The incidence and management of tolerance in intrathecal baclofen therapy

Abstract

Study design: Retrospective study. Objectives: To study the incidence and management of tolerance in patients treated with intrathecal baclofen (ITB) therapy. Setting: Department of neurology and neurosurgery, University Medical Center Groningen, The Netherlands. Methods: Medical records of all patients who had received an implantable ITB pump at our clinic during 1991-2005 were reviewed. Results: A total of 37 patients (representing 116 pump years) were included. Mean follow-up time was 38 months (range 3-120 months). Baclofen dose increased in the first 18 months after implantation (Po0.05), and then stabilized around a mean dose of 350 mg per day. Eight patients (22%) developed tolerance, defined as a dose increase of 4100 mg per year. No predictive factors for development of tolerance could be determined. Three different treatment regimens for tolerant patients were analyzed. Altering the infusion mode from simple to complex continuous (n ¼ 6) had no effect on the development of tolerance. Pulsatile bolus infusion (n ¼ 1) and a drug holiday (n ¼ 2) were both effective in reducing the daily baclofen dose. Patients who needed surgical revision of the pump system because of mechanical failures (n ¼ 11) showed a significant dose decrease during the first month after revision, indicating that the preoperative dose increase most likely had been caused by the pump failure. Pumprelated complications occurred once per 10.5 years of ITB treatment. Drug-related side effects had an annual risk of 13.8%. The reported events were mostly mild. Conclusions: ITB therapy is effective and safe, also in the long term and causes tolerance in only 22% of the treated patients.

Tolerance to continuous intrathecal baclofen infusion can be reversed by pulsatile bolus infusion

“…Tolerance was defined as an ITB dose increase of at least 100 mg during 1 year, to maintain a stable spasmolytic effect. 8 Tolerance was only considered, if no other reasonable explanations, like infections and pain, could be given and after having excluded technical problems with the pump system. Because it has been reported that the ITB dose may increase during the first 12-18 months after implantation, patients were only switched to pulsatile bolus infusion after X18 months of ITB therapy.…”

“…Because it has been reported that the ITB dose may increase during the first 12-18 months after implantation, patients were only switched to pulsatile bolus infusion after X18 months of ITB therapy. 2,4,5,8 Because an ITB pump cannot be stopped in between boluses, the pump was programmed to deliver the lowest possible continuous rate ('minimal infusion rate' which is 3 mg h À1 in case of a baclofen concentration of 1500 mg ml À1 ). The initial bolus dose was calculated as follows: ((Total Daily DoseÀ10%ÀMinimal Infusion Rate)/6).…”

“…2,4,5 However, unexplained dose increases may still occur in up to 20% of ITB patients after these first 18 months. 4,[6][7][8] These dose increases after 18 months are thought to be caused by tolerance, which is one of the major concerns of ITB therapy. Tolerance is defined as a decreasing effect during a stable dose of a drug, requiring a dose increase to produce the same previously obtained effect.…”

“…Altering the infusion mode from simple to complex continuous has shown not to be effective in the development of tolerance. 8 The most advocated strategy nowadays is the drug holiday. During a drug holiday, ITB therapy is tapered off and the patient is treated with an alternative spasmolytic drug for days to weeks, until ITB therapy is restarted.…”

“…During a drug holiday, ITB therapy is tapered off and the patient is treated with an alternative spasmolytic drug for days to weeks, until ITB therapy is restarted. 8,13 During this drug holiday the patient has to be monitored carefully, because of the risk of developing baclofen withdrawal symptoms. 14 Although the exact mechanism behind a drug holiday is unclear, the GABA B receptors are thought to resensitize for baclofen.…”