Hemodialysis in an infant with propoxyphene intoxication A JO-month-old infant was treated with intensive supportive care and hemodialysisfor severe propoxyphene intoxication. Dialysis clearance studies demonstrated that propoxyphene was removedfrom the serum at approximately 50% of the rate of blood urea nitrogen removal. Possibly because of tissue binding ofthe drug, the absolute quantity ofpropoxyphene removed by dialysis was small. The child survived the acute episode of intoxication but died ofpulmonary complications several days later. The role of dialysis in propoxyphene intoxication remains to be established.
S. Michael Mauer, M.D., Charles L. Paxson, M.D., Barry von Hartizsch, M.D., Theodore J. Buselmeier, M.D., and Carl M. Kjellstrand, M.D. Minneapolis, Minn. Departments of Pediatrics, Medicine, and Surgery, University of Minnesota Medical School
Propoxyphene (Darvon) has been very widely used since its introduction in 1957 and is now listed as the most frequently prescribed drug in the United States. 28 There have been reports of serious and fatal propoxyphene poisonings.2, 3, 7, 8, 11-15, 20, 21, 23, 25, 26, 27, 32, 33 Only 10 cases of severe intoxication have been reported in children. A satisfactory approach to the management of propoxyphene poisoning has yet to be described. The published hemodialysis experience in propoxyphene intoxication is limited to a single case report.13 We present here our experience with a lO-monthold infant treated with hemodialysis for propoxyphene intoxication. Studies of clearance of propoxyphene by hemodialysis were performed. Case report One hour after the ingestion of an unknown number of 65-mg propoxyphene hydrochloride capsules, this IO-month-old white female infant weighing 10 kg became somnolent, developed labored respirations, cyanosis, and grand mal seizures, and rapidly progressed to coma. When first seen in the emerReceived for publication Sept. 17, 1974. Accepted for publication Oct. 13. 1974.
88
gency room elsewhere, she was moribund with no spontaneous respirations or detectable blood pressure. Pulse was 40 beats per minute and irregular, rectal temperature was less than 96° F, and the pupils were fixed and dilated. There was no response to deep pain. She was treated with endotracheal intubation, positive pressure ventilation, and intravenous epinephrine, isoproterenol, and sodium bicarbonate. She was given two intravenous doses of nalorphine without effect. Gastric lavage with activated charcoal was carried out. Despite these measures, acidosis, hypotension, bradycardia, and coma persisted and she was transferred to our unit for hemodialysis. On admission she was deeply comatose, cyanotic, had no detectable blood pressure, and had an irregular pulse with a rate of 20 beats per minute. The pH was 6.94, pC0 2 , 123, P02 , 12; blood urea nitrogen (BUN) was 35 and serum creatinine (Cr) , 2.0 mg/ 100 ml, respectively; serum sodium and potassium were 141 and 4.1 mEg/I, respectively. Her vital signs improved somewhat with more effective ventilation, reinstitution of the isoproterenol infusion, and sodium bicarbonate administration. Hemodialysis was begun 7 hours after ingestion. During the course of this 6-hr procedure, her condition improved significantly. Her electrocardiogram reverted from multifocal ventricular beats to sinus rhythm, her blood pressure stabilized at 65/40 mm Hg with isoproterenol support, and her blood gases returned to normal values. Following hemodialysis,
Propoxyphene poisoning
Volume 17 Numher 1
89
Table I. Results of propoxyphene dialysis clearance studies Blood sample source To dialyzer ( p.,glml)
From dialyzer ( p.,glml)
Clearance (mllmin)
First clearance study (after IS min of dialysis)
Propoxyphene Norpropoxyphene
1.52 2.83
0.84 1.76
14.3 12.1
Second clearance study (after 3 hr of dialysis)
Propoxyphene Norpropoxyphene
1.61 3.16
0.68 1.48
18.5 17.0
Post-dialysis (after 6 hr of dialysis)
Propoxyphene Norpropoxyphene
1.76 3.52
probably because of intravenous potassium administration in the face of renal insufficiency, she developed severe hyperkalemia and suffered cardiac arrest but was successfully resuscitated. At this time the BUN was 53 and Cr, 2.0 mg/IOO ml, respectively, and there developed polyuria, hypernatremia (serum sodium 173 mEq/I), and dehydration. Large quantities of fl uids were needed to replace urinary losses. The polyuria gradually diminished over the next two days. Thirty hours after dialysis she had spontaneous movements and respiration, was ventilating adequately without assistance, and was responding to painful stimuli. She required continuous oxygen therapy; when, 2 days after dialysis, this was briefly discontinued, she suffered a second cardiac arrest. She was again resuscitated but, following this episode, an electroencephalogram showed complete absence of electrical brain activity. Vital signs became unstable, and she died on the fifth hospital day. At autopsy severe anoxic encephalopathy, diffuse pulmonary atelectasis, pseudomembranous enterocolitis of the large bowel, and scattered areas of hepatic infarction were found. Methods
Hemodialysis was performed with two cannulas surgically placed in the right atrium via the external jugUlar veins. A Gambro Lundia Minor dialyzer24 was used with a blood flow rate of 32 ml per minute, providing for this patient a BUN clearance of 3.0 ml/kg/min. This BUN clearance is comparable to that used in the hemodialysis of adult patients. 18 Normal aqueous dialysate was pumped at 500 ml/min, single pass, through the dialysate compartment of the dialyzer. Blood samples were taken from blood lines leading to and from the dialyzer at the be-
ginning and middle of the dialysis procedure; a final sample was obtained from the patient at the end of dialysis. Determinations of serum propoxyphene and norpropoxyphene levels were kindly performed by Dr. Frank Nash (Eli Lilly & Co), using gas chromatography.30 Calculations of approximate dialyzer clearance of propoxyphene and norpropoxyphene and total drug removal were performed as described previously.16 Results
At a dialysis blood flow rate of 32 ml/min, the clearances of propoxyphene and its Ndemethylated derivative were approximately 50% of the BUN clearance (Table I). Calculated total drug removal by dialysis was 9.6 mg for propoxyphene and 16.5 mg for norpropoxyphene. Discussion
Although propoxyphene is regarded as a nonnarcotic analgesic, it is chemically similar to methadone and equivalent to codeine in potency.22 The drug is absorbed from the gastrointestinal tract, especially from the stomach, within 30 to 60 minutes. 31 Absorbed propoxyphene quickly localizes in lung, liver, kidney, brain, and other organs, 10, 26, 32, 33 and less than I % of the ingested dose may be present in circulating plasma. In the intoxicated patient, plasma levels may not reflect drug concentration in other tissues nor do they reliably indicate the quantity of drug ingested. However,
90
Mauer et at.
levels of 2 J,Lg/ml or more indicate severe propoxyphene poisoning. 26 The major route of metabolic degradation of propoxyphene appears to be hepatic N-demethylation; the brain is not able to perform this enzymatic function. 19 Within 24 hr of ingestion more than half of the propoxyphene is excreted in bile,IO while approximately 15% is excreted in urine, almost all as the demethylated product. 19 Acute propoxyphene intoxication presents initially with delirium followed rapidly by convulsions, coma, and severe respiratory depression. 23 Frequently, severe pulmonary edema, 3 cardiac arrhythmias, and shock ensue and apnea soon follows. Doses in the range of 25 to 30 mg/kg of body weight23 often result in death within 30 to 45 min after consumption. 27 Ingestion of as little as 10 mg/kg may, however, be lethal. 23 Since death from severe propoxyphene overdosage may occur within the first hour following ingestion, speed is essential to therapy. Activated charcoal given within 30 to 60 min of ingestion has been shown to bind propoxyphene effectively6-S and should be given as soon as possible after emptying the stomach. Early ventilatory support may be life-saving in the management of respiratory depression and pulmonary edema. Isoproterenol infusion may be helpful in maintaining adequate blood pressure. 23 Narcotic antagonists are the specific antidotes for propoxyphene. 15 Nalorphine ,27 levallorphan,11 and naloxone 15 have been shown to rapidly reverse coma and respiratory depression in man and to relieve both the depressive and convulsive actions of propoxyphene in rats.5 Repeated doses of narcotic antagonists may be required as their half-lives are much shorter than that of propoxyphene. In several cases of severe poisoning reported by Bogartz and Miller,3 Frasier, Crudo, and Johnson,12 Karliner,14 and by us, narcotic antagonists had little or no effect. The literature on dialysis therapy of propoxyphene poisoning is limited. Two patients have been treated with peritoneal dialysis. 14 , 20 Both showed some clinical improvement but ultimately died. Karliner14 estimated the quantity of toxin removed by the peritoneal route to be very small and concluded that the therapy was
Clinical Pharmacology and Therapeutics
not helpful. Gary and associates 13 treated a patient who took 1.8 gm of propoxyphene and recovered 4.8% by gastric lavage, 5.3% by forced diuresis, 0.9% by peritoneal dialysis, and 6.9% by 2 courses of hemodialysis, Although this patient recovered from the acute toxicity of propoxyphene, she died two months later from complications of the cerebral anoxia suffered initially, Our patient remained moribund despite treatment with narcotic antagonists and intensive supportive care; therefore, dialysis was undertaken. The procedure did provide several advantages in the medical management of the patient. It allowed for the safe infusion of massive quantities of sodium bicarbonate without the production of hypematremia or fluid overload, Through careful weight monitoring on dialysis, fluid therapy could be controlled with precision, Access to the circulation permitted repeated removal of relatively large quantities of blood for laboratory studies and exact replacement of these losses. During the dialysis procedure there was a marked improvement of vital signs and significant improvement in neurologic status. However, little propoxyphene was removed. If our patient had ingested a fatal dose in the range of 25 to 30 mg/kg dialysis drug removal would then represent less than 4% of the drug as taken and 7% as the detoxified N-demethylated compound. Clearance ofpropoxyphene, at 50% of the rate of BUN removal, is consistent with that expected for a molecule of its size (MW, 377)1 and suggests that protein binding is not a factor in its dializability. We suggest that tissue binding is the factor limiting the removal of propoxyphene by dialysis. It is possible that the small absolute quantity of drug removed contributed to our patient's initial clinical improvement, particularly if dialysis created a concentration gradient between brain cells and the serum, thus allowing for diffusion of the drug out of cerebral tissues. The increasing blood levels of drug during dialysis may have been due to correction of hypoxemia, acidosis, and shock, leading to the re-establishment of gut function and further drug absorption. On the other hand the marked change in blood pH may have caused a redistri-
Propoxyphene poisoning
Volume 17 Numher 1
bution of the drug from tissue binding sites to the serum. The pKa of propoxyphene is 6.3, and it is known that drugs that are weak acids (e. g. , phenobarbital) can be shifted from brain to serum by increasing the serum pH. 29 Acute renal insufficiency has been previously recorded 25 and in our case was probably the consequence of prolonged hypotension. Subsequently, there was polyuria representing either recovery from acute renal tubular injury or the established antidiuretic hormone effect of propoxyphene. 4 Hypotension requiring support persisted for 36 hr in our patient, and residual respiratory problems 3 days after drug ingestion led to her death. This case emphasizes the need for meticulous intensive care for several days in severe propoxyphene poisoning. We know of no therapy that removes large quantities of propoxyphene from the body. The frequency of fatal episodes of propoxyphene poisoning2 1. 27 should stimulate the investigation of better treatments for this condition. Prolonged or repeated hemodialysis, the use of ultrathin dialysis membranes ,17 or dialysis against activated charcoal 9 may be promising approaches to the management of the patient with life-threatening propoxyphene intoxication. At present, intensive supportive care and narcotic antagonists offer the best hopes for recovery. We thank Dr. Bernard Mirkin for his valuable advice in preparing this manuscript and Mrs. Mary 10 Jansen for secretarial assistance.
6. 7. 8. 9.
10.
II. 12.
13.
14. 15. 16.
17.
References I. Babb, A. L., Farrel, P. c., Uvelli, D. A., and Scribner, B. H.: Hemodialyzer evaluation by examination of solute molecular spectra, Trans. Am. Soc. Anif. Intern. Organs 18:98-105, 1972. 2. Billig, N.: Propoxyphene hydrochloride (Darvon) poisoning in a three-year old child, Am. J. Dis. Child. 116:187-189, 1968. 3. Bogartz, L. 1., and Miller, W. c.: Pulmonary edema associated with propoxyphene intoxication, 1. A. M. A. 215:259-262, 1971. 4. Bower, B. F., Wegienka, L. c., and Forsham, P. H.: In vitro studies of the mechanism of polyuria induced by dextropropoxyphene (Darvon), Proc. Soc. Exp. Bio!. Med. 120:155-157, 1965. 5. Chapman, J. E., and Walaszek, E. J.: Antagonism of some toxic effects of dextropropoxy-
18.
19.
20.
21.
91
phene by nalorphine, Toxicol. App!. Pharmacol. 4:752-758, 1962. Chern ish , S. M.: Adsorption of propoxyphene hydrochloride by activated charcoal, Clin. Toxicol. 5:317-329, 1972. Corby, D. G., and Decker, W. J.: An antidote for propoxyphene HCI, J. A. M. A. 203: 1074, 1968. Corby, D. G., and Decker, W. J.: Treatment of propoxyphene poisoning, 1. A. M. A. 205:250251, 1968. Decker, W. J., Combs, H. G., Trueting, J. J., and Banez, R. 1.: Dialysis of drugs against activated charcoal, Toxicol. Appl. Pharmacol. 18:573-578, 1971. Emmerson, J. L., Welles, J. S., and Anderson, R. c.: Studies on the tissue distribution of d-propoxyphene, Toxicol. Appl. Pharmacol. 11: 482-488, 1967. Fraser, H. F.: Propoxyphene antidotes, J. A. M. A. 204:549, 1968. Frasier, S. D., Crudo, F. S., Jr., and Johnson, D. H.: Dextropropoxyphene hydrochloride poisoning in two children, J. Pediat. 63: 158-159, 1963. Gary, N. E., Maher, 1. F., DeMyttenaere, M. H., Liggero, S. H., Scott, K. G., Matusiak, W., and Schreiner, G. E.: Acute propoxyphene hydrochloride intoxication, Arch. Intern. Med. 221:453-457, 1968. Karliner, J. S.: Propoxyphene hydrochloride poisoning. Report of a case treated with peritoneal dialysis, J. A. M. A. 199: 1006-1009, 1967. Kersh, E. S.: Treatment of propoxyphene overdosage with naloxone, Chest 63: 112-1 14, 1973. Kjellstrand, C. M., Campbell, D., von Hartitzsch, B., and Buselmeier, T. J.: Hyperuricemic acute renal failure, Arch. Med. 133:349-359, 1974. Kjellstrand, C. M., Peterson, R. J., Evans, R. L., Shideman, R. J., Santiago, E. A., Buselmeier, T. J., and Rozelle, L. T.: In vivo studies of a new ultrathin membrane for hemodialysis, Trans. Am. Soc. Artif. Intern. Organs 18: 106112, 1972. Kjellstrand, C. M., Shideman, J. R., Santiago, E. A., Mauer. S. M., Simmons, R. L., and Buselmeier, T. J.: Technical advances in hemodialysis of very small pediatric patients, Proc. Dial. Transpl. Forum 1:124-132,1971. Lee, H. M., Scott, E. G., and Pohland, A.: Studies on the metabolic degradation of propoxyphene, J. Pharmacol. Exp. Ther. 125: 14-18, 1969. McCarthy, W. H., and Kennan, R. L.: Propoxyphene hydrochloride poisoning: Report of the first fatality, J. A. M. A. 187:460-461, 1964. Owen, N. L.: Abuse of propoxyphene, J. A. M. A. 216:2016, 1971.
92
Mauer et al.
22. Robbins. E. B.: The pharmacologic effects of a new analgesic, a-4-dimethylamino-1 ,2 diphenyl3-methyl-4-propionyloxybutane, 1. Am. Pharm. Assoc. 44:497-500, 1955. 23. Salter, R. J.: Propoxyphene: Dependence, abuse, and treatment of overdosage, Am. J. Hosp. Pharm. 28:210, 1971. 24. Shideman, J. R., Mayer, R. M., Bosh, R. H., Mauer, S. M., Buselmeier, T. J., and Kjellstrand, C. M.: The lundia minor, a disposable dailyzer for pediatric hemodialysis, J. Renal Tech., Dial. Transplant. 3:12-14, 1974. 25. Sigurd, B. M., and Jensen, G.: Propoxyphene poisoning, Dan. Med. Bull. 18: 166-168,1972. 26. Sturner, W. Q., and Garriott, J. C.: Deaths involving propoxyphene, J. A. M. A. 223: 1125-1130, 1973. 27. Tennant, F. S., Jr.: Complications of propoxyphene abuse, Arch. Intern. Med. 132: 19 1-194, 1973. 28. Therapeutic Category Report in National Pre-
Clinical Pharmacology and Therapeutics
29. 30.
31.
32. 33.
scription Audit, Dedham, Mass., R. A. Gosselin and Company, Inc., 1969, p. 18. Waddell, W. J., and Butler, T. c.: The distribution and excretion of phenobarbital, J. Clin. Invest. 36: 1217- 1226, 1957. Wolen, R. L., and Gruber, C. M., Jr.: Determination of propoxyphene in human plasma by gas chromatography, Anal. Chern. 40: 12431246, 1968. Wolen, R. L., Gruber, C. M., Jr., Kiplinger, G. F., and Scholz, N. E.: Concentration of propoxyphene in human plasma following oral, intramuscular and intravenous administration, Toxicol. Appl. Pharmacol. 19:480-492, 1971. Worm, K.: Determination of dextropropoxyphene in organs from fatal poisoning, Acta Pharmacol. et Toxicol. 30:330-338, 1971. Young, D. J.: Propoxyphene suicides. Report of nine cases, Arch. Intern. Med. 129:62-66, 1972.
S. Michael Mauer, M.D., Charles L. Paxson, M.D., Barry von Hartizsch, M.D., Theodore J. Buselmeier, M.D., and Carl M. Kjellstrand, M.D. Minneapolis, Minn. Departments of Pediatrics, Medicine, and Surgery, University of Minnesota Medical School
Propoxyphene (Darvon) has been very widely used since its introduction in 1957 and is now listed as the most frequently prescribed drug in the United States. 28 There have been reports of serious and fatal propoxyphene poisonings.2, 3, 7, 8, 11-15, 20, 21, 23, 25, 26, 27, 32, 33 Only 10 cases of severe intoxication have been reported in children. A satisfactory approach to the management of propoxyphene poisoning has yet to be described. The published hemodialysis experience in propoxyphene intoxication is limited to a single case report.13 We present here our experience with a lO-monthold infant treated with hemodialysis for propoxyphene intoxication. Studies of clearance of propoxyphene by hemodialysis were performed. Case report One hour after the ingestion of an unknown number of 65-mg propoxyphene hydrochloride capsules, this IO-month-old white female infant weighing 10 kg became somnolent, developed labored respirations, cyanosis, and grand mal seizures, and rapidly progressed to coma. When first seen in the emerReceived for publication Sept. 17, 1974. Accepted for publication Oct. 13. 1974.
88
gency room elsewhere, she was moribund with no spontaneous respirations or detectable blood pressure. Pulse was 40 beats per minute and irregular, rectal temperature was less than 96° F, and the pupils were fixed and dilated. There was no response to deep pain. She was treated with endotracheal intubation, positive pressure ventilation, and intravenous epinephrine, isoproterenol, and sodium bicarbonate. She was given two intravenous doses of nalorphine without effect. Gastric lavage with activated charcoal was carried out. Despite these measures, acidosis, hypotension, bradycardia, and coma persisted and she was transferred to our unit for hemodialysis. On admission she was deeply comatose, cyanotic, had no detectable blood pressure, and had an irregular pulse with a rate of 20 beats per minute. The pH was 6.94, pC0 2 , 123, P02 , 12; blood urea nitrogen (BUN) was 35 and serum creatinine (Cr) , 2.0 mg/ 100 ml, respectively; serum sodium and potassium were 141 and 4.1 mEg/I, respectively. Her vital signs improved somewhat with more effective ventilation, reinstitution of the isoproterenol infusion, and sodium bicarbonate administration. Hemodialysis was begun 7 hours after ingestion. During the course of this 6-hr procedure, her condition improved significantly. Her electrocardiogram reverted from multifocal ventricular beats to sinus rhythm, her blood pressure stabilized at 65/40 mm Hg with isoproterenol support, and her blood gases returned to normal values. Following hemodialysis,
Propoxyphene poisoning
Volume 17 Numher 1
89
Table I. Results of propoxyphene dialysis clearance studies Blood sample source To dialyzer ( p.,glml)
From dialyzer ( p.,glml)
Clearance (mllmin)
First clearance study (after IS min of dialysis)
Propoxyphene Norpropoxyphene
1.52 2.83
0.84 1.76
14.3 12.1
Second clearance study (after 3 hr of dialysis)
Propoxyphene Norpropoxyphene
1.61 3.16
0.68 1.48
18.5 17.0
Post-dialysis (after 6 hr of dialysis)
Propoxyphene Norpropoxyphene
1.76 3.52
probably because of intravenous potassium administration in the face of renal insufficiency, she developed severe hyperkalemia and suffered cardiac arrest but was successfully resuscitated. At this time the BUN was 53 and Cr, 2.0 mg/IOO ml, respectively, and there developed polyuria, hypernatremia (serum sodium 173 mEq/I), and dehydration. Large quantities of fl uids were needed to replace urinary losses. The polyuria gradually diminished over the next two days. Thirty hours after dialysis she had spontaneous movements and respiration, was ventilating adequately without assistance, and was responding to painful stimuli. She required continuous oxygen therapy; when, 2 days after dialysis, this was briefly discontinued, she suffered a second cardiac arrest. She was again resuscitated but, following this episode, an electroencephalogram showed complete absence of electrical brain activity. Vital signs became unstable, and she died on the fifth hospital day. At autopsy severe anoxic encephalopathy, diffuse pulmonary atelectasis, pseudomembranous enterocolitis of the large bowel, and scattered areas of hepatic infarction were found. Methods
Hemodialysis was performed with two cannulas surgically placed in the right atrium via the external jugUlar veins. A Gambro Lundia Minor dialyzer24 was used with a blood flow rate of 32 ml per minute, providing for this patient a BUN clearance of 3.0 ml/kg/min. This BUN clearance is comparable to that used in the hemodialysis of adult patients. 18 Normal aqueous dialysate was pumped at 500 ml/min, single pass, through the dialysate compartment of the dialyzer. Blood samples were taken from blood lines leading to and from the dialyzer at the be-
ginning and middle of the dialysis procedure; a final sample was obtained from the patient at the end of dialysis. Determinations of serum propoxyphene and norpropoxyphene levels were kindly performed by Dr. Frank Nash (Eli Lilly & Co), using gas chromatography.30 Calculations of approximate dialyzer clearance of propoxyphene and norpropoxyphene and total drug removal were performed as described previously.16 Results
At a dialysis blood flow rate of 32 ml/min, the clearances of propoxyphene and its Ndemethylated derivative were approximately 50% of the BUN clearance (Table I). Calculated total drug removal by dialysis was 9.6 mg for propoxyphene and 16.5 mg for norpropoxyphene. Discussion
Although propoxyphene is regarded as a nonnarcotic analgesic, it is chemically similar to methadone and equivalent to codeine in potency.22 The drug is absorbed from the gastrointestinal tract, especially from the stomach, within 30 to 60 minutes. 31 Absorbed propoxyphene quickly localizes in lung, liver, kidney, brain, and other organs, 10, 26, 32, 33 and less than I % of the ingested dose may be present in circulating plasma. In the intoxicated patient, plasma levels may not reflect drug concentration in other tissues nor do they reliably indicate the quantity of drug ingested. However,
90
Mauer et at.
levels of 2 J,Lg/ml or more indicate severe propoxyphene poisoning. 26 The major route of metabolic degradation of propoxyphene appears to be hepatic N-demethylation; the brain is not able to perform this enzymatic function. 19 Within 24 hr of ingestion more than half of the propoxyphene is excreted in bile,IO while approximately 15% is excreted in urine, almost all as the demethylated product. 19 Acute propoxyphene intoxication presents initially with delirium followed rapidly by convulsions, coma, and severe respiratory depression. 23 Frequently, severe pulmonary edema, 3 cardiac arrhythmias, and shock ensue and apnea soon follows. Doses in the range of 25 to 30 mg/kg of body weight23 often result in death within 30 to 45 min after consumption. 27 Ingestion of as little as 10 mg/kg may, however, be lethal. 23 Since death from severe propoxyphene overdosage may occur within the first hour following ingestion, speed is essential to therapy. Activated charcoal given within 30 to 60 min of ingestion has been shown to bind propoxyphene effectively6-S and should be given as soon as possible after emptying the stomach. Early ventilatory support may be life-saving in the management of respiratory depression and pulmonary edema. Isoproterenol infusion may be helpful in maintaining adequate blood pressure. 23 Narcotic antagonists are the specific antidotes for propoxyphene. 15 Nalorphine ,27 levallorphan,11 and naloxone 15 have been shown to rapidly reverse coma and respiratory depression in man and to relieve both the depressive and convulsive actions of propoxyphene in rats.5 Repeated doses of narcotic antagonists may be required as their half-lives are much shorter than that of propoxyphene. In several cases of severe poisoning reported by Bogartz and Miller,3 Frasier, Crudo, and Johnson,12 Karliner,14 and by us, narcotic antagonists had little or no effect. The literature on dialysis therapy of propoxyphene poisoning is limited. Two patients have been treated with peritoneal dialysis. 14 , 20 Both showed some clinical improvement but ultimately died. Karliner14 estimated the quantity of toxin removed by the peritoneal route to be very small and concluded that the therapy was
Clinical Pharmacology and Therapeutics
not helpful. Gary and associates 13 treated a patient who took 1.8 gm of propoxyphene and recovered 4.8% by gastric lavage, 5.3% by forced diuresis, 0.9% by peritoneal dialysis, and 6.9% by 2 courses of hemodialysis, Although this patient recovered from the acute toxicity of propoxyphene, she died two months later from complications of the cerebral anoxia suffered initially, Our patient remained moribund despite treatment with narcotic antagonists and intensive supportive care; therefore, dialysis was undertaken. The procedure did provide several advantages in the medical management of the patient. It allowed for the safe infusion of massive quantities of sodium bicarbonate without the production of hypematremia or fluid overload, Through careful weight monitoring on dialysis, fluid therapy could be controlled with precision, Access to the circulation permitted repeated removal of relatively large quantities of blood for laboratory studies and exact replacement of these losses. During the dialysis procedure there was a marked improvement of vital signs and significant improvement in neurologic status. However, little propoxyphene was removed. If our patient had ingested a fatal dose in the range of 25 to 30 mg/kg dialysis drug removal would then represent less than 4% of the drug as taken and 7% as the detoxified N-demethylated compound. Clearance ofpropoxyphene, at 50% of the rate of BUN removal, is consistent with that expected for a molecule of its size (MW, 377)1 and suggests that protein binding is not a factor in its dializability. We suggest that tissue binding is the factor limiting the removal of propoxyphene by dialysis. It is possible that the small absolute quantity of drug removed contributed to our patient's initial clinical improvement, particularly if dialysis created a concentration gradient between brain cells and the serum, thus allowing for diffusion of the drug out of cerebral tissues. The increasing blood levels of drug during dialysis may have been due to correction of hypoxemia, acidosis, and shock, leading to the re-establishment of gut function and further drug absorption. On the other hand the marked change in blood pH may have caused a redistri-
Propoxyphene poisoning
Volume 17 Numher 1
bution of the drug from tissue binding sites to the serum. The pKa of propoxyphene is 6.3, and it is known that drugs that are weak acids (e. g. , phenobarbital) can be shifted from brain to serum by increasing the serum pH. 29 Acute renal insufficiency has been previously recorded 25 and in our case was probably the consequence of prolonged hypotension. Subsequently, there was polyuria representing either recovery from acute renal tubular injury or the established antidiuretic hormone effect of propoxyphene. 4 Hypotension requiring support persisted for 36 hr in our patient, and residual respiratory problems 3 days after drug ingestion led to her death. This case emphasizes the need for meticulous intensive care for several days in severe propoxyphene poisoning. We know of no therapy that removes large quantities of propoxyphene from the body. The frequency of fatal episodes of propoxyphene poisoning2 1. 27 should stimulate the investigation of better treatments for this condition. Prolonged or repeated hemodialysis, the use of ultrathin dialysis membranes ,17 or dialysis against activated charcoal 9 may be promising approaches to the management of the patient with life-threatening propoxyphene intoxication. At present, intensive supportive care and narcotic antagonists offer the best hopes for recovery. We thank Dr. Bernard Mirkin for his valuable advice in preparing this manuscript and Mrs. Mary 10 Jansen for secretarial assistance.
6. 7. 8. 9.
10.
II. 12.
13.
14. 15. 16.
17.
References I. Babb, A. L., Farrel, P. c., Uvelli, D. A., and Scribner, B. H.: Hemodialyzer evaluation by examination of solute molecular spectra, Trans. Am. Soc. Anif. Intern. Organs 18:98-105, 1972. 2. Billig, N.: Propoxyphene hydrochloride (Darvon) poisoning in a three-year old child, Am. J. Dis. Child. 116:187-189, 1968. 3. Bogartz, L. 1., and Miller, W. c.: Pulmonary edema associated with propoxyphene intoxication, 1. A. M. A. 215:259-262, 1971. 4. Bower, B. F., Wegienka, L. c., and Forsham, P. H.: In vitro studies of the mechanism of polyuria induced by dextropropoxyphene (Darvon), Proc. Soc. Exp. Bio!. Med. 120:155-157, 1965. 5. Chapman, J. E., and Walaszek, E. J.: Antagonism of some toxic effects of dextropropoxy-
18.
19.
20.
21.
91
phene by nalorphine, Toxicol. App!. Pharmacol. 4:752-758, 1962. Chern ish , S. M.: Adsorption of propoxyphene hydrochloride by activated charcoal, Clin. Toxicol. 5:317-329, 1972. Corby, D. G., and Decker, W. J.: An antidote for propoxyphene HCI, J. A. M. A. 203: 1074, 1968. Corby, D. G., and Decker, W. J.: Treatment of propoxyphene poisoning, 1. A. M. A. 205:250251, 1968. Decker, W. J., Combs, H. G., Trueting, J. J., and Banez, R. 1.: Dialysis of drugs against activated charcoal, Toxicol. Appl. Pharmacol. 18:573-578, 1971. Emmerson, J. L., Welles, J. S., and Anderson, R. c.: Studies on the tissue distribution of d-propoxyphene, Toxicol. Appl. Pharmacol. 11: 482-488, 1967. Fraser, H. F.: Propoxyphene antidotes, J. A. M. A. 204:549, 1968. Frasier, S. D., Crudo, F. S., Jr., and Johnson, D. H.: Dextropropoxyphene hydrochloride poisoning in two children, J. Pediat. 63: 158-159, 1963. Gary, N. E., Maher, 1. F., DeMyttenaere, M. H., Liggero, S. H., Scott, K. G., Matusiak, W., and Schreiner, G. E.: Acute propoxyphene hydrochloride intoxication, Arch. Intern. Med. 221:453-457, 1968. Karliner, J. S.: Propoxyphene hydrochloride poisoning. Report of a case treated with peritoneal dialysis, J. A. M. A. 199: 1006-1009, 1967. Kersh, E. S.: Treatment of propoxyphene overdosage with naloxone, Chest 63: 112-1 14, 1973. Kjellstrand, C. M., Campbell, D., von Hartitzsch, B., and Buselmeier, T. J.: Hyperuricemic acute renal failure, Arch. Med. 133:349-359, 1974. Kjellstrand, C. M., Peterson, R. J., Evans, R. L., Shideman, R. J., Santiago, E. A., Buselmeier, T. J., and Rozelle, L. T.: In vivo studies of a new ultrathin membrane for hemodialysis, Trans. Am. Soc. Artif. Intern. Organs 18: 106112, 1972. Kjellstrand, C. M., Shideman, J. R., Santiago, E. A., Mauer. S. M., Simmons, R. L., and Buselmeier, T. J.: Technical advances in hemodialysis of very small pediatric patients, Proc. Dial. Transpl. Forum 1:124-132,1971. Lee, H. M., Scott, E. G., and Pohland, A.: Studies on the metabolic degradation of propoxyphene, J. Pharmacol. Exp. Ther. 125: 14-18, 1969. McCarthy, W. H., and Kennan, R. L.: Propoxyphene hydrochloride poisoning: Report of the first fatality, J. A. M. A. 187:460-461, 1964. Owen, N. L.: Abuse of propoxyphene, J. A. M. A. 216:2016, 1971.
92
Mauer et al.
22. Robbins. E. B.: The pharmacologic effects of a new analgesic, a-4-dimethylamino-1 ,2 diphenyl3-methyl-4-propionyloxybutane, 1. Am. Pharm. Assoc. 44:497-500, 1955. 23. Salter, R. J.: Propoxyphene: Dependence, abuse, and treatment of overdosage, Am. J. Hosp. Pharm. 28:210, 1971. 24. Shideman, J. R., Mayer, R. M., Bosh, R. H., Mauer, S. M., Buselmeier, T. J., and Kjellstrand, C. M.: The lundia minor, a disposable dailyzer for pediatric hemodialysis, J. Renal Tech., Dial. Transplant. 3:12-14, 1974. 25. Sigurd, B. M., and Jensen, G.: Propoxyphene poisoning, Dan. Med. Bull. 18: 166-168,1972. 26. Sturner, W. Q., and Garriott, J. C.: Deaths involving propoxyphene, J. A. M. A. 223: 1125-1130, 1973. 27. Tennant, F. S., Jr.: Complications of propoxyphene abuse, Arch. Intern. Med. 132: 19 1-194, 1973. 28. Therapeutic Category Report in National Pre-
Clinical Pharmacology and Therapeutics
29. 30.
31.
32. 33.
scription Audit, Dedham, Mass., R. A. Gosselin and Company, Inc., 1969, p. 18. Waddell, W. J., and Butler, T. c.: The distribution and excretion of phenobarbital, J. Clin. Invest. 36: 1217- 1226, 1957. Wolen, R. L., and Gruber, C. M., Jr.: Determination of propoxyphene in human plasma by gas chromatography, Anal. Chern. 40: 12431246, 1968. Wolen, R. L., Gruber, C. M., Jr., Kiplinger, G. F., and Scholz, N. E.: Concentration of propoxyphene in human plasma following oral, intramuscular and intravenous administration, Toxicol. Appl. Pharmacol. 19:480-492, 1971. Worm, K.: Determination of dextropropoxyphene in organs from fatal poisoning, Acta Pharmacol. et Toxicol. 30:330-338, 1971. Young, D. J.: Propoxyphene suicides. Report of nine cases, Arch. Intern. Med. 129:62-66, 1972.
