Guanfacine was first described by 1974[13] and was approved for medical use in the United States in 1986.[9] It is available as a
generic medication.[9] In 2021, it was the 231st most commonly prescribed medication in the United States, with more than 1million prescriptions.[14][15]
Medical uses
Guanfacine is FDA-approved as monotherapy or augmentation with stimulants to treat
attention deficit hyperactivity disorder (ADHD).[3][16][17] Unlike stimulant medications, guanfacine is regarded as having no
abuse potential, and may even be used to reduce abuse of drugs including
nicotine and
cocaine.[18] It is also FDA approved to treat
high blood pressure.[6] Guanfacine can offer a synergistic enhancement of stimulants such as
amphetamines and
methylphenidate for treating ADHD, and in many cases can also help control the
side effect profile of stimulant medications.[9] For ADHD, it is claimed that guanfacine helps individuals better control behavior, inhibit inappropriate distractions and impulses, and inhibit inappropriate aggressive impulses.[19]Systematic reviews and
meta-analyses have found guanfacine to be effective in the treatment of ADHD in both children and adults, with a moderate
effect size found in adults (
Hedges' g = -0.66).[20][21][22] A systematic review and meta-analysis also found that guanfacine reduced
oppositional behavior in children and adolescents with ADHD who also had or did not also have
oppositional defiant disorder, with a small-to-moderate effect size.[23] In any case, guanfacine and other α2-adrenergic receptor agonists are considered to be less effective than stimulants in the treatment of ADHD.[23][24][22]
Guanfacine is also used off-label to treat tic disorders, anxiety disorders such as generalized anxiety disorder, and PTSD.[10] Guanfacine and other
α2A-adrenergic receptor agonists have
anxiolytic-like action,[25] thereby reducing the emotional responses of the
amygdala, and strengthening
prefrontal cortical regulation of emotion, action, and thought.[26] These actions arise from both inhibition of
stress-induced
catecholamine release, and from prominent,
post-synaptic actions in the prefrontal cortex.[26] Due to its prolonged
elimination half-life, it also has been seen to improve sleep interrupted by
nightmares in PTSD patients.[27] All of these actions likely contribute to the relief of the
hyperarousal, re-experiencing of
memory, and
impulsivity associated with PTSD.[28] Guanfacine appears to be especially helpful in treating children who have been
traumatized or
abused.[26]
Guanfacine has been reported to cause high rates of
somnolence in children with ADHD, for instance 73% with guanfacine versus 6% with placebo in one trial.[31][32]
Guanfacine availability is significantly affected by the
CYP3A4 and
CYP3A5enzymes. Medications that
inhibit or
induce those enzymes change the amount of guanfacine in circulation and thus its efficacy and rate of adverse effects. Because of its impact on the
heart, it should be used with caution with other
cardioactive drugs. A similar concern is appropriate when it is used with
sedating medications.[30]
In ADHD, guanfacine is thought to work by strengthening the regulation of attention and behavior by the
prefrontal cortex.[43][19] These enhancing effects on prefrontal cortical functions are believed to be due to drug stimulation of post-synaptic α2A-adrenoceptors on
dendritic spines, and are not dependent on activation of pre-synaptic α2A-adrenoceptors.[19]Cyclic adenosine monophosphate (cAMP)-mediated opening of
HCN and
KCNQ channels is inhibited, which enhances prefrontal cortical synaptic connectivity and
neuronal firing.[43][44] In monkeys, guanfacine improves
working memory,
attention regulation, and
behavioral inhibition, and these actions are independent of its sedative effects.[19] The use of guanfacine for treating prefrontal disorders was developed by the Arnsten Lab at
Yale University.[43][19]
Guanfacine is much more selective for α2A-adrenergic receptors than
clonidine, which binds to and activates not only the α2A-adrenergic receptor but also
α2B- and
α2C-adrenergic receptors and the
imidazoline receptor.[19] It is weaker than clonidine in producing
hypotension and
sedation, has weaker
pre-synaptic actions on the α2A-adrenergic receptor than clonidine (10-fold less effective in decreasing
locus coeruleus activity and
norepinephrinerelease), and may have greater efficacy in activating post-synaptic α2A-adrenergic receptors (as suggested by guanfacine being more potent than clonidine in enhancing prefrontal cortex-related
working memory in aged monkeys).[19]
Activation of the 5-HT2B receptor is a well-known
antitarget and is associated with
cardiac valvulopathy.[37][38] However, not all 5-HT2B receptor agonists, for instance
ropinirole, have this effect.[37][38] Guanfacine has not been associated with cardiac valvulopathy despite a long history of use, perhaps due to modest
potency as a 5-HT2B receptor agonist.[40][45][46] In in vitro studies, guanfacine showed 100-fold lower
affinity for the 5-HT2B receptor than for the α2A-adrenergic receptor, 30-fold lower affinity for the 5-HT2B receptor than
serotonin, and 1,000-fold lower potency in activating the 5-HT2B receptor compared to serotonin.[45] It was concluded that at clinically relevant concentrations, guanfacine would not be expected to show significant binding to or activation of 5-HT2B receptors, and that it is unlikely that guanfacine is a cardiac valvulopathogen in humans.[45] In any case, different studies have reported different potencies of guanfacine as a 5-HT2B receptor agonist,[39][40][45][46] and as of 2018, no clinical data on the risk of cardiac valvulopathy with guanfacine were available.[47] As such, while the likelihood is thought to be low, guanfacine might still have a risk of cardiac valvulopathy.[45]
Brand names include Tenex, Afken, Estulic, and Intuniv (an
extended release formulation).
Research
Guanfacine has been studied as a treatment for
post-traumatic stress disorder (PTSD). Evidence of efficacy in adults is limited, but one study found positive results in children with comorbid ADHD.[58] It may be also useful in adult PTSD patients who do not respond to
selective serotonin reuptake inhibitors (SSRIs).[59]
Guanfacine does not appear to be effective for improving
sleep in children with ADHD and behavioral
insomnia.[31] Instead, guanfacine worsened certain sleep parameters, for instance
total sleep time, in one clinical trial.[31][32]
Guanfacine has been investigated for treatment of
withdrawal for
opioids,
ethanol, and
nicotine.[61] Guanfacine has been shown to help reduce stress-induced craving of nicotine in smokers trying to quit, which may involve strengthening of prefrontal cortex-mediated self-control.[62]
^Radonjić NV, Bellato A, Khoury NM, Cortese S, Faraone SV (May 2023). "Nonstimulant Medications for Attention-Deficit/Hyperactivity Disorder (ADHD) in Adults: Systematic Review and Meta-analysis". CNS Drugs. 37 (5): 381–397.
doi:
10.1007/s40263-023-01005-8.
PMID37166701.
S2CID258616507.
^Yu S, Shen S, Tao M (March 2023). "Guanfacine for the Treatment of Attention-Deficit Hyperactivity Disorder: An Updated Systematic Review and Meta-Analysis". J Child Adolesc Psychopharmacol. 33 (2): 40–50.
doi:
10.1089/cap.2022.0038.
PMID36944092.
S2CID257664282.
^Padilha SC, Virtuoso S, Tonin FS, Borba HH, Pontarolo R (October 2018). "Efficacy and safety of drugs for attention deficit hyperactivity disorder in children and adolescents: a network meta-analysis". Eur Child Adolesc Psychiatry. 27 (10): 1335–1345.
doi:
10.1007/s00787-018-1125-0.
PMID29460165.
S2CID3402756.
^Morrow BA, George TP, Roth RH (November 2004). "Noradrenergic alpha-2 agonists have anxiolytic-like actions on stress-related behavior and mesoprefrontal dopamine biochemistry". Brain Research. 1027 (1–2): 173–178.
doi:
10.1016/j.brainres.2004.08.057.
PMID15494168.
S2CID7066842.
^
abcRugino TA (January 2018). "Effect on Primary Sleep Disorders When Children With ADHD Are Administered Guanfacine Extended Release". J Atten Disord. 22 (1): 14–24.
doi:
10.1177/1087054714554932.
PMID25376194.
S2CID22675882.
^
abRoth BL, Driscol J (12 January 2011).
"PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from
the original on 8 November 2013. Retrieved 15 November 2013.
^
abcJasper JR, Lesnick JD, Chang LK, Yamanishi SS, Chang TK, Hsu SA, et al. (April 1998). "Ligand efficacy and potency at recombinant alpha2 adrenergic receptors: agonist-mediated [35S]GTPgammaS binding". Biochemical Pharmacology. 55 (7): 1035–1043.
doi:
10.1016/s0006-2952(97)00631-x.
PMID9605427.
^
abcUhlén S, Porter AC, Neubig RR (December 1994). "The novel alpha-2 adrenergic radioligand [3H]-MK912 is alpha-2C selective among human alpha-2A, alpha-2B and alpha-2C adrenoceptors". The Journal of Pharmacology and Experimental Therapeutics. 271 (3): 1558–1565.
PMID7996470.
^
abcBender AM, Parr LC, Livingston WB, Lindsley CW, Merryman WD (August 2023).
"2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery". J Med Chem. 66 (16): 11027–11039.
doi:
10.1021/acs.jmedchem.3c01178.
PMC11073569.
PMID37584406.
S2CID260924858. These results strongly indicate substantial risks for treatments involving 5-HT2B agonists, and it has been recommended that all serotonergic drugs be screened for this functional profile.43,59 [...] Additionally, there are cases of marketed drugs that were only later determined to have 5-HT2B activity. Of particular note is guanfacine, an FDA-approved medication for the treatment of attention deficit hyperactivity disorder (ADHD) that possesses potent 5-HT2B agonist activity in functional readouts to a similar degree as known valvulopathogens.66
^US3632645A, Bream, John Bernard & Picard, Claude W., "Substituted phenylacetyl derivatives of guanidine o-alkylisoureas s-alkylisothioureas and p-nitrobenzylisothiourea", issued 1972-01-04
^Scholtysik G (1974). "Proceedings: Inhibition of effects of accelerator nerve stimulation in cats and rabbits by BS 100-141 and guanabenz". Naunyn-Schmiedeberg's Arch Pharmacol. 282 (Suppl): suppl 282:R86.
PMID4276642.
^Bream JB, Lauener H, Picard CW, Scholtysik G, White TG (October 1975). "Substituted phenylacetylguanidines: a new class of antihypertensive agents". Arzneimittelforschung. 25 (10): 1477–82.
PMID1243024.
^Saameli K, Scholtysik G, Waite R (1975). "Pharmacology of BS 100-141, a centrally acting antihypertensive drug". Clinical and Experimental Pharmacology & Physiology. 1975 (Suppl 2): 207–212.
PMID241524.
^Dubach UC, Huwyler R, Radielovic P, Singeisen M (1977). "A new centrally action antihypertensive agent guanfacine (BS 100-141)". Arzneimittelforschung. 27 (3): 674–6.
PMID326262.