- Email: [email protected]
Inappropriate use of naloxone in cancer patients with pain
VoL II No. 2 Februarp19%
Pauiaiizre
Journal of P&I and $v@ton Mcnagmnent I31
can? Rounds
Inappropriate Use of Naloxone in Cancer Patients with Pain Paolo L.. Manfredi, MD, Sady Ribeiro, MD, gonja W. Chandler, Pharm D. and Richard Payne. MD Drpnrlmml ofNturoUnco@ Se&m oj Pain and SynptomManogrmmt (PL.,,+i., S R., RI?), and Dikion of phmmacy, The Uniwrrily o/ TexasM.D. AndersonCanon Gnti, Hot&m, Trrar
@iaid atmdmei5 rarelylhepenlq cauw of al&red mentalstatusin cancmpalie?lLs Teceivingofioid therapy The in+propr& administration of nabxonc to rewrse an abnotmol mental s.%atu.s can causesewre rtdJ&awol symp&nu and pain. To illustrate this PmL’Lm,WCnpml the cav of a patid ina#m@auly henlpd wi:h naloxone and the rz3d.s of a retrospeciiveret&w of the medical wcords of 15 consuxlivepafitnfs wifh camzrtnmltdwithnaloxoneinlhe t-mqenq &parlmtnl mm a 5monlh period We of/n guideli~ fm a more lhougtifd appmach to Ihe manqwwnt of patients with cancer who present wi&h enq!.blopnhy. J Pain Symptom Manage 1996;11:131-134. Naloxrme, opioid, overdase,canq sedation, conjusion, enc+a@&hx
Z?lf7dUCtiUn Physicians have been taught that the prompt administration of naloxone to a comatose patient can be lifesaving by reversing respiratory depression due to possible opioid overdose. If the altered mental status does not improve, opioid overdose can be excluded as a cause, usually withotn significant side effects. The administration of naloxone is. therefore, considered a safe and effective therapeutic and diagnostic tool that is especially useful in emergent situations.’ Because of its percep tion as a drug virtually devoid of side effects, naloxone has ;Iro gained widespread use in less urgent situations. Address reprint req~tesl~to: Richard Payne, MD. Depanment of Neurc&ncology, Box 8, The Uniwrsity of Texas M.D. Anderson Cancer Cerrrr 1515 Hokombe Roulevard. Houston, Texas 77050, USA 0 U.S. Chncer Pain Relief Gnnmiact. 1996 Published by Flsevier. New Vork. New York
coma
Approximately 60%~90% of patients with advanced or metastatic cancer and one-third of patients with metastatic cancer have pain that requires the use of analgesics.s Opioids. along dth nonopioid analgesics and adjuvant analgesic medications, are the mainstay of treatment for this group of patien1s.s Although some degree of sedation is relatively common, especially when opioid therapy is ieitinted or when the opioid dose is tapidly escalated, severe lethargy and coma are rarely caused by an opioid overdose in the cancer patient.’ Nonetheless, the possibility of opioid overdose sometimes leads to the administration of naloxone as a diagnostic and thet-apeutic trial. In patients witn cancer who receive chronic opioid therapy, the administrative of naloxone can cause sufferit g and morbidity by precipitating an opioid abstinence syndrome and a return of pain. %813924/%//)15.00 SSDI 0%53924(95)001506
132
Incrppop”fe USCof Nahrone
lrol 11 No. 2Ftbnmrg
19%
was 12 per minute. The patient’s wife stated that she had noted a progressive decline in alertness over a 2 week period. His neurologic examination was otherwise unremarkable. The patient was sent to the emergency department for evaluation. After a history and physical examination, he was promptly given 0.4 mg of intravenous (IV) naloxone, prior to blood chemistry determinations. He became very agitated and confused, and vomited repeatedly. Laboratory tests performed a few minutes later showed an increased serum calcium level of 16.5 mg/dL (normal range: 8.4-10.2 mg/dL). Blood urea nitrogen (60 mg/dL) and creatinine (1.6 mg/dL) levels were also abnormally increased. The patient was admitted to the hospital, and treated with IV fluids and 90 mg of IV pamidronate disodium. He recovered in a few days, coincident with reduction and normaliticion of serum calcium levels. His hydromorphone dose at discharge was 8 mg every 4 hours. the same dose he had been taking for several months.
Figm 1. (A) and (El) Radiogmphs of the shoulder and pelvis. Mukiple osteol@c lesions were e\ident throughout Ihe skeleton.
A 67yearold man with multiple myeloma was treated by the Section of Pain and Symp tom Management at our institution for severe movementrelated pain caused by osteolytic lesions in the right scapula, the right pelvis, and the rib cage (Figure IA and B). He had previously been treated with several cycles of chemotherapy and with radiotherapy at multiple bony sites. ISi analgesic therapy consisted of 8 mg of hydromorphone onshy every 4 hours and 600 mg of ibuprofen every 8 hours. At a routine follow-up tii.sic he was very drowsy, but easily aroused and able to answer questions appropriately; his respiratory rate
This patient is a good examole of the inap propriate use of naloxone in patients with cancer on chronic opioid therapy. At the time naloxone was administered, he was not comatose and respiratory depression was not an immediate threat (the respimlory rate was 12 per minute). The opioid dose had remained stable, which renders overdose unlikely. The cancer, multiple myeloma. is frequently associated with hypercalcemia. which is a wellknown cause of encephalopathy. During the 5-month period between July 1, 1993 and November 30. 1858, 5331 patients were seen in the emergency drpartn -nt of our institution. Fifteen of these patienti were treated with a total of 21 doses of naloxone (0.4 mg per dose). We retrospectively reviewed the charts of ; ese 15 patients and noted the following diagroses: metabolic encephalopathy (7 patiems), sepsis (2 patients), brain metastasis (1 patient) (Figure 2). stroke (1 patient), vasovzgaf attack (1 patient), and opioid overdose (2 patients). The 3 patients diagnosed with opioid overdose had no other apparent cause of abnormal mental status and improved after the administration of naloxone; 2 were sedated but easily arousable
W
IIN..2F&wq1996
Manjkdi d OL
133
all hospital charts for the past 8 yean: over lhis period, no deaths have been attributed to opioid overdose. If a cancer patient treated with opioids is experiencing cIinkally significanl respiratory depression. the immediate administration of naloxonic is an appropria~ therapeutic and diagnostic modaby. However, the more commondinicaipresentuionisthatofasedated and-hutearily-patient,tilh-
out sign&ant rupimory depression. who is ttLing opioids. but has aher potential for the~menalstams.Therushmmakea lapiddiagnosis0fopioidoWdoseShouldbe tempered b the concern for causing severe withdmd sympians and pain: the withdrawal syndromesthatoccurafternaloxoneadministrationaremoresewrethantheonedtatacws
Figure 2. Brain MRI (TR 500; TE II/R. Hz). Multiple -ksions.
EC l/l
16
after receiving meperidine for a procedure that immediateIy preceded their emergency department visis only the third patient was comamse ill the time naloxone wa, adminis tered. This last patient but been given repeated N doses of hydromorphone in the emergency department for pain from progre sive bone memstases. Our experience is consisient with a recendy reported study in which 36 orden of N naloxone (34 patients) were reviewed in a major cancer center. The most common indication for naloxone use was reversal of sedation and lethargy in 16 patients (44.4%). Adverse effects of naloxone use were reported in 65% of patients. For example. 15 administrations of naloxone were apparently associated with increased pain, so &at additional opioid dm were required 10 rescue the patients and provide relief. Titration of dilute solutions of naloxone (which is recommended for opioidtoletanc patients) was used in only 9 cases.S Our case report and retrospective review show that the use of naloxone in patients with cancer receiving chronic opioid therapy is often inappropriate. Life-threatening opioid overdose is a rare complication of opioid treatmenf for cancer pain. Al our institution, the quality improvement department has reviewed
upon abrupt discontinuation ofopioids. In addidon to causing severepain. Ihe adminisuadon of naIoxone to patients receiving chronic opioid Lherapytancompkatetbeclinidpiaureby causing agitation. tachyczdia, and vomiting, wilh possible aspiration pneumonia. Funhermofe, a par&d rmponse to ndoxone in Ibis CJhliiJertingonly-tithCOpiOidir
conuibuting to the mental smms changes. and doeanotp-ttheneedu,searcbforo&er lmuahkA cancer center serves a selected population of patienu. many of whom use chronic opioids for pain control. The prevalence of opioii theriqy and the potendaI of encephalapathy increase with increasing tumor stage. It is generally unwise to treat these patients with opioid antagonbu, unkss Iife-tbreaLening Tespitatory depression is a reasonable concern. ChicaUy signiican~ rapiniory depression from opioid o~rdose does not occur .&cn the padenr is easily arousabk. When in doub& a pulse oximeter can be used to monitor the concentration of oxygen in the blood. whik appropriate diagnostic ceswcan be performed. When an opioid overdose is indeed the cause of sedation and confixion. bu: is no1 causing significant hypoventilation, obsenacion for a few houn is the best diagnostic and therapeutic approach. When the pauenr cannot be aroused and opioii ove&ne is strongty suspected (history of recent increase in opioid dose, pinpoint pupils on physical examination), 0.4 mg of naloxone can be diluted in 10 cc of normal saline and adminisured in 05 cc
134
I-
bolmes every 2 minutes. This careful titt-ation will avoid precipitation of profound withdrawal, as respiratory depression can be twersed prior to the revetsal of analgesia.”
In cancer patients receiving chronic opioid therapy, metabolic encephalopatby. infection, and brain metastasis are by far more common causes of altered meutaf status and coma than is opioid overdose. Therefore, naloxone tbenpy is generally not warranted.
1. Smith MC. Wichter MD. The comatosepatient. In: SchwartzGR. Cayten CC. Mangchen MA, Mayer
Use o/Na&xone
Vd I1 No. 2 Ft-%num~19%
TA. Hanke BR, edn. Principles and Practice of Emergency Medicine, Srd edition. Philadelphia: Lea and Febiger. 1992349. 2. Daut RL, Cleeknd CS. ~lte prevalenceand sewity of pain in cancer.Cancer 1992$6-.191~1918. 3. World Health Organiration. Cancer pain relief and palliative care: report of a W H O expert committee. Gneva: World Heahb Organization, 1999. 4. Clomton PD. de Angclis EM. Pouter JB. The spectrum of neurologic diseasesin Patients with cancer.Ann Neurol 19923126%273. 5. Eagel BA, Derby S. Chin J, Portenoy RR, Foley KM. Naloxone hydrochloride: use and misuse in cancer pant. Presented at the Annual Meeting of the Atnerican Pain Society,1994. 6. Max MB. PayneR, et al. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, 3rd edition. American Pain !Socicty,1993.
Pauiaiizre
Journal of P&I and $v@ton Mcnagmnent I31
can? Rounds
Inappropriate Use of Naloxone in Cancer Patients with Pain Paolo L.. Manfredi, MD, Sady Ribeiro, MD, gonja W. Chandler, Pharm D. and Richard Payne. MD Drpnrlmml ofNturoUnco@ Se&m oj Pain and SynptomManogrmmt (PL.,,+i., S R., RI?), and Dikion of phmmacy, The Uniwrrily o/ TexasM.D. AndersonCanon Gnti, Hot&m, Trrar
@iaid atmdmei5 rarelylhepenlq cauw of al&red mentalstatusin cancmpalie?lLs Teceivingofioid therapy The in+propr& administration of nabxonc to rewrse an abnotmol mental s.%atu.s can causesewre rtdJ&awol symp&nu and pain. To illustrate this PmL’Lm,WCnpml the cav of a patid ina#m@auly henlpd wi:h naloxone and the rz3d.s of a retrospeciiveret&w of the medical wcords of 15 consuxlivepafitnfs wifh camzrtnmltdwithnaloxoneinlhe t-mqenq &parlmtnl mm a 5monlh period We of/n guideli~ fm a more lhougtifd appmach to Ihe manqwwnt of patients with cancer who present wi&h enq!.blopnhy. J Pain Symptom Manage 1996;11:131-134. Naloxrme, opioid, overdase,canq sedation, conjusion, enc+a@&hx
Z?lf7dUCtiUn Physicians have been taught that the prompt administration of naloxone to a comatose patient can be lifesaving by reversing respiratory depression due to possible opioid overdose. If the altered mental status does not improve, opioid overdose can be excluded as a cause, usually withotn significant side effects. The administration of naloxone is. therefore, considered a safe and effective therapeutic and diagnostic tool that is especially useful in emergent situations.’ Because of its percep tion as a drug virtually devoid of side effects, naloxone has ;Iro gained widespread use in less urgent situations. Address reprint req~tesl~to: Richard Payne, MD. Depanment of Neurc&ncology, Box 8, The Uniwrsity of Texas M.D. Anderson Cancer Cerrrr 1515 Hokombe Roulevard. Houston, Texas 77050, USA 0 U.S. Chncer Pain Relief Gnnmiact. 1996 Published by Flsevier. New Vork. New York
coma
Approximately 60%~90% of patients with advanced or metastatic cancer and one-third of patients with metastatic cancer have pain that requires the use of analgesics.s Opioids. along dth nonopioid analgesics and adjuvant analgesic medications, are the mainstay of treatment for this group of patien1s.s Although some degree of sedation is relatively common, especially when opioid therapy is ieitinted or when the opioid dose is tapidly escalated, severe lethargy and coma are rarely caused by an opioid overdose in the cancer patient.’ Nonetheless, the possibility of opioid overdose sometimes leads to the administration of naloxone as a diagnostic and thet-apeutic trial. In patients witn cancer who receive chronic opioid therapy, the administrative of naloxone can cause sufferit g and morbidity by precipitating an opioid abstinence syndrome and a return of pain. %813924/%//)15.00 SSDI 0%53924(95)001506
132
Incrppop”fe USCof Nahrone
lrol 11 No. 2Ftbnmrg
19%
was 12 per minute. The patient’s wife stated that she had noted a progressive decline in alertness over a 2 week period. His neurologic examination was otherwise unremarkable. The patient was sent to the emergency department for evaluation. After a history and physical examination, he was promptly given 0.4 mg of intravenous (IV) naloxone, prior to blood chemistry determinations. He became very agitated and confused, and vomited repeatedly. Laboratory tests performed a few minutes later showed an increased serum calcium level of 16.5 mg/dL (normal range: 8.4-10.2 mg/dL). Blood urea nitrogen (60 mg/dL) and creatinine (1.6 mg/dL) levels were also abnormally increased. The patient was admitted to the hospital, and treated with IV fluids and 90 mg of IV pamidronate disodium. He recovered in a few days, coincident with reduction and normaliticion of serum calcium levels. His hydromorphone dose at discharge was 8 mg every 4 hours. the same dose he had been taking for several months.
Figm 1. (A) and (El) Radiogmphs of the shoulder and pelvis. Mukiple osteol@c lesions were e\ident throughout Ihe skeleton.
A 67yearold man with multiple myeloma was treated by the Section of Pain and Symp tom Management at our institution for severe movementrelated pain caused by osteolytic lesions in the right scapula, the right pelvis, and the rib cage (Figure IA and B). He had previously been treated with several cycles of chemotherapy and with radiotherapy at multiple bony sites. ISi analgesic therapy consisted of 8 mg of hydromorphone onshy every 4 hours and 600 mg of ibuprofen every 8 hours. At a routine follow-up tii.sic he was very drowsy, but easily aroused and able to answer questions appropriately; his respiratory rate
This patient is a good examole of the inap propriate use of naloxone in patients with cancer on chronic opioid therapy. At the time naloxone was administered, he was not comatose and respiratory depression was not an immediate threat (the respimlory rate was 12 per minute). The opioid dose had remained stable, which renders overdose unlikely. The cancer, multiple myeloma. is frequently associated with hypercalcemia. which is a wellknown cause of encephalopathy. During the 5-month period between July 1, 1993 and November 30. 1858, 5331 patients were seen in the emergency drpartn -nt of our institution. Fifteen of these patienti were treated with a total of 21 doses of naloxone (0.4 mg per dose). We retrospectively reviewed the charts of ; ese 15 patients and noted the following diagroses: metabolic encephalopathy (7 patiems), sepsis (2 patients), brain metastasis (1 patient) (Figure 2). stroke (1 patient), vasovzgaf attack (1 patient), and opioid overdose (2 patients). The 3 patients diagnosed with opioid overdose had no other apparent cause of abnormal mental status and improved after the administration of naloxone; 2 were sedated but easily arousable
W
IIN..2F&wq1996
Manjkdi d OL
133
all hospital charts for the past 8 yean: over lhis period, no deaths have been attributed to opioid overdose. If a cancer patient treated with opioids is experiencing cIinkally significanl respiratory depression. the immediate administration of naloxonic is an appropria~ therapeutic and diagnostic modaby. However, the more commondinicaipresentuionisthatofasedated and-hutearily-patient,tilh-
out sign&ant rupimory depression. who is ttLing opioids. but has aher potential for the~menalstams.Therushmmakea lapiddiagnosis0fopioidoWdoseShouldbe tempered b the concern for causing severe withdmd sympians and pain: the withdrawal syndromesthatoccurafternaloxoneadministrationaremoresewrethantheonedtatacws
Figure 2. Brain MRI (TR 500; TE II/R. Hz). Multiple -ksions.
EC l/l
16
after receiving meperidine for a procedure that immediateIy preceded their emergency department visis only the third patient was comamse ill the time naloxone wa, adminis tered. This last patient but been given repeated N doses of hydromorphone in the emergency department for pain from progre sive bone memstases. Our experience is consisient with a recendy reported study in which 36 orden of N naloxone (34 patients) were reviewed in a major cancer center. The most common indication for naloxone use was reversal of sedation and lethargy in 16 patients (44.4%). Adverse effects of naloxone use were reported in 65% of patients. For example. 15 administrations of naloxone were apparently associated with increased pain, so &at additional opioid dm were required 10 rescue the patients and provide relief. Titration of dilute solutions of naloxone (which is recommended for opioidtoletanc patients) was used in only 9 cases.S Our case report and retrospective review show that the use of naloxone in patients with cancer receiving chronic opioid therapy is often inappropriate. Life-threatening opioid overdose is a rare complication of opioid treatmenf for cancer pain. Al our institution, the quality improvement department has reviewed
upon abrupt discontinuation ofopioids. In addidon to causing severepain. Ihe adminisuadon of naIoxone to patients receiving chronic opioid Lherapytancompkatetbeclinidpiaureby causing agitation. tachyczdia, and vomiting, wilh possible aspiration pneumonia. Funhermofe, a par&d rmponse to ndoxone in Ibis CJhliiJertingonly-tithCOpiOidir
conuibuting to the mental smms changes. and doeanotp-ttheneedu,searcbforo&er lmuahkA cancer center serves a selected population of patienu. many of whom use chronic opioids for pain control. The prevalence of opioii theriqy and the potendaI of encephalapathy increase with increasing tumor stage. It is generally unwise to treat these patients with opioid antagonbu, unkss Iife-tbreaLening Tespitatory depression is a reasonable concern. ChicaUy signiican~ rapiniory depression from opioid o~rdose does not occur .&cn the padenr is easily arousabk. When in doub& a pulse oximeter can be used to monitor the concentration of oxygen in the blood. whik appropriate diagnostic ceswcan be performed. When an opioid overdose is indeed the cause of sedation and confixion. bu: is no1 causing significant hypoventilation, obsenacion for a few houn is the best diagnostic and therapeutic approach. When the pauenr cannot be aroused and opioii ove&ne is strongty suspected (history of recent increase in opioid dose, pinpoint pupils on physical examination), 0.4 mg of naloxone can be diluted in 10 cc of normal saline and adminisured in 05 cc
134
I-
bolmes every 2 minutes. This careful titt-ation will avoid precipitation of profound withdrawal, as respiratory depression can be twersed prior to the revetsal of analgesia.”
In cancer patients receiving chronic opioid therapy, metabolic encephalopatby. infection, and brain metastasis are by far more common causes of altered meutaf status and coma than is opioid overdose. Therefore, naloxone tbenpy is generally not warranted.
1. Smith MC. Wichter MD. The comatosepatient. In: SchwartzGR. Cayten CC. Mangchen MA, Mayer
Use o/Na&xone
Vd I1 No. 2 Ft-%num~19%
TA. Hanke BR, edn. Principles and Practice of Emergency Medicine, Srd edition. Philadelphia: Lea and Febiger. 1992349. 2. Daut RL, Cleeknd CS. ~lte prevalenceand sewity of pain in cancer.Cancer 1992$6-.191~1918. 3. World Health Organiration. Cancer pain relief and palliative care: report of a W H O expert committee. Gneva: World Heahb Organization, 1999. 4. Clomton PD. de Angclis EM. Pouter JB. The spectrum of neurologic diseasesin Patients with cancer.Ann Neurol 19923126%273. 5. Eagel BA, Derby S. Chin J, Portenoy RR, Foley KM. Naloxone hydrochloride: use and misuse in cancer pant. Presented at the Annual Meeting of the Atnerican Pain Society,1994. 6. Max MB. PayneR, et al. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, 3rd edition. American Pain !Socicty,1993.