Neurology -- Correspondence for Siddall et al., 67 (10) 1792-1800

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Correspondence published:

Pregabalin in central neuropathic pain associated with spinal cord injury:A placebo-controlled trial: Stefan P. Kruszewski, MD, John A. Shane, M.D. (10 March 2007)

Reply from the Authors: Philip J Siddall, Michael Cousins, Andreas Otte, Teresa Griesing, Richard Chambers, Kevin Murphy (10 March 2007)

Pregabalin in central neuropathic pain associated with spinal cord injury:A placebo-controlled trial 10 March 2007

Stefan P. Kruszewski, MD,
732 Forest Road
Harrisburg, PA 17112-921,
John A. Shane, M.D.
Send Correspondence to journal:
Re: Pregabalin in central neuropathic pain associated with spinal cord injury:A placebo-controlled trial

skruszewski{at}spkmd.com Stefan P. Kruszewski, MD, et al.

Siddall et al conclude with a bullish statement on the effectiveness of pregabalin. The article, acknowledging that all authors worked for or were supported by Pfizer, obfuscates several problems with pregabalin. [1]
The first problem is study design; all patients were permitted to remain on existing pain therapies except the individuals taking gabapentin, who were required to discontinue treatment at least a week before the study protocol began. This intentionally produced a gabapentin withdrawal state in 34 clients. [1] The study may have been biased because: those receiving pregabalin were receiving 'replacement therapy' as a byproduct of pre-study drug manipulation; randomization was completed after gabapentin was withdrawn; and the authors did not report which subjects in gabapentin-withdrawal were randomized to which treatment group.
The second problem concerns safety. The pregabalin group manifested significantly more adverse side effects, including more serious ones. Twenty-one percent more of the pregabalin-treated patients reported treatment-emergent adverse events compared to placebo. The group discontinuing treatment due to pregabalin was 62% higher than those discontinuing treatment due to placebo.
In addition, side effects included somnolence, dizziness, euphoria (3 with pregabalin vs. 0 with placebo) and edema. Adverse reporting of edema (combining peripheral and central) showed a 100% greater expression in pregabalin-treated individuals.
Finally, the pregabalin group had a mean increase in bodyweight of 2.0 kg with 11.4% of the pregabalin group experiencing a weight gain of greater than or equal to 7% over baseline, considered clinically significant.
Another problem is the authors' explanation for pregabalin’s mechanism of action. The authors suggest that the effects of reduced pain sensation are consistent with reduced calcium influx into hyperexcited neurons as a result of its binding to an alpha-2-delta subunit of voltage- gated calcium channels (as previously described for gabapentin), citing several sources. [2,3]
While the above statements may be accurate, the authors ignore a likelier explanation of pregabalin's mechanism of action by omitting a discussion of its GABAergic effects, similar to those that underscore the actions of pregabalin's predecessor, gabapentin. [4] As noted above, the authors cite references about gabapentin to explain pregabalin's actions. [2,3] Analogous to providing a benzodiazepine-like derivative, pregabalin’s GABA agonism, regardless of its specific receptor-site action, can explain its side effects, including the severe withdrawal reaction from pregabalin noted by the authors, as well as explaining the centrally-diminished appreciation of pain due to GABA’s anti-anxiety effects.
References
1. Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK. Pregabalin in central neuropathic pain associated with spinal cord injury: A placebo-controlled trial. Neurology 2006 Nov; 67: 1792-1800.
2. Gee NS, Brown JP, Dissanayake VUK, Offord J, Thurlow R, Woodruff GN. The Novel Anticonvulsant Drug, Gabapentin (Neurontin), Binds to the alpha-2-delta Subunit of a Calcium Channel. The Journal of Biological Chemistry 1996; 271: 5768-5776.
3. Maneuf YP, Hughes J, McKnight AT. Gabapentin inhibits the substance P-facilitated K+-evoked release of [3H] glutamate from rat caudal trigeminal nucleus slices. Pain 2001; 93: 191-196.
4. National Institutes of Health Clinical Center. Effect of Gabapentin on GABA Concentration and Emotional Processing: ClinicalTrials.gov Identifier: NCT00094510 [Online]. 2006 Sept [cited 2007 Jan 25]; [4 screens]. Available from: URL: http://clinicaltrials.gov/ct/show/NCT00094510.
Disclosure: Dr. Kruszewski has been retained as an expert in the science that underscores the mechanism of action of gabapentin (not pregabalin) in multiple district litigation.

Reply from the Authors 10 March 2007

Philip J Siddall,
University of Sydney
Pain Management Centre, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia,
Michael Cousins, Andreas Otte, Teresa Griesing, Richard Chambers, Kevin Murphy
Send Correspondence to journal:
Re: Reply from the Authors

phils{at}med.usyd.edu.au Philip J Siddall, et al.

We thank Kruszewski and Shane for their comments on our study. We were careful to present conclusions that were supported by the data and we stand by our conclusion regarding the effectiveness of pregabalin in this population. Nevertheless, they raise three concerns about study design, tolerability and mechanism of action.
The omission of treatment allocation for patients previously taking gabapentin was an oversight. However, these 34 patients were equally allocated between the two groups so no differential bias is likely. Although the protocol specified discontinuation of gabapentin at least 7 days prior to the first visit, the average time between discontinuation and starting study drug was 17.7 days, thus withdrawal symptoms during the study are unlikely.
As with most drug trials, treatment-emergent adverse events were more frequent in the drug-treated group (96% for pregabalin versus 75% for placebo). Discontinuation from adverse events occurred in 13% of the placebo group and 21% of the pregabalin group. However, lack of efficacy caused discontinuation in 20 (29.9%) placebo patients and just 5 (7.1%) pregabalin patients. Overall, only 55% of placebo-treated patients completed the study versus 70% of patients treated with pregabalin.
Dizziness and somnolence were generally mild to moderate and caused few discontinuations with no patient discontinuing due to dizziness. Euphoria was reported in three pregabalin treated patients, but was mild (two patients) or moderate (one patient), and resulted in one discontinuation. Because this population is at risk for peripheral edema it is not surprising that edema was common. However, no association has been made in preclinical or clinical studies between edema and other potential cardiovascular complications.
Weight gain was spontaneously reported as an adverse event in three (4.3%) patients in the pregabalin group. A pre-defined criterion for clinically relevant weight gain (¡Ý7% increase from baseline) occurred in two (3.1%) patients on placebo and eight (11.4%) on pregabalin. No patient discontinued due to weight gain.
Kruszewski and Shane suggest that GABA-related effects could account for both the "centrally-diminished appreciation of pain" and also the adverse events of pregabalin citing an ongoing and as yet unpublished clinical trial with gabapentin using magnetic resonance spectroscopy (MRS). Although a previous gabapentin study [5] suggested increased total brain GABA, MRS detects almost exclusively GABA within neuronal cytosol and not in extracellular space, where it could interact with GABA receptors. Studies of GABA synaptic function in animal models [6,7,8] show that gabapentin and pregabalin decrease inhibition of GABA release, rather than increasing it, as proposed.
Data refuting a role of GABA receptors as a site of action [9,10] also provide strong evidence that the analgesic-like action of pregabalin requires interaction at the alpha2-delta binding site of voltage-gated calcium channels. While both gabapentin and pregabalin are structurally related to GABA, our review of literature does not support a change in GABA function in the analgesic activity of these compounds. [11]
References
5. Petroff OA, Hyder F, Rothman DL, Collins TL, Mattson RH. 1998. Gabapentin increases human brain GABA within one hour. Epilepsia 1998;39:71-71.
6. Bayer K, Seifollah A, Zeilhofer HU. Gabapentin may inhibit synaptic transmission in the mouse spinal cord dorsal horn through a preferential block of P/Q-type Ca2+ channels. Neuropharmacol 2004;46:743-749.
7. Micheva KD, Taylor CP, Smith SJ. Pregabalin reduces the release of synaptic vesicles from cultured hippocampal neurons. Mol Pharmacol 2006:70;467-476.
8. Stringer JL, Taylor CP, 2000. The effects of gabapentin in the rat hippocampus are mimicked by two structural analogs, but not by nimodipine. Epilepsy Res 2000;41:155-162.
9. Belliotti T, Ekhato IV, Capiris T, et al. Structure-activity relationships of pregabalin and analogs that target the a2-d protein. J.Med.Chem 2005;48:2294-2307.
10. Field MJ, Cox PJ, Stott E, et al. Identification of the aplha2-delta-1 subunit of voltage dependent calcium channels as a novel molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci USA 2006;103:17537-C17542.
11. Dooley, DJ, Taylor CP, Donevan S, Feltner D. Ca2+ channel ¦Á2¦Ä ligands: novel modulators of neurotransmission. Trends Pharmacol Sci 2007;28:75-82.
Disclosures: The study referred to in this correspondence was supported by Pfizer Global Pharmaceuticals, New York, NY. Drs. Otte, Griesing, Chambers, and Murphy are employees of Pfizer. Dr. Siddall and Prof. Cousins have received an honorarium for a presentation at a Pfizer-sponsored symposium at an international meeting.