Guanfacine

Guanfacine

An updated understanding Guanfacine (GXR) in treatment of ADHD

Peter Vang, ADDspeaker.org

Introduction

Guanfacine is the latest drug available to patients with ADHD in the EU (2016) and have been approved and used in the US since 2009. It is still widely unrecognized for its true potential as part of the medicinal treatment of ADHD. It is not a psychostimulant, it contains no potential euphoria and therefor it cannot be abused. In its core it a drug designed to treat hypertension and have been on the market since the 1970’s for this purpose, but was redesigned into an eXtended Release formulation by Shire, Inc. and subsequently approved for treatment of ADHD. Guanfacine is sold under the brand name INTUNIV.

The mean efficacy of Guanfacine (0.62) compared to the other ADHD drugs on the market is that it is on par with Atomoxetine (0.63) (Strattera), less than Methylphenidate (0.72) (Ritalin), and significantly less than Amphetamines (0.99) (Adderall/Vyvanse).

The strength of Guanfacine is not in monotherapy but when it is combined with one of the other ADHD drugs, particularly with Amphetamines, as Guanfacine boosts the efficacy of other drugs, by supplementing their delivery into the prefrontal cortex, as well as suppressing sensory and emotional overstimulation in the peripheral nervous system, reducing frustration, aggression and stress.

Seen from a patient perspective, it is a valuable tool to improve quality of life by reducing ADHD impairments from all core symptoms (hyperactivity, impulsivity, inattention) as well as inhibitory control, emotional self-control, emotional self-regulation and sensory overstimulation. The sum total of this reduction in symptomalogy is increased social functioning, increased cognitive and affective functioning and increased somatic health.

This document is made with the purpose of giving you an updated overview of the latest scientific evidence as well as the latest feedback from patients familiar with the efficacy and benefits from using Guanfacine in their treatment regiment.

ADDspeaker.org is a non-profit, grassroots support organization for adults with ADHD (AdultADHD) which focus in on sharing scientific evidence and real-life experience of managing AdultADHD, for the benefit of both the scientific community and the patients. ADDspeaker.org do no have any affiliation with any religious, political, financial or any other interests and is run solely on the time and effort of the community and its members, who volunteer time, knowledge and compassion to better help each other coping with this mental disorder, ADHD.

Thank you, in advance, for your time and interest in our cause.

Peter Vang

Founder

ADDspeaker.org & AdultADHD.eu

History

Guanfacine have been found to be useful in the treatment of different neuropsychiatric disorders, including ADHD, with the first studies in ADHD dating back to 30 years ago (Hunt et al., 1985, Hunt et al. 1995), and have been used a treatment for high blood pressure in adults since the 1970’s under the brand name Tenex.

In 2009 Guanfacine was approved for treatment of ADHD in the US (FDA) and in 2016 it was approved in the EU (EMA), both under the brand name INTUNIV (Shire, Inc.).

Pharmacology

Guanfacine works by controlling the nerve impulses along certain nerve pathways. As a result, it relaxes the blood vessels so that blood passes through them more easily. This helps to lower blood pressure. (Ruggiero et al., 2014).

Guanfacine eXtended Release (GXR) is a medication that works at the lowest level in the brain, the brainstem level as well as on the locus coeruleous, thalamus and prefrontal Cortex. (Ruggiero et al., 2014).

GXR is an α2 adrenergic receptor agonists, and an older antihypertensive drugs, licensed for use in adults, that induce peripheral sympathoinhibition (inhibition of the peripherial sympathetic nervous system) via the stimulation of receptors located in the brainstem (Ruggiero et al., 2014).

GXR binds preferentially to postsynaptic α 2A-adrenoceptors in the prefrontal cortex (PFC). The GXR selectivity for α 2A receptors in PFC may more efficiently target ADHD symptoms while minimizing the risk of adverse effects. (Ruggiero et al., 2014).

The mechanism through which α 2 adrenoceptor agonists works in ADHD patients is unclear, but abnormal PFC functioning is posited to be a key contributor to the impairments observed in ADHD (Ruggiero et al., 2014).

Patient’s Perspective

GXR is associated with the Noradrenergic System (NE) known for regulating emotions, increases can lead to mania, decreased can lead to depression. NE is also known for reducing hyperactivity/impulsivity in patients suffering from ADHD. Another interaction has been seen in regards to stimulus/response processing, where GXR can help reduce sensory overstimulation, hence reducing internal feelings of anxiety and stress, which in turn leads to reductions in frustration and aggression levels.

GXR is approved for treatment of symptoms of OCD, TICS Disorder and Tourette’s Syndrome, and is widely known among patients suffering from ADHD with comorbid ASD, to help better manage the emotional dysregulation component of ADHD and ASD, and is especially efficient when combined with psychostimulants, bot improving Executive Functioning and Emotional Self-control, Emotional Self-regulation and Inhibitory Control (reduces distractibility from task-irrelevant stimuli), leading to overall improvement in quality of life by limiting severity of (social) impairments related to these disorders. This is yet not established as scientific fact, but clinical practice as well as studies of various of these subcomponents have shown promising validation of this perception from the patients and clinicians.

Side effects

Most patients benefits from Guanfacine treatment; somnolence, headache, and fatigue are the most common adverse events, which generally resolved either spontaneously or after decreasing the dose of the medication (Ruggiero et al., 2014).

Only a small risk of severe side effects are reported in Guanfacine treated patients, and only three serious adverse events judged to be drug related were reported in one study (Newcorn et al., 2013).

Small decreases from baseline in heart rate and blood pressure were noted, but only a few subjects experienced clinically significant ECG abnormalities. (Ruggiero et al., 2014)

The side effects are mainly related to somnolence (30.1%), headache (19.4%), fatigue (11.5%), and upper abdominal pain (8.6%) giving a favorable risk-benefit profile for GXR, making it generally well tolerated, and that most side effects were mild or moderate, with only 7.1% of them classified as severe (Ruggiero et al., 2014).

In conclusion, on the basis of seven randomized, placebo controlled trials, Guanfacine resulted safe and effective in the treatment of children and adolescents with ADHD (Ruggiero et al., 2014).

Patient’s Perspective

Many who begin treatment with GXR may experience a decrease in activity, mentally and physically, which in some cases can lead to a depressed emotional state, a feeling of emptiness or loss of purpose. This is due to ‘withdrawal symptoms’ of having lived a life in high gear, constantly stressed to the max, under the influence of high levels of Adrenaline (Norepinephrine) in the body. Once GXR takes control over the Noradrenergic System and down regulates its production, the patient may experience as withdrawal like feeling, due to the reduction of Norepinephrine in the brain. This is normally self-adjusted within 2-3 weeks and is not a continuous side effect, once the body have readjusted to the new normal state.

Efficacy

With respect to other ADHD medications, based on estimates after pooling results of placebo controlled trials, GXR seems to be similar to Atomoxetine (ATX) (Cheng et al., 2007) but less effective than Methylphenidate (MPH) or Amphetamines (AMP) in reducing ADHD symptoms (Faraone and Buitelaar, 2010).

Scahill et al., in a double blind, randomized, placebo controlled trial, noted that tic severity decreased by 31% in the GXR group, compared to 0% in the placebo group after 8 weeks of treatment (Ruggiero et al., 2014).

In regards to the potential efficacy of GXR in addition to psychostimulant (MPH or AMP) therapy, Wilens et al. evaluated the association GXR + psychostimulants versus psychostimulants alone in 461 children and adolescents diagnosed with ADHD who had had a suboptimal response to psychostimulants alone. (Ruggiero et al., 2014).

The addition of GXR to psychostimulants achieved a significantly greater response in ADHD symptoms and generated no safety warning signs. (Ruggiero et al., 2014).

The combination of GXR and psychostimulants for the management of ADHD is common in clinical practice. (Ruggiero et al., 2014). This combination has been suggested to have an effect on the underlying neurobiology of ADHD by different, but potentially synergistic, mechanisms (Sallee, 2010).

Across multiple studies, the safety and tolerability profile of Guanfacine administered adjunctively to psychostimulants has been consistent with the known profiles of each medication. Together, these data support the use of GXR as an adjunct to psychostimulants for the treatment of ADHD (as approved in the USA), particularly among those children and adolescents not responding optimally to psychostimulant monotherapy. Additional studies may help identify other patients likely to benefit from such therapy (Ruggiero et al., 2014).

Patient’s Perspective

After 2-3 weeks of stabilizing the effect of GXR, many patients experience that their hyperarousal is reduced causing a more calm and less emotional volatile habitual state. One become less sensitive to sounds, smells, lights and emotional fluctuations, and cognitive functioning seems to be improved somewhat better when combining GXR with psychostimulants. Combining GXR with psychostimulants do not seem to cause any adverse interactions, on the contrary most patients will experience a need for decrease in dosages of the psychostimulants, since GXR boosts their effect in the PFC and less in then required for similar or improved functioning. Patients that have been on combined treatment with GXR + psychostimulants for more than 24 months generally agree that their overall quality of life, especially in social interactions with others, have improved significantly due to decreased sensibility to sensory and emotional overstimulation, as well as a better cognitive functioning on regulating emotions and inhibitory control. No serious adverse side effects are known to the author at the time of writing.

References

Simona Ruggiero, Antonio Clavenna, Laura Reale, Annalisa Capuano, Francesco Rossi, Maurizio Bonati,

Guanfacine for attention deficit and hyperactivity disorder in pediatrics: A systematic review and meta-analysis,

European Neuropsychopharmacology, Volume 24, Issue 10, 2014, Pages 1578-1590, ISSN 0924-977X,

https://doi.org/10.1016/j.euroneuro.2014.08.001

Sallee F, Connor DF, Newcorn JH.

A review of the rationale and clinical utilization of α2-adrenoceptor agonists for the treatment of attention-deficit/hyperactivity and related disorders.

J Child Adolesc Psychopharmacol. 2013 Jun;23(5):308-19.

https://doi.org/10.1089/cap.2013.0028

Faraone SV, Buitelaar J.

Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis.

Eur Child Adolesc Psychiatry. 2010 Apr;19(4):353-64.

https://doi.org/10.1007/s00787-009-0054-3

Sallee FR.

The role of alpha2-adrenergic agonists in attention-deficit/hyperactivity disorder.

Postgrad Med. 2010 Sep;122(5):78-87.

https://doi.org/10.3810/pgm.2010.09.2204