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APS Bulletin • Volume 6, Number 6, November/December 1996
Innovations in Practice
Richard B. Patt, MD, Department Editor
Cell Therapy for Cancer Pain Management
Frederick W. Burgess, MD PhD
The recognition and treatment of pain associated with cancer have progressed substantially over the last decade. Barriers to effective pain control are gradually falling as clinical providers learn to better assess their patient's painful symptoms and to offer treatment focused primarily on pain reduction. With the availability of newer medication delivery systems, improvements in pain control and quality of life follow. Despite these many improvements in the availability of analgesics and a willingness to aggressively address the pain control issue, many patients continue to suffer from inadequate pain relief. This problem persists for several reasons (Jacox, Carr, & Payne, 1994), including the overlapping situations of pain resistant to opioid therapy and impaired quality of life secondary to analgesia-induced complications. In some individuals, the systemic administration of an opioid will produce unacceptable side effects, such as sedation, nausea, and dysphoria. This circumstance may persist despite trials of many different opioids and the use of adjuvant medications directed at selected side effects or used for their opioid-sparing effects. Unfortunately, the addition of pharmacologic adjuvant therapy may contribute to additional serious side effects and adverse reactions. Examples include bleeding complications with antiinflammatory agents, hematopoietic depression with anticonvulsants, and additive sedation with tricyclic antidepressants. Opioid-related side effects, such as constipation, will occur in virtually every cancer patient. The result is that every patient will require laxatives, stool softeners, or antiemetics. The need for several medications at frequent intervals can dishearten many patients, and it often reinforces their sense of defeat and loss of control, despite the accompanying improvements in pain control.
Intrathecal and epidural delivery of opioids, local anesthetics, and other analgesics can help overcome these problems. Central neuraxis delivery of an opioid may increase pain relief, and in selected patients it may reduce opioid-related side effects. These improvements, however, come at increased cost, complexity, and risk compared with oral analgesic therapy. Neuraxis opioid delivery systems frequently require specialized physician and nursing supervision for continued maintenance and monitoring, and thus are less widely available. Also, implantation and removal require surgery and hospitalization. Furthermore, repeated or continuous access to the device will involve additional expense and risk of bacterial contamination. An epidural abscess or meningitis could represent life-threatening complications in patients with cancer, whose quality of life is already greatly compromised.
The need for a more continuous and durable means of providing pain control without the encumbrances associated with opioids is clearly evident. Opioid compounds are congeners of naturally occurring endogenous peptides found throughout the nervous system (Rang & Urban, 1995). These naturally occurring opioid peptides are part of a complex neurochemical scheme of neuromodulators capable of either inhibiting or enhancing the conduction of painful afferent sensory impulses within the dorsal horn of the spinal cord and at higher centers (Yaksh & Malmberg, 1994). Attempts to amplify the activity of these endogenous analgesics encompass the systemic administration of catecholamine reuptake inhibitors, such as the heterocyclic antidepressants, the use of spinal cord stimulators, and the administration of alpha adrenergic agonists, such as clonidine. A novel approach that involves the transplantation of adrenal chromaffin tissue into the subarachnoid space may hold considerable promise as a new pain therapy for chronic cancer and benign pain states (Sagen, 1992). Cell transplantation may provide sustained pain control at the spinal cord level without the need for repeated interventions, replenishment, or replacement transplants associated with conventional intrathecal drug delivery systems.
Adrenal cell pain control: Animal models
FIGURE 1. Immunoisolation.
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Adrenal chromaffin cells from a variety of different species, including rodent, bovine, and human, produce and release opioid peptides, catecholamines, and several neuropeptides in small but measurable quantities. These peptides include somatostatin, neuropeptide Y, and neurotensin (Coupland, 1989). All of these substances may participate in the postsynaptic inhibition of afferent nociceptive impulses within the dorsal horn of the spinal cord. Recognizing the potential for chromaffin cells to augment the endogenous antinociceptive pathways, investigators have implanted adrenal medullary tissue grafts into the central neuraxis of rats. Using a variety of standard analgesic drug screening tests, including the hot plate, paw flinch, and tail flick tests, Sagen and colleagues have demonstrated enhanced pain tolerance in rats receiving adrenal medullary implants onto the spinal cord (Hama & Sagen, 1994; Sagen, Kemmler, & Wang, 1991; Sagen, Pappas, & Perlow, 1986; Sagen, Pappas, & Pollard, 1986; Sagen, Wang, & Pappas, 1990; Wang & Sagen, 1994). The pain control effects obtained in the acute pain models required the administration of systemic nicotine to stimulate catecholamine discharge from the chromaffin cells. Elevated catecholamine and enkephalin concentrations were detectable within the cerebrospinal fluid, suggesting a mechanistic relationship (Sagen, Kemmler, & Wang). Concomitant administration of the opioid antagonist naloxone or the adrenergic antagonist phentolamine individually reduced but did not eliminate pain control. The partial attenuation of the chromaffin cell pain control produced by each antagonist supports an independent contribution from each individual analgesic component, catecholamine, or opioid peptide coreleased by the chromaffin cell.
The pain control effects produced by chromaffin cell implants in animal acute pain models do not necessarily represent the sustained effect needed to treat chronic pain conditions such as inflammatory arthropathies and neuropathic pain. Chronic pain associated with nerve injury responds poorly to opioid analgesic drugs and nonsteroidal antiinflammatory agents. Animal chronic pain models exist; they include the rat inflammatory poly-arthritis model and several recent peripheral mononeuropathy models. Chromaffin cell subarachnoid implants tested in these models demonstrate pain control in the inflammatory polyarthritis model and in the sciatic nerve chronic constriction injury (CCI) model (Hama & Sagen, 1994; Sagen, Wang, & Pappas, 1990). Within 1 week of transplantation, Hama and Sagen found that chromaffin cell transplants effectively reversed the cold allodynia, thermal hyperalgesia, and limb temperature associated with the CCI model. These beneficial effects persisted for the entire 9 weeks of the study. In control animals, the pain-related behavior persisted for approximately 8 weeks before spontaneously resolving. These results suggest that adrenal chromaffin cell transplants have a role in managing chronic neuropathic pain and offer evidence of sustained pain control. Unfortunately, the animal chronic pain models are imperfect, because pain symptoms and behaviors will abate without treatment over time or disappear when treatment is applied early in the course of the disease. Confirmation of the benefit of unencapsulated chromaffin cell transplants for chronic pain management will require human trials.
The issue of tolerance in opioid pain control may represent an insurmountable barrier to the success of continuous administration of opioids for treating persistent pain. Animal models using various acute pain stimuli have clearly demonstrated the rapid onset of tolerance following continuous administration of systemic and spinal opioids. However, the development of tolerance in humans is a difficult area of study. Clinical studies have suggested a rapid development of tolerance in patients with acute pain and in many patients with chronic benign pain. Nevertheless, many chronic cancer pain patients appear to exhibit fairly static opioid requirements and show little evidence of tolerance over long periods of time. Escalating opioid consumption in the cancer pain population generally indicates disease progression (Schug et al., 1992). Distinguishing between the psychological aspects of pain management and the physiological benefits of an analgesic drug is extremely difficult. Many patients perceive benefit, but improvement in activity or pain level is often difficult to prove in a convincing fashion.
Analgesic tolerance issues are particularly relevant to adrenal cell transplants. Chronic exposure to the catecholamines and opioid peptides secreted by adrenal cell transplants could contribute to accelerated tolerance to the analgesic substances produced by the implant or produce cross-tolerance to exogenous opioids. Fortunately, animal data from Sagen's laboratory have indicated little evidence of tolerance associated with the basal activity of spinal chromaffin cell implants (Wang & Sagen, 1994). Furthermore, stimulation of the chromaffin cells via systemic intermittent nicotine administration on a daily basis provided sustained and improved analgesia. However, continuous nicotine administration did result in analgesic tolerance. Continuous nicotine probably causes diminished liberation of the analgesic substrates from the chromaffin cells, rather than tolerance to the antinociceptive mediators. Hama and Sagen (1994) also found that chronic exposure to the chromaffin cell implants did not produce cross-tolerance to systemically administered morphine. This is particularly relevant because many chronic pain patients receive oral and spinal opioids.
Adrenal cell transplants for pain control: Human trials
FIGURE 2. Proprietary Cell Therapy Encapsulation Device.
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Winnie and associates (1993) conducted the first human clinical trial involving the transplantation of unencapsulated organ donor adrenal chromaffin cells into the subarachnoid space. Five subjects suffering from intractable pain received intrathecal injections of adrenal chromaffin cell suspensions obtained from organ donors. Single-donor adrenal glands were obtained for each subject. The medullary tissue was isolated and maintained in tissue culture for a period of 5 to 7 days. After verifying viability and functional integrity, the investigators found that approximately 2 ml of medullary tissue were available for injection into the subarachnoid space. The transplant recipients were treated with cyclosporine prior to the implantation and maintained on the immunosuppressant until 2 weeks after they were discharged. Each patient was monitored for pain scores and analgesic consumption and underwent periodic cerebrospinal fluid (CSF) sampling to assay for catecholamine and Met-enkephalin levels.
Four of the five patients with transplants experienced improved pain control beginning within 4 to 6 weeks of their transplants. Three patients demonstrated significant improvements in pain control by sustained reductions in their pain scores and analgesic drug consumption, and by improved activity. Their CSF catecholamine and Met-enkephalin levels were higher than their pretransplant levels. Unfortunately, the catecholamine levels were quite variable. They showed suggestive trends, but there was considerable variability among patients. This variability may reflect differences in the individual donors or in the depletion or enrichment of certain cell types during the tissue culture phase. Each subject received cells from a different donor, which may have contributed to the exhibited heterogeneity.
Although the results reported by Winnie and associates (1994) offer considerable promise, we need controlled trials to demonstrate the validity of this therapy. Clinicians responsible for the management of cancer pain are well aware of the waxing and waning nature of the disease. Many patients exhibit a crescendo pain pattern that often responds poorly to a variety of interventions, only to subside without any obvious relationship to their analgesic drug therapy. Convincing evidence for the chronic pain control effect of adrenal chromaffin transplants will require placebo-controlled trials.
Encapsulated xenogeneic chromaffin cell transplantation
FIGURE 3. Implant Procedure.
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The lack of available organ donors continues to hamper transplant efforts. Thus, widespread demand for homogeneic adrenal chromaffin cell transplants for chronic pain would probably exceed the supply. Furthermore, the need for on-site preparation of the cells prior to implant and the possible requirement for immunosuppression to prevent rejection of the cells might also limit this approach. Allografts from human-derived cell lines represent an alternative to organ donor tissue but carry the risk of tumor formation within the central nervous system. Xenogeneic transplants obtained from a readily available commercial source would be ideal but for the difficulties encountered in preventing rejection. Even with implantation into the immunologically privileged central nervous system and the use of aggressive immunosuppression, prolonged graft viability seems unlikely.
An alternative approach to preventing tissue rejection involves encapsulating the donor tissue into a perm-selective membrane to allow for the flow of nutrients into the donor cells and to enable the egress of analgesic peptides and catecholamines (Lysaght, Frydel, Emerich, & Winn, 1994). This approach has several potential advantages, such as minimal risk for infectious contamination and biological variability. Encapsulated cells also provide a degree of control over the transplantation process by allowing localization of the device in a target region and by allowing for intact removal of the transplant, should the need arise. Should the tissue capsule break, the foreign cells would be eliminated by the host's immune system.
Adrenal chromaffin cell transplants for pain management provide an ideal situation for the application of immunoisolated cell therapy. Chromaffin cells are a nondividing primary cell population and appear to maintain their function and viability in culture for extended periods. Implantation of perm-selective membrane capsules containing bovine adrenal chromaffin (BAC) cells into the subarachnoid space provides the cells with a continuous perfusate of a plasma ultrafiltrate containing glucose, oxygen, and other vital nutrients, thereby creating an optimal environment for maintaining the viability of the transplanted cells (see Figure 1). Preclinical trials in sheep implanted with encapsulated BAC cells have indicated sustained viability and maintained catecholamine release under basal and nicotine-stimulated conditions in devices recovered from the sheep after 4 weeks. At 4 weeks postimplantation (Joseph et al., 1994), the catecholamine liberation assay results for the devices recovered from the sheep were comparable to preimplant levels.
Perm-selective membranes can be constructed from a variety of materials in different configurations, depending on the cell type, site of implantation, and need for specific membrane characteristics such as pore size. A proprietary cell therapy encapsulation device (available from CytoTherapeutics, Inc., Providence, RI) currently under study in Europe and the United States, employs a polymembrane (acrylonitrile-covinyl-chloride) that forms a tubular structure 1 mm in diameter and 5-7 cm in length, sealed at either end by a methacrylate resin (see Figure 2). This membrane will exclude molecular weights greater than approximately 100,000, thus preventing immune cells and most proteins with large molecular weight from entering. A titanium connector, which in turn is attached to a silicon tether, is attached to the proximal end. The BAC cell or other cell lines are introduced into the device as a cell suspension in an alginate matrix. Extensive tissue compatibility testing has been performed on all of the materials.
Encapsulated bovine adrenal cell implants for cancer pain
Human Phase I clinical trials are now under way in the United States and Switzerland. In these studies, 1-3 x 106 BAC cells are encapsulated in the device described above and are maintained in culture for at least 30 days for sterility and catecholamine release testing. These devices are then inserted into the lumbar subarachnoid space of human volunteers suffering from intractable chronic cancer pain (see Figure 3). Preliminary data from the Phase I Swiss and U.S. trials have focused primarily on safety issues (Aebischer et al., 1994; Burgess, Goddard, Savarese, & Wilkinson, 1996.). The uncontrolled design of these trials does not allow for clear evidence of efficacy; however, the preliminary results are encouraging. From a safety standpoint, most of the adverse events observed in trial were directly related to the individual's underlying disease. Of the adverse events related to the cell therapy implants, such as postlumbar puncture headaches, virtually all were self-limited and related to the lumbar puncture performed to insert the device.
Summary
Extensive animal data and limited human data indicate that adrenal chromaffin cells transplanted into the central nervous system may have a role in the control of chronic pain associated with malignant and benign conditions. Primary BAC implants may represent the most expeditious and controllable method of introducing adrenal chromaffin cells into the central nervous system. Controlled human trials are currently under way in Europe and are planned for the United States in the near future.
References
Aebischer, P., Buchser, E., Joseph, J.M., Favre, J., de Tribolet, N., Lysaught, M., Rudnick, S., & Goddard, M. (1994). Transplantation in humans of encapsulated xenogeneic cells without immunosuppression: A preliminary report. Transplantation, 58,1-3.
Burgess, F.W., Goddard, M., Savarese, D., & Wilkinson, H. (1996). Subarachnoid bovine adrenal chromaffin cell implants for cancer pain management [Abstract]. Anesthesiology, 85(3A), A796.
Coupland, R.E. (1989). The natural history of the chromaffin cell: Twenty-five years on the beginning. Archives of Histology and Cytology, 52, S331-341.
Hama, A.T., & Sagen, J. (1994). Alleviation of neuropathic pain symptoms by xenogeneic chromaffin cell grafts in the spinal subarachnoid space. Brain Research, 651, 183-193.
Jacox, A., Carr, D.B., & Payne, R. (1994). Management of cancer pain (AHCPR Publication No. 94-0592). Rockville, MD: U.S. Department of Health and Human Services.
Joseph, J.M., Goddard, M.B., Mills, J., Padrun, V., Zurn, A., Zielinski, B., Favre, J., Gardaz, J.P., Moismann, F., Sagen, J., Christenson, L., & Aebischer, P. (1994). Transplantation of encapsulated bovine chromaffin cells in the sheep subarachnoid space: A preclinical study for the treatment of cancer pain. Cell Transplantation, 3, 355-364.
Lysaght, M., Frydel, B., Emerich, D., & Winn, S. (1994). Recent progress in immunoisolated cell therapy. Journal of Cellular Biochemistry, 56, 1-8.
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Sagen, J. (1992). Chromaffin cell transplants for alleviation of chronic pain. ASAIO Journal, 38, 24-28.
Sagen, J., Kemmler, J.E., & Wang, H. (1991). Adrenal medullary transplants increase spinal cerebrospinal fluid catecholamine levels and reduce pain sensitivity. Journal of Neurochemistry, 56, 623-627.
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Sagen, J., Pappas, G.D., & Pollard, M.J. (1986). Analgesia induced by isolated bovine chromaffin cells implanted in rat spinal cord. Proceedings of the National Academy of Science, USA, 83, 7522-7526.
Sagen, J., Wang, H., & Pappas, G.D. (1990). Adrenal medullary implants in rat spinal cord reduce nociception in a chronic pain model. Pain, 42, 69-79.
Schug, S.A., Zech, D., Grond, S., Jung, H., Meurser, T., & Stobbe, B. (1992). A long-term survey of morphine in cancer pain patients. Journal of Pain and Symptom Management, 7, 259-266.
Wang, H., & Sagen, J. (1994). Absence of appreciable tolerance and morphine cross-tolerance in rats with adrenal medullary transplants in the spinal cord. Neuropharmacology, 33, 681-692.
Winnie, A.P., Pappas, G.D., DasGupta, T.K., Wang, H., Ortega, J.D., & Sagen, J. (1993). Subarachnoid adrenal medullary transplants for terminal cancer pain. Anesthesiology, 79, 644-653.
Yaksh, T.L., & Malmberg, A.B. (1994). Interaction of spinal modulatory receptor systems. In H.L. Fields & J.C. Liebeskind, (Eds.), Progress in Pain Research and Management, Vol. 1 (pp. 151-171). Seattle: IASP Press.
Frederick Burgess is clinical assistant professor of surgery (anesthesiology) at Brown University in Providence, RI, and director of the Interventional Pain Management Clinic in the Department of Anesthesiology at Rhode Island Hospital, Providence, RI.
