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

Yaksh, Tony L.; Hassenbusch, Samuel J.; Burchiel, Kim J.; Hildebrand, Keith R.; Page, Linda M.; Coffey, Robert J.

doi:10.1046/j.1526-4637.2002.02048.x

Cited by 155 publications

(177 citation statements)

References 40 publications

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“…In fact, morphine has the potential to induce the release of these proinflammatory cytokines directly: glial cells express opioid receptors (Maderspach and Solomonia, 1988) and chronic opioid treatment can induce the naloxone-reversible release of IL-1 from mixed brain cell cultures (Das et al, 1995). Thus, intriguing parallels may be found to recent clinical reports that long-term and/or high-dose intrathecal morphine administration is associated with the invasion of spinal tissue with immune cells and development of inflammatory masses at the catheter tip (for review, see Yaksh et al, 2002). Thus, in addition to evidence for glial inflammatory processes induced by shorterterm and lower-dose intrathecal morphine provided by the present study, intrathecal morphine has the capability of altering the function of immune cells as well.…”

Section: Discussionmentioning

confidence: 97%

A Role for Proinflammatory Cytokines and Fractalkine in Analgesia, Tolerance, and Subsequent Pain Facilitation Induced by Chronic Intrathecal Morphine

Johnston¹,

Milligan²,

et al. 2004

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The present experiments examined the role of spinal proinflammatory cytokines [interleukin-1␤ (IL-1)] and chemokines (fractalkine) in acute analgesia and in the development of analgesic tolerance, thermal hyperalgesia, and tactile allodynia in response to chronic intrathecal morphine. Chronic (5 d), but not acute (1 d), intrathecal morphine was associated with a rapid increase in proinflammatory cytokine protein and/or mRNA in dorsal spinal cord and lumbosacral CSF. To determine whether IL-1 release modulates the effects of morphine, intrathecal morphine was coadministered with intrathecal IL-1 receptor antagonist (IL-1ra). This regimen potentiated acute morphine analgesia and inhibited the development of hyperalgesia, allodynia, and analgesic tolerance. Similarly, intrathecal IL-1ra administered after the establishment of morphine tolerance reversed hyperalgesia and prevented the additional development of tolerance and allodynia. Fractalkine also appears to modulate the effects of intrathecal morphine because coadministration of morphine with intrathecal neutralizing antibody against the fractalkine receptor (CX3CR1) potentiated acute morphine analgesia and attenuated the development of tolerance, hyperalgesia, and allodynia. Fractalkine may be exerting these effects via IL-1 because fractalkine (CX3CL1) induced the release of IL-1 from acutely isolated dorsal spinal cord in vitro. Finally, gene therapy with an adenoviral vector encoding for the release of the anti-inflammatory cytokine IL-10 also potentiated acute morphine analgesia and attenuated the development of tolerance, hyperalgesia, and allodynia. Taken together, these results suggest that IL-1 and fractalkine are endogenous regulators of morphine analgesia and are involved in the increases in pain sensitivity that occur after chronic opiates.

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Section: Discussionmentioning

confidence: 97%

A Role for Proinflammatory Cytokines and Fractalkine in Analgesia, Tolerance, and Subsequent Pain Facilitation Induced by Chronic Intrathecal Morphine

Johnston¹,

Milligan²,

et al. 2004

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“…Hypotheses that could explain the formation of catheter tip inflammatory masses, such as foreignbody reaction to silicone and other catheter material, infection, catheter-tip design, and the infusate-especially opioid analgetics, have been proposed [9,11].…”

Section: Discussionmentioning

confidence: 99%

“…Drug concentration and dose are supposed to be potential causative factors in the formation of catheter-associated masses [9,10]. A strong evidence that inflammatory masses at the catheter tips are caused by highly concentrated morphine infusate was identified by Yaksh et al [11] in animal models.…”

Section: Introductionmentioning

confidence: 99%

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Epidural Granuloma by Dislocated Catheter Tip Associated with Spinal Cord Compression in High-Dose Intrathecal Morphine Therapy

R¹

2013

General Med

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Intrathecal drug delivery systems are an option for selected patients with chronic pain. Complications such as intrathecal catheter-tip inflammatory masses are already reported in literature. In the present case report we describe a patient suffering from neuropathic pain located on the anterior aspects of both thighs following failed back surgery. Two years after implantation of an intrathecal morphine pump system the patient experienced symptoms of a spinal cord compression with increasing radicular pain, especially after application of morphine bolus. Within this time frame the average daily intrathecal morphine hydrochloride dose was 3.2 mg per day and the total neuraxial morphine hydrochloride dose was 2460 mg. Magnetic resonance imaging revealed spinal cord compression from an epidural mass measuring 13×11×10 millimeters, originating from an epidural dislocation of the intrathecal catheter. After surgical removal of the mass, histological examination confirmed a disseminated formation of a granuloma. What makes this case so special, is the fact that the granuloma is not located intrathecally, but in the epidural space (epidural granuloma). The formation of a purely epidural granuloma due to a dislocated catheter tip has -according to our research -not been reported about up to the present.

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“…This use of high concentrations in human pumps has led to local toxicity. For opiates, the manifestation of this toxicity is the intrathecal granuloma [37, 116,[461][462][463]. Our group showed that the primary determinant for intrathecal opiate granulomas is the local concentration to which the tissue adjacent to the catheter tip is exposed [49, 51, 52].…”

Section: Drug Dosingmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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

Cited by 155 publications

References 40 publications

A Role for Proinflammatory Cytokines and Fractalkine in Analgesia, Tolerance, and Subsequent Pain Facilitation Induced by Chronic Intrathecal Morphine

A Role for Proinflammatory Cytokines and Fractalkine in Analgesia, Tolerance, and Subsequent Pain Facilitation Induced by Chronic Intrathecal Morphine

Epidural Granuloma by Dislocated Catheter Tip Associated with Spinal Cord Compression in High-Dose Intrathecal Morphine Therapy

Current and Future Issues in the development of spinal agents for the management of pain

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