Just ask the patient


  • An editorial comment to: Cohen D, Loonen AJM ‘Are immediate and extended release drugs interchangeable?’ (1)

In this issue of the Acta Psychiatrica Scandinavica, Cohen and Loonen [1] pose the question ‘are immediate and extended release drugs interchangeable?’ Here, few would argue against the answer being a straight ‘no’. Nonetheless, financial constraints within Western health economics are now provoking health funders into drastic actions that include the restricting of the use of more expensive extended release preparations.

Extended release mechanisms serve two main purposes: to reduce the frequency of administration of a rapidly absorbed, short half-life drug and lessen the so-called ‘peak-to-trough’ fluctuations in plasma levels that arise from the frequent administration of such drugs. With extended release formulations, the rate of absorption and the effective plasma half-life become a function largely of the rate of release of drug from the tablet. This release is slowed and controlled by various mechanisms ranging from the simplistic (hard-compacting of tablets to delay tablet disintegration), through the ingenuous (incorporating drug into a poorly soluble wax matrix) to the sophisticated (using a laser to drill a minute whole in a water-permeable tablet coating to allow the drug to be slowly pushed out of the tablet by osmotic pressure). These and other pharmaceutical techniques are used to provide optional control over drug delivery, and there are numerous examples in psychiatry and neurology. Stimulants used in ADHD are most often presented in a controlled release form [2]. Opioids for pain or replacement therapy are formulated in dosage forms which prevent rapid release and deter abuse and diversion [3]. Anticonvulsants are better tolerated and more effective in epilepsy when given as extended release formulations [4], and there is very strong evidence that the longer an antipsychotic acts (either because of its half-life or because of controlled release) the better its protection against psychotic relapse [5, 6].

Any number of scientific articles can be cited to demonstrate beyond doubt the clear differences in pharmacokinetics between extended and immediate release preparations. Rather fewer reports (but still a larger number) can be set forward as evidence of the better tolerability of extended release drugs and of the improved convenience of less-frequent dosing (which we assume leads to better compliance).

For me, however, this is a question that can be answered with limited recourse to scientific references but merely on the basis of the experiences, related to me, of a handful of patients.

Some 15 years ago, in the process of getting to know a nursing colleague, she revealed that she had epilepsy which was well controlled by carbamazepine alone. Had she tried the recently introduced Tegretol Retard? I asked. Indeed she had and was delighted with it. Not only was she taking the drug less frequently, but, in addition, the peak plasma-level effects (nausea, diplopia and ataxia) had disappeared since starting the extended release formulation. Her life had, she said, been transformed by the change of formulation.

A second patient fell victim to a local policy of switching all patients from generic extended release venlafaxine to an immediate release version. The local health purchaser saved a few thousand pounds but this patient, and probably many others, was not happy. He had previously been well maintained on extended release venlafaxine and was functioning well. On switching formulations (after a cursory explanation from his doctor), he found himself feeling increasing unwell and experienced bouts of dizziness, nausea and bad temper. He soon realised that these symptoms only occurred in the evening. A little later he discovered that if he took his nightly venlafaxine dose a few hours earlier, the symptoms disappeared. The next day the symptoms recurred in the late afternoon. Again, within 1 h of taking venlafaxine they were gone. The patient eventually settled in to a 21-h dosing interval – this he found was the most effective way of preventing what he now realised were withdrawal effects. Hardly an ideal dosing regimen.

The third patient is illustrative of a number of similar examples. A young man was treated with extended release quetiapine following his first psychotic episode. His psychotic symptoms abated but he remained sluggish and apathetic, complaining of tiredness, dry mouth and constipation. Oddly, he also complained of early insomnia, taking 1–2 h to get to sleep at night. As an experiment, his nightly dose of quetiapine was changed to immediate release tablets. That night he fell asleep straight away, and by early afternoon the next day, he was reporting a lifting of his tiredness and an absence of dry mouth. Over the next few days, he continued this improvement and became more active and purposeful.

Each of these cases was compelling enough for them to lodge in my memory as an important lesson learned. Are immediate and extended release drugs interchangeable? Just ask the patient.