Skip to main content
AAN.com
Articles
November 27, 2006
Letter to the Editor

Pregabalin in central neuropathic pain associated with spinal cord injury
A placebo-controlled trial

November 28, 2006 issue
67 (10) 1792-1800

Abstract

Objective: To evaluate pregabalin in central neuropathic pain associated with spinal cord injury.
Methods: A 12-week, multicenter study of patients randomized to either flexible-dose pregabalin 150 to 600 mg/day (n = 70) or placebo (n = 67), administered BID. Patients were allowed to remain on existing, stable pain therapy. The primary efficacy variable was the endpoint mean pain score, derived from patients’ last 7 days daily pain diary entries. Key secondary endpoints included pain responder rates, the SF-MPQ, sleep interference, mood, and the patient global measure of change.
Results: The mean baseline pain score was 6.54 in the pregabalin group and 6.73 in the placebo group. The mean endpoint pain score was lower in the pregabalin group (4.62) than the placebo group (6.27; p < 0.001), with efficacy observed as early as week 1 and maintained for the duration of the study. The average pregabalin dose after the 3-week stabilization phase was 460 mg/day. Pregabalin was significantly superior to placebo in endpoint assessments on the SF-MPQ. The ≥30% and ≥50% pain responder rates were higher with pregabalin than placebo (p < 0.05). Pregabalin was associated with improvements in disturbed sleep (p < 0.001) and anxiety (p < 0.05), and more patients reported global improvement at endpoint in the pregabalin group (p < 0.001). Mild or moderate, typically transient, somnolence and dizziness were the most common adverse events.
Conclusions: Pregabalin 150 to 600 mg/day was effective in relieving central neuropathic pain, improving sleep, anxiety, and overall patient status in patients with spinal cord injury.

Get full access to this article

View all available purchase options and get full access to this article.

References

1.
Bonica JJ. Introduction: Semantic, epidemiologic and educational issues. In: Casey KL, ed. Pain and central nervous system disease. New York: Raven Press, 1991:13–30.
2.
Siddall PJ, Taylor DA, McClelland JM, Rutkowski SB, Cousins MJ. Pain report and the relationship of pain to physical factors in the first 6 months following spinal cord injury. Pain 1999;81:187–197.
3.
Siddall PJ, Yezierski RP, Loeser JD. Taxonomy and epidemiology of spinal cord injury pain. In: Yezierski RP, Burchiel KJ, eds. Spinal cord injury pain: assessment, mechanisms and management. Seattle: IASP Press, 2002:9–24.
4.
Vierck CJ, Siddall PJ, Yezierski RP. Pain following spinal cord injury: animal models and mechanistic studies. Pain 2000:89;1–5.
5.
Finnerup NB, Jensen TS. Spinal cord injury pain—mechanisms and treatment. Eur J Neurol 2004;11:73–82.
6.
Merskey H, Bogduk N, eds. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Seattle: IASP Press, 1994:209–212.
7.
Jensen TS, Gottrup H, Sindrup SH, Bach FW. The clinical picture of neuropathic pain. Eur J Pharmacol 2001;429:1–11.
8.
Eide PK. Pathophysiological mechanisms of central neuropathic pain after spinal cord injury. Spinal Cord 1998;36:601–612.
9.
Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ. A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain 2003;103:249–257.
10.
French JA, Kugler AR, Robbins JL, Knapp LE, Garofalo EA. Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures. Neurology 2003;60:1631–1637.
11.
Arroyo S, Anhut H, Kugler AR, et al. Pregabalin 1008-011 International Study Group. Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures. Epilepsia 2004;45:20–27.
12.
Beydoun A, Uthman BM, Kugler AR, Greiner MJ, Knapp LE, Garofalo EA. Pregabalin 1008-009 Study Group. Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy. Neurology 2005;64:475–480.
13.
Feltner DE, Crockatt JG, Dubovsky SJ, et al. A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol 2003;23:240–249.
14.
Pohl RB, Feltner DE, Fieve RR, Pande AC. Efficacy of pregabalin in the treatment of generalized anxiety disorder: double-blind, placebo-controlled comparison of BID versus TID dosing. J Clin Psychopharmacol 2005;25:151–158.
15.
Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the α2δ subunit of a calcium channel. J Biol Chem 1996;271:5768–5776.
16.
Taylor CP. The biology and pharmacology of calcium channel alpha2-delta proteins. CNS Drug Rev 2004;10:183–188.
17.
Fink K, Dooley DJ, Meder WP, et al. Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology 2002;42:229–236.
18.
Dooley DJ, Mieske CA, Borosky SA. Inhibition of K+-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin. Neurosci Lett 2000;280:107–110.
19.
Dooley DJ, Donovan CM, Pugsley TA. Stimulus-dependent nodulation of [3H]norepinephrine release from rat neocortical slices by gabapentin and pregabalin. J Pharmacol Exp Ther 2000;295:1086–1093.
20.
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.
21.
Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology 2004;63:2104–2110.
22.
Richter RW, Portenoy R, Sharma U, Lamoreaux L, Bockbrader H, Knapp LE. Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain 2005;6:253–260.
23.
Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 2004;110:628–638.
24.
Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain 2005;115:254–263.
25.
Dworkin RH, Corbin AE, Young JP Jr., et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2003;60:1274–1283.
26.
Sabatowski R, Galvez R, Cherry DA, et al. 1008-045 Study Group. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 2004;109:26–35.
27.
Melzack R. The short-form McGill pain questionnaire. Pain 1987;30:191–197.
28.
Hayes RD, Stewart AL. Sleep measures. In: Stewart AL, Ware Jr JE, eds. Measuring functioning and well-being: The Medical Outcomes Study approach. Durham: Duke University Press,1992:235–259.
29.
Zigmond A, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983;67:361–370.
30.
Guy W. ECDEU assessment manual for psychopharmacology, revised. Rockville: US Department of Health, Education and Welfare, 1976.
31.
Ditunno JF, Young W, Donovan WH, Creasey G. The international standards booklet for neurological and functional classification of spinal cord injury. Paraplegia 1994;32:70–80.
32.
Zelman DC, Dukes E, Brandenburg N, Bostrom A, Gore M. Identification of cut-points for mild, moderate and severe pain due to diabetic peripheral neuropathy. Pain 2005;115:29–36.
33.
SAS Institute Inc. SAS/STAT user’s guide, version 6, fourth edition, volumes 1 and 2. Cary: SAS Institute, 1989.
34.
Berry D, ed. Statistical methodology in the pharmaceutical sciences. New York: Marcel Decker, 1990:403–408.
35.
Coding Symbols for a Thesaurus of Adverse Event Reaction Terms (COSTART). 4th Edition. Department of Health and Human Services, US Food and Drug Administration (FDA), 1996.
36.
Farrar JT, Young JP Jr., LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94:149–158.
37.
Finnerup NB, Sindrup SH, Bach FW, Johannesen IL, Jensen TS. Lamotrigine in spinal cord injury pain: a randomized controlled trial. Pain 2002;96:375–383.
38.
Hays RD, Martin SA, Sesti AM, Spritzer KL. Psychometric properties of the Medical Outcomes Study Sleep measure. Sleep Med 2005;6:41–44.
39.
Snaith RP, Zigmond AS. The Hospital Anxiety and Depression Scale manual. Windsor: nferNelson; 1994.
40.
Nicholson B, Verma S. Comorbidities in chronic neuropathic pain. Pain Med 2004;5(suppl 1):S9–S27.
41.
Siddall PJ, Cousins MJ. Persistent pain as a disease entity: implications for clinical management. Anesth Analg 2004;99:510–520.
42.
Richards JS, Meredith RL, Nepomuceno C, Fine PR, Bennett G. Psycho social aspects of chronic pain in spinal cord injury. Pain 1980;8:355–366.
43.
Summers JD, Rapoff MA, Varghese G, Porter K, Palmer RE. Psychosocial factors in chronic spinal cord injury pain. Pain 1991;47:183–189.
44.
Widerström-Noga EG, Duncan R, Turk DC. Psychosocial profiles of people with pain associated with spinal cord injury: identification and comparison with other chronic pain syndromes. Clin J Pain 2004;20:261–271.
45.
Li CY, Song YH, Higuera ES, Luo ZD. Spinal dorsal horn calcium channel alpha (2) delta-1 subunit upregulation contributes to peripheral nerve injury-induced tactile allodynia. J Neurosci 2004;24:8494–8499.
Letters to the Editor
10 March 2007
Pregabalin in central neuropathic pain associated with spinal cord injury:A placebo-controlled trial
Stefan P. Kruszewski, MD, 732 Forest Road
John A. Shane, M.D.

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.

10 March 2007
Reply from the Authors
Philip J Siddall, University of Sydney
Michael Cousins, Andreas Otte, Teresa Griesing, Richard Chambers, Kevin Murphy

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.

Information & Authors

Information

Published In

Neurology®
Volume 67Number 10November 28, 2006
Pages: 1792-1800
PubMed: 17130411

Publication History

Published online: November 27, 2006
Published in print: November 28, 2006

Permissions

Request permissions for this article.

Authors

Affiliations & Disclosures

P. J. Siddall, MBBS, PhD
From the Pain Management Research Institute (P.J.S., M.J.C.), University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia; International Medical Research (A.O.), Pfizer Global Pharmaceuticals, Freiburg, Germany; and Pfizer Pharmaceuticals Group (T.G., R.C., T.K.M.), New York, NY.
M. J. Cousins, MD, DSc
From the Pain Management Research Institute (P.J.S., M.J.C.), University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia; International Medical Research (A.O.), Pfizer Global Pharmaceuticals, Freiburg, Germany; and Pfizer Pharmaceuticals Group (T.G., R.C., T.K.M.), New York, NY.
A. Otte, MD, PhD
From the Pain Management Research Institute (P.J.S., M.J.C.), University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia; International Medical Research (A.O.), Pfizer Global Pharmaceuticals, Freiburg, Germany; and Pfizer Pharmaceuticals Group (T.G., R.C., T.K.M.), New York, NY.
T. Griesing, PhD
From the Pain Management Research Institute (P.J.S., M.J.C.), University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia; International Medical Research (A.O.), Pfizer Global Pharmaceuticals, Freiburg, Germany; and Pfizer Pharmaceuticals Group (T.G., R.C., T.K.M.), New York, NY.
R. Chambers, MSPH
From the Pain Management Research Institute (P.J.S., M.J.C.), University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia; International Medical Research (A.O.), Pfizer Global Pharmaceuticals, Freiburg, Germany; and Pfizer Pharmaceuticals Group (T.G., R.C., T.K.M.), New York, NY.
T. K. Murphy, PhD
From the Pain Management Research Institute (P.J.S., M.J.C.), University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia; International Medical Research (A.O.), Pfizer Global Pharmaceuticals, Freiburg, Germany; and Pfizer Pharmaceuticals Group (T.G., R.C., T.K.M.), New York, NY.

Notes

Address correspondence and reprint requests to Dr. Philip J. Siddall, Pain Management and Research Institute, University of Sydney, Royal North Shore Hospital, Sydney, NSW, 2065, Australia; e-mail: [email protected]

Metrics & Citations

Metrics

Citation information is sourced from Crossref Cited-by service.

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

Cited By
  1. Metabotropic Glutamate Receptor 5: A Potential Target for Neuropathic Pain Treatment, Current Neuropharmacology, 23, 3, (276-294), (2025).https://doi.org/10.2174/1570159X23666241011163035
    Crossref
  2. Study of the Effect of Methyl Eugenol on Gastric Damage Produced by Spinal Cord Injury Model in the Rat, Molecules, 30, 1, (86), (2024).https://doi.org/10.3390/molecules30010086
    Crossref
  3. Exoskeleton Training for Spinal Cord Injury Neuropathic Pain (ExSCIP): Protocol for a Phase 2 Feasibility Randomised Trial, HRB Open Research, 7, (55), (2024).https://doi.org/10.12688/hrbopenres.13949.1
    Crossref
  4. Central Neuropathic Pain, CONTINUUM: Lifelong Learning in Neurology, 30, 5, (1381-1396), (2024).https://doi.org/10.1212/CON.0000000000001490
    Crossref
  5. SPIDOL study protocol for the assessment of intrathecal ziconotide antalgic efficacy for severe refractory neuropathic pain due to spinal cord lesions, Trials, 25, 1, (2024).https://doi.org/10.1186/s13063-024-08387-0
    Crossref
  6. Chapter 14. Antidepressants, Anxiolytics/Hypnotics, and Other Medications: Pharmacokinetics, Drug Interactions, Adverse Effects, and Administration, Handbook of Diagnosis and Treatment of Bipolar Disorders, (611-660), (2024).https://doi.org/10.1176/appi.books.9781615377930.lg14
    Crossref
  7. Mechanisms and Therapeutic Prospects of Microglia-Astrocyte Interactions in Neuropathic Pain Following Spinal Cord Injury, Molecular Neurobiology, (2024).https://doi.org/10.1007/s12035-024-04562-1
    Crossref
  8. Emergency radiation therapy in modern-day practice: Now or never, or never again ?, Supportive Care in Cancer, 32, 2, (2024).https://doi.org/10.1007/s00520-024-08322-8
    Crossref
  9. A Systematic Review of the Interventions for Management of Pain in Patients After Spinal Cord Injury, Cureus, (2023).https://doi.org/10.7759/cureus.42657
    Crossref
  10. An in-Depth Review of Dercum’s disease: Aetiology, Epidemiology, and Treatment, Asian Journal of Research in Pharmaceutical Sciences, (287-295), (2023).https://doi.org/10.52711/2231-5659.2023.00049
    Crossref
  11. See more
Loading...

View Options

Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Purchase Options

The neurology.org payment platform is currently offline. Our technical team is working as quickly as possible to restore service.

If you need immediate support or to place an order, please call or email customer service:

  • 1-800-638-3030 for U.S. customers - 8:30 - 7 pm ET (M-F)
  • 1-301-223-2300 for customers outside the U.S. - 8:30 - 7 pm ET (M-F)
  • [email protected]

We appreciate your patience during this time and apologize for any inconvenience.

View options

PDF and All Supplements

Download PDF and Supplementary Material

Full Text

View Full Text

Full Text HTML

View Full Text HTML

Figures

Tables

Media

Share

Share

Share article link

Share