Pregabalin for Treatment of Generalized Anxiety Disorder: Update

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Mechanism of Action: Pregabalin has a similar molecular structure to the inhibitory neurotransmitter GABA but its mechanism of action does not appear to be mediated through effects on GABA. Instead, its anxiolytic effects may arise through high-affinity binding to the alpha-2-delta sub-unit of the P/Q type voltage-gated calcium channel in “over-excited” presynaptic neurons, thereby reducing the release of excitatory neurotransmitters such as glutamate.



Onset of effect:
- Pregabalin has been found superior to placebo in reducing anxiety in patients prior to undergoing dental or orthopedic procedures, with an onset of effect within a few hours.
- A post hoc analysis of randomized controlled trial data with pregabalin indicates that an onset of overall clinical effect within the first 2 weeks is associated with a 5.3-fold odds ratio of responding to treatment, whereas only one quarter of patients who show no onset of clinical effect by the second week will have responded to treatment at study endpoint.

Dose-Response Relationships:
- Evidence is mixed for pregabalin.
- Meta-analysis of the findings from randomized controlled trials found no evidence for a dose-response curve for daily dosages between 200–600 mg, although a 150 mg daily dosage was associated with a slower onset of efficacy.

Effects of pregabalin in reducing depressive symptoms:
- Pregabalin treatment was effective in reducing depressive symptoms, across the dosing range of 150–600 mg.

Effects of pregabalin in reducing somatic symptoms:
- Pregabalin is licensed for the treatment of neuropathic pain and fibromyalgia. It is effective in reducing the severity of cardiovascular, respiratory, muscular, and gastrointestinal symptoms in GAD.

Effects of pregabalin in reducing sleep disturbance:
- Pregabalin was associated with a significant reduction in sleep disturbance, across the dosing range of 300–600 mg/day
- Pregabalin was found superior to both placebo and venlafaxine XL in reducing sleep disturbance within the context of a double-blind flexible-dose study

Abuse and Dependence:
- “Euphoria” was an adverse event in clinical trials among 1%–10% of patients, depending on dose, compared to 0.5% in patients receiving placebo, which emphasizes the need for careful and continuing evaluation of any potential for abuse.
- Discontinuation symptoms reported after abruptly stopping pregabalin: more prominent after stopping higher daily doses, but there were significantly fewer withdrawal symptoms.

Conclusions:
Pregabalin is efficacious in acute treatment and in the prevention of relapse, has comparable efficacy to alternative medications including certain benzodiazepines and the SNRI venlafaxine, and may have tolerability advantages over some comparator treatments.