Pharmacological principles for safe benzodiazepine and Z-drug dose reduction

Abstract

Many guidelines recommend deprescribing benzodiazepines and z-drugs in most long-term users. Due to physical dependence in those using medication as prescribed (distinct from addiction), discontinuation can be difficult and is often unsuccessful, as withdrawal symptoms can be severe and long-lasting, especially after long-term use. There is a lack of clarity on how to taper patients in a tolerable manner that minimizes discomfort. Current guidelines vary with some suggesting linear reductions (e.g. 1 mg every 1–4 weeks) and some proportionate reductions (e.g. 5%–10% of the most recent dose per month, with smaller reductions as the dose decreases). The shape of the relationship between dose of benzodiazepine and activity at gamma-aminobutyric acid-A (GABA-A) receptors is hyperbolic: steeply inclining at low doses, flattening at higher doses. Consequently, linear dose reductions produce increasingly large changes in receptor occupancy, predicting escalating withdrawal effects, while hyperbolic or proportionate dose reductions produce linear reductions in pharmacological effect. Slower tapering (over months and years) may be more successful than tapering over days or weeks. In practice, rate of tapering should be adjusted according to severity of withdrawal effects. Final doses for some people will need to be very small (equivalent to as little as 0.2 mg of diazepam, or less) so that the last ‘step down’ to zero is not larger than prior tolerated reductions in terms of pharmacological effects. Liquids or compounded formulations of medication can be helpful at low doses to make small reductions. Guidelines should recommend hyperbolic tapering while awaiting randomized trials comparing linear with hyperbolic tapering.