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Is Octreotide a safe drug?
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Lee, J.W., Pedersen, J.E., Moravetz, T.L., Dzerk, A.M., Mundt, A.D. and Shepard, K.V., Sensitive and specific radioimmunoassays for opiates using commercially available methods. I. Methods for the determinations of morphine and hydromorphone, J. Pharm. Sci., 80 (1991) 284-288. Parab, P.V., Ritschel, W.A., Coyle, D.E., Gregg, R.V. and Denson, D.D., Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects, Biopharm. Drug Disp., 9 (1988) 187-199. Reidenberg, M.M., Goodman, H., Erle, H., Gray, G., Lorenzo, B., Leipzig, R.M., Mayer, B.R. and Drayer, D.E., Hydromorphone levels and pain control in patients with severe chronic pain, Clin. Pharmacol. Ther., (19881 376-382. Ritschel, W.A., Parab, P.V., Denson, D.D., Coyle, D.E. and Gregg, R.V., Absolute bioavailability of hydromorphone after peroral and rectal administration in humans: saliva/plasma ratio and clinical effects, J. Clin. Pharmacol., 27 (19871 647-653. Small, L.Y., Eddy, N.B., Mosettig, E. and Himmelsbach, C.K., Studies on drug addiction: with special reference to chemical structures of opium derivatives and allied synthetic substances and their physiological actions, Publ. Hlth Rep. 1938 (Suppl. 1381 US Govt. Printing Office, Washington, DC, 1938, pp. 1-143. Vallner, J.J., Stewart, J.T., Kotzan, J.A., Kirsten, E.B. and Honigberg, IL., Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects, J. Clin. Pharmacol., 21 (1981) 152-156.
Najik Babul Andrew C. Darke Department of Scientific Affairs Purdue Frederick Pickering, Ont. LI W 3W8, Canada
PAIN 02176
Is Octreotide a safe drug? We are very impressed by the paper of Penn et al. (19921 presented in the April issue of PAIN. As described in this article, octreotide, a somatostatin analogue, seems to be an interesting alternative in cases of intrathecal morphine tolerance. As demonstrated in the paper neither neurotoxic effects nor clinical abnormal behaviour could be found. Just as many pain practitioners and clinicians, we are sometimes confronted with intrathecal morphine-tolerant patients for whom octreotide could be an attractive alternative. However, while reviewing literature about SandostatinR, we found the paper of Leblanc et al. (1988) published in Neurology. The authors describe the effects of Sandostatin (SMS 201-995) instilled as well intrathecally as intraventrically in monkeys in dosages of 24-96 Fg/day. Only a few days after starting the continuous infusion, dramatic neurobehaviour complications such as truncal ataxia, dysmetria and severe hypokinesia developed in several monkeys. These effects were attributed to neurotoxicity interfering with dopaminergic mechanisms Leblanc et al. (1988). In the report of Penn et al. (19921 all clinical signs as alertness, gait and behaviour were noted and no complications were detected, although the perfused dose was rather large (40-960 wg/dayl. The experiences of LeBlanc et al. are not cited in the references of the paper of Penn et al. Can we assume that SandostatinR (SMS 201-995) is different from SandostatinR (octreotide) or is octreotide (SandostatinRl still a neurotoxic drug?
References LeBlanc, R., Gauthier, S., Gauvin, M. et al., Neurobehavioral effects of intrathecal somatostatinergic treatment in subhuman primates, Neurology, 38 (1988) 1887-1890. Penn, R., Paice, J. and Kroin, J., Octreotide: a new non-opiate analgesic for intrathecal infusion, Pain, 49 (1992) 13-19.
Jacques Devulder Departmrnt of Anesthesiology Section Pain Clinic, UniLwsity Hospital De Puitelaan 185, 9ooO Gent, Belgium
PAIN 02177
Reply to J. Devulder Dr. Devulder questions the safety of intrathecal octreotide in light of the work of Leblanc et al. (1988). We were well aware of Leblanc’s findings and were also very concerned about the potential for octreotide-induced neurotoxicity. In fact, we arranged a meeting with Dr. Leblanc’s group in 1988 to discuss their methods and subsequent findings in an effort to determine the cause of the ataxia, dysmetria, bradykinesia or death in 4 of 8 monkeys receiving octreotide. However, several factors made interpretation of these results impossible. First, careful autopsy with histological examination of the brains and spinal cords was not performed. Second, the catheter was placed in an unusual area, in front of the brain stem. Generally, catheters are placed intrathecally or intraventricularly. In addition, the Montreal group had made up their own drug vehicle while we used the standard acetate-buffered saline formulation. Because of the difficulty in interpreting these results, we performed several experiments in primates. Four cynomolgus monkeys were given octreotide infusion in the lateral ventricle at 24 pg/h (the equivalent of 40 pg/h in the dog) for 28 days using a totally implanted system with an Alzet 2ML4 minipump. The result was that there were no neurologic changes in the monkeys. The animals were always alert and had normal coordination (no bradykinesial. Histology on the 4 monkeys showed that the brain tissue was within normal limits away from the cannula tip. This means that there was no damage due to drug circulation in the CSF. In animals, especially one, in which the cannula tip missed the ventricle and instead lodged in solid brain tissue nearby, a sterile abscess formed at the tip. The probable reason for this local effect was the high drug concentration (11 mg/mll that directly reached the tissue without first being diluted in the ventricle, as with the dog studies described in our paper. This high concentration was necessitated by the limited flow rate of the implantable minipumps. The FDA was aware of Leblanc’s work as well as our animal studies and allowed us to proceed with the human trials. Furthermore, we have noted no toxicity in the 6 cancer patients described in our paper (Penn et al. 1992) nor in 3 non-malignant pain patients who have received intrathecal octreotide (unpublished data). In fact, 2 of these non-malignant pain patients have received the drug for over 1 year, with continued relief of pain and no side effects. In addition, we have administered octreotide intraventricularly in 4 patients diagnosed with Alzheimer’s disease (unpublished data). These patients exhibited no behavioral or cognitive improvement, but they also experienced no ataxia, bradykinesia or dysmetria. Finally, Leblanc and colleagues noted significant changes in blood glucose levels in the acute animals and early increases in the chronic animals. Again, this is not consistent with our findings in humans, where no changes in blood glucose were noted.
Lee, J.W., Pedersen, J.E., Moravetz, T.L., Dzerk, A.M., Mundt, A.D. and Shepard, K.V., Sensitive and specific radioimmunoassays for opiates using commercially available methods. I. Methods for the determinations of morphine and hydromorphone, J. Pharm. Sci., 80 (1991) 284-288. Parab, P.V., Ritschel, W.A., Coyle, D.E., Gregg, R.V. and Denson, D.D., Pharmacokinetics of hydromorphone after intravenous, peroral and rectal administration to human subjects, Biopharm. Drug Disp., 9 (1988) 187-199. Reidenberg, M.M., Goodman, H., Erle, H., Gray, G., Lorenzo, B., Leipzig, R.M., Mayer, B.R. and Drayer, D.E., Hydromorphone levels and pain control in patients with severe chronic pain, Clin. Pharmacol. Ther., (19881 376-382. Ritschel, W.A., Parab, P.V., Denson, D.D., Coyle, D.E. and Gregg, R.V., Absolute bioavailability of hydromorphone after peroral and rectal administration in humans: saliva/plasma ratio and clinical effects, J. Clin. Pharmacol., 27 (19871 647-653. Small, L.Y., Eddy, N.B., Mosettig, E. and Himmelsbach, C.K., Studies on drug addiction: with special reference to chemical structures of opium derivatives and allied synthetic substances and their physiological actions, Publ. Hlth Rep. 1938 (Suppl. 1381 US Govt. Printing Office, Washington, DC, 1938, pp. 1-143. Vallner, J.J., Stewart, J.T., Kotzan, J.A., Kirsten, E.B. and Honigberg, IL., Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects, J. Clin. Pharmacol., 21 (1981) 152-156.
Najik Babul Andrew C. Darke Department of Scientific Affairs Purdue Frederick Pickering, Ont. LI W 3W8, Canada
PAIN 02176
Is Octreotide a safe drug? We are very impressed by the paper of Penn et al. (19921 presented in the April issue of PAIN. As described in this article, octreotide, a somatostatin analogue, seems to be an interesting alternative in cases of intrathecal morphine tolerance. As demonstrated in the paper neither neurotoxic effects nor clinical abnormal behaviour could be found. Just as many pain practitioners and clinicians, we are sometimes confronted with intrathecal morphine-tolerant patients for whom octreotide could be an attractive alternative. However, while reviewing literature about SandostatinR, we found the paper of Leblanc et al. (1988) published in Neurology. The authors describe the effects of Sandostatin (SMS 201-995) instilled as well intrathecally as intraventrically in monkeys in dosages of 24-96 Fg/day. Only a few days after starting the continuous infusion, dramatic neurobehaviour complications such as truncal ataxia, dysmetria and severe hypokinesia developed in several monkeys. These effects were attributed to neurotoxicity interfering with dopaminergic mechanisms Leblanc et al. (1988). In the report of Penn et al. (19921 all clinical signs as alertness, gait and behaviour were noted and no complications were detected, although the perfused dose was rather large (40-960 wg/dayl. The experiences of LeBlanc et al. are not cited in the references of the paper of Penn et al. Can we assume that SandostatinR (SMS 201-995) is different from SandostatinR (octreotide) or is octreotide (SandostatinRl still a neurotoxic drug?
References LeBlanc, R., Gauthier, S., Gauvin, M. et al., Neurobehavioral effects of intrathecal somatostatinergic treatment in subhuman primates, Neurology, 38 (1988) 1887-1890. Penn, R., Paice, J. and Kroin, J., Octreotide: a new non-opiate analgesic for intrathecal infusion, Pain, 49 (1992) 13-19.
Jacques Devulder Departmrnt of Anesthesiology Section Pain Clinic, UniLwsity Hospital De Puitelaan 185, 9ooO Gent, Belgium
PAIN 02177
Reply to J. Devulder Dr. Devulder questions the safety of intrathecal octreotide in light of the work of Leblanc et al. (1988). We were well aware of Leblanc’s findings and were also very concerned about the potential for octreotide-induced neurotoxicity. In fact, we arranged a meeting with Dr. Leblanc’s group in 1988 to discuss their methods and subsequent findings in an effort to determine the cause of the ataxia, dysmetria, bradykinesia or death in 4 of 8 monkeys receiving octreotide. However, several factors made interpretation of these results impossible. First, careful autopsy with histological examination of the brains and spinal cords was not performed. Second, the catheter was placed in an unusual area, in front of the brain stem. Generally, catheters are placed intrathecally or intraventricularly. In addition, the Montreal group had made up their own drug vehicle while we used the standard acetate-buffered saline formulation. Because of the difficulty in interpreting these results, we performed several experiments in primates. Four cynomolgus monkeys were given octreotide infusion in the lateral ventricle at 24 pg/h (the equivalent of 40 pg/h in the dog) for 28 days using a totally implanted system with an Alzet 2ML4 minipump. The result was that there were no neurologic changes in the monkeys. The animals were always alert and had normal coordination (no bradykinesial. Histology on the 4 monkeys showed that the brain tissue was within normal limits away from the cannula tip. This means that there was no damage due to drug circulation in the CSF. In animals, especially one, in which the cannula tip missed the ventricle and instead lodged in solid brain tissue nearby, a sterile abscess formed at the tip. The probable reason for this local effect was the high drug concentration (11 mg/mll that directly reached the tissue without first being diluted in the ventricle, as with the dog studies described in our paper. This high concentration was necessitated by the limited flow rate of the implantable minipumps. The FDA was aware of Leblanc’s work as well as our animal studies and allowed us to proceed with the human trials. Furthermore, we have noted no toxicity in the 6 cancer patients described in our paper (Penn et al. 1992) nor in 3 non-malignant pain patients who have received intrathecal octreotide (unpublished data). In fact, 2 of these non-malignant pain patients have received the drug for over 1 year, with continued relief of pain and no side effects. In addition, we have administered octreotide intraventricularly in 4 patients diagnosed with Alzheimer’s disease (unpublished data). These patients exhibited no behavioral or cognitive improvement, but they also experienced no ataxia, bradykinesia or dysmetria. Finally, Leblanc and colleagues noted significant changes in blood glucose levels in the acute animals and early increases in the chronic animals. Again, this is not consistent with our findings in humans, where no changes in blood glucose were noted.