Research Update: Toxicology of Intrathecalmorhine
Continuous intrathecal infusion of morphine is widely used in chronic pain management. In spite of, and perhaps because of, its long history of use, there have been no systematic safety studies on the effects of continuously infused morphine sulfate. Now convergent preclinical and clinical observations suggest the consequences of this omission.
Preclinical observations
Recently, we examined the effects of intrathecal morphine sulfate infused over 28 days in the chronically catheterized canine model (Yaksh and Malkmus, 1999) at 1 ml/day in concentrations from 1.5 to 12 mg/ml. We found a time and concentration-dependent increase in the severity of motor dysfunction expressed as increased hind limb motor tone. Histopathology revealed modest pericatheter reaction in all animals. However, at higher morphine concentrations, an inflammatory mass consisting of multifocal accumulations of neutrophils, monocytes, macrophages and plasma cells developed at the catheter tip that produced a local compression of the spinal cord. Aside from compression, there were no other changes in spinal morphology, indicating that even high concentrations of morphine had no direct effect upon axons or cell bodies. Though a reaction was observed at lower doses, at concentrations / doses of 12 mg/mL/day, all dogs displayed granuloma formation. In these dogs, there was a significant increase in cisternal CSF protein and WBC's but not glucose as compared to other treatment dogs that did not develop granulomas. More recently, similar results have been observed in rats (J. Allen, T. Hofer and T. Yaksh, unpublished observations) and in sheep (S. Hassenbusch, personal communication).
Human clinical reports
Seven clinical case reports describe patients receiving chronic morphine infusion who present with a motor or sensory dysfunction secondary to a local compressive lesion. (North, et al, 1991; Aldrete, et al, 1994. Bejjani, et al 1997; Blount, et al, 1996. Schuchard, et al, 1998. North, et al, 1991. Blount et al, 1996; Cabbell et al, 1998; Langsam, 1999, Anderson, et al 2001). In an extensive review by Burchiel and Coffey (2002), 16 previously reported cases and an additional 25 patients receiving high dose opiate infusion between 1990 and 2000 are presented. In humans where masses were surgically resected, the typical histology emphasized, as in the dog, the presence of macrophages, neutrophils and monocytes, with a necrotic center and no evidence of an infectious process (Cabell et al (1998); Langsam, et al 1999). The time required for granuloma development is not certain, as therapy involves progressive incrementation of concentrations and doses over an extended period, but in the Coffey and Burchiel review, only 4 patients had received infusion for less than 6 months. The onset of the neurological symptoms in 23 patients was characterized as sudden in 6 patients, sudden with prodromal symptoms in 2 and slowly progressing in 15.
Underlying mechanisms of intrathecal morphine-induced granuloma
Several possible mechanisms may be considered.
Reaction to catheter or infusion. Current evidence emphasizes that neither the infusion nor the catheter alone is a sufficient explanation. In the canine model, the granulomatous reaction is not observed with low morphine concentrations or with certain other agents including baclofen, clonidine, adenosine, neostigmine (Sabbe et al, 1993, Chiari et al, 1999 Yaksh et al, 1995; unpublished observations). In humans, the doses of morphine associated with granulomas frequently exceeded 20-25 mg/day. Moreover, in spite of its extensive use, I am not aware of any report to date indicating that intrathecal baclofen is associated with granuloma formation. Infection. Failure in the dog to obtain positive CSF or infusate cultures, the absence of positive stains for bacteria in the resected material, and normal CSF glucose emphasizes that the granuloma is not an infectious process. These observations are corroborated by case reports.
Opiate receptor activation. Do the effects of morphine represent an opioid receptor mediated effect? High concentrations of intrathecal morphine produce an allodynia and hyper-reactivity in several species that is not naloxone reversible and may be related to the formation of morphine 3 glucuronide (Yaksh et al, 1986; Yaksh and Harty, 1988). Whether the granuloma can be evoked by other µ opioids or metabolites is not clear. Human data suggests that chronic intrathecal hydromorphone infusion is also associated with granulomas (Burchiel and Coffey, 2001).
Morphine actions. What is the mechanism by which morphine exposure leads to the observed accumulation of these vascularly-derived inflammatory cells? Although µ opioids acting though µ receptors are reported to have a suppressive effect upon chemokine-mediated cell migration (Makman et al, 1995, Choi, et al, 1999), others have shown that morphine serves as a mitogen, activating lymphocyte activity (Chuang et al, 1997). Opiates can initiate release of nitric oxide in human endothelial cells (Stefano, 1998). The continued exposure of immunocytes to morphine in vitro leads to an exaggerated response of monocytes to other pro-inflammatory stimuli. (Stefano, et al, 1995). These observations lead to a working hypothesis that morphine at elevated concentrations and persistent exposure may activate nitric oxide synthase in meningeal vasculature and initiate a cascade that serve to increase local capillary permeability to these activated cells.
Clinical Relevance
At a consensus conference on the continuous infusion of spinal drugs for chronic pain management, several points were noted: morphine is the principle agent employed; that doses up to 20 mg/day were "acceptable" and that concentrations should be adjusted to allow as long an interval between refills as possible (Bennett et al, 2000). Given that patients may receive up to 20 mg/day with long pump refill intervals, it is likely that patients routinely receive morphine at concentrations which exceed even that which is commercially available (e.g. 25 mg/mL), employing concentrations of morphine which are at or near the absolute solubility of morphine sulfate (e.g. 50-55 mg/mL). Market research indicates that approximately 80% of morphine used in implanted pumps is compounded (K Hildebrand, Medtronic Corp. personal communication). We hypothesize, but have not proven, that high concentrations (as compared to total dose) delivered at low infusion rates may account for an increased risk in developing a catheter-tip granuloma.
In view of the efficacy of spinal morphine in the management of various chronic pain syndromes, what should be the practical consequences of these observations? Given: i) the fact that every patient does not develop a granuloma, ii) the absence of definitive data implicating the importance of concentration as opposed to total daily dose, and iii) the advantages of achieving long pump refill intervals with high concentrations, many practitioners will doubtless make the clinical judgment to continue to employ elevated infusate concentrations.
So what is to be done? Medtronic disseminated a "Dear Colleague" letter which indicated the need to consider an inflammatory mass as a potential differential diagnosis in the face of: i) new or different sensory symptoms; ii) occasional/intermittent bowel or bladder dysfunction; iii) new motor symptoms and iv) any neurological symptom that differs from baseline. They suggest that whenever an intraspinal mass is suspected, the case and condition should be thoroughly evaluated, a neuroimaging procedure (MRI) or myelography be performed and surgical decompression considered. At present we cannot say that changing to another opiate or to a lower morphine concentration is a solution. Vigilance and suspicion are critical.
It is important to note that the human observations reflect upon the need to undertake appropriate preclinical observations. The highest concentration previously examined in a large intrathecal animal (dog) model was 10mg/mL given as a daily bolus for 28 days (Sabbe, et al 1993). Hence, until the preclinical studies outlined here, the actual formulation being delivered in humans had never been examined systematically much less with continuous intrathecal infusion. Moreover, while many patients start with morphine, over half will receive either other opioids alone including hydromorphone, methadone, fentanyl, or meperidine, or admixtures of morphine and bupivacaine or clonidine (Bennett et al, 2000a). Without exception, systematic safety evaluations have not been accomplished for these agents alone or in combination. Further, even for those agents that have been studied (as with morphine), the relevance of even the best safety evaluation is minimized when the parameters of clinical drug exposure exceed those examined. To paraphrase Paracelsus....there are no safe drugs, only safe doses.
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Acknowledgment: Work supported in part by DA02110, GM48085 and Medtronic Inc. I would like to thank Kjersti Horais, Jeff Allen Ph.D. and Nicolle Tozier for their contributions to the work cited herein.
Tony L. Yaksh, Ph.D.
Vice chair for Research
Department of Anesthesiology
University of California, San Diego
La Jolla, Ca, 92093
tyaksh@ucsd.edu
