in order to prevent severe and sometimespermanent neurologic consequences that may ensue once a granu-loma develops have not been shown to be clinically preventive orhelpful. The panel can recommend no ideal location for catheterplacement to prevent granuloma formation. This concept is impor-tant because catheter placement in a location distant from the paingenerator may result in higher dose and concentration require-ments. On the basis of currently available data, the panel was able tomake several conclusions about catheter placement: 1) granulomascan occur and cause significant neurologic injury no matter wherecatheters are positioned; 2) many experts feel that thoracic or cer-vical placement improves efficacy, but this has not been scientifi-cally validated; 3) many practitioners continue to place all cathetersat thoracic levels; and 4) many practitioners place all cathetersbelow the conus. However, the panel cannot draw any firm conclu-sions about the best place to position catheters to maximize efficacyand minimize risks.



The placement of the catheter tip should be documented forfuture reference. If CSF flow is poor at the time of catheter place-ment, a myelogram study can be performed to quantify the level offlow. Such a study may help to determine whether there is a cath-eter obstruction that may cause the localized accumulation of ahigh concentration of analgesics at the infusion site. Catheterobstruction may be suspected if poor CSF flow is seen at the time ofcatheter placement, and it may be more likely in patients with ahistory of arachnoiditis. Myelographic studies carry significant risk,including allergy, inadvertent injection of a mismatched drug, andtissue injury due to injection. Therefore, such studies should beavoided in cases when flow is optimal.

Screening, Detection, and DiagnosisPhysicians who manage patients on IT therapy should remain vigi-lant in order to identify early clinical signs and symptoms of granu-loma formation, especially when opioids are infused (10). Patientswho are receiving IT therapy should be examined at each visit by aclinician familiar with the patient’s baseline examination and detailsof the patient’s spinal therapy. In the majority of cases, these exami-nations should occur at least every three months during the courseof ongoing IT therapy. Not all home care agency personnel arequalified to adequately monitor patients receiving IT therapy. If thepump is being refilled by a home care nursing service, it is importantthat the patient be seen at least quarterly by the treating team,whenever possible.

If a granuloma is suspected, a careful patient history and neuro-logic examination should be completed. Signs and symptoms com-monly associated with IT granulomas are listed in Table 4. If suchsigns and symptoms are reported, an imaging study should beobtained promptly to confirm or rule out granuloma (10). If a granu-loma is detected, the following factors should be documented: 1)the location of the granulomatous mass in relation to the cathetertip; 2) type of implant used; 3) length of time since implantation; 4)daily drug dose (mg) and volume; 5) highest achieved drug concen-tration; 6) histopathologic analyses (if surgical resection is neces-sary); and 7) any confounding factors, such as occurrence ofinfection or tumors (16). The presence of either infection or tumorsuggests that a granuloma is unlikely, and the identified diseaseshould be treated, as appropriate.

The PACC 2012 panel members acknowledged that detectinggranulomas by using imaging techniques could be challenging, as itmay be difficult to distinguish between a granuloma and asymp-tomatic catheter-tip fibrosis.

MRIFor most patients, the imaging modality of choice for diagnosinggranuloma is MRI. It is important that an MRI with contrast be used(if not contraindicated) because granulomas are more likely to bemissed if MRI is performed without the use of contrast. Granuloma-tous lesions are relatively isointense in T1-weighted images in rela-tion to the spinal cord (16). Additionally, T2-weighted scans thatreveal a hyperintense image with a hypointense rim (or ringenhancement) could indicate the occurrence of either spinal cordcompression or combined compression and local inflammation dueto the presence of a granuloma (16). Although MRI remains the goldstandard for detection and diagnosis of granuloma, routine use ofMRI for screening purposes might not be cost-effective becausegranulomas occur with a low frequency. Therefore, costs associatedwith MRI must be considered when recommendations are maderegarding the frequency of imaging tests. However, in the face of aneurologic deficit or unexplained increased pain, an MRI should beperformed.

CTIn cases where an MRI is not readily available or is cost prohibitive, orfor patients in whom MRI is contraindicated, a CT-myelogram can beused to detect IT catheter-tip granulomas. The procedure typicallyinvolves the injection of nonionic radiographic contrast through thepump side port or by a separate lumbar puncture below the level ofthe catheter entry site. To avoid complications or damage to thepump or catheter, contrast injection should be performed underfluoroscopic guidance with the use of the catheter access port kit(not the standard pump refill kit). If it is not possible to aspirate CSFfrom the access port, contrast should not be injected through theside port. The inability to aspirate CSF through the side port may because for concern but is not diagnostic for granuloma or catheterdisruption. In such cases, a CT-myelogram with injection of the con-trast directly into the CSF via a separate puncture is recommended.

2012 PACC RecommendationsPanel recommendations for the prevention of and screening for ITgranulomas are presented in Table 5.

Table 4. Signs and Symptoms Associated With Granuloma.

• New or different sensory symptoms (e.g., numbness, tingling, burning,hyperesthesia, hyperalgesia, hypothesia, anesthesia)

• New, occasional, or intermittent bowel or bladder sphincterdysfunction

• New motor weakness, change in gait, or difficulty walking• Any neurologic symptoms or signs that differ from baseline (e.g., reflex

changes, clonus)• Change in the character, quality, or intensity of pain• The need for frequent or large escalations of the daily drug dose to

maintain the analgesic effect• Only temporary alleviation of increasing pain after rapid dose

escalations• Reports of new radicular pain, especially at or near the dermatomal

level of the catheter tip

Table 5. 2012 Recommendations: Prevention, Diagnosis, and Treat-ment of Catheter-Tip Granulomas.

Prevention1. Use the lowest effective concentration and dose of IT opioid agents,

especially of morphine sulfate.2. Use bolus dosing instead of continuous infusion for IT drug

administration.3. Consider placing the tip of the intraspinal catheter in the lumbar

thecal sac, below the conus medullaris.4. Implement adjuvant therapy with nonopioid analgesics if concerned

about granuloma formation.5. Switch from IT opioid therapy to ziconotide if concerned about a

recurrence of granuloma.

Screening/detection1. Take patient history and perform physical examinations on patients

receiving IT opioid or baclofen therapy at least every three months.2. Routinely monitor patients receiving opioids or baclofen for prodromal

clinical signs or symptoms of granuloma.3. Monitor the yearly rate of increase in drug dose.4. Educate clinicians and radiologists about the radiologic signs of

granuloma.

MRI, magnetic resonance imaging; CT, computed tomography; IT,intrathecal.

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DEER ET AL.


TreatmentThe treatment of granuloma depends on the urgency of thepatient’s clinical condition and the impact of the granuloma onneurologic function. Treatment decisions can vary depending onwhether the patient is asymptomatic and has not experienced achange in pain level or the patient is symptomatic with neurologicimpairment and a loss of drug efficacy.

Figure 1 shows the consensus treatment algorithm for IT granu-lomas. In patients who display signs or symptoms of a granuloma,an imaging study (MRI or CT-myelogram) should be performed. Ifthe imaging study results are negative, but the signs/symptomspersist, an increase in the IT medication dose, a change in IT medi-cation, or repositioning of the IT catheter should be considered. Ifthe imaging study confirms the presence of a granuloma (Fig. 2), thetreatment course depends, in part, on the patient’s neurologicsymptoms. If the patient has a significant, progressive neurologicdeficit, prompt surgical removal of the granuloma should be con-sidered after consultation with a neurosurgeon or orthopedic spinesurgeon. If this is the patient’s first granuloma occurrence, one ofthe following interventions are recommended (10): 1) reduction inthe IT drug concentration, dose, or both; 2) switch to an alternateagent; 3) withdrawal of the catheter to a level 2 to 3 cm below the

Perform imaging study (MRI or CT-myelogram)

Patient has loss of pain relief consistent with granuloma development

Imaging study results are negative but increased pain persists Imaging study confirms presence of granuloma

Consider the following• Increase IT medication dose • Change IT medication • Add another synergistic IT

medication • Move IT catheter

Does patient have significant, progressive neurologic deficit?

No

Is this the first occurrence of a granuloma in this patient?

Yes

Arrange surgical consult

No

Avoid IT opioids in this patient and

switch to ziconotide

No

Is granuloma small and not impinging

the spine?

Yes Keep same

catheter

Replace orremove catheter

Consider the following• Move catheter down by 2-3 cm • Reduce drug concentration/dose • Change to another opioid (e.g., a

lipophilic agent) or ziconotide

Symptoms resolve Symptoms persist

Repeat imaging study in six months

Yes

Replace catheter; wean patient off IT opioids and replace with saline;

administer oral analgesics

or has significant changes in sensory, motor, or proprioceptive function

Figure 1. Algorithm for treatment of granuloma. MRI, magnetic resonance imaging; CT, computed tomography; IT, intrathecal.

Figure 2. Granuloma at T1-T2 as seen on magnetic resonance imaging. 11CATHETER-TIP GRANULOMA CONSENSUS


granuloma, a change that might result in a more beneficial drugdistribution; or 4) removal of the catheter. In order to minimizesurgical intervention, the distal catheter can be replaced and con-nected to the existing proximal catheter. This can be accomplishedby removing the indwelling catheter by direct vision and retraction.The patient should be alert during removal to inform the implanterof any paresthesia. Paresthesia or resistance to removal shouldresult in conversion to an open surgical removal at the time of theinitial attempt or at a later date if the implanter does not have theability to do a laminotomy or laminectomy and, as necessary, intra-dural and even microsurgical dissection. Forcibly removing thecatheter can result in significant neurologic injury. Once the cath-eter is successfully removed, a new catheter is placed in the stan-dard fashion with assurance of proper flow.

If, after the above steps are taken, the patient’s signs and symp-toms resolve, an imaging study should be repeated in six months.However, if signs and symptoms persist after the steps above arefollowed, the patient should be weaned off IT opioids, the pumpshould be filled with saline, and oral analgesics should be adminis-tered as needed until signs and symptoms resolve. Data exist tosupport the expectation that granulomas resolve with cessation oftherapy and instillation of preservative-free saline (8).

ConclusionThe occurrence of granuloma is now a well-recognized complica-tion of IT drug delivery, and it should be suspected in certain clinicalsituations. The panel has recommended steps to reduce occurrence,improve identification, and modify treatment to improve overalllong-term outcomes. Additional investigation is needed to furthercharacterize the natural history of granuloma formation, moreclearly define risk factors, and evaluate strategies for prevention andtreatment.

APPENDIXSurvey Questions on GranulomaIn May 2011, three detailed surveys on IT infusion use, safety, andreimbursement were sent to more than 15,000 physicians and clini-cians in the United States and internationally by the PolyanalgesicConsensus Committee. A total of 206 clinicians responded to thethree detailed surveys. Of those respondents, approximately 55%were licensed anesthesiologists, 8% were physical medicine andrehabilitation physicians, and 7% were neurosurgeons. Nearly halfof respondents (47.5%) were in private practice, 18% were in aca-demic institutions, and 11% worked in private hospital systems.More than 55% of respondents had been working in pain manage-ment for longer than ten years. Seventy-five percent of respondentsindicated that they dedicated at least 75% of their time to painmanagement in patient populations with an even distribution ofneuropathic and nociceptive pain pathologies.

Among respondents, 34.6% denied ever having a patient developa granuloma while under their care, 11.2% indicated they had had asingle patient in their practice develop a granuloma, and 29% indi-cated they had seen between two and five patients with a granu-loma. Of respondents who had seen at least one granuloma developin their patient population, 38% noted that the granuloma(s) haddeveloped while a programmable system was in use. Granulomawas confirmed via MRI 78.2% of the time; 32.3% of respondentsindicated that they had confirmed granuloma via CT-myelogram,12.3% via CT, and 23.0% via side port study (respondents wereallowed to select more than one answer).

After confirmation of granuloma, 41.5% of respondents con-sulted a neurosurgeon, 40.0% removed and replaced the catheter,26.1% repositioned the catheter, 13.8% left the catheter in place andmerely changed the drug, and 9.2% completely removed the cath-eter (respondents were allowed to select more than one answer).

These survey responses may be a helpful reflection of clinicalpractice but may have the limitations of recall bias, low responserate (which might cause a biased selection of those on either end ofthe granuloma spectrum), and question bias due to survey creationflaws.

Acknowledgements

Authors would also like to acknowledge the support provided bythe International Neuromodulation Society, the staff at the JournalNeuromodulation for publication support; Audrey J. Suh, PharmD,for contributions to manuscript drafting and preparations; S.William Stuart, RPh; and Linda Page M. Page, PharmD, fromMedtronic Neuromodulation.

Special acknowledgement: Christopher Bernards, MD.Sources of financial support: This project was supported by

grants from Medtronic, Inc. (Minneapolis, Minnesota, USA) and AzurPharma Ltd (Dublin, Ireland).

Authorship statement

Drs. Allen Burton, Eric Buchser, David Caraway, Michael Cousins,José De Andrés, Sudhir Diwan, Michael Erdeck, Eric Grigsby, MarcHuntoon, Marilyn Jacobs, Philip Kim, Krishna Kumar, Michael Leong,Liong Liem, Gladstone McDowell, Nagy Mekhail, Sunil Panchal,Richard Rauck, Michael Saulino, Peter Staats, Michael Stanton-Hicks,Lisa Stearns, B. Todd Sitzman, Mark Wallace, K. Dean Willis, WilliamWitt, and Tony Yaksh are contributing authors, attended multipleface-to-face and phone conferences, contributed greatly to thereview of the data and literature, evaluated the same, contributedsurvey questions and topics and contributed important intellectualinput to the overall manuscript, evaluated the content, and pro-vided feedback on the same.

Drs. Timothy Deer, Joshua Prager, and Robert Levy chaired theproject, led discussions, and garnered contributions from the con-sensus panel. Dr. James Rathmell performed a final review of themanuscript prior to final submission to the consensus panel forreview and approval.

How to Cite this Article:Deer T.R., Prager J., Levy R., Rathmell J., Buchser E.,Burton A., Caraway D., Cousins M., De Andrés J., DiwanS., Erdek M., Grigsby E., Huntoon M., Jacobs M., Kim P.,Kumar K., Leong M., Liem L., McDowell G., Panchal S.,Rauck R., Saulino M., Sitzman B.T., Staats P., Stanton-Hicks M., Stearns L., Wallace M., Willis K.D., Witt W., YakshT., Mekhail N. 2012. Polyanalgesic ConsensusConference—2012: Consensus on Diagnosis, Detec-tion, and Treatment of Catheter-Tip Granulomas(Inflammatory Masses).Neuromodulation 2012; e-pub ahead of print. DOI:10.1111/j.1525-1403.2012.00449.x

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