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Are sodium channel blockers useless in peripheral neuropathic pain?
Pain 128 (2007) 6–7 www.elsevier.com/locate/pain
Editorial
Are sodium channel blockers useless in peripheral neuropathic pain?
Ectopic activity in damaged small afferent nerve fibres due to abnormal or upregulated sodium channels is considered to be an important mechanism for neuropathic pains of peripheral origin (Devor, 2006). So, drugs that block sodium channels are obvious candidates for the treatment of peripheral neuropathic pain. Small trials with intravenous infusions of the non-selective sodium channel blocker lidocaine support this concept (Kastrup et al., 1987; Rowbotham et al., 1991). However, trials with longer term treatment with lidocaine’s oral analogue, mexiletine (Finnerup et al., 2005), failed to find a clear-cut pain relieving effect. Also in some studies the pain relieving effect of systemic lidocaine is limited to evoked pain with no effect on spontaneous, ongoing pain (Gottrup et al., 2006). Lamotrigine is an anticonvulsant that blocks voltage-dependent sodium channels and it has in a small placebo-controlled trial (n = 59) shown a substantial pain relief in diabetics with painful polyneuropathy (Eisenberg et al., 2001). In this issue of PAIN Vinik et al., 2007 report the results of two large trials (n = 360 each study) with lamotrigine in painful diabetic polyneuropathy. The trials show either no or very limited pain relief with lamotrigine. First of all the researchers and the company behind these studies are to be thanked for publishing these negative trials instead of hiding them in internal files. Clinicians and researchers need these results in their search for a rational pharmacotherapy of peripheral neuropathic pain and also in directing future drug research for patients with neuropathic pain. However, the studies do raise two important questions that deserve attention: 1. Why did these large scale trials with adequate sample sizes fail to confirm the results of the initial small trial? One possibility is that the initial study came out positive by chance (Type I error) and we do not know if other small trials with negative outcome were left unpublished (publication bias). The large scale trials may also have a tendency to minimize effect of active
treatment. These trials often show a large placebo effect, which is also the case in the present studies as compared to a smaller placebo effect in the study carried out by Eisenberg and colleagues (2001). Another point is drop-out rates, which are typically higher in large multi-center trials than in small single-center trials, as was the case in the study by Vinik et al., 2007 where 35–50% dropped out versus a drop-out rate of 25% in the positive study by Eisenberg et al. (2001). If this is combined with an intention-to-treat analysis in the large trials and per-protocol analysis in the small trials, it may explain part of the difference in outcome. The high drop-out rate also points to a low tolerability of the effective doses as an important factor. 2. If we accept the results of these large trials as a valid sign of a limited or no effect of lamotrigine the next question is why this type of drug apparently does not work for peripheral neuropathic pain. This issue becomes even more important when recent data on oxcarbazepine, a non-specific sodium channel blocker, are taken into account. In one trial oxcarbazepine showed a minor effect in painful diabetic neuropathy (Dogra et al., 2005), and abstracts from two other trials with oxcarbazepine report lack of effect. One possible explanation could be that ectopic activity initiated and maintained by increased number of ion channels does not play a role in these clinical conditions as opposed to what is seen in experimental animal studies (Devor, 2006). Alternatively, a sodium channel mediated ‘‘pain’’ generator is only present in a fraction of the patients and the effect of sodium channel blockade in these may be undetectable when outcome is analysed on the entire study population (dilution effect). This raises an additional problem with large scale drug company sponsored trials, where detailed clinical data on the patients are rarely available. Subgroup analysis that includes, for example, only patients with signs of an ‘‘irritable nociceptor’’ (Fields et al., 1998) as determined by thorough sensory examination and quantitative sensory testing cannot be performed. Insufficient
0304-3959/$32.00 Ó 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2006.09.010
Editorial / Pain 128 (2007) 6–7
dosing is another possible explanation for the treatment failure. Perhaps the therapeutic window between sufficient sodium blockade and intolerable side effect is just too narrow so that a clinically relevant effect cannot be demonstrated. With the current information lamotrigine and other sodium channel blockers should probably not be for routine clinical use in peripheral neuropathic pain, but we cannot eliminate them completely. Trials that characterise the patient population better so as to subsequently identify possible responders are needed, as are face-toface comparison of different drugs and drug combinations. This approach may clarify contributing mechanisms of neuropathic pain and as such represents a brick in our struggle for practicing evidence-based medicine. It is unlikely that these trials will be performed by the industry without regulatory changes, since such data are not requested by the authorities for drug registration and marketing. These questions can only be determined in a research setting. This is a case for independent drug research. There is, therefore, a need for international collaboration among research groups on pharmacotherapy; a research that obviously requires increased funding.
7
Devor M. Sodium channels and mechanisms of neuropathic pain. J Pain 2006;7(Suppl. 1):S3–S12. Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A. Lamotrigine reduces painful diabetic neuropathy. A randomised, controlled study. Neurology 2001;57:505–9. Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 1998;5:209–27. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 2005;118:289–305. Gottrup H, Bach FW, Juhl G, Jensen TS. Differential effect of ketamine and lidocaine on spontaneous and mechanical evoked pain in patients with nerve injury pain. Anesthesiology 2006;104:527–36. Kastrup J, Petersen P, Dejgaard A, Angelo HR, Hilsted J. Intravenous lidocaine infusion – a new treatment of chronic painful diabetic polyneuropathy. Pain 1987;28:69–75. Rowbotham MC, Reisner-Keller LA, Fields HL. Both intravenous lidocaine and morphine reduce pain in postherpetic neuralgia. Neurology 1991;41:1024–8. Vinik AI, Tuchman M, Safirstein B, Corder C, Kirby L, Wilks K, et al. Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies. Pain 2007;128:169–79.
Søren H. Sindrup * Department of Neurology, Odense University Hospital, Denmark E-mail address: [email protected]
References
Troels S. Jensen Danish Pain Research Centre, Aarhus University Hospital, Denmark
Dogra S, Beydoun S, Mazzola J, Hopwood M, Wan Y. Oxcarbazepine in painful diabetic neuropathy: a randomized, placebo-controlled study. Eur J Pain 2005:543–54.
*
Corresponding author. Tel.: +45 65412471.
Editorial
Are sodium channel blockers useless in peripheral neuropathic pain?
Ectopic activity in damaged small afferent nerve fibres due to abnormal or upregulated sodium channels is considered to be an important mechanism for neuropathic pains of peripheral origin (Devor, 2006). So, drugs that block sodium channels are obvious candidates for the treatment of peripheral neuropathic pain. Small trials with intravenous infusions of the non-selective sodium channel blocker lidocaine support this concept (Kastrup et al., 1987; Rowbotham et al., 1991). However, trials with longer term treatment with lidocaine’s oral analogue, mexiletine (Finnerup et al., 2005), failed to find a clear-cut pain relieving effect. Also in some studies the pain relieving effect of systemic lidocaine is limited to evoked pain with no effect on spontaneous, ongoing pain (Gottrup et al., 2006). Lamotrigine is an anticonvulsant that blocks voltage-dependent sodium channels and it has in a small placebo-controlled trial (n = 59) shown a substantial pain relief in diabetics with painful polyneuropathy (Eisenberg et al., 2001). In this issue of PAIN Vinik et al., 2007 report the results of two large trials (n = 360 each study) with lamotrigine in painful diabetic polyneuropathy. The trials show either no or very limited pain relief with lamotrigine. First of all the researchers and the company behind these studies are to be thanked for publishing these negative trials instead of hiding them in internal files. Clinicians and researchers need these results in their search for a rational pharmacotherapy of peripheral neuropathic pain and also in directing future drug research for patients with neuropathic pain. However, the studies do raise two important questions that deserve attention: 1. Why did these large scale trials with adequate sample sizes fail to confirm the results of the initial small trial? One possibility is that the initial study came out positive by chance (Type I error) and we do not know if other small trials with negative outcome were left unpublished (publication bias). The large scale trials may also have a tendency to minimize effect of active
treatment. These trials often show a large placebo effect, which is also the case in the present studies as compared to a smaller placebo effect in the study carried out by Eisenberg and colleagues (2001). Another point is drop-out rates, which are typically higher in large multi-center trials than in small single-center trials, as was the case in the study by Vinik et al., 2007 where 35–50% dropped out versus a drop-out rate of 25% in the positive study by Eisenberg et al. (2001). If this is combined with an intention-to-treat analysis in the large trials and per-protocol analysis in the small trials, it may explain part of the difference in outcome. The high drop-out rate also points to a low tolerability of the effective doses as an important factor. 2. If we accept the results of these large trials as a valid sign of a limited or no effect of lamotrigine the next question is why this type of drug apparently does not work for peripheral neuropathic pain. This issue becomes even more important when recent data on oxcarbazepine, a non-specific sodium channel blocker, are taken into account. In one trial oxcarbazepine showed a minor effect in painful diabetic neuropathy (Dogra et al., 2005), and abstracts from two other trials with oxcarbazepine report lack of effect. One possible explanation could be that ectopic activity initiated and maintained by increased number of ion channels does not play a role in these clinical conditions as opposed to what is seen in experimental animal studies (Devor, 2006). Alternatively, a sodium channel mediated ‘‘pain’’ generator is only present in a fraction of the patients and the effect of sodium channel blockade in these may be undetectable when outcome is analysed on the entire study population (dilution effect). This raises an additional problem with large scale drug company sponsored trials, where detailed clinical data on the patients are rarely available. Subgroup analysis that includes, for example, only patients with signs of an ‘‘irritable nociceptor’’ (Fields et al., 1998) as determined by thorough sensory examination and quantitative sensory testing cannot be performed. Insufficient
0304-3959/$32.00 Ó 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2006.09.010
Editorial / Pain 128 (2007) 6–7
dosing is another possible explanation for the treatment failure. Perhaps the therapeutic window between sufficient sodium blockade and intolerable side effect is just too narrow so that a clinically relevant effect cannot be demonstrated. With the current information lamotrigine and other sodium channel blockers should probably not be for routine clinical use in peripheral neuropathic pain, but we cannot eliminate them completely. Trials that characterise the patient population better so as to subsequently identify possible responders are needed, as are face-toface comparison of different drugs and drug combinations. This approach may clarify contributing mechanisms of neuropathic pain and as such represents a brick in our struggle for practicing evidence-based medicine. It is unlikely that these trials will be performed by the industry without regulatory changes, since such data are not requested by the authorities for drug registration and marketing. These questions can only be determined in a research setting. This is a case for independent drug research. There is, therefore, a need for international collaboration among research groups on pharmacotherapy; a research that obviously requires increased funding.
7
Devor M. Sodium channels and mechanisms of neuropathic pain. J Pain 2006;7(Suppl. 1):S3–S12. Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A. Lamotrigine reduces painful diabetic neuropathy. A randomised, controlled study. Neurology 2001;57:505–9. Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 1998;5:209–27. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 2005;118:289–305. Gottrup H, Bach FW, Juhl G, Jensen TS. Differential effect of ketamine and lidocaine on spontaneous and mechanical evoked pain in patients with nerve injury pain. Anesthesiology 2006;104:527–36. Kastrup J, Petersen P, Dejgaard A, Angelo HR, Hilsted J. Intravenous lidocaine infusion – a new treatment of chronic painful diabetic polyneuropathy. Pain 1987;28:69–75. Rowbotham MC, Reisner-Keller LA, Fields HL. Both intravenous lidocaine and morphine reduce pain in postherpetic neuralgia. Neurology 1991;41:1024–8. Vinik AI, Tuchman M, Safirstein B, Corder C, Kirby L, Wilks K, et al. Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies. Pain 2007;128:169–79.
Søren H. Sindrup * Department of Neurology, Odense University Hospital, Denmark E-mail address: [email protected]
References
Troels S. Jensen Danish Pain Research Centre, Aarhus University Hospital, Denmark
Dogra S, Beydoun S, Mazzola J, Hopwood M, Wan Y. Oxcarbazepine in painful diabetic neuropathy: a randomized, placebo-controlled study. Eur J Pain 2005:543–54.
*
Corresponding author. Tel.: +45 65412471.