- Email: [email protected]
Reply to Jacques Devulder
Pain 86 (2000) 211±212 www.elsevier.nl/locate/pain
Letters to the Editor Pain, 86 (2000) 211 PAIN 4194 Is 200 mg lamotrigine daily analgesic or not? With great interest I read the article about the effects of 200 mg lamotrigine used in neuropathic pain: a randomized, double blind, placebo controlled trial (Mc Cleane, 1999). This nice study concludes that lamotrigine, in a dose increasing to 200 mg daily is ineffective as an analgesic for neuropathic pain. Some comments seem necessary: the author states that Lunardi (Lunardi et al., 1997) report a direct relationship between daily dose, plasma level of lamotrigine and analgesic effects. Nevertheless, the author argues that in this ®eld we lack the dose ®nding studies indicating target doses we should aim at. A nice article about the effects and target doses of lamotrigine is presented by Grunze (Grunze et al., 1998). Lamotrigine is not only modulating NMDA receptors, glutamate release but has an important modulation role in calcium and potassium currents. Especially calcium contributes to pain mechanisms by gene induction and phosphorylation of different receptors and ion channels (Rajadhyaksha et al., 1999). As described in the article of Grunze (Grunze et al., 1998) a free lamotrigine plasma concentration of about 2±20 mmol/l is mandatory to have suf®cient effects on voltage dependent sodium channels and the L- and N-type calcium channels. To in¯uence potassium currents a clinically relevant concentration of 25 mmol/l should be obtained. Lamotrigine can modulate central neurons, involved in chronic pain, by preventing in¯ux of calcium either by a loss of the magnesium block on the NMDA receptors either on voltage gated calcium channels. Even if depolarization should occur, it can restore the membrane potential by opening the potassium channel. In doing so, lamotrigine seems a very attractive drug, not only by alleviating pain but also restoring cell functioning. As chronic pain (61 months in the placebo group and 87 months in the treatment group) can have induced important cell modulation and cell apoptosis it seems very unlikely that an oral intake of 200 mg lamotrigine obtained after 56 days will change those complex cellular mechanisms in such a short time. As stated by Grunze et al. (1998) a minimal plasma level of 25 mmol/l should be required. Probably protracted time, 4 weeks or more after steady state plasma concentrations are necessary to notify some cellular restoration. Although the author refers to some of these items, I wanted to stress them in this letter hoping that false conclusions by the reader as lamotrigine not being analgesic are prevented.
References Grunze H, von Wegener J, Green R, Walden J. Modulation of calcium and potassium currents by lamotrigine Neuropsychobiology 1998;38:131± 138. Lunardi G, Leandri M, Albano C, Cultrera S, Fracassi M, Rubino V, Favale E. Clinical effectiveness of lamotrigine and plasma levels in essential and symptomatic trigeminal neuralgia. Neurology 1997;48:1714±1717. Mc Cleane G. 200 mg of lamotrigine has no analgesic effect in neuropathic pain: a randomised, double-blind, placebo controlled trial. Pain 1999;83:105±107. Rajadhyaksha A, Barczak A, Macias W, Leveque J, Lewis S, Konradi CC. L-Type Ca(21) channels are essential for glutamate-mediated CREB phosphorylation and c-fos gene expression in striatal neurons. J Neurosci 1999;19:6348±6359.
Jacques Devulder University Hospital of Gent, Department of Anesthesia ± Section Pain Clinic, De Pintelaan 185, 9000 Gent, Belgium PII: S0304 -3 959(00)00246 -3
Pain, 86 (2000) 211±212 PAIN 4195 Reply to Jacques Devulder I agree entirely with Dr. Devulder that it may be possible to conclude from this paper that lamotrigine is not an analgesic, and that such a conclusion may be false. Two issues arise. First, does lamotrigine have analgesic properties? I would contend, despite my own results in this study, that lamotrigine is analgesic when appropriately used, and it remains my ®rst choice anticonvulsant when treating neuropathic pain. Our failure to demonstrate this effect is, I think, a failure of study design rather than an indication of lack of effect. My mistake in this study was to accept too low a dose of lamotrigine (winch would concur with Dr. Devulder's comments), but of equal importance was the use of a dose escalation regime which took 42 days to reach the 200 mg level when, in our clinical practice, such an increase is normally achieved in 28 days. The reason for the slow escalation used in this study was an attempt to avoid side effects. I suppose one cannot be surprised about the negative results of a study which,
0304-3959/00/$20.00 q 2000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.
212
Letters to the Editor
based on clinical experience, one expects positive results from if one changes from ones normal treatment regime during a study. Second, this study emphasizes the dif®culty clinicians face when examining evidence of effect of drugs. This study gives a narrow `snapshot' of the lamotrigine story. All this study tells us is that lamotrigine, when increased over 42 days to 200 mg a day is not analgesic. It tells us nothing about the potential for analgesia when differing regimes are used. Here in lies the value of the much maligned case report which can describe successful treatment with a drug and can give the dose range, albeit in a small number of patients, which can produce effect. Do we place too much value in studying increasing numbers of patients with a ®xed dose regime so that the statistical power of the study is high when perhaps we should be taking a broader view of drugs which our basic science colleagues suggest may be effective and ®nding out how we maximize that effect in our patients? When one thinks back several years ago, lamotrigine was used in what now seems tiny doses of 25 and 50 mg daily. As time has progressed we now feel more
con®dent using gradually increasing dose levels, and with Dr. Devulder's suggestions about the mode of action and time to effect of lamotrigine, I will more con®dently be encouraging patients, side effects permitting, to try the drug for a more prolonged time and at a higher dose level. If only we had dose-®nding studies carried out when the ®rst suggestions of an analgesic effect with lamotrigine were made, then our use of this drug would be more rationally based now. Gary McCleane Pain Clinic, Craigavon Area Hospital, 68 Lurgan Road, Craigavon, BT63 5QQ, UK PII: S0 304-3959(00 )00 247-5
Letters to the Editor Pain, 86 (2000) 211 PAIN 4194 Is 200 mg lamotrigine daily analgesic or not? With great interest I read the article about the effects of 200 mg lamotrigine used in neuropathic pain: a randomized, double blind, placebo controlled trial (Mc Cleane, 1999). This nice study concludes that lamotrigine, in a dose increasing to 200 mg daily is ineffective as an analgesic for neuropathic pain. Some comments seem necessary: the author states that Lunardi (Lunardi et al., 1997) report a direct relationship between daily dose, plasma level of lamotrigine and analgesic effects. Nevertheless, the author argues that in this ®eld we lack the dose ®nding studies indicating target doses we should aim at. A nice article about the effects and target doses of lamotrigine is presented by Grunze (Grunze et al., 1998). Lamotrigine is not only modulating NMDA receptors, glutamate release but has an important modulation role in calcium and potassium currents. Especially calcium contributes to pain mechanisms by gene induction and phosphorylation of different receptors and ion channels (Rajadhyaksha et al., 1999). As described in the article of Grunze (Grunze et al., 1998) a free lamotrigine plasma concentration of about 2±20 mmol/l is mandatory to have suf®cient effects on voltage dependent sodium channels and the L- and N-type calcium channels. To in¯uence potassium currents a clinically relevant concentration of 25 mmol/l should be obtained. Lamotrigine can modulate central neurons, involved in chronic pain, by preventing in¯ux of calcium either by a loss of the magnesium block on the NMDA receptors either on voltage gated calcium channels. Even if depolarization should occur, it can restore the membrane potential by opening the potassium channel. In doing so, lamotrigine seems a very attractive drug, not only by alleviating pain but also restoring cell functioning. As chronic pain (61 months in the placebo group and 87 months in the treatment group) can have induced important cell modulation and cell apoptosis it seems very unlikely that an oral intake of 200 mg lamotrigine obtained after 56 days will change those complex cellular mechanisms in such a short time. As stated by Grunze et al. (1998) a minimal plasma level of 25 mmol/l should be required. Probably protracted time, 4 weeks or more after steady state plasma concentrations are necessary to notify some cellular restoration. Although the author refers to some of these items, I wanted to stress them in this letter hoping that false conclusions by the reader as lamotrigine not being analgesic are prevented.
References Grunze H, von Wegener J, Green R, Walden J. Modulation of calcium and potassium currents by lamotrigine Neuropsychobiology 1998;38:131± 138. Lunardi G, Leandri M, Albano C, Cultrera S, Fracassi M, Rubino V, Favale E. Clinical effectiveness of lamotrigine and plasma levels in essential and symptomatic trigeminal neuralgia. Neurology 1997;48:1714±1717. Mc Cleane G. 200 mg of lamotrigine has no analgesic effect in neuropathic pain: a randomised, double-blind, placebo controlled trial. Pain 1999;83:105±107. Rajadhyaksha A, Barczak A, Macias W, Leveque J, Lewis S, Konradi CC. L-Type Ca(21) channels are essential for glutamate-mediated CREB phosphorylation and c-fos gene expression in striatal neurons. J Neurosci 1999;19:6348±6359.
Jacques Devulder University Hospital of Gent, Department of Anesthesia ± Section Pain Clinic, De Pintelaan 185, 9000 Gent, Belgium PII: S0304 -3 959(00)00246 -3
Pain, 86 (2000) 211±212 PAIN 4195 Reply to Jacques Devulder I agree entirely with Dr. Devulder that it may be possible to conclude from this paper that lamotrigine is not an analgesic, and that such a conclusion may be false. Two issues arise. First, does lamotrigine have analgesic properties? I would contend, despite my own results in this study, that lamotrigine is analgesic when appropriately used, and it remains my ®rst choice anticonvulsant when treating neuropathic pain. Our failure to demonstrate this effect is, I think, a failure of study design rather than an indication of lack of effect. My mistake in this study was to accept too low a dose of lamotrigine (winch would concur with Dr. Devulder's comments), but of equal importance was the use of a dose escalation regime which took 42 days to reach the 200 mg level when, in our clinical practice, such an increase is normally achieved in 28 days. The reason for the slow escalation used in this study was an attempt to avoid side effects. I suppose one cannot be surprised about the negative results of a study which,
0304-3959/00/$20.00 q 2000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.
212
Letters to the Editor
based on clinical experience, one expects positive results from if one changes from ones normal treatment regime during a study. Second, this study emphasizes the dif®culty clinicians face when examining evidence of effect of drugs. This study gives a narrow `snapshot' of the lamotrigine story. All this study tells us is that lamotrigine, when increased over 42 days to 200 mg a day is not analgesic. It tells us nothing about the potential for analgesia when differing regimes are used. Here in lies the value of the much maligned case report which can describe successful treatment with a drug and can give the dose range, albeit in a small number of patients, which can produce effect. Do we place too much value in studying increasing numbers of patients with a ®xed dose regime so that the statistical power of the study is high when perhaps we should be taking a broader view of drugs which our basic science colleagues suggest may be effective and ®nding out how we maximize that effect in our patients? When one thinks back several years ago, lamotrigine was used in what now seems tiny doses of 25 and 50 mg daily. As time has progressed we now feel more
con®dent using gradually increasing dose levels, and with Dr. Devulder's suggestions about the mode of action and time to effect of lamotrigine, I will more con®dently be encouraging patients, side effects permitting, to try the drug for a more prolonged time and at a higher dose level. If only we had dose-®nding studies carried out when the ®rst suggestions of an analgesic effect with lamotrigine were made, then our use of this drug would be more rationally based now. Gary McCleane Pain Clinic, Craigavon Area Hospital, 68 Lurgan Road, Craigavon, BT63 5QQ, UK PII: S0 304-3959(00 )00 247-5