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

• GSK investigated a potential safety signal after suspected CRPS cases were reported following HPV vaccination in Japan
• Little is known of CRPS. We used database reviews and statistical methods to maximise case detection and reduce uncertainty
• There is not sufficient evidence to suggest an increased risk of CRPS following HPV-16/18-adjuvanted vaccineIn 2013 the Japanese health authority temporarily suspended proactive recommendation of HPV vaccination after reports of a chronic pain condition (CRPS) in Japan. GSK, who manufactures one of the two available HPV vaccines (Cervarix®), investigated this potential safety issue by reviewing its safety database for all cases of CRPS ever reported after HPV vaccination, and by various statistical analyses. None of the reviews or analyses suggested a safety concern. The observed rate of CRPS after vaccination was lower than what might be expected by chance. At this time there is not enough evidence to suggest that Cervarix® causes CRPS.

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.