Pain, 51(1992) 255-258
255
0 1992 Elsevier Science Publishers B.V. All rights reserved 0304-3959/92/%05.00
PAIN 02194
Grand ma1 seizures associated with high-dose intravenous morphine infusions: incidence and possible etiology R. Elizabeth
Gregory
a,b,d, Stuart
Grossman
b,d and Vivian R. Sheidler
‘.UI
’ The Johns Hopkins Hospital Pharmacy, Baltimore, MD 21205 (USA), b Department of Oncology, Johns Hopkins Unil,ersity, Baltimore, MD 21205 (USA) ’ Johns Hopkins University School of Nursing, Baltimore, MD 21205 (USA) and d Johns Hopkins Oncology Center, Baltimore, MD 21205 (USA) (Received 26 March 1992, revision received and accepted 19 August 1992)
Summary
A retrospective review of pharmacy records during a 7-year period at the Johns Hopkins Oncology Center revealed that 6 patients received greater than 4 g of morphine sulfate per day by continuous infusion (CD. Three patients received high-dose infusions for more than 24 h. Two of these 3 patients developed grand ma1 seizures, while the third was receiving a neuromuscular blocking agent making detection of seizures difficult. Prolonged administration of high concentrations of the sodium bisulfite preservative contained in the morphine solution is a possible explanation for the development of these seizures. Caution is suggested in using CI, preservative-containing morphine at high doses. Key words: Morphine;
Seizures; Sodium bisulfite
Introduction
High doses of intravenous (i.v.) opiates given by continuous infusion (CI) are an important treatment modality in the management of severe pain in patients with cancer (Portenoy and Foley 1986). Patients commonly require dramatic increases in opiate doses during the terminal phase of this illness (Foley 1989). Generalized seizures in 2 patients receiving high doses of i.v. morphine by CI prompted a retrospective review of the toxicities associated with this treatment. Six patients at the Johns Hopkins Oncology Center (JHOC) had received greater than 4 g of morphine sulfate per day by CI. Two of these patients had grand ma1 seizures associated with the morphine infusions and had no other identifiable reasons for their seizures. Calculations of the amount of sulfite in the infusions suggest that these preservatives could play a significant role in the development of this toxicity. Caution is
Correspondence to: R. Elizabeth Gregory, Pharm. D., Clinical Coordinator, Johns Hopkins Oncology Center Pharmacy, 600 N. Wolfe Street, Baltimore, MD 21205, USA. Tel.: (410) 955-6591; FAX: (405) 955-0287.
suggested in using preservative-containing doses higher than 4 g/day.
morphine at
Patients and methods Pharmacy records from 1 April 1985 to 5 February 1992 were retrospectively reviewed to determine the doses of i.v. morphine administered to inpatients at JHOC. Patients who received greater than or equal to 4 g of iv. morphine/day were selected for chart review since high doses of morphine sulfate would be required to provide the large amounts of i.v. bisulfite that might produce seizures. The following information was collected: morphine dose, duration of treatment, evidence of seizure activity while receiving high-dose morphine infusions, and subsequent pain treatment. If a patient had seizures, the medical evaluation of the seizure was also reviewed.
Results
During this 7-year period, 2495 inpatients received morphine. Six patients were identified as having received greater than or equal to 4 g/day of i.v. morphine by CI. Three of 6 patients received their morphine for less than 24 h before they were changed to i.v. hydromorphone (2 patients) or epidural fentapyl (1
256
patient). None of these patients developed seizures (Table I). The other 3 patients had infusions that lasted for more than 24 h and 2 of these 3 patients developed generalized seizures on the 2nd and 3rd days of these infusions. The 3rd patient was treated with pancuronium during her high-dose morphine CI, making detection of seizure activity impossible. The following case reports describe the courses of the 2 patients who developed seizures.
severe back pain which was unresponsive to 60-99 mg/h of i.v. morphine. Her morphine dose was rapidly escalated to a maximum of 300 mg/h without adequate relief, but with sedation. She had received between 6.0 and 7.2 g/day of morphine for 62 h when she began having muscle twitching and a jerking motion of her lower extremities and abdomen. This rapidly progressed to a grand ma1 seizure accompanied by a post-ictal period. Her seizures were treated with phenytoin, and i.v. morphine was discontinued, and an equi-analgesic dose of 60 mg/h of preservative-free hydromorphone was begun. Follow-up neurological examinations revealed no focal findings and a head CT scan was normal. She was unable to tolerate phenytoin which was discontinued without seizure recurrence. Pain was subsequently well controlled on i.v. hydromorphone.
Case No. I
M.G. was a 6%year-old woman with metastatic colon cancer and back pain. Her pain regimen consisted of 360 mg of controlled-release morphine daily and 8 mg of immediate-release morphine for breakthrough pain. She initially received CI morphine at 2 mg/h which was rapidly escalated to 350 mg/h within the first 24 h without pain relief. On the 2nd hospital day, i.v. morphine was discontinued and attempts for improved pain control were made with epidural bupivacaine and fentanyl, and intrathecal (i.t.1 morphine and fentanyl, without success. Intravenous morphine was reinstituted and rapidly escalated to a maximum of 200 mg/h (4.8 g/day). After approximately 46 h on this dose, the patient developed shakiness, tremulousness, and hallucinations, followed by 3 grand ma1 seizures. She experienced increased agitation, a left lateral gaze, and generalized movements associated with a post-ictal period. She was treated with i.v. phenytoin and diazepam, and her i.v. morphine was changed to an initial equi-analgesic dose of 40 mg/h of preservative-free hydromorphone. Repeat neurological exams were normal and an EEG and CT scan performed the’following day were normal. The patient received high-dose hydromorphone for 5 days without recurrence of seizures. After a median myelotomy and a low dose of i.v. hydromorphone, she was discharged with almost complete pain relief.
Discussion
This retrospective review suggests that prolonged, iv. infusions of high doses of morphine may place patients at risk for seizures. Two of 3 patients who received greater than 4 g/day of i.v. morphine sulfate developed grand ma1 seizures after 46 and 62 h of treatment. These patients had no evidence of structural lesions or metabolic abnormalities to cause their seizures. It is also unlikely that the rapid increase in dose was responsible for seizures since Case No. 1 had a very rapid initial dose escalation without seizures but went on to develop seizures after a prolonged infusion at a lower rate. Also, Table I shows that dose escalations were more rapid in patients who did not have seizures. Both patients with seizures remained seizure-free until death once the morphine was discontinued. Studies have documented seizures produced by very high doses of intrathecally and intracerebroventricularly administered morphine sulfate and in animals with seizure-producing brain lesions (Frenk 1983; Massotti and Gale 1989). To date, grand ma1 seizures have been reported to occur only with the administration of i.v. morphine sulfate in neonates and in a patient with
Case No. 2
L.W. was a 47-year-old woman with metastatic breast cancer with lung, bone, epidural and leptomeningeal metastases. She was admitted to the hospital with
TABLE
I
PATIENTS
RECEIVING
MORPHINE
SULFATE
2 4 g/day
Patient
Age
Sex
Site of disease
Duration
AS. W.M. G.L. M.G. L.W. I.G.
48 52 65 68 48 43
F M M F F F
endometrium parotid colon colon breast lymphoma
0.6 0.5 0.6 1.9 2.6 7.6
* Received
neuromuscular
blocking
agent during
of infusion
(days)
Total dose morphine 4.0 4.1 5.2 9.2 12.2 44.5
entire
morphine
infusion.
(g)
Total sulfite exposure 266 273 343 613 815 2967
(mg)
Seizure No No No Yes Yes No *
257
a known underlying seizure disorder (Karen et al. 1985; Borgeat et al. 1988). In addition, myoclonic seizures have been reported in 2 patients following high doses of i.t. morphine and epidural hydromorphone (Parkinson et al. 1990). Morphine has also been shown to possess anticonvulsant properties in humans and animals (Frenk 1983; Bullard 1987). The role of bisulfite toxicity was not addressed in any of the previously reported cases. Seizures observed in patients described in this report could have resulted from the toxicities of the bisulfite preservatives in morphine. The 15 mg/ml parenteral morphine solutions used during the time of our review contained 1 mg/ml of sodium bisulfite and 5 mg/ml of chlorobutanol as preservatives (Eli Lilly and Co., Product Information; Schein Pharmaceutical Inc., Product Information). Thus, each of the patients who had seizures received greater than 300 mg/day of i.v. sodium bisulfite in the morphine infusion alone. Little is known about the toxic effects of parenteral sulfites in humans. They are used as antioxidants in foods and drugs and also have antimicrobial activity, making them suitable for use as a preservative. They have been reported to cause seizures in animals and humans at very high doses (Hoppe and Goble 1951; Halaby and Mattocks 1965) and in humans with congenital sulfite oxidase deficiencies at normal doses (Shih et al. 1977). Although maximum tolerated exposures have not been determined in man, accidental oral ingestion of more than 4 g have produced nausea and vomiting (Hosen 1987). Generalized seizures have been reported in patients receiving lo-12 l/day of peritoneal dialysis solution for an unspecified period of time that contained 0.5 mg/ml of sulfites (Halaby and Mattocks 1965). The exposure to intraperitoneal (i.p.) sulfites in these patients was over 5 g on each day of dialysis, but actual absorption was unknown. Since sulfite toxicity was suspected, subsequent studies in mice were performed. They showed that rapid, but incomplete, absorption occurred following i.p. injection and the ability to eliminate sulfites decreased as blood levels increased (Halaby and Mattocks 1965). This suggested a saturable elimination process and the possibility of sulfite accumulation when given in high doses. Of note, sulfite preservatives have subsequently been removed from peritoneal dialysis solutions. Bisulfite is oxidized in the liver by sulfite oxidase to form sulfates of which 90% are eliminated in the urine (Petering and Shin 1975; Gunnison and Palmes 1976). The fate of the remaining 10% is unknown. The half-life of sulfites is also unknown in humans, but is approximately 10 min in monkeys (Gunnison and Jacobsen 1983). Chlorobutanol is the other preservative found in i.v. morphine solutions. Somnolence produced by chloro-
butanol intoxication has been described in a patient who received i.v. morphine sulfate at 275 mg/h (DeChristoforo et al. 1983). This compound has not been noted to result in seizures. Another possible explanation for seizures could be the morphine metabolite, normorphine, that can accumulate in renal failure and cause myoclonus (Glare et al. 1990). However, neither of the 2 patients in our report had renal dysfunction (assessed by serum creatinine, calculated creatinine clearance and BUN) and they had typical grand ma1 seizures rather than myoclonus. This makes normorphine as the source of seizures unlikely. Further research is needed to prove conclusively that seizures in patients receiving high-dose infusions of morphine are secondary sulfite accumulation, The case reports in this manuscript and the knowledge that sulfite oxidase deficiency and i.p. sulfites can cause seizures in humans, suggest caution in using morphine at doses over 4 g/day. Prolonged exposure to sulfites may result in their accumulation, placing patients with liver or kidney dysfunction or with a predisposition to seizures at higher risk for seizures. Therefore, preservative-free opiates may be advisable. Preservative-free drugs are considerably more costly and should be reserved for selected patients.
References Borgeat, A., Biollaz, J., Depierraz, B. and Neff, R., Grand mal seizure after extradural morphine analgesia, Br. J. Anaesth., 60 (1988) 733-735. Bullard, D.E., Diencephalic seiures: responsiveness to bromocriptine and morphine, Ann. Neurol., 21 (1987) 609-611. DeChristoforo, R., Corden, B.J. and Hood, J.C., High-dose morphine infusion complicated by chlorobutanol-induced somnolence, Ann. Int. Med., 98 (1983) 335-336. Eli Lilly Co., Product Information, 1992. Foley, K.M., Controversies in cancer pain: medical perspectives, Cancer, 63 (1989) 2257-2265. Frenk, H., Pro- and anticonvulsant actions of morphine and the endogenous opioids: involvement and interactions of multiple opiate and non-opiate systems, Br. Res. Rev., 6 (1983) 197-210. Glare, P.A., Walsh, T.D. and Pippenger, C.E., Normorphine, a neurotoxic metabolite?, Lancet, 335 (1990) 725-726. Gunnison, A.F. and Jacobsen, D.W., Hypersensitivity to sulfites: a reappraisal of sulfite toxicity, Prepared for International Life Sciences Inst., Washington, DC, 1983. Gunnison, A.F. and Palmes, E.D., A model for the metabolism of sulfite in mammals, Toxicol. Appl. Pharmacol., 38 (1976) 111-126. Halaby, SF. and Mattocks, A.M., Absorption of sodium bisulfite from peritoneal dialysis solutions, J. Pharm. Sci., 54 (1965) 52-55. Hoppe, J.O. and Goble, F.C., The intravenous toxicity of sodium bisulfite, J. Pharmacol. Exp. Ther. 101 (1951) 101-105. Hosen, H., Specific immunological therapy with sulfite chemicals. J. Asthma, 24 (1987) 219-221. Koren, G., Butt, W., Pape, K. and Chinyanga, H., Morphine-induced seizures in newborn infants, Vet. Hum. Toxicol., 27 (1985) 519520.
Massotti, M. and Gale, K., Electroencephalographic evidence for a dose-related biphasic effect of morphine on bicuculline-induced seizures in the rat, Epilepsy Res., 4 (1989) 81-89. Parkinson, S.K., Bailey, S.L., Little, W.L. and Mueller, J.B., Myoclonic seizure activity with chronic high-dose spinal opioid administration, Anesthesiology, 72 (1990) 743-745.
Petering, D.H. and Shih, N.T., Biochemistry of bisulfite-sulfur dioxide, Environ. Res., 9 (1975) 55-65. Portenoy, R.K. and Foley, K.M., Chronic use of opioid analgesic in non-malignant pain: report of 38 cases, Pain, 25 (1986) 171-86. Shih, V.E., Abroms, I.F., Johnson, J.L. et al., Sulfite oxidase deficiency, N. Engl. J. Med., 297 (1977) 1022-1028.
255
0 1992 Elsevier Science Publishers B.V. All rights reserved 0304-3959/92/%05.00
PAIN 02194
Grand ma1 seizures associated with high-dose intravenous morphine infusions: incidence and possible etiology R. Elizabeth
Gregory
a,b,d, Stuart
Grossman
b,d and Vivian R. Sheidler
‘.UI
’ The Johns Hopkins Hospital Pharmacy, Baltimore, MD 21205 (USA), b Department of Oncology, Johns Hopkins Unil,ersity, Baltimore, MD 21205 (USA) ’ Johns Hopkins University School of Nursing, Baltimore, MD 21205 (USA) and d Johns Hopkins Oncology Center, Baltimore, MD 21205 (USA) (Received 26 March 1992, revision received and accepted 19 August 1992)
Summary
A retrospective review of pharmacy records during a 7-year period at the Johns Hopkins Oncology Center revealed that 6 patients received greater than 4 g of morphine sulfate per day by continuous infusion (CD. Three patients received high-dose infusions for more than 24 h. Two of these 3 patients developed grand ma1 seizures, while the third was receiving a neuromuscular blocking agent making detection of seizures difficult. Prolonged administration of high concentrations of the sodium bisulfite preservative contained in the morphine solution is a possible explanation for the development of these seizures. Caution is suggested in using CI, preservative-containing morphine at high doses. Key words: Morphine;
Seizures; Sodium bisulfite
Introduction
High doses of intravenous (i.v.) opiates given by continuous infusion (CI) are an important treatment modality in the management of severe pain in patients with cancer (Portenoy and Foley 1986). Patients commonly require dramatic increases in opiate doses during the terminal phase of this illness (Foley 1989). Generalized seizures in 2 patients receiving high doses of i.v. morphine by CI prompted a retrospective review of the toxicities associated with this treatment. Six patients at the Johns Hopkins Oncology Center (JHOC) had received greater than 4 g of morphine sulfate per day by CI. Two of these patients had grand ma1 seizures associated with the morphine infusions and had no other identifiable reasons for their seizures. Calculations of the amount of sulfite in the infusions suggest that these preservatives could play a significant role in the development of this toxicity. Caution is
Correspondence to: R. Elizabeth Gregory, Pharm. D., Clinical Coordinator, Johns Hopkins Oncology Center Pharmacy, 600 N. Wolfe Street, Baltimore, MD 21205, USA. Tel.: (410) 955-6591; FAX: (405) 955-0287.
suggested in using preservative-containing doses higher than 4 g/day.
morphine at
Patients and methods Pharmacy records from 1 April 1985 to 5 February 1992 were retrospectively reviewed to determine the doses of i.v. morphine administered to inpatients at JHOC. Patients who received greater than or equal to 4 g of iv. morphine/day were selected for chart review since high doses of morphine sulfate would be required to provide the large amounts of i.v. bisulfite that might produce seizures. The following information was collected: morphine dose, duration of treatment, evidence of seizure activity while receiving high-dose morphine infusions, and subsequent pain treatment. If a patient had seizures, the medical evaluation of the seizure was also reviewed.
Results
During this 7-year period, 2495 inpatients received morphine. Six patients were identified as having received greater than or equal to 4 g/day of i.v. morphine by CI. Three of 6 patients received their morphine for less than 24 h before they were changed to i.v. hydromorphone (2 patients) or epidural fentapyl (1
256
patient). None of these patients developed seizures (Table I). The other 3 patients had infusions that lasted for more than 24 h and 2 of these 3 patients developed generalized seizures on the 2nd and 3rd days of these infusions. The 3rd patient was treated with pancuronium during her high-dose morphine CI, making detection of seizure activity impossible. The following case reports describe the courses of the 2 patients who developed seizures.
severe back pain which was unresponsive to 60-99 mg/h of i.v. morphine. Her morphine dose was rapidly escalated to a maximum of 300 mg/h without adequate relief, but with sedation. She had received between 6.0 and 7.2 g/day of morphine for 62 h when she began having muscle twitching and a jerking motion of her lower extremities and abdomen. This rapidly progressed to a grand ma1 seizure accompanied by a post-ictal period. Her seizures were treated with phenytoin, and i.v. morphine was discontinued, and an equi-analgesic dose of 60 mg/h of preservative-free hydromorphone was begun. Follow-up neurological examinations revealed no focal findings and a head CT scan was normal. She was unable to tolerate phenytoin which was discontinued without seizure recurrence. Pain was subsequently well controlled on i.v. hydromorphone.
Case No. I
M.G. was a 6%year-old woman with metastatic colon cancer and back pain. Her pain regimen consisted of 360 mg of controlled-release morphine daily and 8 mg of immediate-release morphine for breakthrough pain. She initially received CI morphine at 2 mg/h which was rapidly escalated to 350 mg/h within the first 24 h without pain relief. On the 2nd hospital day, i.v. morphine was discontinued and attempts for improved pain control were made with epidural bupivacaine and fentanyl, and intrathecal (i.t.1 morphine and fentanyl, without success. Intravenous morphine was reinstituted and rapidly escalated to a maximum of 200 mg/h (4.8 g/day). After approximately 46 h on this dose, the patient developed shakiness, tremulousness, and hallucinations, followed by 3 grand ma1 seizures. She experienced increased agitation, a left lateral gaze, and generalized movements associated with a post-ictal period. She was treated with i.v. phenytoin and diazepam, and her i.v. morphine was changed to an initial equi-analgesic dose of 40 mg/h of preservative-free hydromorphone. Repeat neurological exams were normal and an EEG and CT scan performed the’following day were normal. The patient received high-dose hydromorphone for 5 days without recurrence of seizures. After a median myelotomy and a low dose of i.v. hydromorphone, she was discharged with almost complete pain relief.
Discussion
This retrospective review suggests that prolonged, iv. infusions of high doses of morphine may place patients at risk for seizures. Two of 3 patients who received greater than 4 g/day of i.v. morphine sulfate developed grand ma1 seizures after 46 and 62 h of treatment. These patients had no evidence of structural lesions or metabolic abnormalities to cause their seizures. It is also unlikely that the rapid increase in dose was responsible for seizures since Case No. 1 had a very rapid initial dose escalation without seizures but went on to develop seizures after a prolonged infusion at a lower rate. Also, Table I shows that dose escalations were more rapid in patients who did not have seizures. Both patients with seizures remained seizure-free until death once the morphine was discontinued. Studies have documented seizures produced by very high doses of intrathecally and intracerebroventricularly administered morphine sulfate and in animals with seizure-producing brain lesions (Frenk 1983; Massotti and Gale 1989). To date, grand ma1 seizures have been reported to occur only with the administration of i.v. morphine sulfate in neonates and in a patient with
Case No. 2
L.W. was a 47-year-old woman with metastatic breast cancer with lung, bone, epidural and leptomeningeal metastases. She was admitted to the hospital with
TABLE
I
PATIENTS
RECEIVING
MORPHINE
SULFATE
2 4 g/day
Patient
Age
Sex
Site of disease
Duration
AS. W.M. G.L. M.G. L.W. I.G.
48 52 65 68 48 43
F M M F F F
endometrium parotid colon colon breast lymphoma
0.6 0.5 0.6 1.9 2.6 7.6
* Received
neuromuscular
blocking
agent during
of infusion
(days)
Total dose morphine 4.0 4.1 5.2 9.2 12.2 44.5
entire
morphine
infusion.
(g)
Total sulfite exposure 266 273 343 613 815 2967
(mg)
Seizure No No No Yes Yes No *
257
a known underlying seizure disorder (Karen et al. 1985; Borgeat et al. 1988). In addition, myoclonic seizures have been reported in 2 patients following high doses of i.t. morphine and epidural hydromorphone (Parkinson et al. 1990). Morphine has also been shown to possess anticonvulsant properties in humans and animals (Frenk 1983; Bullard 1987). The role of bisulfite toxicity was not addressed in any of the previously reported cases. Seizures observed in patients described in this report could have resulted from the toxicities of the bisulfite preservatives in morphine. The 15 mg/ml parenteral morphine solutions used during the time of our review contained 1 mg/ml of sodium bisulfite and 5 mg/ml of chlorobutanol as preservatives (Eli Lilly and Co., Product Information; Schein Pharmaceutical Inc., Product Information). Thus, each of the patients who had seizures received greater than 300 mg/day of i.v. sodium bisulfite in the morphine infusion alone. Little is known about the toxic effects of parenteral sulfites in humans. They are used as antioxidants in foods and drugs and also have antimicrobial activity, making them suitable for use as a preservative. They have been reported to cause seizures in animals and humans at very high doses (Hoppe and Goble 1951; Halaby and Mattocks 1965) and in humans with congenital sulfite oxidase deficiencies at normal doses (Shih et al. 1977). Although maximum tolerated exposures have not been determined in man, accidental oral ingestion of more than 4 g have produced nausea and vomiting (Hosen 1987). Generalized seizures have been reported in patients receiving lo-12 l/day of peritoneal dialysis solution for an unspecified period of time that contained 0.5 mg/ml of sulfites (Halaby and Mattocks 1965). The exposure to intraperitoneal (i.p.) sulfites in these patients was over 5 g on each day of dialysis, but actual absorption was unknown. Since sulfite toxicity was suspected, subsequent studies in mice were performed. They showed that rapid, but incomplete, absorption occurred following i.p. injection and the ability to eliminate sulfites decreased as blood levels increased (Halaby and Mattocks 1965). This suggested a saturable elimination process and the possibility of sulfite accumulation when given in high doses. Of note, sulfite preservatives have subsequently been removed from peritoneal dialysis solutions. Bisulfite is oxidized in the liver by sulfite oxidase to form sulfates of which 90% are eliminated in the urine (Petering and Shin 1975; Gunnison and Palmes 1976). The fate of the remaining 10% is unknown. The half-life of sulfites is also unknown in humans, but is approximately 10 min in monkeys (Gunnison and Jacobsen 1983). Chlorobutanol is the other preservative found in i.v. morphine solutions. Somnolence produced by chloro-
butanol intoxication has been described in a patient who received i.v. morphine sulfate at 275 mg/h (DeChristoforo et al. 1983). This compound has not been noted to result in seizures. Another possible explanation for seizures could be the morphine metabolite, normorphine, that can accumulate in renal failure and cause myoclonus (Glare et al. 1990). However, neither of the 2 patients in our report had renal dysfunction (assessed by serum creatinine, calculated creatinine clearance and BUN) and they had typical grand ma1 seizures rather than myoclonus. This makes normorphine as the source of seizures unlikely. Further research is needed to prove conclusively that seizures in patients receiving high-dose infusions of morphine are secondary sulfite accumulation, The case reports in this manuscript and the knowledge that sulfite oxidase deficiency and i.p. sulfites can cause seizures in humans, suggest caution in using morphine at doses over 4 g/day. Prolonged exposure to sulfites may result in their accumulation, placing patients with liver or kidney dysfunction or with a predisposition to seizures at higher risk for seizures. Therefore, preservative-free opiates may be advisable. Preservative-free drugs are considerably more costly and should be reserved for selected patients.
References Borgeat, A., Biollaz, J., Depierraz, B. and Neff, R., Grand mal seizure after extradural morphine analgesia, Br. J. Anaesth., 60 (1988) 733-735. Bullard, D.E., Diencephalic seiures: responsiveness to bromocriptine and morphine, Ann. Neurol., 21 (1987) 609-611. DeChristoforo, R., Corden, B.J. and Hood, J.C., High-dose morphine infusion complicated by chlorobutanol-induced somnolence, Ann. Int. Med., 98 (1983) 335-336. Eli Lilly Co., Product Information, 1992. Foley, K.M., Controversies in cancer pain: medical perspectives, Cancer, 63 (1989) 2257-2265. Frenk, H., Pro- and anticonvulsant actions of morphine and the endogenous opioids: involvement and interactions of multiple opiate and non-opiate systems, Br. Res. Rev., 6 (1983) 197-210. Glare, P.A., Walsh, T.D. and Pippenger, C.E., Normorphine, a neurotoxic metabolite?, Lancet, 335 (1990) 725-726. Gunnison, A.F. and Jacobsen, D.W., Hypersensitivity to sulfites: a reappraisal of sulfite toxicity, Prepared for International Life Sciences Inst., Washington, DC, 1983. Gunnison, A.F. and Palmes, E.D., A model for the metabolism of sulfite in mammals, Toxicol. Appl. Pharmacol., 38 (1976) 111-126. Halaby, SF. and Mattocks, A.M., Absorption of sodium bisulfite from peritoneal dialysis solutions, J. Pharm. Sci., 54 (1965) 52-55. Hoppe, J.O. and Goble, F.C., The intravenous toxicity of sodium bisulfite, J. Pharmacol. Exp. Ther. 101 (1951) 101-105. Hosen, H., Specific immunological therapy with sulfite chemicals. J. Asthma, 24 (1987) 219-221. Koren, G., Butt, W., Pape, K. and Chinyanga, H., Morphine-induced seizures in newborn infants, Vet. Hum. Toxicol., 27 (1985) 519520.
Massotti, M. and Gale, K., Electroencephalographic evidence for a dose-related biphasic effect of morphine on bicuculline-induced seizures in the rat, Epilepsy Res., 4 (1989) 81-89. Parkinson, S.K., Bailey, S.L., Little, W.L. and Mueller, J.B., Myoclonic seizure activity with chronic high-dose spinal opioid administration, Anesthesiology, 72 (1990) 743-745.
Petering, D.H. and Shih, N.T., Biochemistry of bisulfite-sulfur dioxide, Environ. Res., 9 (1975) 55-65. Portenoy, R.K. and Foley, K.M., Chronic use of opioid analgesic in non-malignant pain: report of 38 cases, Pain, 25 (1986) 171-86. Shih, V.E., Abroms, I.F., Johnson, J.L. et al., Sulfite oxidase deficiency, N. Engl. J. Med., 297 (1977) 1022-1028.
