concern regarding a review published by Plested et al. 2010 on various medications for refractory neuropathic pain
Detlef von Zabern, Grünenthal GmbH
8 June 2012
1. Definition of refractory neuropathic pain (NeP)
The authors state in their inclusion/exclusion criteria that `Owing to the lack of a consensus definition of refractory NeP, this review took a pragmatic approach to define refractory NeP broadly as patients who had failed to receive adequate pain relief from or were intolerant to previous therapy irrespective of the duration, dose and type of previous therapy¿. According to common understanding, this should encompass all patients with partial, incomplete or no response to previous neuropathic pain therapy. Thus, while the definition is very broad and may require rewording, it may well serve for practical purposes but should as a result apply to a broader range of publications than analysed in this manuscript. Indeed, when following the December 2008 cut-off point chosen by the authors, a search of duloxetine and lidocaine publications found lidocaine plaster studies such as White et al. 2003 [1 `Patients with postherpetic neuralgia, painful diabetic neuropathy, or low back pain with partial responses (average daily pain intensity >4/10) to their current analgesic treatment regimen were included¿] and Argoff et al. 2004 [2 `Patients with PHN, painful DN, and LBP were enrolled if they had partial response to gabapentin-containing analgesic regimens and if they reported moderate-to-severe pain on the NPS at study enrolment¿] which should have been included.
In addition, criteria for studies included in this review appear to differ throughout the paper thus inclusion criterion for the pregabalin study by Obermann et al. 2008 [3] was ¿All but three of patients had received prior therapy, therefore may be considered refractory¿. According to the reported mean baseline pain intensity score and pain duration, the majority of patients in this study were likely refractory however, this is pure speculation, not stated in the paper and may or may not apply to almost any other study in which patients received prior medication. If the inclusion criteria used to include the study by Obermann et al. are used (and we are not suggesting they should), then they should also have been applied e.g. to include the study by Meier et al. [4] and - with a more up-to-date literature research (see point 2 below) - also the studies by Hans et al. 2009 [5] and Baron et al. 2009 [6].
2. Literature search cut-off point
By the time the review was available online (Nov 2010), the literature search data with a cut-off point of Dec 2008 were nearly two years old. The authors included two 2009 pregabalin references in their discussion but did not extend this update to new lidocaine plaster publications such as Fleming and O¿Connor 2009 [7], Wilhelm et al. Feb 2010 [8], and Baron et al. Jul 2009 [6]. Considering the authors¿ mention of the lack of head-to-head trials in the review discussion, we do not understand why the latter study in particular was not included prior to publication of the review. The study by Baron et al. [6] describes a randomised trial in patients with PHN or DPN. Patients received either pregabalin or lidocaine plaster as monotherapy for 4 weeks (55.5% patients were sufficiently treated with lidocaine plaster monotherapy and 56.4% were sufficiently treated with pregabalin monotherapy). For the following 8 weeks, sufficiently treated patients continued monotherapy and if treatment had been insufficient during the first 4 weeks (=refractory) patients received the other treatment as an add-on for 8 weeks. Improvements were comparable in both add-on groups. Although this study does not completely meet the inclusion criteria set for the review since both drugs were administered together to these refractory patients, we, however, feel that this study provides important information concerning successful treatment of refractory patients with both drugs and should not have been omitted in the discussion of the review.
3. Inclusion of pregabalin study reference 34 (Sommer et al. 2007)
The study by Sommer and colleagues [9] investigated the use of pregabalin in the treatment of (mostly secondary) RLS. Only seven of the 19 RLS patients suffered from neuropathic pain. Sixteen patients had been previously treated with dopaminergic medication (for their RLS) and were refractory to their previous RLS medication. Eight patients received gabapentin and four patients opioids as previous treatment (from the wording we assume that this medication was also for the treatment of RLS symptoms). This study clearly does not investigate pregabalin for the treatment of neuropathic pain but for the treatment of RLS. In fact the authors scored relief from core RLS symptoms only (i.e. relief from neuropathic pain is not reported) and they tried to distinguish between the two by asking the patients to score the RLS symptoms with a diurnal rhythm rather than permanent symptoms. This very interesting study pointing to a relationship between neuropathy and RLS clearly does not refer to refractory neuropathic pain and should therefore not have been included in the review. Furthermore, inclusion of this study indicates the lack of thoroughness by which the search was conducted and highlights the biased and random inclusion of citations used.
4. Availability of cited references
Unfortunately, not all review references are available for perusal. Despite an extensive search, we were unable to locate review ref. 41 (abstract by Douglas et al. 2008). The full paper given as a link to this reference (ref. 31, Douglas et al. 2006) could also not be found with the provided citation.
Although our research did not find any pre- or post-2008 duloxetine studies which fit the inclusion criteria, several lidocaine plaster studies did. Exclusion of these studies and exclusion of duloxetine studies (apparently because prior therapies were not reported) misguides the reader into believing that pregabalin is the only effective treatment in the context of refractory neuropathic pain. Differences in safety profiles of the included medications is given very little consideration and the discussion is almost entirely focussed on pointing out benefits of pregabalin. All this can surely not be the purpose of a comparative review and is certainly not going to be for the best benefit of the patients concerned.
References
1. White WT, Patel N, Drass M, Nalamachu S. Lidocaine patch 5% with systemic analgesics such as gabapentin: a rational polypharmacy approach for the treatment of chronic pain. Pain Med 2003 Dec, 4(4): 321-330.
2. Argoff CE, Galer BS, Jensen MP, Oleka N, Gammaitoni AR. Effectiveness of the lidocaine patch 5% on pain qualities in three chronic pain states: assessment with the Neuropathic Pain Scale. Curr Med Res Opin 2004, 20 Suppl 2: S21-28.
3. Obermann M, Yoon MS, Sensen K, Maschke M, Diener HC, Katsarava Z. Efficacy of pregabalin in the treatment of trigeminal neuralgia. Cephalalgia 2008, 28: 174-181.
4. Meier T, Wasner G, Faust M, Kuntzer T, Ochsner F, Hueppe M, Bogousslavsky J, Baron R. Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 2003 Nov, 106(1-2): 151-158.
5. Hans G, Joukes E, Verhulst J, Vercauteren M. Management of neuropathic pain after surgical and non-surgical trauma with lidocaine 5% patches: study of 40 consecutive cases. Curr Med Res Opin 2009, 25(11): 2737-2743.
6. Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I, Serpell M. Efficacy and safety of combination therapy with 5% lidocaine medicated plaster and pregabalin in post-herpetic neuralgia and diabetic polyneuropathy. Curr Med Res Opin 2009 Jul, 25(7): 1677-1687.
7. Fleming JA, O'Connor BD. Use of lidocaine patches for neuropathic pain in a comprehensive cancer centre. Pain Res Manag 2009 Sep-Oct, 14(5): 381-388.
8. Wilhelm IR, Tzabazis A, Likar R, Sittl R, Griessinger N. Long-term treatment of neuropathic pain with a 5% lidocaine medicated plaster. Eur J Anaesthesiol 2010 Feb, 27(2): 169-173.
concern regarding a review published by Plested et al. 2010 on various medications for refractory neuropathic pain
8 June 2012
1. Definition of refractory neuropathic pain (NeP)
The authors state in their inclusion/exclusion criteria that `Owing to the lack of a consensus definition of refractory NeP, this review took a pragmatic approach to define refractory NeP broadly as patients who had failed to receive adequate pain relief from or were intolerant to previous therapy irrespective of the duration, dose and type of previous therapy¿. According to common understanding, this should encompass all patients with partial, incomplete or no response to previous neuropathic pain therapy. Thus, while the definition is very broad and may require rewording, it may well serve for practical purposes but should as a result apply to a broader range of publications than analysed in this manuscript. Indeed, when following the December 2008 cut-off point chosen by the authors, a search of duloxetine and lidocaine publications found lidocaine plaster studies such as White et al. 2003 [1 `Patients with postherpetic neuralgia, painful diabetic neuropathy, or low back pain with partial responses (average daily pain intensity >4/10) to their current analgesic treatment regimen were included¿] and Argoff et al. 2004 [2 `Patients with PHN, painful DN, and LBP were enrolled if they had partial response to gabapentin-containing analgesic regimens and if they reported moderate-to-severe pain on the NPS at study enrolment¿] which should have been included.
In addition, criteria for studies included in this review appear to differ throughout the paper thus inclusion criterion for the pregabalin study by Obermann et al. 2008 [3] was ¿All but three of patients had received prior therapy, therefore may be considered refractory¿. According to the reported mean baseline pain intensity score and pain duration, the majority of patients in this study were likely refractory however, this is pure speculation, not stated in the paper and may or may not apply to almost any other study in which patients received prior medication. If the inclusion criteria used to include the study by Obermann et al. are used (and we are not suggesting they should), then they should also have been applied e.g. to include the study by Meier et al. [4] and - with a more up-to-date literature research (see point 2 below) - also the studies by Hans et al. 2009 [5] and Baron et al. 2009 [6].
2. Literature search cut-off point
By the time the review was available online (Nov 2010), the literature search data with a cut-off point of Dec 2008 were nearly two years old. The authors included two 2009 pregabalin references in their discussion but did not extend this update to new lidocaine plaster publications such as Fleming and O¿Connor 2009 [7], Wilhelm et al. Feb 2010 [8], and Baron et al. Jul 2009 [6]. Considering the authors¿ mention of the lack of head-to-head trials in the review discussion, we do not understand why the latter study in particular was not included prior to publication of the review. The study by Baron et al. [6] describes a randomised trial in patients with PHN or DPN. Patients received either pregabalin or lidocaine plaster as monotherapy for 4 weeks (55.5% patients were sufficiently treated with lidocaine plaster monotherapy and 56.4% were sufficiently treated with pregabalin monotherapy). For the following 8 weeks, sufficiently treated patients continued monotherapy and if treatment had been insufficient during the first 4 weeks (=refractory) patients received the other treatment as an add-on for 8 weeks. Improvements were comparable in both add-on groups. Although this study does not completely meet the inclusion criteria set for the review since both drugs were administered together to these refractory patients, we, however, feel that this study provides important information concerning successful treatment of refractory patients with both drugs and should not have been omitted in the discussion of the review.
3. Inclusion of pregabalin study reference 34 (Sommer et al. 2007)
The study by Sommer and colleagues [9] investigated the use of pregabalin in the treatment of (mostly secondary) RLS. Only seven of the 19 RLS patients suffered from neuropathic pain. Sixteen patients had been previously treated with dopaminergic medication (for their RLS) and were refractory to their previous RLS medication. Eight patients received gabapentin and four patients opioids as previous treatment (from the wording we assume that this medication was also for the treatment of RLS symptoms). This study clearly does not investigate pregabalin for the treatment of neuropathic pain but for the treatment of RLS. In fact the authors scored relief from core RLS symptoms only (i.e. relief from neuropathic pain is not reported) and they tried to distinguish between the two by asking the patients to score the RLS symptoms with a diurnal rhythm rather than permanent symptoms. This very interesting study pointing to a relationship between neuropathy and RLS clearly does not refer to refractory neuropathic pain and should therefore not have been included in the review. Furthermore, inclusion of this study indicates the lack of thoroughness by which the search was conducted and highlights the biased and random inclusion of citations used.
4. Availability of cited references
Unfortunately, not all review references are available for perusal. Despite an extensive search, we were unable to locate review ref. 41 (abstract by Douglas et al. 2008). The full paper given as a link to this reference (ref. 31, Douglas et al. 2006) could also not be found with the provided citation.
Although our research did not find any pre- or post-2008 duloxetine studies which fit the inclusion criteria, several lidocaine plaster studies did. Exclusion of these studies and exclusion of duloxetine studies (apparently because prior therapies were not reported) misguides the reader into believing that pregabalin is the only effective treatment in the context of refractory neuropathic pain. Differences in safety profiles of the included medications is given very little consideration and the discussion is almost entirely focussed on pointing out benefits of pregabalin. All this can surely not be the purpose of a comparative review and is certainly not going to be for the best benefit of the patients concerned.
References
1. White WT, Patel N, Drass M, Nalamachu S. Lidocaine patch 5% with systemic analgesics such as gabapentin: a rational polypharmacy approach for the treatment of chronic pain. Pain Med 2003 Dec, 4(4): 321-330.
2. Argoff CE, Galer BS, Jensen MP, Oleka N, Gammaitoni AR. Effectiveness of the lidocaine patch 5% on pain qualities in three chronic pain states: assessment with the Neuropathic Pain Scale. Curr Med Res Opin 2004, 20 Suppl 2: S21-28.
3. Obermann M, Yoon MS, Sensen K, Maschke M, Diener HC, Katsarava Z. Efficacy of pregabalin in the treatment of trigeminal neuralgia. Cephalalgia 2008, 28: 174-181.
4. Meier T, Wasner G, Faust M, Kuntzer T, Ochsner F, Hueppe M, Bogousslavsky J, Baron R. Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 2003 Nov, 106(1-2): 151-158.
5. Hans G, Joukes E, Verhulst J, Vercauteren M. Management of neuropathic pain after surgical and non-surgical trauma with lidocaine 5% patches: study of 40 consecutive cases. Curr Med Res Opin 2009, 25(11): 2737-2743.
6. Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I, Serpell M. Efficacy and safety of combination therapy with 5% lidocaine medicated plaster and pregabalin in post-herpetic neuralgia and diabetic polyneuropathy. Curr Med Res Opin 2009 Jul, 25(7): 1677-1687.
7. Fleming JA, O'Connor BD. Use of lidocaine patches for neuropathic pain in a comprehensive cancer centre. Pain Res Manag 2009 Sep-Oct, 14(5): 381-388.
8. Wilhelm IR, Tzabazis A, Likar R, Sittl R, Griessinger N. Long-term treatment of neuropathic pain with a 5% lidocaine medicated plaster. Eur J Anaesthesiol 2010 Feb, 27(2): 169-173.
Competing interests
None declared