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Naloxone in Treating Central Adverse Effects During Opioid Titration for Cancer Pain
Vol. 26 No. 2 August 2003
nucleus caudatus. Euro J Pharmacol 1973;22:206– 208. 8. Walker JM, Thompson LA, Frascella J, Friederich MW. Opposite effects of µ and δ opiates on the firingrate of dopamine cells in the substantia nigra of the rat. Eur J Pharmacol 1987;134:53–59. 9. Wood PL, Stotland M, Richard JW, et al. Actions of mu, kappa, sigma, delta and agonist/antagonist opiates on striatal dopaminergic function. J Pharmacol Exp Ther 1980;215:697–703. 10. Wassermann S, Yahr MD. Choreic movements induced by the use of methadone. Arch Neurol 1980;37:727–728. 11. Eibergen RD, Carlson KR. Dyskinesias elicited by methamphetamine: susceptibility of former methadone-consuming monkeys. Science 1975;190: 588–590. 12. Tani T, Piao YS, Mori S, et al. Chorea resulting from paraneoplastic striatal encephalitis. J Neurol Neurosurg Psychiatr 2000;69:512–515. 13. Vernino S, Tuite P, Adler CH, et al. Paraneoplastic chorea associated with CRMP-5 neuronal antibody and lung carcinoma. Ann Neurol 2002;51:625:630. 14. Abbadie C, Pan YX, Drake CT, et al. Comparative immunohistochemical distributions of carboxy terminus epitopes from the mu-opioid receptor splice variants MOR-1D, MOR-1 and MOR-1C in the mouse and rat CNS. Neurosci 2000;100(1):141–153. 15. Pan YX, Xu J, Mahurter L, et al. Identification and characterization of two new human mu opioid receptor splice variants, hMOR-10 and hMOR-1X. Biochem Biophys Res Commun 2003;301(4):1057– 1061.
Naloxone in Treating Central Adverse Effects During Opioid Titration for Cancer Pain To the Editor: Opioids, administered for chronic cancer pain, may cause some degree of sedation, especially when opioid therapy is initiated or when the opioid dose is rapidly escalated.1 In these circumstances, opioid titration is stopped or an opioid substitution may be required, making pain control difficult to reach. Despite discontinuing the opioid, the effects may be prolonged due to low renal and hepatic clearance. Naloxone is an opioid-antagonist used in different circumstances to control opioid-related adverse effects; when used in minimal doses, naloxone may offer a promising opportunity for coanalgesia in this setting.2 Naloxone has
Letters
691
been used for treating respiratory depression, constipation, and pruritus, but it has never reported to balance central opioid toxicity during opioid escalation. Recently, we observed three patients with advanced cancer who used naloxone in the treatment of opioid-induced central toxicity. Presentation of an illustrative case is informative.
Case Report A 72-year-old man with non-Hodgkin’s lymphoma was admitted for unbearable pain in the left arm due to bone metastases. Intravenous titration of morphine relieved his pain, from an initial pain level of 10/10 to 2/10 on a numerical scale (0–10). As the patient refused to remain in the hospital, his morphine regimen was converted to oral morphine 30 mg three times a day. Frequent phone contacts were solicited. Two days later, he was admitted to hospital for severe drowsiness (Level 3 on a scale 0–3). Pain was apparently well controlled and he was almost unresponsive to verbal stimulation, but did not show signs of respiratory depression. An intravenous infusion of naloxone 0.05 mg per hour was started, together with a saline infusion of 100 ml per hour. The patient was strictly monitored, regularly assessed every thirty minutes for possible events. Thirty minutes after starting the treatment, the patient was alert and interactive while maintaining good pain control (3/10 on a numerical 0–10 scale). The same naloxone infusion rate was maintained for eight hours. After the termination of the infusion, the patient was assessed by a symptom checklist. Given his good clinical condition, he was discharged to home. He was told to increase his fluid intake and morphine doses were decreased to 60 mg daily, to be initiated the day after (that is, skipping the nightly dose). The following day, pain control was optimal (3/10) and he did not require further dose adjustment. No adverse effects were reported. Follow-up was maintained for the next week, without evidencing any clinical opioid-related problems; then, contact was lost.
Comment Naloxone is commonly used to reverse opioid-induced life-threatening conditions, such as respiratory depression and coma due to an opioid overdose. However, in patients with cancer who receive chronic opioid therapy, the
692
administration of naloxone can cause suffering and morbidity by precipitating an opioid abstinence syndrome and a return of pain.3 For these reasons, naloxone therapy is generally not warranted in such a setting. The therapeutic use of naloxone has been extended for other opioid-related symptoms, such as constipation, pruritus or nausea, using either high doses by the oral route or very low doses by the epidural route.4,5 However, the use of low doses of naloxone for reversing opioid-induced central toxicity during dose titration, while maintaining analgesia, has never been reported in the setting of cancer patients with pain. Doses of 0.05 mg per hour were arbitrarily chosen, based on local anecdotal experience in titrating naloxone without minimally interfering with basal analgesia. At these doses, naloxone, administered with a slow infusion in minimal doses, allowed recovery from central toxicity while maintaining adequate analgesia. The effect observed in this patient is likely to be due to a “balanced” presence at receptor level. Although a strict surveillance is necessary to prevent complication from abrupt withdrawal, such low doses of naloxone did not have any consequence in terms of pain or symptom emergency. The infusion time was sufficient to allow the elimination of opioids or their metabolites, or, more likely, to reduce their plasmatic levels under the toxic threshold. Other than reducing opioid toxicity, low doses of naloxone may have other potentially therapeutic benefits in patients receiving morphine for their pain. In the past several years, studies on the neural basis of such central changes have indicated a crucial role of excitatory amino acid receptors and consequent intracellular neurochemical cascade in the development of injury-induced central hyperactive states, producing hyperalgesia. These excitatory states produce a reduction of opioid nociception prior to exposure to an opioid, as if animals have an acquired tolerance to opioids before receiving them. Hyperalgesia and morphine tolerance may be interrelated by common neural substrates that interact at the level of excitatory amino acid receptor activation and related intracellular events.6 Opioid-induced abnormal pain is commonly associated with high doses. However, anti-hyperalgesic effects
Letters
Vol. 26 No. 2 August 2003
have been found even with low receptor concentration of opioids in a recent experimental bimodal way of opioid receptor activity.2 This kind of modulation of the action potential of nociceptive neurons appears to be mediated by activation of GM1-regulated interconvertible opioid receptors that can occur either in a inhibitory mode or in an excitatory mode. These modes seem to be induced by higher (µg) and low opioid concentration (pM range), respectively. Selective blockade of excitatory opioid effects in neurons by cotreatment with pM naloxone attenuates the “anti-analgesic” effects of opioid agonists and thereby enhancing their “analgesic” efficacy. The inhibitory mode, leading to inhibitory effects, that is “analgesia,” is blocked by relatively high doses of naloxone (nM range). In vitro and in vivo studies have demonstrated that direct competitive antagonism of Gs-coupled excitatory opioid receptor functions by cotreatment with extremely low doses of naloxone markedly enhances morphine’s analgesic potency and simultaneously attenuates opioid tolerance and dependence. Excitation would produce hyperalgesia or tolerance, whereas inhibition would produce typical opioid effects. Low concentrations of opioid antagonist, like naloxone, have been found to have selective antagonist actions on excitatory, but not inhibitory, opioid receptor-mediated function in dorsal root ganglion neurons. This can enhance morphine’s analgesic potency and simultaneously attenuate opioid tolerance and dependence.7,8 The opioid-sparing effect of low naloxone doses has been disputed in the literature with contradictory results in human postoperative studies.9,10 Relatively high doses and the use of intermittent boluses, as well methodological limits, may explain the different results which compromised the outcome reported by Cepeda et al.11 Opioid antagonism obtained with transient and high doses of naloxone had been already shown to enhance opioid tolerance.12 Nevertheless, naloxone infusion, even in low doses, may pose some clinical problems, requiring expertise and monitoring, and should be carefully followed. According to these observations, a careful administration of low doses of naloxone, other then reverse adverse central effects occurring during opioid titration in cancer patients, is potentially able to improve
Vol. 26 No. 2 August 2003
the analgesic effects of opioids. Further controlled studies are needed to confirm this preliminary observation. Sebastiano Mercadante, MD Patrizia Villari, MD Patrizia Ferrera, MD Anesthesia and Intensive Care Unit Pain Relief and Palliative Care Unit La Maddalena Cancer Center Palermo, Italy doi:10.1016/S0885-3924(03)00250-1
References 1. Bruera E, Macmillan K, Hanson J, et al. The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain 1989;39:13–16. 2. Crain SM, Shen KF. Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability. Pain 2000;84:121–131. 3. Manfredi P, Ribeiro S, Chandler S, et al. Inappropriate use of naloxone in cancer patients with pain. J Pain Symptom Manage 1996;11:131–134. 4. Meissner W, Schimdt U, Hartmann M, et al. Oral naloxone reverses opioid-associated constipation. Pain 2000;84:105–109. 5. Choi JH, Lee J, Choi JH, et al. Epidural naloxone reduces pruritus and nausea without affecting analgesia by epidural morphine in bupivacaine. Can J Anesth 2000;47:33–37. 6. Mao JR, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995;62:259–274. 7. Crain SM, Shen KF. Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment. Proc Natl Acad Sci USA 1995;92:10540–10544. 8. Crain SM, Shen KF. Acute thermal hyperalgesia elicited by low-dose morphine in normal mice is blocked by ultra-low-dose naltrexone, unmasking potent analgesia. Brain Res 2001;888:75–82. 9. Gan TJ, Ginsberg B, Glass PSA, et al. Opioidsparing effects of a low-dose infusion of naloxone in patient-administered morphine sulphate. Anesthesiology 1997;87:1075–1081. 10. Cepeda MS, Africano JM, Manrique AM, et al. The combination of low dose of naloxone and morphine in PCA does not decrease opioid requirements in the postoperative period. Pain 2002;96:73–79. 11. Mehlisch DR. Comments on: The combination of low dose of naloxone and morphine in PCA does
Letters
693
not decrease opioid requirements in the postoperative period. Pain 2003;101:209–212. 12. Ibuki T, Dunbar SA, Yaksh TL. Effcet of transient naloxone antagonism on tolerance development in rats receiving continuous spinal morphine infusion. Pain 1997;70:125–132.
Poor Social Conditions, Criminality and Urban Violence: Unmentioned Barriers for Effective Cancer Pain Control at the End of Life To the Editor: The active total care of patients whose disease is not responsive to curative treatment is the aim of palliative care. Effective control of symptoms, psychological, spiritual and social problems is the focus of palliative care according to the World Health Organization (WHO).1 The correct use of WHO guidelines for cancer pain management can result in pain control in around 90% of cancer patients. However there is some evidence that cancer patients continue to experience pain, many of them at the end of life. Inadequate pain relief in cancer patients is not always the result of refractory pain syndromes such as breakthrough pain or neural compression by the tumor. Different reports have addressed the barriers for effective pain control, and several causes have been identified, such as poor adherence to the treatment,2 inadequate pain assessment,3 religious beliefs,4 costs due to treatment,5 and lack of education and training in pain management among health care professionals.6–9 Other potential barriers include poor social conditions, criminality and urban violence, which are present in many developing countries. The following two cases illustrate the problem and its impact on the delivery of palliative care in Rio de Janeiro, Brazil.
Case 1 A 45-year-old man with gastric cancer was admitted to our Palliative Care Center due to severe abdominal pain. The patient had been treated with oral morphine 300 mg/day, amitriptyline 50 mg/day, and gabapentin 1200 mg/ day. After admission, morphine was switched to transdermal fentanyl 100 µg/h with good pain
nucleus caudatus. Euro J Pharmacol 1973;22:206– 208. 8. Walker JM, Thompson LA, Frascella J, Friederich MW. Opposite effects of µ and δ opiates on the firingrate of dopamine cells in the substantia nigra of the rat. Eur J Pharmacol 1987;134:53–59. 9. Wood PL, Stotland M, Richard JW, et al. Actions of mu, kappa, sigma, delta and agonist/antagonist opiates on striatal dopaminergic function. J Pharmacol Exp Ther 1980;215:697–703. 10. Wassermann S, Yahr MD. Choreic movements induced by the use of methadone. Arch Neurol 1980;37:727–728. 11. Eibergen RD, Carlson KR. Dyskinesias elicited by methamphetamine: susceptibility of former methadone-consuming monkeys. Science 1975;190: 588–590. 12. Tani T, Piao YS, Mori S, et al. Chorea resulting from paraneoplastic striatal encephalitis. J Neurol Neurosurg Psychiatr 2000;69:512–515. 13. Vernino S, Tuite P, Adler CH, et al. Paraneoplastic chorea associated with CRMP-5 neuronal antibody and lung carcinoma. Ann Neurol 2002;51:625:630. 14. Abbadie C, Pan YX, Drake CT, et al. Comparative immunohistochemical distributions of carboxy terminus epitopes from the mu-opioid receptor splice variants MOR-1D, MOR-1 and MOR-1C in the mouse and rat CNS. Neurosci 2000;100(1):141–153. 15. Pan YX, Xu J, Mahurter L, et al. Identification and characterization of two new human mu opioid receptor splice variants, hMOR-10 and hMOR-1X. Biochem Biophys Res Commun 2003;301(4):1057– 1061.
Naloxone in Treating Central Adverse Effects During Opioid Titration for Cancer Pain To the Editor: Opioids, administered for chronic cancer pain, may cause some degree of sedation, especially when opioid therapy is initiated or when the opioid dose is rapidly escalated.1 In these circumstances, opioid titration is stopped or an opioid substitution may be required, making pain control difficult to reach. Despite discontinuing the opioid, the effects may be prolonged due to low renal and hepatic clearance. Naloxone is an opioid-antagonist used in different circumstances to control opioid-related adverse effects; when used in minimal doses, naloxone may offer a promising opportunity for coanalgesia in this setting.2 Naloxone has
Letters
691
been used for treating respiratory depression, constipation, and pruritus, but it has never reported to balance central opioid toxicity during opioid escalation. Recently, we observed three patients with advanced cancer who used naloxone in the treatment of opioid-induced central toxicity. Presentation of an illustrative case is informative.
Case Report A 72-year-old man with non-Hodgkin’s lymphoma was admitted for unbearable pain in the left arm due to bone metastases. Intravenous titration of morphine relieved his pain, from an initial pain level of 10/10 to 2/10 on a numerical scale (0–10). As the patient refused to remain in the hospital, his morphine regimen was converted to oral morphine 30 mg three times a day. Frequent phone contacts were solicited. Two days later, he was admitted to hospital for severe drowsiness (Level 3 on a scale 0–3). Pain was apparently well controlled and he was almost unresponsive to verbal stimulation, but did not show signs of respiratory depression. An intravenous infusion of naloxone 0.05 mg per hour was started, together with a saline infusion of 100 ml per hour. The patient was strictly monitored, regularly assessed every thirty minutes for possible events. Thirty minutes after starting the treatment, the patient was alert and interactive while maintaining good pain control (3/10 on a numerical 0–10 scale). The same naloxone infusion rate was maintained for eight hours. After the termination of the infusion, the patient was assessed by a symptom checklist. Given his good clinical condition, he was discharged to home. He was told to increase his fluid intake and morphine doses were decreased to 60 mg daily, to be initiated the day after (that is, skipping the nightly dose). The following day, pain control was optimal (3/10) and he did not require further dose adjustment. No adverse effects were reported. Follow-up was maintained for the next week, without evidencing any clinical opioid-related problems; then, contact was lost.
Comment Naloxone is commonly used to reverse opioid-induced life-threatening conditions, such as respiratory depression and coma due to an opioid overdose. However, in patients with cancer who receive chronic opioid therapy, the
692
administration of naloxone can cause suffering and morbidity by precipitating an opioid abstinence syndrome and a return of pain.3 For these reasons, naloxone therapy is generally not warranted in such a setting. The therapeutic use of naloxone has been extended for other opioid-related symptoms, such as constipation, pruritus or nausea, using either high doses by the oral route or very low doses by the epidural route.4,5 However, the use of low doses of naloxone for reversing opioid-induced central toxicity during dose titration, while maintaining analgesia, has never been reported in the setting of cancer patients with pain. Doses of 0.05 mg per hour were arbitrarily chosen, based on local anecdotal experience in titrating naloxone without minimally interfering with basal analgesia. At these doses, naloxone, administered with a slow infusion in minimal doses, allowed recovery from central toxicity while maintaining adequate analgesia. The effect observed in this patient is likely to be due to a “balanced” presence at receptor level. Although a strict surveillance is necessary to prevent complication from abrupt withdrawal, such low doses of naloxone did not have any consequence in terms of pain or symptom emergency. The infusion time was sufficient to allow the elimination of opioids or their metabolites, or, more likely, to reduce their plasmatic levels under the toxic threshold. Other than reducing opioid toxicity, low doses of naloxone may have other potentially therapeutic benefits in patients receiving morphine for their pain. In the past several years, studies on the neural basis of such central changes have indicated a crucial role of excitatory amino acid receptors and consequent intracellular neurochemical cascade in the development of injury-induced central hyperactive states, producing hyperalgesia. These excitatory states produce a reduction of opioid nociception prior to exposure to an opioid, as if animals have an acquired tolerance to opioids before receiving them. Hyperalgesia and morphine tolerance may be interrelated by common neural substrates that interact at the level of excitatory amino acid receptor activation and related intracellular events.6 Opioid-induced abnormal pain is commonly associated with high doses. However, anti-hyperalgesic effects
Letters
Vol. 26 No. 2 August 2003
have been found even with low receptor concentration of opioids in a recent experimental bimodal way of opioid receptor activity.2 This kind of modulation of the action potential of nociceptive neurons appears to be mediated by activation of GM1-regulated interconvertible opioid receptors that can occur either in a inhibitory mode or in an excitatory mode. These modes seem to be induced by higher (µg) and low opioid concentration (pM range), respectively. Selective blockade of excitatory opioid effects in neurons by cotreatment with pM naloxone attenuates the “anti-analgesic” effects of opioid agonists and thereby enhancing their “analgesic” efficacy. The inhibitory mode, leading to inhibitory effects, that is “analgesia,” is blocked by relatively high doses of naloxone (nM range). In vitro and in vivo studies have demonstrated that direct competitive antagonism of Gs-coupled excitatory opioid receptor functions by cotreatment with extremely low doses of naloxone markedly enhances morphine’s analgesic potency and simultaneously attenuates opioid tolerance and dependence. Excitation would produce hyperalgesia or tolerance, whereas inhibition would produce typical opioid effects. Low concentrations of opioid antagonist, like naloxone, have been found to have selective antagonist actions on excitatory, but not inhibitory, opioid receptor-mediated function in dorsal root ganglion neurons. This can enhance morphine’s analgesic potency and simultaneously attenuate opioid tolerance and dependence.7,8 The opioid-sparing effect of low naloxone doses has been disputed in the literature with contradictory results in human postoperative studies.9,10 Relatively high doses and the use of intermittent boluses, as well methodological limits, may explain the different results which compromised the outcome reported by Cepeda et al.11 Opioid antagonism obtained with transient and high doses of naloxone had been already shown to enhance opioid tolerance.12 Nevertheless, naloxone infusion, even in low doses, may pose some clinical problems, requiring expertise and monitoring, and should be carefully followed. According to these observations, a careful administration of low doses of naloxone, other then reverse adverse central effects occurring during opioid titration in cancer patients, is potentially able to improve
Vol. 26 No. 2 August 2003
the analgesic effects of opioids. Further controlled studies are needed to confirm this preliminary observation. Sebastiano Mercadante, MD Patrizia Villari, MD Patrizia Ferrera, MD Anesthesia and Intensive Care Unit Pain Relief and Palliative Care Unit La Maddalena Cancer Center Palermo, Italy doi:10.1016/S0885-3924(03)00250-1
References 1. Bruera E, Macmillan K, Hanson J, et al. The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain 1989;39:13–16. 2. Crain SM, Shen KF. Antagonists of excitatory opioid receptor functions enhance morphine’s analgesic potency and attenuate opioid tolerance/dependence liability. Pain 2000;84:121–131. 3. Manfredi P, Ribeiro S, Chandler S, et al. Inappropriate use of naloxone in cancer patients with pain. J Pain Symptom Manage 1996;11:131–134. 4. Meissner W, Schimdt U, Hartmann M, et al. Oral naloxone reverses opioid-associated constipation. Pain 2000;84:105–109. 5. Choi JH, Lee J, Choi JH, et al. Epidural naloxone reduces pruritus and nausea without affecting analgesia by epidural morphine in bupivacaine. Can J Anesth 2000;47:33–37. 6. Mao JR, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995;62:259–274. 7. Crain SM, Shen KF. Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment. Proc Natl Acad Sci USA 1995;92:10540–10544. 8. Crain SM, Shen KF. Acute thermal hyperalgesia elicited by low-dose morphine in normal mice is blocked by ultra-low-dose naltrexone, unmasking potent analgesia. Brain Res 2001;888:75–82. 9. Gan TJ, Ginsberg B, Glass PSA, et al. Opioidsparing effects of a low-dose infusion of naloxone in patient-administered morphine sulphate. Anesthesiology 1997;87:1075–1081. 10. Cepeda MS, Africano JM, Manrique AM, et al. The combination of low dose of naloxone and morphine in PCA does not decrease opioid requirements in the postoperative period. Pain 2002;96:73–79. 11. Mehlisch DR. Comments on: The combination of low dose of naloxone and morphine in PCA does
Letters
693
not decrease opioid requirements in the postoperative period. Pain 2003;101:209–212. 12. Ibuki T, Dunbar SA, Yaksh TL. Effcet of transient naloxone antagonism on tolerance development in rats receiving continuous spinal morphine infusion. Pain 1997;70:125–132.
Poor Social Conditions, Criminality and Urban Violence: Unmentioned Barriers for Effective Cancer Pain Control at the End of Life To the Editor: The active total care of patients whose disease is not responsive to curative treatment is the aim of palliative care. Effective control of symptoms, psychological, spiritual and social problems is the focus of palliative care according to the World Health Organization (WHO).1 The correct use of WHO guidelines for cancer pain management can result in pain control in around 90% of cancer patients. However there is some evidence that cancer patients continue to experience pain, many of them at the end of life. Inadequate pain relief in cancer patients is not always the result of refractory pain syndromes such as breakthrough pain or neural compression by the tumor. Different reports have addressed the barriers for effective pain control, and several causes have been identified, such as poor adherence to the treatment,2 inadequate pain assessment,3 religious beliefs,4 costs due to treatment,5 and lack of education and training in pain management among health care professionals.6–9 Other potential barriers include poor social conditions, criminality and urban violence, which are present in many developing countries. The following two cases illustrate the problem and its impact on the delivery of palliative care in Rio de Janeiro, Brazil.
Case 1 A 45-year-old man with gastric cancer was admitted to our Palliative Care Center due to severe abdominal pain. The patient had been treated with oral morphine 300 mg/day, amitriptyline 50 mg/day, and gabapentin 1200 mg/ day. After admission, morphine was switched to transdermal fentanyl 100 µg/h with good pain