subjects, sympathetically independent pain (SIP) patients, and sympathetically maintained pain (SMP) patients to determine if intradermal injection of phenylephrine elicits a response similar to that elicited by norepinephrine. The SIP and SMP patients were diagnosed with either type I or type II CRPS. Intradermal injection of a placebo or 1 percent solution of phenylephrine were administered to the forearm, shin of the lower leg, or the suprapatellar area of the upper leg. Pain to each of the injections was rated by the participants. None of the participants reported unusual pain to the placebo. All participants reported stinging or burning pain lasting 15–90 seconds developing after intradermal injection of phenylephrine. Furthermore, all SMP patients reported burning pain developing after intradermal injection of phenylephrine in the symptomatic limb. In addition, three SMP patients reported the development of pain after intradermal injection of phenylephrine administered to the unaffected limb.

Weight of Mechanistic Evidence

The publications, described above, presented clinical evidence suggestive but not sufficient for the committee to conclude that the injection of a vaccine was a contributing cause of CRPS. The clinical description in one case provided by Jastaniah et al. (2003) included evidence of vaccine rechallenge and was consistent with CRPS. Furthermore, the latency between injection of a vaccine and the development of CRPS in the vaccine rechallenge case described above was 30 minutes or less, suggesting injury resulting from the injection of the vaccine. Approximately 50 percent of patients with CRPS have a history of antecedent trauma to the affected limb (Littlejohn, 2008). This is supported by controlled studies, not using vaccines, conducted by Ali and colleagues (2000) and Mailis-Ganon and Bennett (2004) in which pain was elicited after injection of norepinephrine and phenylephrine.

However, the three other cases described by Jastaniah et al. (2003) and cases described by other authors (Bensasson et al., 1977; Genc et al., 2005; Jastaniah et al., 2003; Palao Sanchez et al., 1997; Pirrung, 2010) did not include convincing evidence beyond a temporal relationship between injection of a vaccine and development of CRPS.

The committee assesses the mechanistic evidence regarding an association between the injection of a vaccine and CRPS as low-intermediate based on experimental evidence and one case.

Causality Conclusion

Conclusion 12.1: The evidence is inadequate to accept or reject a causal relationship between the injection of a vaccine and CRPS.



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