The association between ACE inhibitors and the complex regional pain syndrome: Suggestions for a neuro-inflammatory pathogenesis of CRPS

de Mos, M.; Huygen, F.J.P.M.; Stricker, B.H.Ch.; Dieleman, J.P.; Sturkenboom, M.C.J.M.

doi:10.1016/j.pain.2008.12.032

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Volume 142, Issue 3 , Pages 218-224, April 2009

The association between ACE inhibitors and the complex regional pain syndrome: Suggestions for a neuro-inflammatory pathogenesis of CRPS

M. de Mos
- Erasmus University Medical Center, Pharmaco-epidemiology Unit, Departments of Medical Informatics and Epidemiology & Biostatistics, Dr. Molewaterplein 50, Room 2157, 3015 GE, Rotterdam, The Netherlands
- Corresponding author. Address: Erasmus University Medical Center, Pharmaco-epidemiology Unit, Department of Medical Informatics, Dr. Molewaterplein 50, Room 2157, 3015 GE Rotterdam, The Netherlands. Tel.: +31 10 7044128; fax: +31 10 7044722.
F.J.P.M. Huygen
- Erasmus University Medical Center, Department of Pain Treatment, ‘s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
B.H.Ch. Stricker
- Erasmus University Medical Center, Pharmaco-epidemiology Unit, Departments of Medical Informatics and Epidemiology & Biostatistics, Dr. Molewaterplein 50, Room 2157, 3015 GE, Rotterdam, The Netherlands
J.P. Dieleman
- Erasmus University Medical Center, Pharmaco-epidemiology Unit, Departments of Medical Informatics and Epidemiology & Biostatistics, Dr. Molewaterplein 50, Room 2157, 3015 GE, Rotterdam, The Netherlands
M.C.J.M. Sturkenboom
- Erasmus University Medical Center, Pharmaco-epidemiology Unit, Departments of Medical Informatics and Epidemiology & Biostatistics, Dr. Molewaterplein 50, Room 2157, 3015 GE, Rotterdam, The Netherlands

Received 15 August 2008; received in revised form 2 December 2008; accepted 23 December 2008. published online 05 February 2009.

Abstract

Antihypertensive drugs interact with mediators that are also involved in complex regional pain syndrome (CRPS), such a neuropeptides, adrenergic receptors, and vascular tone modulators. Therefore, we aimed to study the association between the use of antihypertensive drugs and CRPS onset. We conducted a population-based case-control study in the Integrated Primary Care Information (IPCI) database in the Netherlands. Cases were identified from electronic records (1996–2005) and included if they were confirmed during an expert visit (using IASP criteria), or if they had been diagnosed by a medical specialist. Up to four controls per cases were selected, matched on gender, age, calendar time, and injury. Exposure to angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, β-blockers, calcium channel blockers, and diuretics was assessed from the automated prescription records. Data were analyzed using multivariate conditional logistic regression. A total of 186 cases were matched to 697 controls (102 confirmed during an expert visit plus 84 with a specialist diagnosis). Current use of ACE inhibitors was associated with an increased risk of CRPS (OR^adjusted: 2.7, 95% CI: 1.1–6.8). The association was stronger if ACE inhibitors were used for a longer time period (OR^adjusted: 3.0, 95% CI: 1.1–8.1) and in higher dosages (OR^adjusted: 4.3, 95% CI: 1.4–13.7). None of the other antihypertensive drug classes was significantly associated with CRPS. We conclude that ACE inhibitor use is associated with CRPS onset and hypothesize that ACE inhibitors influence the neuro-inflammatory mechanisms that underlie CRPS by their interaction with the catabolism of substance P and bradykinin.

Keywords: Complex regional pain syndrome, Angiotensin converting enzyme (ACE), Neurogenic inflammation, Epidemiology, Risk, Antihypertensive drugs