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*University of Sydney Pain Management and Research Institute and
Department of Radiology, Royal North Shore Hospital, St. Leonards, Australia
Address correspondence and reprint requests to Paul M. Murphy, MB, MRCPI, FCARCSI, University of Sydney Pain Management and Research Institute, Department of Radiology, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia. Address e-mail to: drpmurphy{at}hotmail.com
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| Introduction |
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motor neurons. Significant spasticity is associated with numerous problems, including poor perineal hygiene resultant upon adductor spasm, contractures, and decubitus ulceration, which all adversely affect on the individual's quality of life. Several pharmacological and surgical options may be used in the treatment of patients with severe SCI-induced spasticity. Surgical options have included ablative procedures, such as anterior or posterior root rhizotomy, myelotomy, and myotomy; however, these procedures are associated with significant morbidity, including therapeutic failure, loss of residual neurological function, and muscle atrophy. A number of clinical reports suggest that spinal cord stimulation may have a role in ameliorating spasm post-SCI; however, this therapeutic modality has thus far failed to gain widespread acceptance (2). A number of drugs have been used in the management of SCI-associated spasm, including diazepam, dantrolene, and botulinum toxin A. Potential roles have also been suggested for the a2-adrenergic agonist, clonidine, the gamma-aminobutyric acid (GABA) analog, gabapentin, and the imidazole derivative, tizanidine. Despite extensive research into all of these therapeutic options, the GABAB receptor agonist baclofen remains pivotal in the management of post-SCI spasticity. Baclofen seems to mediate its effect by binding to presynaptic GABAB receptors, inhibiting calcium influx, and thus excitatory neurotransmitter release. It has been shown to be extremely effective in reducing both increased flexor tone and the frequency and severity of flexor and extensor spasms and, in addition, has been effective in both complete and incomplete cord transection (3). Baclofen is commercially available as both 10- and 20-mg tablets, and careful titration is required to identify the optimal dosage for each individual patient. The initial dose is often 1015 mg/d gradually increasing to a maximal dose of 80 mg/d, although occasionally much larger doses may be required. Because baclofen predominantly undergoes direct renal elimination, it must be administered with caution in the setting of renal impairment to avoid excessive neurological side effects including, drowsiness, dizziness, insomnia, confusion, and ataxia. Withdrawal phenomena including anxiety, convulsions, tachyarrhythmias, and both auditory and visual hallucinations have been reported after abrupt discontinuation of the drug. Overdose has been associated with respiratory depression, coma, and seizure activity, and the seizure threshold may be reduced in epileptic patients. When effective symptom control cannot be achieved using oral baclofen administration, intrathecal (IT) delivery can offer improved symptom control and a lower side effect profile.
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| Discussion |
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The efficacy of IT baclofen administration in patients who have failed oral therapy has been demonstrated in a double-blind, randomized, crossover study (6). Twenty patients suffering from spasticity secondary to SCI or multiple sclerosis were followed for a mean period of 19.2 months after commencement of IT baclofen administration. Significant reductions in muscle tone and spasm severity were demonstrated. The study was complicated by two episodes of catheter displacement and one episode of pump failure; however, no significant side effects attributable to baclofen were noted. The authors concluded that IT administration is an effective and safe long-term therapy in the management of patients with spasticity of spinal origin that is unresponsive to oral baclofen therapy. In addition, IT baclofen administration has a potential role in the management of central pain (7,8) and has been classified as a fourth-line drug when used in a pain management capacity (9).
In 1991, North et al. (10) reported the first case of an IT catheter tip inflammatory mass in a patient receiving morphine. Since then, there have been multiple reports of catheter-associated masses (1116). A review of 41 cases compiled from the medical literature (16 cases) (as of November 2000) and from clinical reports (25 cases) to Medtronic Inc or to the U.S. Food and Drugs Administration revealed that in all cases, the IT drug delivery system was used in the management of a chronic pain condition. Drugs used included morphine or hydromorphone, either alone or in combination with another drug. The mean duration over which patients had been receiving IT drugs was 24.5 months. Importantly, catheter-associated masses were not described in any patient who had received baclofen as their only IT drug (17). Of the 41 patients reported, 30 underwent surgery to relieve spinal cord or cauda equina compression, and 11 were rendered nonambulatory. Increased physician awareness and a postal survey in 2001 resulted in an additional 51 cases being reported (18). These reports described noninfectious chronic inflammatory masses surrounding the tip of the IT drug delivery catheter; clinical indications for therapy and IT drugs used closely paralleled those described by Coffey and Burchiel (17).
In a review of the 92 cases identified by Yaksh et al. 18 between 1990 and 2002, most patients (74 cases) received their IT drug delivery system for the management of chronic noncancer pain. The main duration of therapy was 29 months; 46 patients received morphine alone, whereas a further 11 received it in combination with other drugs (bupivacaine, tetracaine, or clonidine). Dosage information data were available in 40 patients, 12 of whom were treated with the dose <10 mg/d, with 2 groups of 14 patients each receiving 1014 mg/d and >15 mg/d of morphine. The IT morphine concentration was >50 mg/mL in 18 of the 30 patients in whom the concentration was reported. Other drugs that were in use at the time of catheter tip mass diagnosis include hydromorphone, either alone (seven cases) or in combination (eight cases), tramadol (one case), and fentanyl (one case). No drug information was available in 18 cases. There was, however, no report of a catheter-associated inflammatory mass in a patient who had received baclofen as the only IT drug. The presenting symptoms that led to the diagnosis of catheter-associated mass were reported as loss of drug efficacy or onset of new neurological symptoms, including radicular pain, para/monoparesis, and cauda equina syndrome.
Radiological confirmation was obtained with MRI in 45 cases, myelogram with or without CT in 17 cases, and MRI, myelogram, and CT in 4 cases. Patients in whom the catheter-associated mass did not fill the spinal canal or cause neurological impairment were effectively treated by discontinuing the IT infusion or replacing it with sterile normal saline infusing at a minimal infusion rate, with resultant stabilization or resolution of the mass. In patients demonstrating neurological sequelae, prompt neurosurgical intervention was warranted. Using data obtained from these cases, the estimated cumulative risk of developing an IT mass in the chronic pain population has been reported as 0.04% over one year, 0.12% over two years, and extending to 1.15% over six years. Because no cases have been reported that involved patients treated with IT baclofen for spasticity, incidence and relative risk rates were only calculated for patients treated using IT drug pumps for chronic pain. These studies concluded that patients receiving large-dose IT opioid either as a sole drug or in an admixture, or those receiving drugs not approved for IT administration, should be monitored closely for evidence of IT mass formation and prompt action should be taken if required.
Potential mechanisms for catheter tip granuloma formation have included catheter-based mechanisms, such as catheter tip design, placement-associated trauma, final tip position, infection, and silicone hypersensitivity, and drug-related mechanisms, such as impure/contaminated drugs and the action of opioid agonists on immunological function and the blood-central nervous system barrier. Chronic infection has effectively been discounted as a potential cause because of the absence of positive microbial staining and culture in human reports and experimental animal models (10,11,18). Endotoxin-induced aseptic meningitis-like mechanisms (19) have been proposed; however, IT morphine sulfate has been shown to be a nonendotoxin inducer (20). Initial case reports involved a catheter design in which a single hole was used; however, more recent reports have involved newer closed-end multi-hole catheters, a design which was considered less likely to provoke granuloma formation. Silicone allergy is also an unlikely mechanism, given that granuloma formation only occurs at points of active drug infusion and has not been demonstrated on silicone lumbar shunts or silicone breast implants (2123).
In their sentinel paper, North et al. (10) raised the possibility of arachnoiditis as an important etiological factor; however, the reports of granuloma formation in the absence of previous spinal surgery argue against this. Previous spinal surgery can lead to the formation of blind ending pouches, which by influencing local drug concentration, may modulate the process of granuloma formation. Implantation-associated trauma has been suggested as a possible cause; however, the prolonged latency period would seem to argue against this (17,24). An outbreak of granuloma formation was reported consequent upon drug contamination; however, this seems to be an isolated event (25). The most plausible explanations for IT granuloma formation synthesized from animal and human data include the properties of the IT drug (particularly morphine), cerebrospinal fluid (CSF) flow dynamics, and possibly catheter tip location (17). Large-dose IT morphine administration has been demonstrated to induce catheter tip granuloma formation in a canine model (26). These masses consisted of multifocal accumulations of neutrophils monocytes, macrophages, and plasma cells. Whether this is a µ receptor-mediated response, or a local effect of morphine glucuronide metabolites, remains to be elucidated. In an animal study (26), a mild local pericatheter response consistent with foreign body reaction was demonstrated in all animals including the saline-treated control group. This local pericatheter reaction was no more florid in those animals that later developed a catheter tip-associated granuloma than in the control group; however, it has been proposed that this local foreign body response may be a required continuing stimulus for granuloma formation (26). Experimentally, in a canine model, chronic IT baclofen delivery (2 mg/mL) for a 28-day period was not shown to result in granuloma formation (18), but this does not exclude the -potential for this complication in long-term infusion. The possibility of a role for regional CSF flow dynamics, which determine local drug concentration, must be considered.
In the setting of significant spinal cord trauma, spinal cord trauma syringomyelia or myelomalacia have been suggested to be associated with altered CSF flow dynamics, which may be demonstrable on MRI (27). It is possible that significantly altered CSF dynamics may result in increased local drug concentrations, thereby increasing the potential for granuloma formation. Additionally, it is plausible that the trauma of repeated-catheter implantations may induce a localized inflammatory response that may be sufficient to induce granuloma formation irrespective of the drug administered.
A consensus paper has established guidelines for the prevention, diagnosis, and management of catheter tip-associated masses (Table 1) (28). The authors point out that baclofen-associated masses have not been reported and that, therefore, the guidelines are predominantly concerned with patients receiving IT opioids. They suggest that baseline neurological variables should be assessed and closely monitored for early signs of neural compression by an expanding IT mass.
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Preventive measures suggested include maintaining the IT opioid dose and concentration at a small level and lumbar versus thoracic placement of the catheter, although this may simply reduce the potential neurological sequelae of granuloma formation. Any alteration in drug efficacy or neurological status must alert the attending physician to the possibility of a catheter-associated mass, and appropriate investigations must be undertaken. Noninvasive diagnosis may be effectively achieved using either CT-myelogram or T1-weighted MRI. A number of acceptable therapeutic options are available depending upon the patient's clinical status. Surgical removal and decompression are considered preferable in situations where there is profound or progressive neurological impairment. For small masses diagnosed during investigation of diminished analgesic efficacy, discontinuation of IT drug delivery or withdrawal of catheter to a lower IT site may be associated with significant shrinkage or disappearance of the mass (17).
IT drug delivery systems are frequently used in the management of chronic pain states and spasticity. This method of drug delivery provides an effective method for symptom control when oral administration proves ineffective, or is associated with intolerable side effects. Perhaps the most significant potential complication associated with this system is the development of a catheter-tip associated inflammatory mass. Not only can this complication reduce the efficacy of the drug delivery system, but it may also cause serious neurological sequelae. Granuloma formation has been demonstrated only in the presence of chronic IT opioid administration and, consequently, all consensus recommendations relate to delivery of this drug group only. In reporting the first case of IT granuloma associated with baclofen, we suggest that the consensus recommendations for catheter-associated granuloma prevention, diagnosis, and treatment (28) must additionally be applied to all patients receiving prolonged IT administration of baclofen, particularly in the setting of SCI and potential derangement of CSF flow dynamics.
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R. J. Coffey and J. W. Allen Not All Intrathecal Catheter Tip MRI Findings Are Inflammatory Masses Anesth. Analg., June 1, 2007; 104(6): 1600 - 1602. [Full Text] [PDF] |
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S. N. Narouze and N. A. Mekhail Intrathecal Catheter Granuloma with Baclofen Infusion Anesth. Analg., January 1, 2007; 104(1): 209 - 209. [Full Text] [PDF] |
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M. J. Cousins and P. M. Murphy Intrathecal Catheter Granuloma with Baclofen Infusion Anesth. Analg., January 1, 2007; 104(1): 209 - 210. [Full Text] [PDF] |
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