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. 2015 Jul 6;2(9):1114-21.
doi: 10.1016/j.ebiom.2015.07.003. eCollection 2015 Sep.

Investigating Reports of Complex Regional Pain Syndrome: An Analysis of HPV-16/18-Adjuvanted Vaccine Post-Licensure Data

Frank Huygen  1 , Kristin Verschueren  2 , Candida McCabe  3 , Jens-Ulrich Stegmann  4 , Julia Zima  2 , Olivia Mahaux  5 , Lionel Van Holle  5 , Maria-Genalin Angelo  2
Affiliations

Investigating Reports of Complex Regional Pain Syndrome: An Analysis of HPV-16/18-Adjuvanted Vaccine Post-Licensure Data

Frank Huygen et al. EBioMedicine. .

Abstract

Complex regional pain syndrome (CRPS) is a chronic pain disorder that typically follows trauma or surgery. Suspected CRPS reported after vaccination with human papillomavirus (HPV) vaccines led to temporary suspension of proactive recommendation of HPV vaccination in Japan. We investigated the potential CRPS signal in relation to HPV-16/18-adjuvanted vaccine (Cervarix®) by database review of CRPS cases with independent expert confirmation; a disproportionality analysis and analyses of temporality; an observed versus expected analysis using published background incidence rates; systematic reviews of aggregate safety data, and a literature review. The analysis included 17 case reports of CRPS: 10 from Japan (0.14/100,000 doses distributed) and seven from the United Kingdom (0.08/100,000). Five cases were considered by independent experts to be confirmed CRPS. Quantitative analyses did not suggest an association between CRPS and HPV-16/18-adjuvanted vaccine. Observed CRPS incidence after HPV-16/18 vaccination was statistically significantly below expected rates. Systematic database reviews using search terms varying in specificity and sensitivity did not identify new cases. No CRPS was reported during clinical development and no unexpected results found in the literature. There is not sufficient evidence to suggest an increased risk of developing CRPS following vaccination with HPV-16/18-adjuvanted vaccine. Post-licensure safety surveillance confirms the acceptable benefit-risk of HPV-16/18 vaccination.

Keywords: Chronic pain; Complex regional pain syndrome; Human papillomavirus vaccine; Safety.

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Figures

Fig. 1
Fig. 1
Schematic representation of search strategy and breakdown of selected cases. The safety database was searched for cases reporting any of the selected MedDRA PTs (n = 2730). From this dataset, cases were selected reporting pain and/or pain in extremity (n = 1616) which was further narrowed down by identifying cases reporting a duration of ≥ 2 weeks or with unspecified event duration (n = 231). Cases reporting the MedDRA PT of CRPS (n = 9) were not further considered as they were evaluated separately. Most of the cases retained for further evaluation reported pain together with motor disturbances. Refer to boxes highlighted in grey for breakdown of cases according to the combination of events reported.
Fig. 2
Fig. 2
Spontaneous reports of CRPS (n = 16*) and number of doses distributed each month since launch of HPV-16/18-adjuvanted vaccine. *Following the initial analysis, one of the 17 originally identified CRPS cases was voided as the girl had received Gardasil™. Hence this case is not shown. Note that HPV-16/18-adjuvanted vaccine was licenced in the UK two years before it was licenced in Japan.
Fig. 3
Fig. 3
Heat maps of the observed-to-expected analysis conclusion in the parameter plane defined by the background incidence rate and the under-reporting (two unknown parameters). Risk period of six days post HPV-16/18 immunisation and considering all cases irrespective of whether classified as confirmed/unconfirmed or unlikely to be CRPS.
Fig. 4
Fig. 4
Flow digram illustrating the assessment of potential cases with chronic pain.
See this image and copyright information in PMC

Comment in

References

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