- Email: [email protected]
Comment on: Doverty et al., Hyperalgesic responses in methadone maintenance patients (Pain 2001;90;91–6)
608
Letters to the Editor
Gertz BJ. Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther 1999;65:336–347. Gobel S. An electron microscopic analysis of the trans-synaptic effects of peripheral nerve injury subsequent to tooth pulp extirpations on neurons in laminae I and II of the medullary dorsal horn. J Neurosci 1984;4:2281–2290. Gordon SM, Dubner R, Dionne RA. Antihyperalgesic effect of the Nmethyl-d-aspartate receptor antagonist dextromethorphan in the oral surgery model. J Clin Pharmacol 1999;39:139–146. Hargreaves KM, Swift JQ, Roszkowski MT, Bowles W, Garry MG, Jackson DL. Pharmacology of peripheral neuropeptide and inflammatory mediator release. Oral Surg Oral Med Oral Pathol 1994;78:503–510. Hersh EV, Levin LM, Cooper SA, Doyle G, Waksman J, Wedell D, Hong D, Secreto SA. Ibuprofen liquigel for oral surgery pain. Clin Ther 2000;22:1306–1318. Hockfield S, Gobel S. An anatomical demonstration of projections to the medullary dorsal horn (trigeminal nucleus caudalis) from rostral trigeminal nuclei and the contralateral caudal medulla. Brain Res 1982;252:203–211. Jacquin MF, Semba K, Rhoades RW, Egger MD. Trigeminal primary afferents project bilaterally to dorsal horn and ipsilaterally to cerebellum, reticular formation, and cuneate, solitary, supratrigeminal and vagal nuclei. Brain Res 1982;246:285–291. Lipton JA, Ship JA, Larach-Robinson D. Estimated prevalence and distribution of reported orofacial pain in the United States. J Am Dent Assoc 1993;124:115–121. Malmstrom K, Daniels S, Kotey P, Seidenberg BC, Desjardins PJ. Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial. Clin Ther 1999;21:1653–1663. Mantyh PW, Demaster E, Malhotra A, Ghilardi JR, Rogers SD, Mantyh CR, Liu HT, Basbaum AI, Vigna SR, Maggio JE, Simone DA. Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 1995;268:1629–1632. Marfurt CF, Rajchert DM. Trigeminal primary afferent projections to ‘nontrigeminal’ areas of the rat central nervous system. J Comp Neurol 1991;303:489–511. Morrison BW, Christensen S, Yuan WY, Brown J, Amlani S, Seidenberg B. Analgesic efficacy of the cyclooxygenase-2-specific inhibitor rofecoxib in post-dental surgery pain: a randomized, controlled trial. Clin Ther 1999;21:943–953. Norholt SE. Treatment of acute pain following removal of mandibular third molars. Use of the dental pain model in pharmacological research and development of a comparable animal model. Int J Oral Maxillofac Surg 1998;27:1–41. Roszkowski MT, Swift JQ, Hargreaves KM. Effect of NSAID administration on tissue levels of immunoreactive prostaglandin E2, leukotriene B4, and (S)-flurbiprofen following extraction of impacted third molars. Pain 1997;73:339–345. Seymour RA, Moore U, Hawkesford J, Coulthard P, Jackson-Leech D, Thomas D, Hill M, Combs ML, Renton T, McGurk M. An investigation into the efficacy of intravenous diclofenac in post-operative dental pain. Eur J Clin Pharmacol 2000;56:447–452. Sugimoto T, Fujiyoshi Y, He YF, Xiao C, Ichikawa H. Trigeminal primary projection to the rat brain stem sensory trigeminal nuclear complex and surrounding structures revealed by anterograde transport of cholera toxin B subunit-conjugated and Bandeiraea simplicifolia isolectin B4conjugated horseradish peroxidase. Neurosci Res 1997a;28:361–371. Sugimoto T, Fujiyoshi Y, Xiao C, He YF, Ichikawa H. Central projection of calcitonin gene-related peptide (CGRP)- and substance P (SP)-immunoreactive trigeminal primary neurons in the rat. J Comp Neurol 1997b;378:425–442. Swift JQ, Garry MG, Roszkowski MT, Hargreaves KM. Effect of flurbiprofen on tissue levels of immunoreactive bradykinin and acute postoperative pain. J Oral Maxillofac Surg 1993;51:112–116 discussion p. 116–7.
Troullos E, Hargreaves KM, Dionne RA. Ibuprofen elevates immunoreactive beta-endorphin levels in humans during surgical stress. Clin Pharmacol Ther 1997;62:74–81. Valmaseda-Castellon E, Berini-Aytes L, Gay-Escoda C. Inferior alveolar nerve damage after lower third molar surgical extraction: a prospective study of 1117 surgical extractions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:377–383. Yoshida A, Dostrovsky JO, Sessle BJ, Chiang CY. Trigeminal projections to the nucleus submedius of the thalamus in the rat. J Comp Neurol 1991;307:609–625.
Mary Ann C. Sabino*, Patrick W. Mantyh Departments of Preventive Sciences, Neuroscience, Psychiatry and Cancer Center, Schools of Dentistry and Medicine, University of Minnesota, Minneapolis, MN 55455, USA
* Corresponding author. Tel.: 11-612-626-0179; fax: 11-612-626-2565. E-mail address: [email protected] (M.A.C. Sabino). PII: S0 304-3959(02 )00 309-3
Comment on: Doverty et al., Hyperalgesic responses in methadone maintenance patients (Pain 2001;90;91–6) To the Editor, I read with great interest the report of Doverty et al. dealing with the possibility of hyperalgesia in methadone maintained addicts (Doverty et al., 2001). The key observations reported were, (1) that using electrical stimulation methadone maintained addicts had similar pain thresholds but reduced pain tolerance at a time immediately prior to daily methadone dosing, and (2) that using the cold pressor test methadone maintained addicts had lower pain thresholds and pain tolerance at this same time point. At this pre-daily methadone administration time point the authors documented significant plasma concentrations of methadone. There was no mention of symptoms of overt opioid withdrawal syndrome in any of these patients, nor would that be common for addicts maintained on once daily methadone dosing. In the discussion section of the report, the authors briefly touch on the issue of opioid-induced hyperalgesia (OIH) as others have attempted to model the condition in rats (Dunbar and Pulai, 1998; Mao et al., 1994) and mice (Li et al., 2001), though our understanding of this phenomenon is rudimentary at best. However, I would have enjoyed more text devoted to the implications of their data and that of others relating to OIH and the management of clinical pain using opioids. Understandably, the authors and editors may have wished to avoid inappropriate speculation. However, their report begs the question of whether the clinical use of opioids for the management of pain in some way increases the sensitivity of patients to pain and therefore may cause harm rather than provide help. Opioids may not be considered “first line” drugs for chronic pain, particularly chronic pain of non-malignant
Letters to the Editor
etiologies, but the use of this class of drugs is undeniably common and growing. This despite the absence of substantial blinded randomized trials of long (years) duration which one would think would necessary to support this practice. It is commonly observed, however, that many patients who use opioids for chronic pain obtain at least short term gains in pain control, functional status, sleep or other aspects of their pain problem in the absence of severe side effects. This has certainly been my experience. Moreover, all of us wish to provide compassionate care to chronic pain sufferers. But the specter of therapeutic opioids eventually worsening rather than relieving pain is cause for concern if not alarm. Are there similarities between the manner in which Doverty’s patients were treated and currently used approaches to opioid prescribing for pain? There are many. Methadone is commonly used for the management of chronic pain as well as addiction. Not only is this a potent, highly bioavailable opioid, but it’s long half-life, multiple formulations and NMDA receptor blocking properties lend themselves well to the treatment of many pain syndromes. One might wonder if the once daily dosing common to methadone maintenance programs somehow causes or worsens OIH in methadone maintained addicts. It has been shown, for example, that intermittent opioid dosing or opioid administration punctuated by episodes of naloxone precipitated withdrawal leads to increased hyperalgesia in lab animals (Ibuki et al., 1997; Li et al., 2001; Mao et al., 1994; Mayer et al., 1999). It should be recalled that the half-life of methadone is quite long, and that the Doverty study reported less than 50% reductions in plasma methadone concentrations approximately 24 h after the previous dose. This observation combined with the NMDA receptor blocking properties of methadone would seem to make methadone one of the less likely opioids to cause OIH. It has been shown that NMDA receptor blockers reduce the likelihood that OIH will develop after opioid administration, and NMDA blockers also reduce OIH once OIH is established (Celerier et al., 1999; Dunbar and Pulai, 1998; Li et al., 2001). If animal data were to be extrapolated to human clinical situations we would predict that short acting opioids given on an intermittent basis would be the most effective at inducing OIH in humans. The prescription of potent but relatively short acting opioids to be used several times per day is common practice, at least in the US. Thus, it is possible that common opioid prescribing practices are the ones most likely to induce OIH in chronic pain patients. Hyperalgesia has, in fact, been reported in humans given systemic or intrathecal opioids for pain in the setting of abrupt cessation (Devulder et al., 1996; Lipman and Blumenkopf, 1989; Miser et al., 1986). Given the findings of Doverty and other clinical and laboratory reports, it would seem imperative that we more fully investigate under what circumstances opioid analgesics lead to hyperalgesia in clinical populations. Even if hyperalgesia from therapeutically prescribed opioids were
609
found to be common, we may be able to alter the type, route or schedule of administration to reduce or eliminate OIH in humans. Alternatively, additional agents such as NMDA receptor antagonists administered with opioids might reduce the hyperalgesic effects. However, the first step is additional research. It is in the best interest of patients that we aggressively address this issue in an expedited fashion. References Celerier E, Laulin J, Larcher A, Le Moal M, Simonnet G. Evidence for opiate-activated NMDA processes masking opiate analgesia in rats. Brain Res 1999;847:18–25. Devulder J, Bohyn P, Castille F, De Laat M, Rolly G. A case of uncommon withdrawal symptoms after a short period of spinal morphine administration. Pain 1996;64:589–591. Doverty M, White JM, Somogyi AA, Bochner F, Ali R, Ling W. Hyperalgesic responses in methadone maintenance patients. Pain 2001;90:91– 96. Dunbar SA, Pulai IJ. Repetitive opioid abstinence causes progressive hyperalgesia sensitive to N-methyl-d-aspartate receptor blockade in the rat. J Pharmacol Exp Ther 1998;284:678–686. Ibuki T, Dunbar SA, Yaksh TL. Effect of transient naloxone antagonism on tolerance development in rats receiving continuous spinal morphine infusion. Pain 1997;70:125–132. Li X, Angst MS, Clark JD. A murine model of opioid-induced hyperalgesia. Brain Res Mol Brain Res 2001;86:56–62. Lipman JJ, Blumenkopf B. Comparison of subjective and objective analgesic effects of intravenous and intrathecal morphine in chronic pain patients by heat beam dolorimetry. Pain 1989;39:249–256. Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 1994;14:2301–2312. Mayer DJ, Mao J, Holt J, Price DD. Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. Proc Natl Acad Sci USA 1999;96:7731–7736. Miser AW, Chayt KJ, Sandlund JT, Cohen PS, Dothage JA, Miser JS. Narcotic withdrawal syndrome in young adults after the therapeutic use of opiates. Am J Dis Child 1986;140:603–604.
J. David Clark a,b,* Veterans Affairs Palo Alto Health Care System, 112A, 3801 Miranda Avenue, Palo Alto, CA 94304, USA b Stanford University Department of Anesthesiology, Palo Alto, CA, USA
a
* Tel.: 11-650-493-5000, ext. 6-7184; fax: 11-650-852-3423. E-mail address: [email protected] (J.D. Clark). PII: S0304 -3 959(02)00310 -X
Reply to Dr. Clark’s comment on Doverty et al., hyperalgesic responses in methadone maintenance patients (Pain 2001;90:91–96) We thank Dr Clark for the very thoughtful and considered comments, and agree that our findings raise issues, which
Letters to the Editor
Gertz BJ. Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther 1999;65:336–347. Gobel S. An electron microscopic analysis of the trans-synaptic effects of peripheral nerve injury subsequent to tooth pulp extirpations on neurons in laminae I and II of the medullary dorsal horn. J Neurosci 1984;4:2281–2290. Gordon SM, Dubner R, Dionne RA. Antihyperalgesic effect of the Nmethyl-d-aspartate receptor antagonist dextromethorphan in the oral surgery model. J Clin Pharmacol 1999;39:139–146. Hargreaves KM, Swift JQ, Roszkowski MT, Bowles W, Garry MG, Jackson DL. Pharmacology of peripheral neuropeptide and inflammatory mediator release. Oral Surg Oral Med Oral Pathol 1994;78:503–510. Hersh EV, Levin LM, Cooper SA, Doyle G, Waksman J, Wedell D, Hong D, Secreto SA. Ibuprofen liquigel for oral surgery pain. Clin Ther 2000;22:1306–1318. Hockfield S, Gobel S. An anatomical demonstration of projections to the medullary dorsal horn (trigeminal nucleus caudalis) from rostral trigeminal nuclei and the contralateral caudal medulla. Brain Res 1982;252:203–211. Jacquin MF, Semba K, Rhoades RW, Egger MD. Trigeminal primary afferents project bilaterally to dorsal horn and ipsilaterally to cerebellum, reticular formation, and cuneate, solitary, supratrigeminal and vagal nuclei. Brain Res 1982;246:285–291. Lipton JA, Ship JA, Larach-Robinson D. Estimated prevalence and distribution of reported orofacial pain in the United States. J Am Dent Assoc 1993;124:115–121. Malmstrom K, Daniels S, Kotey P, Seidenberg BC, Desjardins PJ. Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial. Clin Ther 1999;21:1653–1663. Mantyh PW, Demaster E, Malhotra A, Ghilardi JR, Rogers SD, Mantyh CR, Liu HT, Basbaum AI, Vigna SR, Maggio JE, Simone DA. Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 1995;268:1629–1632. Marfurt CF, Rajchert DM. Trigeminal primary afferent projections to ‘nontrigeminal’ areas of the rat central nervous system. J Comp Neurol 1991;303:489–511. Morrison BW, Christensen S, Yuan WY, Brown J, Amlani S, Seidenberg B. Analgesic efficacy of the cyclooxygenase-2-specific inhibitor rofecoxib in post-dental surgery pain: a randomized, controlled trial. Clin Ther 1999;21:943–953. Norholt SE. Treatment of acute pain following removal of mandibular third molars. Use of the dental pain model in pharmacological research and development of a comparable animal model. Int J Oral Maxillofac Surg 1998;27:1–41. Roszkowski MT, Swift JQ, Hargreaves KM. Effect of NSAID administration on tissue levels of immunoreactive prostaglandin E2, leukotriene B4, and (S)-flurbiprofen following extraction of impacted third molars. Pain 1997;73:339–345. Seymour RA, Moore U, Hawkesford J, Coulthard P, Jackson-Leech D, Thomas D, Hill M, Combs ML, Renton T, McGurk M. An investigation into the efficacy of intravenous diclofenac in post-operative dental pain. Eur J Clin Pharmacol 2000;56:447–452. Sugimoto T, Fujiyoshi Y, He YF, Xiao C, Ichikawa H. Trigeminal primary projection to the rat brain stem sensory trigeminal nuclear complex and surrounding structures revealed by anterograde transport of cholera toxin B subunit-conjugated and Bandeiraea simplicifolia isolectin B4conjugated horseradish peroxidase. Neurosci Res 1997a;28:361–371. Sugimoto T, Fujiyoshi Y, Xiao C, He YF, Ichikawa H. Central projection of calcitonin gene-related peptide (CGRP)- and substance P (SP)-immunoreactive trigeminal primary neurons in the rat. J Comp Neurol 1997b;378:425–442. Swift JQ, Garry MG, Roszkowski MT, Hargreaves KM. Effect of flurbiprofen on tissue levels of immunoreactive bradykinin and acute postoperative pain. J Oral Maxillofac Surg 1993;51:112–116 discussion p. 116–7.
Troullos E, Hargreaves KM, Dionne RA. Ibuprofen elevates immunoreactive beta-endorphin levels in humans during surgical stress. Clin Pharmacol Ther 1997;62:74–81. Valmaseda-Castellon E, Berini-Aytes L, Gay-Escoda C. Inferior alveolar nerve damage after lower third molar surgical extraction: a prospective study of 1117 surgical extractions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:377–383. Yoshida A, Dostrovsky JO, Sessle BJ, Chiang CY. Trigeminal projections to the nucleus submedius of the thalamus in the rat. J Comp Neurol 1991;307:609–625.
Mary Ann C. Sabino*, Patrick W. Mantyh Departments of Preventive Sciences, Neuroscience, Psychiatry and Cancer Center, Schools of Dentistry and Medicine, University of Minnesota, Minneapolis, MN 55455, USA
* Corresponding author. Tel.: 11-612-626-0179; fax: 11-612-626-2565. E-mail address: [email protected] (M.A.C. Sabino). PII: S0 304-3959(02 )00 309-3
Comment on: Doverty et al., Hyperalgesic responses in methadone maintenance patients (Pain 2001;90;91–6) To the Editor, I read with great interest the report of Doverty et al. dealing with the possibility of hyperalgesia in methadone maintained addicts (Doverty et al., 2001). The key observations reported were, (1) that using electrical stimulation methadone maintained addicts had similar pain thresholds but reduced pain tolerance at a time immediately prior to daily methadone dosing, and (2) that using the cold pressor test methadone maintained addicts had lower pain thresholds and pain tolerance at this same time point. At this pre-daily methadone administration time point the authors documented significant plasma concentrations of methadone. There was no mention of symptoms of overt opioid withdrawal syndrome in any of these patients, nor would that be common for addicts maintained on once daily methadone dosing. In the discussion section of the report, the authors briefly touch on the issue of opioid-induced hyperalgesia (OIH) as others have attempted to model the condition in rats (Dunbar and Pulai, 1998; Mao et al., 1994) and mice (Li et al., 2001), though our understanding of this phenomenon is rudimentary at best. However, I would have enjoyed more text devoted to the implications of their data and that of others relating to OIH and the management of clinical pain using opioids. Understandably, the authors and editors may have wished to avoid inappropriate speculation. However, their report begs the question of whether the clinical use of opioids for the management of pain in some way increases the sensitivity of patients to pain and therefore may cause harm rather than provide help. Opioids may not be considered “first line” drugs for chronic pain, particularly chronic pain of non-malignant
Letters to the Editor
etiologies, but the use of this class of drugs is undeniably common and growing. This despite the absence of substantial blinded randomized trials of long (years) duration which one would think would necessary to support this practice. It is commonly observed, however, that many patients who use opioids for chronic pain obtain at least short term gains in pain control, functional status, sleep or other aspects of their pain problem in the absence of severe side effects. This has certainly been my experience. Moreover, all of us wish to provide compassionate care to chronic pain sufferers. But the specter of therapeutic opioids eventually worsening rather than relieving pain is cause for concern if not alarm. Are there similarities between the manner in which Doverty’s patients were treated and currently used approaches to opioid prescribing for pain? There are many. Methadone is commonly used for the management of chronic pain as well as addiction. Not only is this a potent, highly bioavailable opioid, but it’s long half-life, multiple formulations and NMDA receptor blocking properties lend themselves well to the treatment of many pain syndromes. One might wonder if the once daily dosing common to methadone maintenance programs somehow causes or worsens OIH in methadone maintained addicts. It has been shown, for example, that intermittent opioid dosing or opioid administration punctuated by episodes of naloxone precipitated withdrawal leads to increased hyperalgesia in lab animals (Ibuki et al., 1997; Li et al., 2001; Mao et al., 1994; Mayer et al., 1999). It should be recalled that the half-life of methadone is quite long, and that the Doverty study reported less than 50% reductions in plasma methadone concentrations approximately 24 h after the previous dose. This observation combined with the NMDA receptor blocking properties of methadone would seem to make methadone one of the less likely opioids to cause OIH. It has been shown that NMDA receptor blockers reduce the likelihood that OIH will develop after opioid administration, and NMDA blockers also reduce OIH once OIH is established (Celerier et al., 1999; Dunbar and Pulai, 1998; Li et al., 2001). If animal data were to be extrapolated to human clinical situations we would predict that short acting opioids given on an intermittent basis would be the most effective at inducing OIH in humans. The prescription of potent but relatively short acting opioids to be used several times per day is common practice, at least in the US. Thus, it is possible that common opioid prescribing practices are the ones most likely to induce OIH in chronic pain patients. Hyperalgesia has, in fact, been reported in humans given systemic or intrathecal opioids for pain in the setting of abrupt cessation (Devulder et al., 1996; Lipman and Blumenkopf, 1989; Miser et al., 1986). Given the findings of Doverty and other clinical and laboratory reports, it would seem imperative that we more fully investigate under what circumstances opioid analgesics lead to hyperalgesia in clinical populations. Even if hyperalgesia from therapeutically prescribed opioids were
609
found to be common, we may be able to alter the type, route or schedule of administration to reduce or eliminate OIH in humans. Alternatively, additional agents such as NMDA receptor antagonists administered with opioids might reduce the hyperalgesic effects. However, the first step is additional research. It is in the best interest of patients that we aggressively address this issue in an expedited fashion. References Celerier E, Laulin J, Larcher A, Le Moal M, Simonnet G. Evidence for opiate-activated NMDA processes masking opiate analgesia in rats. Brain Res 1999;847:18–25. Devulder J, Bohyn P, Castille F, De Laat M, Rolly G. A case of uncommon withdrawal symptoms after a short period of spinal morphine administration. Pain 1996;64:589–591. Doverty M, White JM, Somogyi AA, Bochner F, Ali R, Ling W. Hyperalgesic responses in methadone maintenance patients. Pain 2001;90:91– 96. Dunbar SA, Pulai IJ. Repetitive opioid abstinence causes progressive hyperalgesia sensitive to N-methyl-d-aspartate receptor blockade in the rat. J Pharmacol Exp Ther 1998;284:678–686. Ibuki T, Dunbar SA, Yaksh TL. Effect of transient naloxone antagonism on tolerance development in rats receiving continuous spinal morphine infusion. Pain 1997;70:125–132. Li X, Angst MS, Clark JD. A murine model of opioid-induced hyperalgesia. Brain Res Mol Brain Res 2001;86:56–62. Lipman JJ, Blumenkopf B. Comparison of subjective and objective analgesic effects of intravenous and intrathecal morphine in chronic pain patients by heat beam dolorimetry. Pain 1989;39:249–256. Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 1994;14:2301–2312. Mayer DJ, Mao J, Holt J, Price DD. Cellular mechanisms of neuropathic pain, morphine tolerance, and their interactions. Proc Natl Acad Sci USA 1999;96:7731–7736. Miser AW, Chayt KJ, Sandlund JT, Cohen PS, Dothage JA, Miser JS. Narcotic withdrawal syndrome in young adults after the therapeutic use of opiates. Am J Dis Child 1986;140:603–604.
J. David Clark a,b,* Veterans Affairs Palo Alto Health Care System, 112A, 3801 Miranda Avenue, Palo Alto, CA 94304, USA b Stanford University Department of Anesthesiology, Palo Alto, CA, USA
a
* Tel.: 11-650-493-5000, ext. 6-7184; fax: 11-650-852-3423. E-mail address: [email protected] (J.D. Clark). PII: S0304 -3 959(02)00310 -X
Reply to Dr. Clark’s comment on Doverty et al., hyperalgesic responses in methadone maintenance patients (Pain 2001;90:91–96) We thank Dr Clark for the very thoughtful and considered comments, and agree that our findings raise issues, which