Discussion
According to our knowledge, this is the first study reporting TDM of
pregabalin in course of continuous and prolonged intermittent KRT in a
critically ill patient. These modalities of KRT, often used as
complementary therapies, are considered the preferred dialysis
modalities for critically ill patients with AKI, especially in those
with hemodynamic instability [13]. As each treatment session is
performed over a long-time span, these KRT modalities allow for slower
fluid and solute removal, with better hemodynamic tolerance and lower
risk of rapid osmolal shift [14]. In addition, due to their extended
duration, prolonged KRTs usually provides an efficient daily solute
clearance [15]. As detailed in Table 1 , pregabalin has
small molecular weight, negligible protein binding and low volume of
distribution, thus it is characterized by a significant theorical
extracorporeal clearance by KRTs. Data regarding the target therapeutic
concentration are still limited. Studies on patients with epilepsy with
normal kidney function receiving 150-600 mg daily of the drug, reported
a serum level ranging from 2 - 8 microg/mL [10-12, 16]. Optimal
therapeutic plasma concentrations for neuropathic pain control have not
been established yet. However, studies have demonstrated a dose-response
relationship for pregabalin in the treatment of painful conditions, like
post-herpetic neuralgia. Given the linear absorption of pregabalin, with
plasma concentrations increasing proportionately with increasing dose,
pregabalin plasma concentration stability likely plays a crucial role in
analgesic effect maintenance [17].
Given the increased adoption of pregabalin also in the ICU, not only as
a continuation therapy in patients with chronic neuropathic pain, but
also in the setting of multimodal analgesia [6-8, 18], a great
degree of attention should be required to avoid the risk of inadequate
therapeutic concentrations. Indeed, given the prevalent renal
metabolism, a dose adjustment is usually recommended in patients with
impaired kidney function (Table 1 ). However, according to the
pharmacokinetic profile and in line with the different KRT modalities
techniques, our data showed a slow but progressive reduction of
pregabalin serum levels in course of the prolonged KRTs (CKRT and SLED,Figure 1 A-B ), while a more rapid and significant reduction
during conventional IHD was observed (Figure 1 C ). In this
regard, we found that when a modality of continuous KRT is applied for
incident AKI (e.g. CVVHDF), the usual recommended pregabalin dose may
become insufficient to maintain the therapeutic concentration range
(Figure 1A ). Indeed, despite the double daily administration, a
slow but progressive decline in serum levels was observed, as reported
in a case of gabapentin intoxication treated with CKRT [19]. While
in course of the SLED session serum levels remained within the suggested
therapeutic range (Figure 1B ), a more severe reduction may be
supposed with longer duration (e.g. 12-16 hours) and increased dialysis
fluid rate (until 300 ml/min). Finally, as already previously reported
in chronic hemodialysis patients [4, 5, 20], TDM data obtained
during and after the IHD session confirmed a rapid reduction of serum
concentration during the treatment session, along with a subsequent
normalization after dialysis, also thanks to the double daily
administration (Figure 1C ).
In conclusion, even though more data are needed to confirm our findings,
the TDM of pregabalin may represent a useful therapeutic option in
critically ill patients, especially in those requiring continuous or
prolonged intermittent KRT. This approach could help to achieve the
therapeutic effect while minimizing the risk of side effects.