What is the efficacy of clonidine and guanfacine in treating anxiety?

What is the efficacy of clonidine and guanfacine in treating anxiety?

Comment by InpharmD Researcher

There are limited data suggesting that clonidine may not carry a significant benefit for managing general anxiety disorders or preoperative anxiety. A pilot study of guanfacine use for managing pediatric anxiety disorders reported high rates of treatment-emergent adverse events without clear evidence of anxiety reduction in comparison to placebo. More quality data is needed to establish the efficacy of clonidine and guanfacine for managing anxiety.

Background

Clonidine and guanfacine are alpha-2 adrenergic receptor agonists approved by the Food and Drug Administration (FDA) for the treatment of hypertension and attention-deficit hyperactivity disorder (ADHD). According to a 2020 review article on anxiety disorders, clonidine had been investigated in older clinical trials for general anxiety disorders with unimpressive results. A pilot study found guanfacine extended-release (ER) to be safe and well-tolerated for pediatric anxiety disorder, but the effectiveness is uncertain (see Table 3). The authors failed to identify any other studies for clonidine and guanfacine. Due to the lack of proven efficacy along with the potential for adverse events (e.g., sedation and hypotension), their use for general anxiety cannot be recommended. [1]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the efficacy of clonidine and guanfacine in treating anxiety?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

Preoperative anxiety in preschool children: A randomized clinical trial comparing midazolam, clonidine, and dexmedetomidine
Design	Double-blinded, randomized, clinical trial N= 90
Objective	To compare the effect of three different premedication regimens on preoperative anxiety and sedation in preschool children scheduled for elective ear-, nose-and-throat (ENT) surgery
Study Groups	Oral midazolam (n= 27) Oral clonidine (n= 27) Intranasal dexmedetomidine (n= 30)
Inclusion Criteria	Age 2-6 years, American Society of Anesthesiologists Physical Status (ASA-PS) I−II, ≤ 30 kg, scheduled for elective ENT surgery
Exclusion Criteria	ASA-PS > II; heart, lung, neurologic, or central nervous system disorders; use of psychotropic medications; history of recent surgery
Methods	Patients were randomized to receive either oral midazolam 0.5 mg/kg 40 min pre-operatively, oral clonidine 4 µg/kg 60 min pre-operatively, or intranasal dexmedetomidine 2 µg/kg 40 min pre-operatively. Timing was determined based on the bioavailability of the agents (oral midazolam and intranasal dexmedetomidine were believed to have a faster onset compared to oral clonidine). Blinding of the patient, providers, and researchers was achieved by administering dummy oral and intranasal saline products. Due to limited resources and early findings, the study was terminated early
Duration	Up to 60 minutes at the time of anesthesia preparation and induction
Outcome Measures	Primary: anxiety at anesthesia preparation measured with modified Yale Preoperative Anxiety Scale (mYPAS; 27-item category scale from 0-100 points with higher scores signifying anxiety) Secondary: distress during peripheral venous catheter (PVC) insertion measured with the five-point behavioral distress scale (BDS), compliance at induction measured with the induction compliance checklist (ICC), level of sedation measured with the Ramsay sedation scale (RSS), need for rescue inhalation
Baseline Characteristics		Oral midazolam (n= 27)	Oral clonidine (n= 27)	Intranasal dexmedetomidine (n= 30)
	Age, years	4.2	4.4	4.2
	Female, n	10	11	13
	American Society of Anesthesiologists (ASA) status, n I II	21 6	21 6	25 5
Results	Endpoint	Oral midazolam (n= 27)	Oral clonidine (n= 27)	Intranasal dexmedetomidine (n= 30)	p-value
	mYPAS score Baseline (interquartile range [IQR]; min-max) Anesthesia preparation (IQR; min-max) Difference between baseline and anesthesia preparation p-value between baseline and anesthesia preparation	23 (0; 23-37) 23 (0; 23-87) 0 (0; -13-77) 0.733	23 (0; 23-45) 23 (15; 23-87) 0 (13; -8-67) 0.016	23 (0; 23-43) 23 (11; 23-82) 0 (6; -13-63) 0.007	0.818 0.061 0.036 --
	BDS score during PVC insertion	1.4 ± 0.6	1.3 ± 0.7	1.2 ± 1.0	0.17
	ICC score at induction	0.4 ± 1.3	1.6 ± 1.7	0.6 ± 1.6	0.87
	RSS score 60 minutes after the first study intervention	2.26 ± 0.45	3.56 ± 1.12	4.03 ± 0.72	< 0.001
	Patients that needed rescue inhalation	2	3	4	Not significant
Adverse Events	N/A
Study Author Conclusions	In preschool children, midazolam resulted in a more effective anxiolysis and less sedation compared to clonidine and dexmedetomidine.
InpharmD Researcher Critique	The study was terminated early due to limited resources and the findings that supported oral midazolam over clonidine and dexmedetomidine. The rejection rate of oral clonidine was approximately 10%. Safety was not assessed within the study.

References:

Bromfalk Å, Myrberg T, Walldén J, Engström Å, Hultin M. Preoperative anxiety in preschool children: A randomized clinical trial comparing midazolam, clonidine, and dexmedetomidine. Paediatr Anaesth. 2021;31(11):1225-1233. doi:10.1111/pan.14279

Preoperative Anxiety Among Cardiac Surgery Patients and Its Impact on Major Adverse Cardiac Events and Mortality– A Randomized, Parallel-Group Study
Design	Randomized, single-blinded study N= 75
Objective	To assess the baseline anxiety levels in the Indian cardiac surgical population, the impact of clonidine and gabapentin in reducing preoperative anxiety, and the role of preoperative anxiety in causing major cardiac adverse events (MACE) and 30-day mortality
Study Groups	Gabapentin (n= 37) Clonidine (n= 38)
Inclusion Criteria	Age 18 to 80 years, scheduled for elective coronary artery bypass graft (CABG) for triple vessel disease
Exclusion Criteria	Pregnancy, lactation, and menstruating females; drug/alcohol abuse; chronic pain; psychiatric distress; peripheral vascular disease; severe renal or hepatic disease; on medications that can affect the nervous system (e.g., hypnotics, sedatives, benzodiazepines, etc.)
Methods	Patients were randomized to receive either gabapentin 800 mg (two 400 mg tablets) PO or clonidine 300 mcg (three 100 mcg tablets) 90-120 minutes prior to induction. Reported results within this table focused on anxiety outcomes.
Duration	January 2020 to January 2021 90-120 minutes prior to induction
Outcome Measures	Primary: reduction in anxiety scale (STAI)
Baseline Characteristics		Gabapentin (n= 37)	Clonidine (n= 38)
	Age, years	38.7	35.9
	Female, n	15	22
	Weight, kg	54.65	55.03
	Left ventricular ejection fraction	42.12	41.11
	Number of grafts	3.13	3.11
Results	Endpoint	Gabapentin (n= 37)	Clonidine (n= 38)	p-Value
	STAI score Mild anxiety (< 30) Moderate anxiety (30-45) Severe anxiety (> 45)	2 (2.7%) 5 (13.51%) 30 (81.08%)	1 (2.63%) 8 (21.05%) 29 (76.21%)	0.54 0.389 0.61
	STAI scores before treatment (baseline) STAI scores in the operation room	69.2 ± 16.5 53.1 ± 15.9	68.4 ± 14.7 32.4 ± 11.8	0.4876 0.07504
Adverse Events	There was no difference in the occurrence of MACE between groups. One event of acute myocardial infarction occurred in the gabapentin group, and one event of congestive heart failure occurred in the clonidine group. The patient who experienced acute myocardial infarction died of severe left ventricular dysfunction after a week of surgery.
Study Author Conclusions	The preoperative anxiety levels were high among cardiac surgery patients. Both clonidine and gabapentin were equally effective in reducing the levels of preoperative anxiety. Preoperative STAI scores in the range of 32-53 is not associated with MACE and 30-day mortality among cardiac surgery patients.
InpharmD Researcher Critique	The study took place in India which may not reflect the U.S. healthcare landscape and consisted of a small patient population.

References:

Mudgalkar N, Kandi V, Baviskar A, Kasturi RR, Bandurapalli B. Preoperative anxiety among cardiac surgery patients and its impact on major adverse cardiac events and mortality- A randomized, parallel-group study. Ann Card Anaesth. 2022;25(3):293-296. doi:10.4103/aca.aca_80_21

Extended Release Guanfacine in Pediatric Anxiety Disorders: A Pilot, Randomized, Placebo-Controlled Trial
Design	Double-blind, placebo-controlled, phase 2 study N= 83
Objective	To evaluate the safety, tolerability, and potential anxiolytic efficacy of the α2 agonist guanfacine extended-release (GXR) in children and adolescents with generalized anxiety disorder (GAD), separation anxiety disorder (SAD), or social phobia/social anxiety disorder
Study Groups	GXR (n= 62) Placebo (n= 21)
Inclusion Criteria	Age 6-17 years; primary diagnosis of GAD, SAD, or social anxiety disorder confirmed by psychiatric evaluation at screening; score ≥4 on the Anxiety Disorder Interview Schedule for DSM-IV Child and Parent Version (ADIS-C/P) Clinical Severity Rating (CSR) scale
Exclusion Criteria	Major depressive disorder, bipolar disorder, psychosis, attention-deficit hyperactivity disorder (ADHD), eating disorder, substance use disorder, pervasive developmental disorder
Methods	Patients were randomized (3:1) to receive either GXR 1-6 mg per day or matching placebo. GXR was titrated weekly starting at 1 mg to a max of 6 mg per day based on the investigator's assumption of a clinical response along with tolerability. Patients weighing < 50 kg were titrated to a daily dose of 0.06-0.12 mg/kg while patients weighing ≥ 50 kg were titrated to a daily dose of 3-6 mg.
Duration	12 weeks
Outcome Measures	Primary: safety and tolerability of GXR treatment Secondary: Change in Pediatric Anxiety Rating Scale (PARS), the Clinical Global Impressions (CGI) scale, and the Screen for Child Anxiety Related Disorders (SCARED)
Baseline Characteristics		GXR (n= 62)	Placebo (n= 21)
	Age, years	11.7	11.8
	Male	24 (38.7%)	11 (52.4%)
	White Non-white	51 (82.3%) 11 (17.7%)	17 (81.0%) 4 (19.0%)
	Diagnosis GAD SAD Social anxiety disorder	59 (95.2%) 29 (46.8%) 41 (66.1%)	20 (95.2%) 14 (66.7%) 16 (76.2%)
Results	Endpoint	GXR (n= 62)	Placebo (n= 21)
	Treatment-emergent adverse events (TEAEs)	51 (82.3%)	13 (61.9%)
	Change in PARS score at week 12	-6.9 ± 6.6	-5.6 ± 6.3
	Change in SCARED scores at week 12 Scored by children Scored by parents	-12.6 ± 13.8 -15.2 ± 14.6	-10.6 ± 12.5 -10.1 ± 10.1
	CGI-I score ≤ 2 at week 12	32 (54.2%)	6 (31.6%)
Adverse Events	The majority of TEAEs were of mild to moderate severity and consisted of headache (35.5), somnolence (27.4%), and fatigue (21.0%) in the GXR group. Eight patients discontinued in the GXR group due to TEAEs including tachycardia, blurred vision, fatigue, dizziness, postural dizziness, anxiety, emotional disorder, mood-related changes, and panic attack
Study Author Conclusions	GXR was well tolerated in pediatric subjects with GAD, SAD, and/or social anxiety disorder.
InpharmD Researcher Critique	Despite being a study of adequate design, no formal statistical calculations were performed and the results should be considered exploratory and not definitive.

References:

Strawn JR, Compton SN, Robertson B, Albano AM, Hamdani M, Rynn MA. Extended Release Guanfacine in Pediatric Anxiety Disorders: A Pilot, Randomized, Placebo-Controlled Trial. J Child Adolesc Psychopharmacol. 2017;27(1):29-37. doi:10.1089/cap.2016.0132