Intravenous immunoglobulin in the treatment of primary trigeminal neuralgia refractory to carbamazepine: a study protocol [ISRCTN33042138]

Abstract

Background: We have recently reported successful treatment of patients with chronic pain syndromes using human pooled intravenous immunoglobulin (IVIG) in a prospective, open-label cohort study. A randomised, placebo controlled, double blinded study is needed to confirm these results. We chose to study patients with carbamazepine resistant primary Trigeminal Neuralgia (rpTN), as these had responded particularly well to IVIG.A protocol involving the use of IVIG in rpTN is complex for three reasons: 1. The effect of IVIG does not follow simple dose-response rules; 2. The response pattern of patients to IVIG was variable and ranged between no effect at all and pain free remission between two weeks and >1 year; 3. TN is characterized by extremely severe pain, for which operative intervention is (if temporarily) helpful in most patients.

Design: A placebo controlled, parallel, add-on model was developed and the primary outcome variable defined as the length of time during which patients remain in the study. Study groups are compared using Kaplan-Maier survival analysis. Patients record their response to treatment ("severe, moderate, slight, no pain"). The study coordinator monitors pain diaries. Severe or moderate pain of three days duration will result in termination of the study for that patient.

Conclusions: This study design utilizes a method of survival analysis and is novel in chronic pain research. It allows for both early departure from the study and voluntary crossover upon non-response. It may be applicable to the analysis of IVIG efficacy in other chronic pain syndromes.

Figure 1

Time flow diagram of the study algorithm. All patients are assessed for 7 days in a recruitment period before commencement of the main study. They receive IVIG or Placebo on alternating days (day 1, 3, 5). Subsequently, a three-day period without monitoring is implemented because transitional pain increase has been noted in some patients, with no correlation with the ultimate efficacy of IVIG. Diary entries will be reviewed from day 9 onward. The main study ends at day 28. Crossover (upper half of diagram): all patients who leave the main study before 28 days will be offered crossover to the alternative treatment arm. Time points (day 1 C, 3 C, 5 C, etc.) are similar to those in the main study. Patients are being offered surgery if they have insufficient pain relief: either upon leaving the main study (as an alternative to crossover), or following crossover treatment. The treatment allocations will be unblinded when all patients have completed the study. Plac: Placebo