Thursday, March 27, 2008

Guanfacine and lessons about off-label drug use

Guanfacine, marketed as Tenex, was once used to treat hypertension. These days it's also used, off-label, for the management of behavioral disorders in children.

Very off-label. You won't find this mentioned in most drug references. You also won't find mention that guanfacine alters the course of neuronal development in mice, or that Guanfacine ... Improve Paired Associates Learning, but not Delayed Matching to Sample, in Humans:

Neuropsychopharmacology (1999) 20 119-130.10.1038/sj.npp.1395238...

... The present study compares the effects of two alpha2-agonists, clonidine (0.5, 2, and 5 mug/kg, PO) and guanfacine (7 and 29 mug/kg, PO) in young healthy volunteers on their performance in visual paired associates learning (PAL) and delayed matching to sample (DMTS) visual short-term recognition memory tests.

In the PAL test, clonidine 2 and guanfacine 29 mug/kg improved the subjects' performance.

In the DMTS test, clonidine at 5 mug/kg delay-dependently impaired performance accuracy, and at 2 and 5 mug/kg it also slowed responses. Guanfacine had no effect on DMTS test performance. Clonidine 5 and guanfacine 29 mug/kg equally increased subjective feelings of sedation and reduced blood pressure.

The results suggest that both clonidine and guanfacine facilitated PAL learning by improving "frontal strategies," but only clonidine disrupted "mnemonic processing" decreasing DMTS accuracy. The greater selectivity of guanfacine for alpha2A-adrenoceptor subtype may explain the different profile of action of the drugs.

This isn't a new study by the way, it's nine years old. It turns out there's an extensive literature on Guanfacine and cognition, much of it based on animal studies done in the 199os.

More recently, guanfacine is being studied for the treatment of schizotypal personality disorder because "there is evidence that guanfacine enhances cognition and diminishes impulsivity". In fact, today there are 19 Clinical Trials that reference guanfacine, one of which was completed and resulted in a publication in January 2008 -- "Guanfacine extended release met the primary and secondary efficacy end points. It was well tolerated and effective compared with placebo." (, by the way, is impressive.)

Phew. I thought I was relatively clued into this world, but I'd have bet real money there wouldn't be any studies of Guanfacine in children -- it's off-patent. I'd have been very wrong.

So what lessons can I draw about off-label med use from this experience:

  1. We didn't learn much from the responsible clinicians. I suspect that's typical.
  2. You won't learn about off-label medication use by reading medication references -- they tend to avoid these topics.
  3. is very impressive. Enter your off-label drug there and learn.
  4. and PubMed cover the publication field, though I've found odd bugs in the former (links pointing to the wrong article).
  5. Animal studies are particularly interesting.

Does this mean we're more comfortable with use of the drug? Yes, somewhat -- particularly because of the Jan 2008 publication in Pediatrics. I really hadn't expected to see real trials in children. On the other hand, guanfacine seems to be a relatively powerful medication, and we really don't know what the effects of longterm use are on the developing brain. It could be helpful in the short term and harmful in the long term (see: estrogen).

I've created an RSS feed in PubMed for guanfacine, so I'll be notified of new publications.

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