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Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain
Pain 69 (1997) 199–201
Clinical note
Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain Eduardo Bruera*, Jose Pereira Palliative Care Program, Grey Nuns Community Health Centre, University of Alberta, Edmonton, Canada Received 30 March 1996; revised version received 11 July 1996; accepted 25 July 1996
Abstract A 62-year-old man receiving subcutaneous fentanyl for the management of cancer pain developed generalized central excitation after an overdose of 5000 mg of fentanyl. The patient developed acute confusion, restlessness, generalized myoclonus, visual hallucinations, and hyperalgesia and tremors upon tactile stimulation of the arms or legs. These symptoms rapidly disappeared after the administration of 0.2 mg of naloxone. Within an hour the symptoms reappeared and once again, responded immediately after a second injection of 0.2 mg of naloxone. Our findings suggest that fentanyl overdose can occasionally present with general central irritability that responds to naloxone. Keywords: Neuropsychiatric; Fentanyl; Cancer
1. Introduction Opioid overdoses cause CNS depression, consisting mostly of sedation, coma, and respiratory depression (Inturrisi, 1990; Skinner and Thompson, 1992). In addition, patients frequently develop respiratory distress due to non-cardiogenic pulmonary edema (Bruera and Miller, 1989; Henderson, 1991) and autonomic changes including sweating, myosis and hypotension (Inturrisi, 1990; Skinner and Thompson, 1992). Most of these effects respond rapidly to parenteral naloxone. We report the case of a patient who experienced confusion, agitation and cutaneous hyperalgesia after an overdose of fentanyl. 2. Case report A 62-year-old man was admitted to the Palliative Care Unit because of abdominal pain, nausea and vomiting. Eight months before, he had undergone a gastrectomy because of adenocarcinoma of the stomach. One month before admission, a laparotomy demonstrated the presence of advanced intra-abdominal disease. There was no prior
* Corresponding author.
evidence of delirium, seizures, chronic neurologic disorder or drugs with excitatory effects. Upon admission, he was maintained for 8 days on a continuous subcutaneous infusion of fentanyl at 100 mg/hr with excellent pain control (less than 2 extra analgesic doses per day were required and pain intensity in the visual analogue scale 0 = best, 10 = worst, ranged from 2 to 4 for the last three days). His cognitive status had been normal (4 routine Mini-Mental State Questionnaire scores had been normal, the last one being 28/30 2 days before) (Folstein et al., 1975). On day 8 of the infusion, the patient became acutely confused, with mild restlessness and hand movements suggesting visual hallucinations. His eyes were open but there was no response to simple commands. A subcutaneous dose of haloperidol of 2 mg was administered with no significant change. In the following 30 minutes, the patient developed generalized tremor and hyperalgesia upon tactile stimulation of the arms or legs or loud noises, progressive generalized myoclonus, profuse sweating and miosis. At this time, the nurse realized that he had been mistakenly administered a dose of 5000 mg of fentanyl as an intravenous infusion over the last hour (approximately 50 times the hourly dose). The respiratory rate was 10–15 per minute and oxygen saturation was 88%–92% on room air. An assessment by an intern revealed no evidence of severe sedation or respiratory depression. However, be-
0304-3959/97/$17.00 1997 International Association for the Study of Pain. Published by Elsevier Science Ireland Ltd. PII S0304-3959 (96 )0 3238-1
200
E. Bruera, J. Pereira / Pain 69 (1997) 199–201
cause of the sudden onset of the neuropsychiatric changes and the evidence of opioid overdose, an intravenous bolus injection of 0.1 mg of naloxone was administered, followed by a second 0.1 mg bolus within 5 min. Within 2–3 min after the second injection, the patient became completely conscious and cognitively normal. Hallucinations, agitation, cutaneous hyperalgesia and generalized myoclonus, as well as sweating and miosis, all resolved completely. Within an hour of observation, all symptoms reappeared. A second injection of 0.2 mg of naloxone resulted again in complete resolution of the symptoms within 2–3 min. At this time, a continuous intravenous infusion of naloxone 0.2 mg/hour was started. Neurological vital signs every 15 min and pain control remained excellent for the next 7 h. At that point, after a cumulative dose of 1.8 mg of naloxone, the patient started complaining of his usual abdominal pain. The infusion of naloxone was discontinued and within 15–20 minutes, the pain disappeared. Three hours later, the pain reappeared and a continuous subcutaneous infusion of fentanyl was restarted at a dose of 100 m/hr. The infusion was maintained for several days with no further evidence of toxicity. The respiratory rate, oxygen saturation and blood pressure remained normal during the whole episode. 3. Discussion This patient presented with an acute and highly unusual neurological syndrome. The most common manifestations of severe opioid toxicity including somnolence, respiratory depression or hypotension were absent. Instead, there were signs of agitation, myoclonus and cutaneous hyperalgesia suggesting an impending grand mal seizure. In recent years, new central side-effects of opioids have been described including generalized myoclonus, hyperalgesia, grand mal seizures and agitation (Sjogren et al., 1994; Sjogren and Erikson, 1994; de Stoutz et al., 1995). These effects have been described mostly in patients receiving high doses of morphine for a long period of time, and have been ascribed to non-opioid binding effects of morphine or two of its metabolites, morphine-3-glucuronide or nor-morphine (Sjogren et al., 1994; Sjogren and Erikson, 1994). Some authors have suggested an anti-glycinergic effect of morphine or its metabolites similar to those observed after strychnine intoxication (Sjogren et al., 1994). However, fentanyl has not been found to have any significant non-opioid binding (Frenk et al., 1984). The immediate occurrence of toxicity after this intravenous overdose suggests that the neuropsychiatric effects were due to the active drug rather than metabolites. Previous reports of fentanyl overdoses found CNS depression (Martin et al., 1991; Marquardt and Tharratt, 1994). However, these patients were usually non-tolerant and received low doses of fentanyl (Henderson, 1991; Martin et al., 1991; Marquardt and Tharratt, 1994). Our patient had been exposed to a high dose of fentanyl (100
mg/hr) for eight days before receiving a massive overdose. Animal studies suggest that morphine, fentanyl and meperidine exhibit a biphasic dose response relationship with respect to their effects on seizure thresholds: low doses are anticonvulsant and high doses are proconvulsant. Naloxone reversed the effects of the higher doses of morphine and fentanyl on seizure threshold (Lauretti et al., 1994). Some studies have found that naloxone is able to block morphine-induced susceptibility to seizure in some animal models (Thomas et al., 1993). Naloxone was also able to block the anticonvulsant effect of endorphins (Koide et al., 1993) and low dose fentanyl (Koide et al., 1992) in other animal models. Our findings suggest that an acute opioid overdose can cause central excitation that responds to naloxone. However, central excitation during chronic opioid administration is probably due to activation of non-opioid receptors by active metabolites and, therefore, non-responsive to naloxone (Sjogren and Erikson, 1994; de Stoutz et al., 1995). In these patients, naloxone might decrease seizure threshold (Koide et al., 1992; Koide et al., 1993) and potentially cause seizures by blocking the depressant effect of the circulating opioids and allowing the expression of the convulsant activity of active metabolites to manifest (Inturrisi, 1990). Finally, our patient demonstrates that even in the case of liposoluble drugs of short half-life such as fentanyl, a continuous infusion of naloxone may be required in order to prevent a repetition of the toxicity of massive overdoses. The reason why prolonged administration of naloxone was needed is probably that the elimination half-life of the drug on steady state can be quite prolonged, since it reflects both the clearance of the drug and redistribution from fat stores. In the case of fentanyl, the large fat compartment will result in blood levels being maintained for several hours. Our findings suggest that an opioid overdose should be suspected in patients presenting with acute central hyperactive symptoms and that these symptoms may respond to naloxone. It is possible that some cases of central irritability during chronic opioid administration might also respond to naloxone. Even in the case of liposoluble drugs of short half-life such as fentanyl, a continuous infusion of naloxone may be required in order to prevent a repetition of the toxicity in cases of massive overdose. References Bruera, E. and Miller, M.J., Non-cardiogenic pulmonary edema after narcotic treatment for cancer pain, Pain, 39 (1989) 297–300. de Stoutz, N.D., Bruera, E. and Suarez-Almazor, M., Opioid rotation (OR) for toxicity reduction in terminal cancer patients, J. Pain Symptom Manage., 10 (1995) 378–384. Folstein, M.F., Folstein, S. and McHugh, P.R., ’Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician, J. Psych. Res., 12 (1975) 189–198. Frenk, H., Watkins, L.R. and Mayer, D.J., Differential behavioural
E. Bruera, J. Pereira / Pain 69 (1996) 199–201 effects induced by intrathecal microinjection of opiates: comparison of convulsive and cataleptic effects produced by morphine, methadone, and D-Ala-Methionine-enkephalinamide, Brain Res., 299 (1984) 41– 42. Henderson, G.L., Fentanyl-related deaths: demographics, circumstances and toxicology of 112 patients, J. Forensic Sci., 36 (1991) 422– 433. Inturrisi, C.E., Opioid analgesic therapy in cancer pain. In: K.M. Foley, J.J. Bonica, V. Ventafridda (Eds.), Advances in Pain Research and Therapy, Raven Press, New York, 16 (1990) pp. 133–154. Koide, S., Onishi, H., Yamagami, S., and Kawakita, Y., Effects of morphine and D-Ala2-D-Leu5-enkephalin in the seizure-susceptible E1 mouse, Neurochem. Res., 17 (1992) 779–783. Koide, S., Onishi, H., Katayama, M. and Yamagami, S., Endogenous methionine enkephalin may plan an anticonvulsant role in the seizure-susceptible E1 mouse, Neurochem. Res., 18 (1993) 1259–1262. Lauretti, G.R., Ahmad, I. and Pleuvry, B.J., The activity of opioid analgesics in seizure models utilizing N-methyl-DL-aspartic acid, kai-
201
nic acid, bicuculline and pentylenetetrazole, Neuropharmacology, 33 (1994) 155–160. Marquardt, K.A. and Tharratt, R.S., Inhalation abuse of fentanyl patch, J. Toxicol. Clin. Toxicol., 31 (1994) 75–78. Martin, M., Hecker, J., Clark, R., Frye, J., Jehle, D., Lucid, E.J. et al., China White epidemic: an eastern United States emergency department experience, Ann. Emerg. Med., 20 (1991) 158–164. Sjogren, P., and Erikson, J., Opioid toxicity, Curr. Opin. Anesthesiol., 7 (1994) 465–469. Sjogren, P., Jensen, N.H. and Jensen, T.S., Disappearance of morphineinduced hyperalgesia after discontinuing or substituting morphine with other opioid agonists, Pain, 59 (1994) 313–316. Skinner, M. and Thompson, A., Pharmacologic considerations in the treatment of substance abuse (review), Soc. Med. J., 85 (1992) 1207–1219. Thomas, J., Nores, W.L., Kenigs, V., Olson, G.A. and Olson, R.D. Picrotoxin-induced seizures modified by morphine and opiate antagonists, Pharmacol. Biochem. Behav., 45 (1993) 615–617.
Clinical note
Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain Eduardo Bruera*, Jose Pereira Palliative Care Program, Grey Nuns Community Health Centre, University of Alberta, Edmonton, Canada Received 30 March 1996; revised version received 11 July 1996; accepted 25 July 1996
Abstract A 62-year-old man receiving subcutaneous fentanyl for the management of cancer pain developed generalized central excitation after an overdose of 5000 mg of fentanyl. The patient developed acute confusion, restlessness, generalized myoclonus, visual hallucinations, and hyperalgesia and tremors upon tactile stimulation of the arms or legs. These symptoms rapidly disappeared after the administration of 0.2 mg of naloxone. Within an hour the symptoms reappeared and once again, responded immediately after a second injection of 0.2 mg of naloxone. Our findings suggest that fentanyl overdose can occasionally present with general central irritability that responds to naloxone. Keywords: Neuropsychiatric; Fentanyl; Cancer
1. Introduction Opioid overdoses cause CNS depression, consisting mostly of sedation, coma, and respiratory depression (Inturrisi, 1990; Skinner and Thompson, 1992). In addition, patients frequently develop respiratory distress due to non-cardiogenic pulmonary edema (Bruera and Miller, 1989; Henderson, 1991) and autonomic changes including sweating, myosis and hypotension (Inturrisi, 1990; Skinner and Thompson, 1992). Most of these effects respond rapidly to parenteral naloxone. We report the case of a patient who experienced confusion, agitation and cutaneous hyperalgesia after an overdose of fentanyl. 2. Case report A 62-year-old man was admitted to the Palliative Care Unit because of abdominal pain, nausea and vomiting. Eight months before, he had undergone a gastrectomy because of adenocarcinoma of the stomach. One month before admission, a laparotomy demonstrated the presence of advanced intra-abdominal disease. There was no prior
* Corresponding author.
evidence of delirium, seizures, chronic neurologic disorder or drugs with excitatory effects. Upon admission, he was maintained for 8 days on a continuous subcutaneous infusion of fentanyl at 100 mg/hr with excellent pain control (less than 2 extra analgesic doses per day were required and pain intensity in the visual analogue scale 0 = best, 10 = worst, ranged from 2 to 4 for the last three days). His cognitive status had been normal (4 routine Mini-Mental State Questionnaire scores had been normal, the last one being 28/30 2 days before) (Folstein et al., 1975). On day 8 of the infusion, the patient became acutely confused, with mild restlessness and hand movements suggesting visual hallucinations. His eyes were open but there was no response to simple commands. A subcutaneous dose of haloperidol of 2 mg was administered with no significant change. In the following 30 minutes, the patient developed generalized tremor and hyperalgesia upon tactile stimulation of the arms or legs or loud noises, progressive generalized myoclonus, profuse sweating and miosis. At this time, the nurse realized that he had been mistakenly administered a dose of 5000 mg of fentanyl as an intravenous infusion over the last hour (approximately 50 times the hourly dose). The respiratory rate was 10–15 per minute and oxygen saturation was 88%–92% on room air. An assessment by an intern revealed no evidence of severe sedation or respiratory depression. However, be-
0304-3959/97/$17.00 1997 International Association for the Study of Pain. Published by Elsevier Science Ireland Ltd. PII S0304-3959 (96 )0 3238-1
200
E. Bruera, J. Pereira / Pain 69 (1997) 199–201
cause of the sudden onset of the neuropsychiatric changes and the evidence of opioid overdose, an intravenous bolus injection of 0.1 mg of naloxone was administered, followed by a second 0.1 mg bolus within 5 min. Within 2–3 min after the second injection, the patient became completely conscious and cognitively normal. Hallucinations, agitation, cutaneous hyperalgesia and generalized myoclonus, as well as sweating and miosis, all resolved completely. Within an hour of observation, all symptoms reappeared. A second injection of 0.2 mg of naloxone resulted again in complete resolution of the symptoms within 2–3 min. At this time, a continuous intravenous infusion of naloxone 0.2 mg/hour was started. Neurological vital signs every 15 min and pain control remained excellent for the next 7 h. At that point, after a cumulative dose of 1.8 mg of naloxone, the patient started complaining of his usual abdominal pain. The infusion of naloxone was discontinued and within 15–20 minutes, the pain disappeared. Three hours later, the pain reappeared and a continuous subcutaneous infusion of fentanyl was restarted at a dose of 100 m/hr. The infusion was maintained for several days with no further evidence of toxicity. The respiratory rate, oxygen saturation and blood pressure remained normal during the whole episode. 3. Discussion This patient presented with an acute and highly unusual neurological syndrome. The most common manifestations of severe opioid toxicity including somnolence, respiratory depression or hypotension were absent. Instead, there were signs of agitation, myoclonus and cutaneous hyperalgesia suggesting an impending grand mal seizure. In recent years, new central side-effects of opioids have been described including generalized myoclonus, hyperalgesia, grand mal seizures and agitation (Sjogren et al., 1994; Sjogren and Erikson, 1994; de Stoutz et al., 1995). These effects have been described mostly in patients receiving high doses of morphine for a long period of time, and have been ascribed to non-opioid binding effects of morphine or two of its metabolites, morphine-3-glucuronide or nor-morphine (Sjogren et al., 1994; Sjogren and Erikson, 1994). Some authors have suggested an anti-glycinergic effect of morphine or its metabolites similar to those observed after strychnine intoxication (Sjogren et al., 1994). However, fentanyl has not been found to have any significant non-opioid binding (Frenk et al., 1984). The immediate occurrence of toxicity after this intravenous overdose suggests that the neuropsychiatric effects were due to the active drug rather than metabolites. Previous reports of fentanyl overdoses found CNS depression (Martin et al., 1991; Marquardt and Tharratt, 1994). However, these patients were usually non-tolerant and received low doses of fentanyl (Henderson, 1991; Martin et al., 1991; Marquardt and Tharratt, 1994). Our patient had been exposed to a high dose of fentanyl (100
mg/hr) for eight days before receiving a massive overdose. Animal studies suggest that morphine, fentanyl and meperidine exhibit a biphasic dose response relationship with respect to their effects on seizure thresholds: low doses are anticonvulsant and high doses are proconvulsant. Naloxone reversed the effects of the higher doses of morphine and fentanyl on seizure threshold (Lauretti et al., 1994). Some studies have found that naloxone is able to block morphine-induced susceptibility to seizure in some animal models (Thomas et al., 1993). Naloxone was also able to block the anticonvulsant effect of endorphins (Koide et al., 1993) and low dose fentanyl (Koide et al., 1992) in other animal models. Our findings suggest that an acute opioid overdose can cause central excitation that responds to naloxone. However, central excitation during chronic opioid administration is probably due to activation of non-opioid receptors by active metabolites and, therefore, non-responsive to naloxone (Sjogren and Erikson, 1994; de Stoutz et al., 1995). In these patients, naloxone might decrease seizure threshold (Koide et al., 1992; Koide et al., 1993) and potentially cause seizures by blocking the depressant effect of the circulating opioids and allowing the expression of the convulsant activity of active metabolites to manifest (Inturrisi, 1990). Finally, our patient demonstrates that even in the case of liposoluble drugs of short half-life such as fentanyl, a continuous infusion of naloxone may be required in order to prevent a repetition of the toxicity of massive overdoses. The reason why prolonged administration of naloxone was needed is probably that the elimination half-life of the drug on steady state can be quite prolonged, since it reflects both the clearance of the drug and redistribution from fat stores. In the case of fentanyl, the large fat compartment will result in blood levels being maintained for several hours. Our findings suggest that an opioid overdose should be suspected in patients presenting with acute central hyperactive symptoms and that these symptoms may respond to naloxone. It is possible that some cases of central irritability during chronic opioid administration might also respond to naloxone. Even in the case of liposoluble drugs of short half-life such as fentanyl, a continuous infusion of naloxone may be required in order to prevent a repetition of the toxicity in cases of massive overdose. References Bruera, E. and Miller, M.J., Non-cardiogenic pulmonary edema after narcotic treatment for cancer pain, Pain, 39 (1989) 297–300. de Stoutz, N.D., Bruera, E. and Suarez-Almazor, M., Opioid rotation (OR) for toxicity reduction in terminal cancer patients, J. Pain Symptom Manage., 10 (1995) 378–384. Folstein, M.F., Folstein, S. and McHugh, P.R., ’Mini-mental state’: a practical method for grading the cognitive state of patients for the clinician, J. Psych. Res., 12 (1975) 189–198. Frenk, H., Watkins, L.R. and Mayer, D.J., Differential behavioural
E. Bruera, J. Pereira / Pain 69 (1996) 199–201 effects induced by intrathecal microinjection of opiates: comparison of convulsive and cataleptic effects produced by morphine, methadone, and D-Ala-Methionine-enkephalinamide, Brain Res., 299 (1984) 41– 42. Henderson, G.L., Fentanyl-related deaths: demographics, circumstances and toxicology of 112 patients, J. Forensic Sci., 36 (1991) 422– 433. Inturrisi, C.E., Opioid analgesic therapy in cancer pain. In: K.M. Foley, J.J. Bonica, V. Ventafridda (Eds.), Advances in Pain Research and Therapy, Raven Press, New York, 16 (1990) pp. 133–154. Koide, S., Onishi, H., Yamagami, S., and Kawakita, Y., Effects of morphine and D-Ala2-D-Leu5-enkephalin in the seizure-susceptible E1 mouse, Neurochem. Res., 17 (1992) 779–783. Koide, S., Onishi, H., Katayama, M. and Yamagami, S., Endogenous methionine enkephalin may plan an anticonvulsant role in the seizure-susceptible E1 mouse, Neurochem. Res., 18 (1993) 1259–1262. Lauretti, G.R., Ahmad, I. and Pleuvry, B.J., The activity of opioid analgesics in seizure models utilizing N-methyl-DL-aspartic acid, kai-
201
nic acid, bicuculline and pentylenetetrazole, Neuropharmacology, 33 (1994) 155–160. Marquardt, K.A. and Tharratt, R.S., Inhalation abuse of fentanyl patch, J. Toxicol. Clin. Toxicol., 31 (1994) 75–78. Martin, M., Hecker, J., Clark, R., Frye, J., Jehle, D., Lucid, E.J. et al., China White epidemic: an eastern United States emergency department experience, Ann. Emerg. Med., 20 (1991) 158–164. Sjogren, P., and Erikson, J., Opioid toxicity, Curr. Opin. Anesthesiol., 7 (1994) 465–469. Sjogren, P., Jensen, N.H. and Jensen, T.S., Disappearance of morphineinduced hyperalgesia after discontinuing or substituting morphine with other opioid agonists, Pain, 59 (1994) 313–316. Skinner, M. and Thompson, A., Pharmacologic considerations in the treatment of substance abuse (review), Soc. Med. J., 85 (1992) 1207–1219. Thomas, J., Nores, W.L., Kenigs, V., Olson, G.A. and Olson, R.D. Picrotoxin-induced seizures modified by morphine and opiate antagonists, Pharmacol. Biochem. Behav., 45 (1993) 615–617.