Kapvay vs Intuniv: Which is Best For ADHD?

Kapvay vs Intuniv Summary

Kapvay vs Intuniv Comparison (Source: NYTimes)Kapvay vs Intuniv – what are the important differences?

Kapvay and Intuniv are non-stimulant treatments for ADHD. They have a number of advantages over psychostimulants like Adderall. But there’s a trade-off, because as monotherapy, Kapvay and Intuniv aren’t quite as effective as psychostimulants.

My verdict on Kapvay vs Intuniv: each drug is better suited in different situations.

Doctors regard Intuniv as more effective by itself for ADHD. However, doctors prescribe Kapvay for a wider range of disorders. They use it for migraines, for example. Many people find Kapyvay more sedating than Intuniv, but this side effect is a double-edged sword.

I always had trouble tolerating sedation as a side effect. Being alert is so important to productivity. But others simply take the medicine at bedtime and enjoy enhanced sleep quality. You might considering taking Kapvay at night an activating stimulant in the morning. But if you’re looking for one medicine to treat all the symptoms of ADHD, Intuniv is your best bet.

What Are Kapvay and Intuniv?

First, what is Kapvay? It’s is an extended release formulation of clonidine that was approved to treat of ADHD in 2010.
Along the same lines, Intuniv is extended-release guanfacine, which was approved by the FDA in 2009.

Both drugs are non-stimulant treatments for ADHD and hypertension with similar mechanisms. One difference is that physicians also prescribe Kapvay for other indications such as opioid withdrawal, migraines, anxiety, and pain.

Clonidine – the active ingredient in Kapvay – is an α2 adrenergic agonist and imidazoline receptor agonist that’s been in use for over 40 years. Intuniv (guanfacine), by comparison, is a selective α2a adrenergic agonist. Later on, we’ll discuss how these differences in pharmacodynamics impact the patient.

According to one double-blind, placebo-controlled study comparing clonidine vs guanfacine, Intuniv (guanfacine) may be more effective as monotherapy for ADHD.

Kapvay vs Intuniv: Indications

intuniv-vs-kapvay-disorganizedKapvay treats ADHD, hypertension (high blood pressure), anxiety disorders, acute drug withdrawal, migraines, menopausal flushing, and diarrhea.

Like Kapvay, Intuniv also treats ADHD and hypertension. But Intuniv doesn’t have these additional indications.

Half-Life and Duration of Effects
The half-life of Intuniv in adults is 10-30 hours, with an average of 17 hours. In children, Intuniv’s half-life is 14 hours.

(Just in case you’re unfamiliar with half-lives: the half-life of a drug is the amount of time for plasma concentrations of a drug to be halved.)

Researchers report that Kapvay has a plasma half-life of 12-16 hours, with peak clonidine concentrations at the 3-5 hour mark.

In short, Intuniv is a little longer-acting than Kapvay.

Dosage

Doctors usually start with a dose of 0.1 mg Kapvay. The prescribing physician may choose to titrate this dose up to 0.4 mg.

Guanfacine, by comparison, is ordinarily started at a dose of 1 mg per day. Some patients take as much as 7 mg per day in divided doses. The target dosage depends on your age, body weight, and drug sensitivity. For example, the maximum recommended dose in children is 4 mg/day, but adults can take more.

Potency

Kapvay is more potent than Intuniv. Physicians can prescribe lower doses of Kapvay to attain the same therapeutic effects.

Efficacy

Both Kapvay and Intuniv enhance concentration and executive function by activating α adrenergic receptors in the brain.

These medications can have a sleep-promoting effect. Their usefulness as a sleep aid may be secondary to treating hyperactivity in patients with ADHD.

Kapvay and Intuniv are also effective antihypertensive agents (they decrease blood pressure).

One double-blind, placebo-controlled trial reported that guanfacine (Intuniv) but no clonidine (Kapvay) improves planning and working memory in humans. The authors reported that “the greater selectivity of guanfacine for α 2A-adrenoreceptor subtype may underlie its differences from clonidine” [1]. This finding suggests that Intuniv may be the more robust ADHD medication.

Efficacy of Guanfacine

kapvay-vs-intuniv-nonstimulants-slideIntuniv was approved in 2009 and is indicated for treating ADHD as both monotherapy and adjunctive to stimulant medications [2]. The utilization of Intuniv in pediatric patients continues to be evaluated in two clinical trials conducted in patients aged 6-17 years who fulfilled DSM-IV criteria for ADHD.

The first study, conducted by Biederman et al., was an eight-week, placebo-controlled efficacy and safety study of Intuniv in a cohort of patients aged 6 to 17 years.

The primary result was improvement in overall scores on the ADHD-RS IV from baseline compared with placebo. Intuniv was pioneered at 1 mg/day and increased to a dose of 2 – 4 mg per day. ADHD-RS IV scores at study completion revealed a statistically significant decline in the Intuniv group (16.7 points) compared with placebo (8.9 points; p0.0001). Common adverse effects associated with guanfacine included sedation, fatigue, upper abdominal pain, and somnolence [3].

Withdrawal in the study because of adverse effects seemed to be dose-related, with one patient removing in the placebo group as compared to nine patients in the Intuniv 2 mg group, 13 in the 3 mg group, and 20 in the 4 milligrams group [3]. Treatment-emergent adverse effects were also dose-related; 3.5% of patients reported somnolence in the placebo group as compared to 24.1%, 33.7%, and 38.4% in the 2 mg, 3 mg, and 4 mg Intuniv cohorts, respectively.

A study conducted by Sallee et al evaluated Intuniv in 324 patients 6 to 17 years old over a 25-month time period. Patients were randomized to receive Intuniv alone or with a stimulant (either amphetamine or methylphenidate products) and were titrated up to four milligrams of Intuniv per day.

In this study, ADHD-RS IV complete scores showed statistically significant improvement from baseline in patients taking Intuniv as monotherapy or in conjunction with stimulants (mean change overall, 20.1 points; p < 0.001) [4]. Statistically significant score improvement was seen at each experimental group compared to baseline (24.3 points for the 1 mg, 23.8 dose for the 2 milligrams, 22.1 for the 3 milligrams, and 18.0 for the 4 milligrams arms; all p < 0.001).

Significant improvement was also noted in the combination groups for the 2 mg, 3 mg, and 4 milligrams arms verses baseline (p < 0.006, p < 0.001, p < 0.001, respectively) but not in the 1 mg group. Treatment-emergent adverse effects were reported in 87.4% of patients on monotherapy and 86.8% of patients in the combination therapy group. Common adverse effects reported in patients receiving the study medication were somnolence, headache, and weariness [4].

The negative effects of sedation, somnolence, and fatigue occurred in roughly 58.7% of patients on guanfacine treatment and 11.3% of patients on combination therapy. The lower prevalence of negative effects in the combined group may be due to the stimulating effects of the psychostimulant. When examining somnolence alone as a side effect of Intuniv monotherapy, the effects appear to have similar frequency as that reported with immediate-release guanfacine in early dose-response studies [?].

Efficacy of Clonidine

Two placebo-controlled trials examined Kapvay in the treatment of ADHD. These studies were conducted in patients aged 6-17, who met DSM IV criteria for hyperactive or ADHD hyperactive /inattentive subtypes. To assess symptoms of ADHD, the ADHD Rating Scale-IV-Parent Version (ADHDRS-IV) total score was used [5][6]. The first study was an 8-week randomized, double-blind, placebo-controlled, fixed dose study of 236 children and teens.

The main endpoint was mean change in ADHD-RS-IV total score from baseline to week 5 versus placebo. Kollins et al examined the efficacy of Kapvay in an 8-week study in 198 patients aged 6 to 17 with a 5-week primary efficacy endpoint of mean change in ADHD-RS-IV score from baseline after 5 weeks versus placebo [7]. Patients were previously treated with a stimulant – either methylphenidate or amphetamine – for four weeks using an insufficient response. Patients were randomly assigned to receive flexible-dosed Kapvay (0.1 to 0.4 mg daily) as an adjunct to their stimulant or continue the stimulant with placebo.

ADHD symptoms were reduced in the combined stimulant plus Kapvay group, with changes in both hyperactivity/impulsivity and inattention subscales revealing statistically significant improvement by week 5. In this trial, Kapvay had lower rates of somnolence, fatigue, and sedation than the authors reported in the treatment study. Similarly, rates of fatigue were 4% in the stimulant and placebo group and 16% in the clonidine and stimulant group [7].

Side Effects

Kapvay and Intuniv induce similar side effects since these drugs have pharmacological overlap. Common Kapvay Side EffectsDizziness, orthostatic hypotension, somnolence (dose-dependent), dry mouth, headache, fatigue, skin reactions (if administered transdermally), hypotension.Common Intuniv Side EffectsDry mouth, somnolence (sleepiness), fatigue, dizziness, headache, constipation, abdominal pain.”]”>Dry mouth, somnolence (sleepiness), fatigue, dizziness, headache, constipation, abdominal pain.

Drug Interactions

Kapyvay is metabolized to 4-hydroxyclonidine by CYP2D6. Other hepatic enzymes are also responsible, but CYP2D6 accounts for approximately 2/3 of the activity. Thus, CYP2D6 inhibitors may interact with clonidine by decreasing clearance of the drug. Many prescription drugs strongly inhibit CYP2D6.

Intuniv is metabolized by the liver enzyme CYP3A4. Many drugs, foods, and dietary supplements inhibit this enzyme. That means that you should watch out for potential drug interactions. Make sure to disclose all the supplements you take to your physician.

As an example, grapefruit, gingko biloba, and quercetin all inhibit CYP3A4. Since Intuniv is metabolized by CYP3A4, co-administration of these supplements could increase drug levels of Intuniv.

Mechanism

kapyvay-vs-intuniv-ADHD (Source: Medscape)Under normal conditions, epinephrine and norepinephrine bind to adrenergic receptors. These catecholamines release under stress or when you’re threatened or challenged (fight-or-flight). It’s no surprise then that catecholamines help us get stuff done and stay concentrated. To invoke a cliche example, it’s not good to be distracted while a bear chases you.

Both Kapvay and Intuniv bind α 2 adrenergic receptors. The main difference is that Intuniv selectively binds postsynaptic α 2a adrenergic receptors. Kapvay is less discriminate: it binds both presynaptic and postsynaptic α adrenergic receptors.

Intuniv’s selectivity for postsynaptic receptors makes the drug less sedating.

Moreover, Kapvay also binds the imidazoline receptor. This activation of the imidazoline receptor also contributes to Kapyvay’s antihypertensive (blood pressure lowering) effects.

Kapvay’s applications in medicine are broader because it binds more receptors than Intuniv.

For example, Kapvay can treat opioid withdrawal because it decreases the response of the sympathetic nervous system during withdrawal. Tachycardia, hypertension, sweating, insomnia, restlessness – Kapvay mitigates all of these symptoms of drug withdrawal.

Guanfacine, like clonidine, is an α 2-agonist [8]. There are 5 general categories of adrenergic receptors, α1, α2, beta1, beta2, and beta3 [9]. The α 2A subtype is found both presynaptically on norepinephrine neurons, and postsynaptically on non-norepinephrine neurons [10]. Indeed, the majority of α 2A receptors are postsynaptic to norepinephrine neurons [11].

Stimulation of the presynaptic α 2 receptors reduces norepinephrine release from terminals in the locus coeruleus (LC). Clonidine is 10 times more potent than guanfacine at presynaptic terminals [12], while guanfacine is more potent at postsynaptic receptors [13].

The therapeutic properties of guanfacine originate from its activity in the prefrontal cortex (PFC). The PFC plays a role in executive functions, e.g., regulation of attention, planning, impulse control, and processing [13]. Executive dysfunction causes forgetfulness, distractibility, impulsivity, impairment in working memory, and mental flexibility [13]. Dislocation in the PFC, and its own projections to the striatum and cerebellum, are also connected with ADHD symptoms [14]. Inattention, impulsivity, and distractibility are all core features of ADHD.

Guanfacine improves prefrontal cortical regulation of attention and impulse control by strengthening PFC functions. In animal studies, infusion of guanfacine directly into the PFC enhances its function [13][15]. This improvement can be detected at the cellular level, where electrophysiology demonstrates that guanfacine reinforces the links between PFC networks, increasing network fire rate [15].

PFC neuronal networks interconnect via glutamate synapses on dendritic spines. Stimulation of these α 2A receptors with norepinephrine or guanfacine inhibits local cAMP generation, which closes nearby leaky ion channels. Closing these channels strengthens glutamatergic synaptic input signals onto the spine, raising network firing and permitting greater control over attention and behavior [15]. This strengthening of PFC neuronal firing is accompanied by greater cerebral blood flow to the PFC in monkeys and humans [16].

Conversely, blockade of these channels recapitulates the symptoms of ADHD, and α 2 receptors in PFC with yohimbine weakens PFC functions. Yohimbine induces a failure in PFC network firing, silencing PFC neurons [15]. Infusions of yohimbine into the monkey PFC weaken working memory and impulse control and cause locomotor hyperactivity (Ma et al 2003, 2005).

The PFC is among the few inputs to the LC, and so guanfacine-induced enhancement of PFC function may also accentuate regulation of LC noradrenergic release throughout the brain (Sara and Herve-Minvielle 1995; Arnsten et al 1996). Ideally, LC firing is prompted by related but not irrelevant stimuli (Aston-Jones et al 2000). On the other hand, if poorly regulated, the LC fires in response to distractors (Aston-Jones et al 2000). The PFC also controls attention and behavior through massive projections to the sensory and motor cortices, the basal ganglia, and cerebellum (Goldman-Rakic 1987). Thus, fortifying PFC networks optimizes orchestration of brain function.

Conclusion

Both Kapvay and Intuniv are effective non-stimulant treatments for ADHD. Kapvay is associated with more side effects, but may improve sleep quality when taken at nighttime. Intuniv is a more selective drug and enhances executive function.

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