Pain Medicine 2015; 16: 19–20 Wiley Periodicals, Inc.

Response to Ethics Forum: Low Dose Targeted Drug Approaches Need Highlighting and Consideration Dear Editor:

Traditional approaches to targeted drug delivery involve conversion of large doses of opiates to an intrathecal equivalent (300:1). Logically, it does not follow that if oral opioids fail, then equivalent dose intrathecal opioids would be any more effective. However, expanding on the groundbreaking work of Dr. William Witt, Dr Jay Grider, and Dr. Maged Hamza have demonstrated that weaning patients off of their oral dose equivalent, and allowing central nervous system receptors to “reset” results in a sustainable response to low dose intrathecal administration of opioids [1,2]. The mechanism of this reset, and the physiologic response to low doses of opioids combined with a new understanding of cerebrospinal fluid (CSF) “flow” appears to prevent central sensitization (thalamic) with resultant tolerance with predictable dose escalation, or eventual opioid induced hyperalgesia. The precise physiologic mechanisms are not yet clearly elucidated but are being actively studied. The article suggests that targeted drug delivery may not be economically sustainable. Evidence for this argument centers on cost of compounding medications and managing complications, including granuloma formation. Both of these concerns are addressed in the ultra-low dose targeted drug delivery approach. First, ultra-low dose opioid delivery involves daily doses of morphine equivalent no greater than 400 mg per day. Many patients are successfully treated with as little as 100 mg equivalent of morphine per day. Therefore, the traditional pump refill involves only 20 mL of commercially available preservative free morphine. This eliminates the costly custom compounding fees, keeps use of the pump on label, and reduces potential disaster from inadvertent pocket fill. To the Medicare patient ultra-low dose targeted delivery provides a significant advantage, in that Medicare part B covers the refill of these pumps. There is no charge to the patient’s “doughnut hole” through Medicare part D. From a pharmacy cost perspective, commercially available preservative free morphine costs as little as $300. In some dosing strategies, the refill interval could be extended to 6 months, not accounting for drug stability concerns. Making the yearly

In conclusion, the article highlights the failures of high dose approaches to intrathecal dosing of opioids, but it also exposes the promise of a new approach to targeted drug delivery. This paradigm shift deserves further scientific scrutiny, and indeed industry in partnership with academic institutions is actively performing robust clinical research to validate the new approach. The low dose strategy should cause all interventional pain management physicians to pause and rethink their traditional approach to conventional medical or intrathecal management of chronic benign pain. MICHAEL H VERDOLIN, MD Medical Director San Diego Region, Synovation Medical Group, Chula Vista, California, USA

References 1 Grider JS, Harned ME, Etscheidt MA. Patient selection and outcomes using a low-dose intrathecal

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I read with great interest the ethics forum case presentation by renowned physicians, Dr. Tim Deer and Dr. John Loeser. In this presentation regarding a search for balance with respect to targeted drug delivery several points made deserve clarification and expansion. In reality, the appropriate dose for opioids in targeted drug delivery may not have been clarified yet. It is clear, as pointed out, that high-dose oral and transdermal delivery of opioids has been an abject failure from the perspective of chronic benign pain management.

cost for drug as low as $600. Compared with traditional oral opiate dosing strategies, including oxycontin, the cost is nearly $5,000 a year. Custom compounded high dose intrathecal medication preparation is costly but is actually cheaper than oral or transdermal medication in a year over year basis. Second, with respect to granuloma formation, it is widely agreed that granuloma formation occurs based on the incredibly high concentration required in compounded opiates for traditional intrathecal delivery. At concentrations greater than 25 mg per cc of morphine, in a very low flow state, granuloma formation has been shown to develop likely as a result of mast cell degranulation due to histamine release. With ultra-low dose approaches, and traditional commercially available preservative morphine concentrations, this has not been described to cause granuloma. This then allows placement of the intrathecal catheter closer to the site of action, that is, higher than T12 in the case of post laminectomy syndrome, at T8-9 for example. This fulfills the point of intrathecal targeted drug delivery, which is chemical neuromodulation at the intended site of action. Combining this information with the newly published paradigm shift in our understanding of CSF “flow,” oscillation in reality, this makes more sense. Indeed, I have several patients who have been stable now for nearly 4 years at the same dose of commercially available preservative free morphine, who had previously been on gargantuan doses of oral medications. They submitted to a weaning protocol, were successfully trialed and implanted, and there has been no significant dose escalation. These numerous experiences have caused me to look at targeted drug delivery in a whole new light.

Verdolin opioid trialing method for chronic nonmalignant pain. Pain Physician 2011;14(4):343–51.

life in chronic pain patients treated with continuous intrathecal drug therapy. Pain Med 2011;12(4):571–6.

2 Hamza M, Doleys D, Wells M, et al. Prospective study of 3-year follow-up of low-dose intrathecal opioids in the management of chronic nonmalignant pain. Pain Med 2012;13(10):1304–13.

4 Coffey RJ, Burchiel K. Inflammatory mass lesions associated with intrathecal drug infusion catheters: Report and observations on 41 patients. Neurosurgery 2002;50(1):78–86; discussion 86–7.

3 Perruchoud C, Eldabe S, Durrer A, et al. Effects of flow rate modifications on reported analgesia and quality of

5 Brinker et al. A new look at cerebrospinal fluid circulation. Fluids Barriers CNS 2014;11:10.

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Response to ethics forum: Low dose targeted drug approaches need highlighting and consideration.

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