The two letters by Drs. McMillan and Aldrete address the clinical issues raised in the two Laboratory Investigations published in Anesthesiology1,2with respect to intrathecal morphine–induced granuloma formation. There is little doubt that the studies reflect the potential for granuloma formation in the human patient and are in accord with the literature that is beginning to appear with increasing frequency since the first reports in 1991 by North et al. 3We would make three points.
The preclinical studies emphasize the likely role of concentration as in important contributor to these observed effects. Historic perusal of the daily morphine doses used since the inception of long-term spinal morphine as a therapy for chronic pain has typically revealed that it has been remarkably stable at somewhere between 5 and 10 mg/day (see the retrospective survey by Yaksh and Onofrio4and the recent consensus conference proceedings5). Although there are no systematic data, to the best of our knowledge, the earlier (1980s) use typically employed concentrations on the order of 10 mg/ml. The reports of granulomas, in contrast, although using similar daily doses, have all used concentrations in excess of 20–25 mg/ml.6
The time course of granuloma development, as evidenced by changes in behavioral function, clearly occurred by 2–4 weeks and corresponded with the development of the granuloma. This raises two issues. The time course of the human condition “appears” much longer. Although this may reflect the conditions relevant to the dog and sheep spinal canals, we suspect that the true time of onset in humans is not known. Clearly, the temporal development of neurologic signs may reflect the progressive refill-to-refill incrementation of drug dose/concentration over the early days of the infusion.
In reference to Dr. Aldrete’s comments, the evolution of neurologic signs in the animals, as indicated in the articles, are erratic. This would be expected of any slowly growing mass, where the deficit depends on the particular locus and degree of compression. In recent work, we have followed granuloma development in dogs with magnetic resonance imaging and have demonstrated that masses may occur at intervals as short as 7 days and that, as expected, the evolution of the behavioral deficit corresponded with the growth and spatial disposition of the mass (e.g. , compression of the dorsal midline leading to allodynia but no motor deficit, encroachment of the mass on the dorsolateral and ventral aspects leading to caudal spasticity). This emphasizes that the absence of a neurologic sign is no guarantee of the absence of a mass. This is clearly the message arising from the excellent report of McMillan.7
Many issues remain. From a practical standpoint, we do not know the time course versus spinal dose in humans (although concentrations may be clearly relevant). If a patient undergoes imaging and is negative for a mass, will there be any mass development over time if there is no change in infusion parameters? Of equal importance, once a granuloma is noted, will it resolve if the infusion is turned off or if the catheter location is altered? What is the pharmacology of the process leading to the granuloma formation? Preclinical imaging studies should allow some of these questions to be addressed.
In the meantime, as nonclinical contributors to the conversation, we would counsel caution. If the benefits of higher concentrations to permit extended refill intervals are weighed and found advantageous, care should be exercised in the form of some imaging at an early interval. Should imaging be repeated if there are no changes? At the moment, we do not know. One of the interesting aspects of our studies was that in animals with granulomas, cerebral spinal fluid morphine concentrations decreased remarkably in the cisterna, although plasma concentrations were as expected. This suggests that there was an enhanced clearance of the cerebral spinal fluid morphine, perhaps secondary to a misdistribution and increased local dural clearance. Our current work suggests that epidural fat levels adjacent to the granuloma show very high morphine concentrations. Perhaps one telling indication of something being amiss is the apparent loss of analgesia with a given dose.
* University of California, San Diego, California. email@example.com