Clonidine

What it is

Clonidine is a prescription medicine that acts on alpha-2 adrenergic receptors in the brainstem, reducing the sympathetic (fight-or-flight) outflow from the central nervous system. It has been in use since 1974. The immediate-release tablet is licensed for high blood pressure; a separate extended-release tablet is licensed for attention deficit hyperactivity disorder in children, alone or added to a stimulant. It is also widely used off-label for opioid withdrawal, where its close relative lofexidine holds the US approval.

What the research says

Clonidine lowers blood pressure and calms the noradrenaline surge that drives opioid withdrawal, and it reduces the core symptoms of ADHD. The quality of the evidence differs a lot by use. For ADHD, a meta-analysis of 12 trials in 2,276 children found alpha-2 agonist monotherapy reduced overall ADHD symptoms with a standardised mean difference of -0.59, at the price of sedation and somnolence common enough to give numbers needed to harm of 17 and 4. For opioid withdrawal, a Cochrane review found clonidine and lofexidine better than placebo for severe withdrawal (risk ratio 0.32) but no better than tapering methadone, with significantly more low blood pressure. For blood pressure itself, the systematic review we found was confined to dialysis patients and concluded there is no evidence for long-term use. Its most distinctive risk is what happens when it stops: a rebound surge in blood pressure and catecholamines.

Evidence grade: Limited evidence.

How it works

Drug class: Centrally acting alpha-2 adrenergic receptor agonist (imidazoline antihypertensive)

Clonidine stimulates alpha-2 adrenergic receptors in the brainstem. That reduces the sympathetic nervous signal leaving the brain, which lowers peripheral and kidney vascular resistance, heart rate and blood pressure. The same damping of noradrenaline traffic is what quietens the sweating, agitation, racing heart and restlessness of opioid withdrawal, and is thought to underlie its effect on ADHD symptoms. Because the drug is holding sympathetic outflow down, stopping it suddenly lets catecholamines rebound: the label records a rapid rise in blood pressure with elevated plasma catecholamine concentrations after sudden cessation. (Source 1)

What it is used for

• Clonidine lowers blood pressure, but the systematic review we retrieved was restricted to haemodialysis patients: short-term use lowered systolic pressure by about 13 mm Hg on pooled analysis of three small studies, risk of bias was high in all included studies, and the authors concluded there is no evidence supporting long-term use. We did not retrieve cardiovascular outcome trials (heart attack, stroke, death) for clonidine in general hypertension. Evidence: limited. (Source 2)
• A meta-analysis of 12 randomised trials in 2,276 young people found alpha-2 agonists (clonidine and guanfacine) reduced overall ADHD symptoms as monotherapy (standardised mean difference -0.59) and as an add-on to stimulants (-0.36), with smaller effects when added on. Sedation, fatigue and somnolence were significantly more common than placebo. Evidence: established. (Source 3)
• Only the extended-release tablet carries the ADHD licence; plain immediate-release clonidine used for ADHD is off-label. The same meta-analysis found the immediate-release form of clonidine was the one associated with significantly greater hypotensive and bradycardic effects. Evidence: limited. (Source 3)
• A Cochrane review found moderate-quality evidence that alpha-2 agonists including clonidine beat placebo for severe withdrawal (risk ratio 0.32) and for completing treatment (risk ratio 1.95), each from three studies totalling 148 people. Against reducing doses of methadone there was no significant difference in completion of withdrawal treatment, and low blood pressure and other adverse effects were significantly more likely with the alpha-2 agonists. Evidence: limited. (Source 4)

Interactions

• Alcohol (label): Clonidine adds to the drowsiness and slowed thinking caused by alcohol, barbiturates and other sedating drugs. Since sedation is already one of clonidine's most common effects, the combination can be markedly more impairing than either alone. (Source 5)
• Diltiazem or verapamil (calcium channel blockers), digitalis, beta-blockers (case reports): These drugs slow the heart's natural pacemaker, and so does clonidine. Combined, the heart rate can fall far enough to need hospital treatment: cases of sinus bradycardia leading to hospitalisation and pacemaker insertion have been reported with clonidine plus diltiazem or verapamil. (Source 5)
• Tricyclic antidepressants (for example amitriptyline) (label): Tricyclic antidepressants blunt clonidine's blood-pressure-lowering effect, so someone whose blood pressure was controlled may lose that control when a tricyclic is started, and may regain too much effect if it is stopped. (Source 5)
• Antipsychotics (neuroleptics) (label): Adding an antipsychotic to clonidine can bring on or worsen problems with standing up: orthostatic hypotension, dizziness and fatigue. This matters for anyone taking clonidine alongside quetiapine or aripiprazole. (Source 5)

Stopping it

• Clonidine has a genuine withdrawal syndrome. Sudden cessation has produced nervousness, agitation, headache and tremor followed by a rapid rise in blood pressure with raised plasma catecholamines. The risk is greater after higher doses or when a beta-blocker is being taken at the same time, and rare cases of hypertensive encephalopathy, stroke and death have been reported. The immediate-release label instructs a gradual dose reduction over 2 to 4 days. (Source 1)
• For the extended-release tablets used in ADHD, the label notes that no study of abrupt discontinuation has been done in children with ADHD, and instructs that the dose be reduced in steps of no more than 0.1 mg every 3 to 7 days to limit the risk of rebound hypertension. In adults, sudden stopping of the 0.2 to 0.6 mg/day extended-release range produced headache, tachycardia, nausea, flushing, chest tightness and anxiety. (Source 6)
• A small prospective placebo-substitution study in seven patients measured what happens physiologically after stopping. Urinary catecholamine metabolites returned to pretreatment levels within 3 to 5 days without a significant overshoot, but plasma MHPG, heart rate and mean arterial pressure were all significantly above pretreatment values at 72 hours, consistent with a noradrenaline rebound. The study was in normotensive psychiatric patients, not people with hypertension, and seven people is a very small sample. (Source 7)

What goes wrong

Sedation, fatigue and somnolence were significantly more common with alpha-2 agonists than placebo in ADHD trials, and immediate-release clonidine lowered blood pressure and heart rate. (Source 3)

• Meta-analysis, Moderate certainty.
• Size: 12 studies, N = 2,276.
• Who: Children and adolescents with ADHD.
• How long: Short-term randomised trials.
• Result: Numbers needed to harm: somnolence 4, fatigue 10, sedation 17 for monotherapy; somnolence 10 when added to stimulants. Significantly greater hypotensive and bradycardic effects with immediate-release clonidine; QTc prolongation with extended-release guanfacine.
• Funding: not stated.

significantly more common fatigue (NNH = 10), sedation (NNH = 17), and somnolence (NNH = 4) and significantly greater hypotensive (clonidine-IR), bradycardic (clonidine-IR), and QTc prolonging (guanfacine-XR) effects

Low blood pressure and other adverse effects were significantly more likely with clonidine and similar drugs than with tapering methadone for opioid withdrawal. (Source 8)

• Systematic review, Low certainty.
• Size: 464 participants across 6 studies.
• Who: People withdrawing from opioids.
• How long: Days to weeks.
• Result: Hypotensive or other adverse effects RR 1.92 (95% CI 1.19 to 3.10), low quality evidence. Lofexidine did not reduce blood pressure to the same extent as clonidine.
• Funding: independent (Cochrane review)

Hypotensive or other adverse effects were significantly more likely with alpha2-adrenergic agonists (RR 1.92, 95% CI 1.19 to 3.10; 6 studies; 464 participants; low quality)

Clonidine in dialysis patients was associated with hypotension, light-headedness, drowsiness, dry mouth, rebound hypertension and contact dermatitis from the patch. (Source 2)

• Systematic review, Low certainty.
• Size: 8 studies in the systematic review; the 3 studies pooled in the meta-analysis contained 24 people in total.
• Who: Adult haemodialysis patients.
• How long: 2 to 12 weeks in the pooled studies.
• Result: No rates were pooled for adverse effects; they are listed as significant and as a reason the authors advise against long-term use.
• Funding: independent (unfunded)

Limit of this finding: This is a list of what was reported, not a measure of how often any of it happens: the review pools no rates for these adverse effects, and the studies it meta-analysed contained 24 people in total, all rated high risk of bias. The same review prints its systolic blood pressure confidence interval with the bounds reversed and misprints its risk-of-bias tool as "ROBINS-1" (the instrument is ROBINS-I), so its numbers should be read with care.

Significant adverse effects reported included hypotension, light-headedness, drowsiness, dry mouth, rebound hypertension, and contact dermatitis from patch application.

Stopping clonidine suddenly can cause a rapid rise in blood pressure with raised plasma catecholamines, and rare cases of hypertensive encephalopathy, stroke and death have been reported. (Source 1)

• Official position, Certainty not rated.
• Size: Not stated; the label describes case reports.
• Who: People taking clonidine for hypertension, particularly at higher doses or on a beta-blocker as well.
• How long: Within days of the last dose.
• Result: No rates are given in the label. Symptoms listed are nervousness, agitation, headache and tremor, followed by a rapid rise in blood pressure; rare hypertensive encephalopathy, cerebrovascular accidents and death.
• Funding: Not applicable (regulatory position, label revision 9/2022)

Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal.

In a small prospective study of placebo substitution, heart rate and mean arterial pressure were significantly raised 72 hours after the last clonidine dose. (Source 7)

• Case series, Very low certainty.
• Size: 7 patients.
• Who: Normotensive patients receiving clonidine 6 micrograms/kg/day for 3 weeks for alcohol amnestic disorder.
• How long: 3 weeks of treatment, then placebo substitution; measurements to 5 days.
• Result: Total plasma MHPG, heart rate and mean arterial pressure significantly elevated above pretreatment values at 72 hours. Urinary catecholamine metabolites returned to pretreatment levels 3-5 days after stopping without significant overshoot.
• Funding: not stated.

Total plasma MHPG, heart rate, and mean arterial pressure were significantly elevated above pretreatment values 72 h after the last dose of clonidine.

What the evidence supports

Alpha-2 agonists including clonidine reduced overall ADHD symptoms in children and adolescents compared with placebo. (Source 3)

• Meta-analysis, Moderate certainty.
• Size: 12 studies, N = 2,276; monotherapy analyses 9 studies, n = 1,550.
• Who: Children and adolescents with ADHD.
• How long: Short-term randomised trials (weeks)
• Result: Monotherapy: overall ADHD symptoms SMD -0.59, hyperactivity/impulsivity -0.56, inattention -0.57, ODD symptoms -0.44. Add-on to stimulants: overall -0.36. All-cause discontinuation lower than placebo (RR 0.70, number needed to treat 10).
• Funding: not stated.

α-2 agonist monotherapy significantly reduced overall ADHD symptoms (SMD = −0.59, p < .00001), hyperactivity/impulsivity (SMD = −0.56, p < .00001), inattention (SMD = −0.57, p < .00001), and ODD symptoms (SMD = −0.44, p = .0004)

Alpha-2 agonists including clonidine were more effective than placebo at reducing severe opioid withdrawal and at getting people through withdrawal treatment. (Source 4)

• Systematic review, Moderate certainty.
• Size: 148 participants across 3 studies for each outcome.
• Who: People withdrawing from heroin or methadone.
• How long: Days to a few weeks.
• Result: Likelihood of severe withdrawal RR 0.32 (95% CI 0.18 to 0.57); completion of treatment RR 1.95 (95% CI 1.34 to 2.84)
• Funding: independent (Cochrane review)

We found moderate-quality evidence that alpha2-adrenergic agonists were more effective than placebo in ameliorating withdrawal in terms of the likelihood of severe withdrawal (risk ratio (RR) 0.32, 95% confidence interval (CI) 0.18 to 0.57; 3 studies; 148 participants).

What the evidence does not support

There is no evidence supporting long-term clonidine use for blood pressure control in haemodialysis patients. (Source 9)

• Systematic review, Low certainty.
• Size: 8 studies reviewed.
• Who: Adult haemodialysis patients.
• How long: Longest included studies were 12 weeks.
• Result: No long-term efficacy data existed; the authors recommend fluid removal strategies and other antihypertensives instead for long-term control.
• Funding: independent (unfunded)

There is no evidence supporting the long-term use of clonidine in the HD population and a significant side-effect profile.

Against reducing doses of methadone, clonidine and similar drugs did not improve the chance of completing opioid withdrawal treatment. (Source 8)

• Systematic review, Low certainty.
• Size: 659 participants across 9 studies.
• Who: People withdrawing from opioids.
• How long: Treatment was significantly longer with reducing doses of methadone.
• Result: Completion of withdrawal treatment RR 0.85 (95% CI 0.69 to 1.05), low quality evidence; peak withdrawal severity possibly greater with alpha-2 agonists (RR 1.18, 95% CI 0.81 to 1.73, not significant)
• Funding: independent (Cochrane review)

there was no significant difference in rates of completion of withdrawal treatment (RR 0.85, 95% CI 0.69 to 1.05; 9 studies; 659 participants; low quality)

Where the evidence is mixed

Short-term clonidine lowered systolic blood pressure in haemodialysis patients, but diastolic pressure did not change significantly. (Source 2)

• Systematic review, Low certainty.
• Size: 3 studies pooled in the meta-analysis with a collective sample size of 24 people (8 studies in the wider systematic review)
• Who: Adult haemodialysis patients, ages 12-77.
• How long: 2 to 12 weeks.
• Result: Systolic BP pooled effect -12.985 mm Hg, p < 0.001; the source prints the 95% CI as [-7.878, -18.092], with its bounds in reverse order, so the interval runs from -18.092 to -7.878 mm Hg. Diastolic BP -11.119 mm Hg (95% CI -22.725 to 0.487, p = 0.060, not statistically significant). The three meta-analysed studies contained 24 people in total, aged 12 to 77, and risk of bias was high for every included study.
• Funding: independent (the review states it was unfunded)

Limit of this finding: The review prints this confidence interval with its bounds the wrong way round, as "95% CI [-7.878, -18.092]". Read in the normal order it runs from -18.092 to -7.878 mm Hg. Either way the whole interval sits below zero, so the direction of the effect is not in question; what is wrong is how the source typesets it. Two things limit what the number can support: the pooled estimate comes from three studies containing 24 people in total, and the review rated the risk of bias high for all of them (it also misprints the name of the tool it used as "ROBINS-1"; the instrument is ROBINS-I). A reader should take this as weak short-term evidence that blood pressure falls, not as a reliable estimate of how far it falls, and the review itself says nothing supports long-term use.

Short-term clonidine use was associated with significant improvement in systolic BP (pooled effect: −12.985 mm Hg, 95% CI [−7.878, −18.092], p < 0.001), while changes in diastolic BP were not statistically significant (−11.119 mm Hg, 95% CI [−22.725, 0.487], p = 0.060).

Where the research disagrees

Whether clonidine or a reducing dose of methadone is the better way to manage opioid withdrawal

• Cochrane review, on completion of withdrawal and speed of symptoms, Systematic review of randomised trials: Opioid withdrawal was similar with alpha2-adrenergic agonists and reducing doses of methadone, but the duration of treatment was longer and there were fewer adverse effects with methadone. (Source 10)
• Cochrane review, on placebo comparisons, Systematic review of randomised trials: Clonidine and lofexidine were more effective than placebo in managing withdrawal from heroin or methadone, and were associated with higher chances of completing treatment. (Source 10)

How much

• Reference intake: There is no reference intake for clonidine; it is a prescription medicine and the dose is set by the prescriber. The US immediate-release tablet label (revision 9/2022) describes an initial 0.1 mg twice daily with a usual maintenance range of 0.2 to 0.6 mg daily in divided doses for hypertension. The extended-release tablet label (revision 04/2020) is for ADHD. Both are recorded here as regulatory positions with their dates, not as recommendations. (Source 1)
• Upper limit: The immediate-release label (revision 9/2022) states a maximum effective daily dose of 2.4 mg for hypertension. The extended-release label for ADHD (revision 04/2020) states a maximum of 0.4 mg/day, given as 0.2 mg twice daily. Neither label carries a boxed warning. These are regulatory positions with their dates. (Source 6)
• Studied: The ADHD meta-analysis pooled 12 randomised trials of clonidine and guanfacine, immediate-release and extended-release, in 2,276 children and adolescents, as monotherapy and added to stimulants. (Source 3)
• Studied: The haemodialysis meta-analysis pooled three studies of 2 to 12 weeks' duration with a collective sample of 24 people aged 12 to 77. (Source 2)
• Studied: The small withdrawal study gave clonidine 6 micrograms/kg/day for 3 weeks before substituting placebo. (Source 7)

A common belief, and what the research shows

The belief: Clonidine is an old, mild blood pressure pill, so missing a few doses does not matter.

What the research shows: Stopping clonidine suddenly is its most distinctive danger. The US label records that "Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma." and that "Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal." A small physiological study found heart rate and mean arterial pressure significantly above baseline 72 hours after the last dose.

Questions and answers

What is it?

Clonidine is a prescription tablet or skin patch that acts on alpha-2 adrenergic receptors in the brainstem. The immediate-release tablet is licensed for high blood pressure; a separate extended-release tablet is licensed for ADHD in children, alone or added to a stimulant. It is also used off-label for opioid withdrawal. (Source 6)

What does it do in the body?

It turns down the sympathetic nervous system's output from the brain, which lowers blood pressure and heart rate. In haemodialysis patients, short-term use lowered systolic blood pressure by about 13 mm Hg on pooled analysis, though the change in diastolic pressure was not statistically significant. The same damping of noradrenaline traffic is what eases opioid withdrawal symptoms and reduces ADHD symptoms. That pooled blood pressure figure rests on three studies containing 24 people in total, and the paper prints the confidence interval with its bounds in reverse order, so it is a weak signal rather than a reliable number. (Source 2)

Is it good or bad for you?

It helps in specific situations and costs sedation in all of them. For ADHD the benefit is real but so is the drowsiness: somnolence had a number needed to harm of 4, meaning roughly one extra child in four became sleepy because of the drug. For opioid withdrawal it beats placebo but causes more low blood pressure than tapering methadone. For long-term blood pressure control in dialysis patients a systematic review found no supporting evidence and a significant side-effect profile. (Source 3)

How do you get more of it?

Clonidine is prescription-only and no food or supplement contains it. The dose is set by a prescriber: the immediate-release hypertension label describes 0.1 mg twice daily to start and a usual range of 0.2 to 0.6 mg daily, and the extended-release ADHD label caps at 0.4 mg a day. Doses studied in trials ranged widely, including 6 micrograms per kilogram per day in a small withdrawal study. (Source 6)

If it is harmful, what reduces it?

It clears from the body on its own, but it must not be stopped abruptly. The immediate-release label instructs a gradual reduction over 2 to 4 days; the extended-release label instructs steps of no more than 0.1 mg every 3 to 7 days. Stopping suddenly can produce agitation, headache, tremor and a rapid rise in blood pressure. (Source 1)

Why might someone be low in it or missing it?

The commonest reason a dose stops working is that something else is blunting it. Tricyclic antidepressants reduce clonidine's blood-pressure-lowering effect, so the same dose does less. Missed doses matter more with clonidine than with most blood pressure drugs because the drug's effect falls away quickly and the sympathetic system rebounds. (Source 5)

Which whole foods contain it or feed it?

None. Clonidine is a manufactured medicine, not a nutrient, and no whole food contains it or feeds it. The only dietary interaction documented in the label is with alcohol, which adds to its sedative effect rather than supplying it. (Source 5)

What happens if you do not have it?

For someone who has been taking clonidine, the risk of it being absent is not deficiency but rebound. Blood pressure and catecholamines surge, and the label records rare cases of hypertensive encephalopathy, stroke and death after clonidine withdrawal. For someone who has never taken it, nothing happens: it is a treatment, not a substance the body needs. (Source 1)

How can you test for it?

There is no blood test used to check clonidine levels in routine practice. What is measured is its effect and its harm: blood pressure and heart rate. In research, plasma and urinary catecholamine metabolites have been used to demonstrate the withdrawal rebound, but these are research measures rather than clinical tests. (Source 7)

References

1. DailyMed, US National Library of Medicine. Clonidine Hydrochloride Tablets, USP - WARNINGS, Withdrawal. 2022. Read the source
2. Pharmacology (Karger). The Safety and Efficacy of Clonidine in Hemodialysis Patients: A Systematic Review and Meta-Analysis - Results. 2022. DOI 10.1159/000525424. Read the source
3. Journal of the American Academy of Child & Adolescent Psychiatry. Alpha-2 Agonists for Attention-Deficit/Hyperactivity Disorder in Youth: A Systematic Review and Meta-Analysis of Monotherapy and Add-On Trials to Stimulant Therapy. 2014. PMID 24472251, DOI 10.1016/j.jaac.2013.11.009. Read the source
4. Cochrane Database of Systematic Reviews. Alpha2-adrenergic agonists for the management of opioid withdrawal (Cochrane Review) - Main results versus placebo. 2016. PMID 27140827, DOI 10.1002/14651858.CD002024.pub5. Read the source
5. DailyMed, US National Library of Medicine. Clonidine Hydrochloride Tablets, USP - DRUG INTERACTIONS. 2022. Read the source
6. Ingenus Pharmaceuticals, LLC, label published on DailyMed, US National Library of Medicine. CLONIDINE- clonidine tablet, extended release - indication and abrupt discontinuation. 2020. Read the source
7. Psychopharmacology. Catecholamine metabolism during clonidine withdrawal. 1984. PMID 6436892, DOI 10.1007/BF00432025. Read the source
8. Cochrane Database of Systematic Reviews. Alpha2-adrenergic agonists for the management of opioid withdrawal (Cochrane Review) - Main results versus reducing doses of methadone. 2016. PMID 27140827, DOI 10.1002/14651858.CD002024.pub5. Read the source
9. Pharmacology (Karger). The Safety and Efficacy of Clonidine in Hemodialysis Patients: A Systematic Review and Meta-Analysis - Conclusions. 2022. DOI 10.1159/000525424. Read the source
10. Cochrane Database of Systematic Reviews. Alpha2-adrenergic agonists for the management of opioid withdrawal (Cochrane Review) - Key results. 2016. PMID 27140827, DOI 10.1002/14651858.CD002024.pub5. Read the source