Metabolic Considerations in a Case of Pregabalin-induced Edema

The GABA analogue pregabalin (PGB) is a newer antiepileptic drug (AED) and has been demonstrated to be safe and effective as adjunctive therapy for partial seizures, with or without secondary generalization [5] [8] [11]. In addition to its further use in the treatment of neuropathic pain syndromes [9], PGB was found to effectively reduce the symptoms of general anxiety disorder (GAD) and – besides this licenced indication – other anxiety states [3] [17]. For the treatment of GAD a dose-response relationship of PGB was obtained [4]. The most commonly reported adverse events in PGB clinical trials were transient dizziness and somnolence, followed by dry mouth, nausea and ataxia and less frequently among others also edema [17]. However, a search in MEDLINE using the terms “pregabalin” and “edema” revealed only two indicatory reports about splenial edema and lower extremity pain, respectively [14] [16]. Furthermore, to our knowledge the underlying mechanisms of the metabolic effects of PGB, such as those leading to edema, remain obscure. Based on a subject with a depressive-anxious syndrome who displayed peripheral edema during PGB therapy we have tried to elucidate its peripheral pharmacological effects.

A 45-year-old woman with a known post-traumatic stress disorder, a borderline personality disorder and an alcohol dependency experienced a depressive-anxious syndrome. After admission to hospital she suffered from alcohol withdrawal that first required medication with clomethiazol. Due to her depressive-anxious symptoms and an agoraphobia with panic disorder in the history she was then treated with PGB (150 mg per day). Following an asymptomatic Candida detection from her urine an amphotericin B treatment was administered. About 24 h later the patient suffered from progressive lower leg and ankle edema on both sides. Despite discontinuation of antimycotic treatment the edema persisted during the following days without abating. Hence, the edema might be attributed to PGB. Consequently we changed the psychopharmacological agent and applied duloxetine. After discontinuation of PGB therapy and re-application of amphotericin B the edema decreased. After another 10d we discharged the patient, who did not show any side effects then, from the clinic for further outpatient treatment.

Individuals with symptoms of depression and anxiety have an increased risk of developing cardiovascular disease and type 2 diabetes mellitus [1] [10]. Furthermore it is known that several psychopharmacological substances, such as some antidepressants, antipsychotics and mood stabilizers, i.e., especially the AEDs carbamazepine, gabapentin and valproate, may increase the risk of metabolic complications frequently associated with dose-related weight gain [18]. However, neither in the CNS nor peripherally are specific effects, which might explain metabolic events of PGB, clear.

Due to the GABA system as one of the most widely accepted mediators known to play a central role in the pathophysiology of anxiety disorders, PGB induces anxiolytic effects by increasing brain GABA levels [15]. Simular to valproate and gabapentin, PGB increases the activity of glutamic acid decarboxylase which is the most important enzyme in the synthesis of GABA. Furthermore, it has been suggested that PGB may reduce the release of excitatory neurotransmitters, including glutamate, noradrenaline and substance P, through binding to the alpha(2)-delta protein and subsequent allosteric modulation of P/Q-type voltage-gated calcium channels [6] [7]. In addition, a recent study on differentiated hippocampal neuron-derived H19-7 cells concluded that the opening effect on adenosine triphosphate (ATP)-sensitive K⁺ (K_ATP) channels in the presence of PGB could be one of the underlying mechanisms responsible for the reduction of neuronal excitability [12].

K_ATP channels can be found in a wide variety of cell types, including cardiac cells, pancreatic ? cells, skeletal and smooth muscle cells, and neurons [13]. These channels are well known to provide a link between the electrical activity of cell membranes and cellular metabolism [2]. In addition to their regulation by intracellular ATP, various pharmacological agents (e.g., diazoxide and glibenclamide) can modulate the activity of these channels.

From a physiological point of view the development of edema might be explained by the following process at the cellular level. Presumably, PGB has an opening effect on plasmalemmal K_ATP channels in smooth muscle cells. This leads to hyperpolarization of the cell membrane potential which causes the voltage-dependent calcium channels to close. Consequently a decrease of the intracellular Ca²⁺ concentration reduces smooth muscle contractility and results in vasodilatation and edema. Furthermore, the opening effect on ATP-sensitive potassium channels in smooth muscles could directly lead to vasodilatation of vessels, which also could subsequently cause edema. However, this suggested mechanism is speculation; it still needs to be substantiated by further experimental or clinical data.

This case indicates that – like other psychopharmacological agents, too – PGB may induce peripheral edema. The above described process might explain that phenomenon. The fact of concurrent medication with amphotericin B and different psychiatric and somatic comorbidity might also account for this finding. In particular, the Candida infection might be a possible cause of the edema as well. On the other hand, there was no evidence of another metabolic or cardiac disorder. Edema as an adverse event in PGB treatment is not uncommon. However, in clinical practice it is possibly transient and self-limited, and therefore not frequently found unless the patient spontaneously complains, or the physician intentionally seeks for it. Then diuretic treatment seems to be unnecessary. In conclusion, we suggest to take special care when prescribing PGB to patients who are otherwise predisposed to develop edema. Further research in this area will be of interest.

References

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