Intrathecal Granuloma in Patients Receiving High‐dose Intrathecal Morphine Therapy: A Report of Two Cases

Anderson, Susan R.; Orbegozo, Mauricio; Racz, Gabor B.; Raj, Prithvi

doi:10.1111/j.1533-2500.2001.01008.x

Cited by 12 publications

(17 citation statements)

References 39 publications

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“…North et al (4) were the first to report the formation of a granuloma composed of inflammatory tissue surrounding the tip of an infusion catheter during the intrathecal administration of morphine. This finding was confirmed by subsequent reports (5)(6)(7)(8). The prevalence of granuloma induced by morphine (Infumorph) is 0.5-3% (9)(10)(11)(12), but the real number of events may be incompletely reported.…”

supporting

confidence: 61%

A Mast Cell–Specific Receptor Is Critical for Granuloma Induced by Intrathecal Morphine Infusion

Zhang

Liu

Che

et al. 2019

The Journal of Immunology

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Intrathecal morphine infusion is often applied to treat chronic pain related to cancer and other conditions. However, persistent pain can be caused by nerve compression because of granuloma formation. In this study, a mouse model of morphine-induced granuloma formation by intrathecal catheterization morphine infusion into the atlanto-occipital membrane of the foramen magnum was established in wild-type mice, MrgprB2 mutant (MrgprB2 2/2) mice, and in mast cell-deficient W-sash c-kit mutant (Kit W-sh/W-sh) mice. Heat-related pain after surgery was performed to investigate the antipain effect of morphine. H&E staining and immunofluorescence staining of the spinal cord were applied to analyze the mechanism of granuloma formation. Morphineinduced mast cell degranulation was assessed by measuring the Ca 2+ influx and mediator release. Anaphylactoid reactions were measured after s.c. morphine infusion to the paws. Chemokine release by mast cells was determined by Human XL Cytokine Array. Experiments with wild-type, MrgprB2 mutant, and mast cell-deficient W-sash c-kit mutant mice demonstrated that morphine activated mast cells and inflammatory cell aggregation through MrgprB2 in intrathecal infusion sites. The chemokine production of human mast cells demonstrated that granuloma formation is correlated with chemokines release. In addition, morphine activated mouse primary mast cells and de novo chemokine synthesis via the MRGPRX2 in human LAD2 cells. We concluded that granuloma formation during intrathecal morphine infusion was associated with MrgprB2/X2. Reducing MRGPRX2 potentially blocks morphine-induced side effects, including granuloma formation.

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supporting

confidence: 61%

A Mast Cell–Specific Receptor Is Critical for Granuloma Induced by Intrathecal Morphine Infusion

Zhang

Liu

Che

et al. 2019

The Journal of Immunology

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“…Before the 2002 review by Coffey and Burchiel, etiologic hypotheses included drug‐related mechanisms, infection, pyrogens, silicone hypersensitivity, surgical trauma, catheter‐tip design, and predisposing patient conditions, such as arachnoiditis [1–8, 16,17]. Other possible hypotheses include catheter tip location, impure or contaminated drugs, and the effects of opioid drugs on the immune system and/or the blood–central nervous system (CNS) barrier (Table 13).…”

Section: Discussionmentioning

confidence: 99%

“…Recently reported cases were similar to previously reported ones. These reports typically described chronic inflammatory masses that were not infectious in origin and that surrounded the tip of intrathecal drug administration catheters in patients treated for chronic intractable pain [1–7]. Previous investigators described a variety of clinical scenarios that appeared to be associated with growth of the masses and that differed from the fibrotic reaction that occurs around the tip of chronically implanted epidural catheters [8–14].…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Masses Associated with Intrathecal Drug Infusion: A Review of Preclinical Evidence and Human Data

et al. 2002

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Objectives. The phenomenon of inflammatory masses at the tips of intrathecal drug administration catheters was the subject of a recent case-compilation report and a number of animal studies. We sought to synthesize current clinical and preclinical data to formulate hypotheses about the etiology of catheter-tip masses.Methods. We reviewed the published human clinical data, new unpublished clinical data, and the results of preclinical studies in two mammalian species, beagle dogs and sheep.Results. Intrathecal morphine sulfate studies in beagle dogs suggested that the observed inflammatory reaction was dose or concentration dependent. Masses occurred after 28 days in one of three animals at 1.5 mg/day (the lowest morphine dose tested); in two of three animals at 3 and 9 mg/day; and in three of three animals at 12 mg/day. The addition of various amounts of clonidine to 1.5 mg/day of morphine revealed no mass formation when the clonidine dose was Ͼ 0.25 mg/day. A morphine sulfate study that was performed in sheep using a commercially marketed drug administration system found catheter tip masses in two of three animals that received 12 or 18 mg/day of morphine, the highest doses tested. Human cases have occurred only in pain patients who received intrathecal opioids, alone or mixed with other drugs, or in patients who received investigational agents (such as superoxide dismutase or the partial -opioid-receptor agonist, tramadol) that were not labeled for long-term intrathecal use.Discussion/Conclusions. The evidence suggests that the long-term administration of opioids, especially morphine, caused the masses that were observed in humans and in two species of animals. A relationship probably exists between mass formation and intrathecal morphine doses or concentration. Other factors remain to be investigated.

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“…The most commonly reported treatment for masses that caused significant or rapidly evolving neurological deficits was complete or subtotal surgical removal. Patients with apparently fixed deficits of short duration also have been operated upon because of concern that delayed treatment could foreclose the possibility of neurological recovery [1,2,12–14,20–22]. Surgical intervention to remove the mass and/or decompress the spinal canal has restored neurological function or prevented further neurological deterioration in several reported cases [2].…”

Section: Treatment Of the Mass And Management Of The Drug Infusion Symentioning

confidence: 99%

Management of Intrathecal Catheter-Tip Inflammatory Masses: A Consensus Statement

et al. 2002

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Objectives. In a companion article, we synthesized current clinical and preclinical data to formulate hypotheses about the etiology of drug administration catheter-tip inflammatory masses. In this article, we communicate our recommendations for the detection, treatment, mitigation, and prevention of such masses.Methods. We reviewed published and unpublished case reports and our own experiences to find methods to diagnose and treat catheter-tip inflammatory masses in a manner that minimized adverse neurological sequelae. We also formulated hypotheses about theoretical ways to mitigate, and possibly, prevent the formation of such masses.Results. Human cases have occurred only in patients with chronic pain who received intrathecal opioid drugs, alone or mixed with other drugs, or in patients who received agents that were not labeled for long-term intrathecal use. Most patients had noncancer pain owing to their large representation among the population with implanted pumps. Such patients also had a longer life expectancy and exposure to intrathecal drugs, and they received higher daily doses than patients with cancer pain. Clues to diagnosis included the loss of analgesic drug effects accompanied by new, gradually progressive neurological symptoms and signs. When a mass was diagnosed before it filled the spinal canal or before it caused severe neurological symptoms, open surgery to remove the mass often was not required. Anecdotal reports and the authors' experiences suggest that cessation of drug administration through the affected catheter was followed by shrinkage or disappearance of the mass over a period of 2-5 months.Conclusions. Attentive follow-up and maintenance of an index of suspicion should permit timely diagnosis, minimally invasive treatment, and avoidance of neurological injury from catheter-tip inflammatory masses. Whenever it is feasible, positioning the catheter in the lumbar thecal sac and/or keeping the daily intrathecal opioid dose as low as possible for as long possible may mitigate the seriousness, and perhaps, reduce the incidence of such inflammatory masses.

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Intrathecal Granuloma in Patients Receiving High‐dose Intrathecal Morphine Therapy: A Report of Two Cases

Cited by 12 publications

References 39 publications

A Mast Cell–Specific Receptor Is Critical for Granuloma Induced by Intrathecal Morphine Infusion

A Mast Cell–Specific Receptor Is Critical for Granuloma Induced by Intrathecal Morphine Infusion

Inflammatory Masses Associated with Intrathecal Drug Infusion: A Review of Preclinical Evidence and Human Data

Management of Intrathecal Catheter-Tip Inflammatory Masses: A Consensus Statement

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