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Clonidine is an antihypertensive drug originally synthesized in the early 1960s by chemists employed under the pharmaceutical company Boehringer Ingelheim. At the time, the chemists intended to develop a peripherally-active adrenergic nasal decongestant to be administered in the form of nose drops. In the process, the chemists sought to modify amidines to fit the chemical structure of imidazoline-derived decongestants, however, they encountered a challenging obstacle in which a methylene bridge needed to be replaced with nitrogen monohydride [at multiple positions (2- and 6-) of the phenyl ring].
For this to work, the chemists utilized chlorine atoms, ultimately leading to the synthesis of clonidine. After its synthesis, preliminary trials evaluated clonidine as a nasal decongestant, and at low doses, a decongestive response occurred. However, since hypotension was its most prominent effect, Boehringer Ingelheim shifted trials evaluating clonidine as a decongestant, to trials of clonidine as an antihypertensive agent. By 1966, clonidine had received FDA approval for the treatment of hypertension and became widely used among individuals with high blood pressure.
Years later, clonidine attained subsequent FDA approval for the treatment of attention-deficit/hyperactivity disorder (ADHD), and its popularity increased as an off-label intervention for many medical conditions and circumstances, including to help individuals undergoing opiate withdrawal. Clonidine is understood to attenuate the severity of opiate/opioid withdrawal symptoms, ultimately increasing likelihood of a successful detox. That said, anyone who uses clonidine during opiate detox should understand its mechanism of action, the withdrawal symptoms it may reduce, and the benefits/drawbacks associated with its usage.
How Clonidine May Help with Opiate Withdrawal Symptoms
The principal means by which clonidine is likely to provide therapeutic benefit to individuals undergoing opiate withdrawal is via the attenuation of withdrawal symptoms. Within days of detoxifying from opiates/opioids, a combination of debilitating physical and psychological symptoms can overwhelm patients to such an extent that many will relapse; they'd prefer to continue using opiates/opioids than face the harshness of detox. If clonidine is administered, the physical and psychological symptoms become easier for patients to manage.
When withdrawal symptoms are easier for patients to manage, they are less likely to relapse and more likely to refrain from further opiate use. It is important to realize that not everyone taking clonidine during opiate withdrawal will derive the same degree of benefit. Some individuals may respond exceptionally well to clonidine for opiate withdrawal, others may attain mild-to-moderate benefit, and another group of persons may derive minimal or zero benefit from its administration.
The significance of therapeutic benefit that a person derives from clonidine will be largely subject to individual variation. Individuals with an extremely high tolerance to opiates probably won't derive as much benefit from clonidine than persons with a lower tolerance. Moreover, various factors such as: co-administered substances, environment, genetics/epigenetic expression, medical conditions, and neurochemistry – can influence the severity of opiate withdrawal symptoms and the corresponding magnitude of benefit derived from clonidine. Listed below are a set of symptoms associated with opiate withdrawal that may respond well to clonidine.
- Agitation: In the early weeks of opiate withdrawal, many individuals experience agitation, or a state of constant nervous excitement. Agitation, sometimes described as an uncomfortable internal stirring sensation, often makes it difficult for an individual to sit still even when physically and/or psychologically fatigued. Although physical activity and psychological relaxation tactics might minimize some agitation, they are often inadequately effective. Administration of clonidine during withdrawal is considered an effective way to manage agitation. Recipients of clonidine generally notice some degree of agitation relief, likely facilitated by the drug's ability to counteract withdrawal-related CNS hyperactivity.
- Anger: A host of negative emotions generally surface during opiate detoxification, one of which could be anger. When the anger hits, it may seem so extreme that it becomes difficult to control. You may find yourself more argumentative around friends/family, and in extreme cases, you may develop the urge to damage property or physically attack others. Although with time the anger will subside, when you're caught up in the heat of withdrawal, it may seem as if you'll stay forever angry. The underlying cause of anger is likely a withdrawal-related neurochemical imbalance. One potential way of ameliorating the withdrawal-related neurochemical imbalance and corresponding anger is through administration of clonidine. Clonidine counteracts excessive noradrenergic activity seen in withdrawal, ultimately reducing negative emotions like anger.
- Anxiety: Another symptom that can be downright debilitating for some individuals during opiate withdrawal is anxiety. From a general macro perspective, the anxiety occurring during opiate withdrawal may stem from a detoxification "rebound effect" in which excitatory transmission transiently spikes (or becomes hyperactive) and inhibitory transmission is reduced. The flood of excitatory transmission promotes physical symptoms of anxiety (e.g. headache, shaking, sweating, etc.), as well as psychological symptoms (e.g. uncontrollable/intrusive thoughts). Given clonidine's pharmacodynamics, users may find it helpful for neutralizing the anxiety emerging in opiate withdrawal. (For more information read: "Clonidine for Anxiety Disorders").
- Cognitive deficits: During opiate withdrawal, it is expected that most individuals will experience a transient decline in cognitive function. Attentional deficits, "brain fog" (unclear thinking), incoherent thinking, learning/memory impairment, and poor impulse control – are all fairly common symptoms of withdrawal. Although the exact cause(s) of opiate withdrawal-related cognitive deficits aren't fully elucidated, neurochemical abnormalities are likely at least partially responsible. Since cognitive deficits may detrimentally affect academic and/or occupational performance, persons undergoing withdrawal may desire a medical solution. Clonidine may be an ideal intervention because it is a non-stimulant medication that can increase noradrenergic tone within the prefrontal cortex to enhance cognition during withdrawal.
- Cravings: If detoxifying from opiates without medical guidance, it often becomes difficult for individuals to resist cravings, or internal urges to reinstate opiate usage. There are many reasons as to why individuals might experience these cravings, including: preexisting connectivity (or "wiring") within the brain and/or concentrations of neurochemicals in specific regions – each of which reinforce an addiction to the opioidergic pleasure. Because of these cravings, persons who attempt to detoxify without medical help are highly prone to relapsing. To attenuate and/or negate the onset of these cravings, medications like clonidine are helpful. Clonidine modifies neurochemistry and connectivity in such a way, that cravings may become less frequent and/or noticeable. Specifically, the alpha-2 adrenergic agonism facilitated by clonidine has been shown to prevent cue-induced opiate cravings.
- Depression: When a person first starts using opiates, he/she may experience profound mood enhancement or an antidepressant effect. With continuous regular usage, the mood enhancement experienced in early days of opiate administration dwindles and/or becomes nonexistent. This is because the brain will have adapted to the opiate, primarily via upregulation of mu-opioid receptors. Due to an upregulated concentration of mu-opioid receptors and other downstream neurochemical irregularities, when a person ceases opiates such as during detox, he/she is will be highly prone to depression. While not an antidepressant, clonidine can normalize some of the downstream neurochemical irregularities associated with long-term opiate usage, possibly helping with detox-related depression. Clonidine may also reduce depression indirectly through the management of anxiety, cognitive deficits, and stress.
- Diarrhea: It is known that regular opiate users are increasingly prone to constipation. Although opiates bind to mu-opioid receptors in the CNS to treat pain, they also bind to peripheral mu-opioid receptors in other areas such as the gastrointestinal (GI) tract, whereby they disrupt digestive processes and cause constipation. Assuming a long-time opiate user undergoes detoxification, he/she may experience diarrhea as a rebound effect [opposite of constipation]. To manage detox-induced diarrhea, many individuals use over-the-counter agents like Imodium. That said, the drug clonidine may also function as an antidiarrheal during opiate withdrawal. A systematic review of 24 trials revealed that clonidine strongly decreases both stool frequency and volume.
- Facial flushing: Opiates suppress norepinephrine release, and when discontinued, an opposing "rebound" effect may occur in which individuals exhibit noradrenergic hyperactivity. This noradrenergic hyperactivity may account for some of the facial flushing that is sometimes reported during opiate withdrawal. The administration of clonidine is known to modulate noradrenergic activity, whereby it regulates the dilation/constriction of blood vessels implicated in a facial flushing response. As a result, some individuals will report that clonidine counteracts facial flushing experienced in withdrawal.
- Fever: Fluctuations in body temperature can occur during opiate withdrawal, sometimes to the extent that an individual develops a fever. In most cases, the fever will be mild-to-moderate and will subside within a week or so of detoxification. Additionally, most individuals derive adequate fever relief from the administration of over-the-counter acetaminophen or NSAIDs. In addition to managing many other symptoms of opiate withdrawal, preliminary evidence suggests that clonidine might facilitate an antipyretic effect to treat a fever.
- Headaches / Migraines: Among the most common symptoms of opiate withdrawal is headache and/or migraine. During opiate detoxification, any number of neurochemical and/or hormonal imbalances may trigger vasoconstriction or vasodilation of intracranial blood vessels, such that blood flow is either: restricted to cause a tension-type headache, increased to induce a throbbing migraine, respectively. While detoxification-related headaches and migraines generally diminish in time, some individuals struggle to cope with the pain. Clonidine is a medication that can modulate neurotransmitters implicated in vasoconstriction and vasodilation, thereby alleviating detox-related headache or migraine in a subset of persons.
- Hot flashes: Unexpected surges of intense or feverish heat, commonly referred to as "hot flashes," can occur with increased regularity for some individuals during opiate withdrawal. Although hot flashes are undesirable, they are generally easy to manage and not a big deal compared to other opiate withdrawal symptoms. The precise causes of hot flashes during opiate withdrawal remain unclear, however, a combination of neurochemical and/or neuroendocrine irregularities are probably liable. Research suggests that clonidine treats hot flashes associated with menopause by downregulating sympathetic tone and expanding the thermoneutral zone. Based on these findings, there's reason to believe that clonidine may also attenuate hot flashes during opiate detoxification.
- Insomnia: At some point during opiate detoxification, most individuals will experience insomnia, roughly defined as the inability to fall asleep and/or stay asleep at desired or intended times. Insomnia can negatively affect sleep quality and/or duration, as well as disrupt a person's circadian rhythm. If withdrawal-related insomnia remains severe and/or is unaddressed, it may potentiate the severity of other opiate withdrawal symptoms and/or prolong the entire withdrawal process. Although a variety of prescription medications such as nonbenzodiazepines or "Z-drugs" can treat withdrawal-related insomnia, clonidine might be a useful alternative. Studies indicate that clonidine effectively treats insomnia among individuals with ADHD, and considering its inhibitory effect throughout the CNS, there's reason to think that it may promote sedation and/or sleepiness to override the neurobiology of withdrawal-related insomnia. What's more, clonidine is known to mitigate symptoms of withdrawal that may directly cause, or indirectly contribute to insomnia, including: agitation, anxiety, and restlessness.
- Irritability: Most individuals who've gone through opiate withdrawal will have experienced some irritability. When irritable, it may seem as if every little thing gets on your nerves and/or evokes internal anger or hostility. Things that wouldn't have bothered you while taking opiates may seem to "get on your nerves" or "under your skin." The irritability is likely due, in part, to imbalanced neurochemistry in withdrawal. Due to its anxiolytic effect without impairing cognition, clonidine can improve a person's ability to cope with irritability during opiate withdrawal. Furthermore, clonidine may address certain neurochemical underpinnings of irritability during withdrawal.
- Mood swings: A person's mood during opiate withdrawal is often subject to fluctuation. During the initial weeks of withdrawal, individuals may experience a combination of negative emotions such as: anger, anxiety, depression, irritability, etc. In other words, one moment a person may experience extreme anger, the next moment he/she may experience some depression, and later he/she may feel anxious. It may seem as if the individual is stuck in an incessant cycle of negative emotions. Sometimes a bit of positive emotion may creep back into one's consciousness, but then negativity may reemerge. This unpredictable emotional fluctuation is attributable to neurochemistry readjusting from a state of opiate dependence to homeostasis. The medication clonidine may modulate neurochemistry to stabilize mood during withdrawal.
- Pain: It is understood that the reason most individuals end up using opiates is to manage chronic pain conditions. Unfortunately, even when administered at a fixed-dose, the long-term administration of opiates leads the user to develop tolerance whereby the pain relief derived from the opiate diminishes. During opiate detoxification, someone with chronic pain will be prone to intense rebound pain. Even among persons detoxifying from opiates without chronic pain conditions, bodily aches and physical pains commonly emerge during withdrawal. To mitigate the aches and pains during withdrawal, usage of a medication may be necessary. Although an unconventional option, clonidine appears to exert an analgesic effect which may reduce debilitating physical pain for some individuals during withdrawal.
- Restlessness: Most people who've gone through opiate detoxification will experience restlessness and feel a constant and/or uncontrollable urge to fidget or move around. The restlessness generally goes hand-in-hand with other symptoms of opiate withdrawal such as agitation, anxiety, insomnia, and irritability. Staying physically active throughout the day and engaging in relaxation exercises at night can help combat some of the restlessness, however, these nonpharmacological interventions are often inadequately effective. For this reason, it is common for individuals experiencing restlessness during opiate withdrawal to pursue pharmacological interventions. Although clonidine may not be a first-line treatment for restlessness, there's reason to suspect that it could help by decreasing excitatory transmission and corresponding CNS activity.
- Restless leg: While restlessness is sometimes experienced throughout many regions of a person's body during opiate withdrawal, it is usually most noticeable within the legs and referred to as restless leg syndrome. Restless leg syndrome, referred to under the acronym RLS, can be described as an irresistible urge to move the legs. What's troubling for most is that RLS can interfere with the ability to focus throughout the day in an academic or occupational setting due to excessive fidgeting, and can significantly disrupt sleep at night. In fact, most individuals who experience RLS report that it worsens at night whereby it induces [or potentiates preexisting] insomnia. To endure unwanted RLS that emerges during withdrawal, it is often helpful for individuals to use medication. Though not formally endorsed for the treatment of RLS, preliminary evidence suggests that clonidine can reduce RLS in a subset of persons.
- Sleep disturbances: Without the strategic usage of prescription medications and/or supplements, getting enough quality sleep during opiate withdrawal is impossible for most. Sleep disturbances during withdrawal are generally a consequence of imbalanced neurochemistry. Briefly explained, when a person first uses opiates, the opiates modulate neurotransmitters to induce sedation and relaxation, making it easier to fall asleep. Over time, the central nervous system (CNS) adjusts itself to the effect of the opiate, and the significance of sedation and relaxation diminishes. Because of the CNS adjustment, when a person finally detoxifies from opiates, activity in the CNS is excessive and arousal remains high – making it difficult to get enough quality sleep. The administration of clonidine during opiate withdrawal reduces sympathetic activation and the release of excitatory neurotransmitters, which for most, should result in better sleep.
- Spasms: Some individuals will experience intermittent or nonstop muscle spasms or involuntary sudden muscle contractions during opiate withdrawal. Although muscle spasms are unwanted, most individuals realize that in time, the spasms will diminish and eventually stop altogether. Drinking enough water and correcting micronutrient/electrolyte deficiencies can minimize spasms during opiate withdrawal, however, not all will benefit from this simple advice. Another option involves the usage of medication. Despite the fact that clonidine is not a myorelaxant, it reduces sympathetic activation, and hypothetically, might prevent muscle spasms by interfering with the release of excitatory transmitters.
- Tension: There's reason to think that clonidine could help reduce muscle tension during opiate withdrawal. Studies show that clonidine can significantly attenuate spasticity, or involuntary muscle stiffness whereby individuals perceive their muscles as heavy and/or difficult to move. Considering these findings, it's possible that muscle tension that typically increases among patients detoxifying from opiates, may decrease with clonidine usage. Tension throughout the body may also result from excessive norepinephrine release and/or arousal, each of which clonidine can reduce.
- Tremor: In the days after discontinuing an opiate, many individuals will experience tremor or the "shakes." These shakes are generally uncontrollable and a byproduct of peripheral and central chemical imbalances. As the body readapts to functioning without the influence of an opiate, the withdrawal-induced tremor should subside. That said, in the meantime, ongoing tremor can be anxiety-provoking and/or downright distracting for patients. Research supports the idea that clonidine can treat essential tremor, and when this is considered, it's not a stretch to assume that clonidine can reduce tremor associated with opiate detox.
- Twitching: A reported opiate withdrawal symptom that is relatively similar to tremor and often regarded as synonymous to muscle spasms, is twitching. Twitching is described as a brief, uncontrollable jerking movement. During opiate withdrawal, individuals may notice twitching in one specific region of the body (e.g. the face) or throughout multiple regions. Although there are many potential causes of twitching during opiate withdrawal, stress and anxiety are often implicated. Since clonidine is able to effectively reduce stress and anxiety by downregulating sympathetic tone, it may improve twitching.
How Clonidine Works to Reduce Withdrawal Symptoms (Mechanisms of Action)
To understand the specific mechanisms by which clonidine likely attenuates symptoms of opiate withdrawal, it is necessary to examine its pharmacodynamics. Pharmacodynamic research indicates that clonidine functions primarily as an agonist of alpha-2 adrenergic receptors and I1-imidazoline receptors. Simultaneous agonism of alpha-2A adrenergic receptors and I1-imidazoline receptors is hypothesized to facilitate a bulk of the therapeutic effect derived from clonidine during opiate detoxification.
In addition to its primary action upon alpha-2A and I1 receptors, clonidine exerts a less substantial secondary effect upon alpha-2B and alpha-1D receptors. It is possible that this secondary effect upon alpha-2B and alpha-1D receptors yields distinct therapeutic benefit [from that associated with its primary action] during opiate withdrawal. Another possibility is that the secondary effect of alpha-2B and alpha-1D receptor agonism synergistically bolsters the principal therapeutic effect attributable to alpha-2A and I1 receptor agonism.
To a negligible extent, clonidine interacts with other pharmacological targets including: alpha-2C, alpha-1A, and alpha-1B receptors. That said, at low-to-moderate dosages, there's likely no therapeutic benefit justifiably attributable to the agonism of alpha-2C, alpha-1A, and/or alpha-1B receptors during opiate withdrawal. Included below are descriptions of the specific mechanisms of clonidine's action in respect to how each could alleviate symptoms of opiate withdrawal.
Alpha-2A receptor agonist: Alpha-2A adrenergic receptors are G protein-coupled receptors (GPCRs) found within many regions of the brain including the: brainstem (especially the locus coeruleus), cerebral cortex, cerebellum, midbrain, hippocampus, hypothalamus, and septum. As was already mentioned, clonidine predominantly functions as an agonist of alpha-2A adrenergic receptors. For many individuals, the agonism of alpha-2A receptors facilitated by clonidine is capable of attenuating a majority of withdrawal symptoms that emerge following opiate detoxification.
When agonized by clonidine, alpha-2A receptors inhibit adenylyl cyclase whereby concentrations of cAMP (cyclic-adenosine monophosphate) decrease. The decrease in concentrations of cAMP inevitably induces hyperpolarization of noradrenergic neurons such that their firing (i.e. secretion of norepinephrine) diminishes. If theories suggesting that noradrenergic hyperactivity occurs during opiate withdrawal are accurate, the ability of clonidine to normalize noradrenergic activity may explain some of its therapeutic effect in the treatment of withdrawal symptoms.
The reduction in central norepinephrine secretion as a result of alpha-2A receptor agonism is known to inhibit activity within various noradrenergic pathways. When activity is inhibited within noradrenergic pathways, sympathetic tone and peripheral vascular resistance decrease, causing blood pressure and heart rate to drop. For this reason, it's logical to suspect that alpha-2A receptor agonism will effectively reduce high blood pressure, rapid heart rate, and/or palpitations that might occur during opiate withdrawal.
Reduced excitatory transmission in the CNS resulting from alpha-2A agonism might also prove helpful in attenuating unwanted muscle pain, restlessness/RLS, spasms, tension, and twitching – associated with detox. Furthermore, any substantial [alpha-2A receptor-mediated] sympathetic tone reduction may induce anxiolytic, hypnotic, and/or sedative effects such that symptoms of agitation, anger, anxiety, insomnia, and/or irritability become easier for patients to manage during withdrawal. Withdrawal-related migraines may also improve directly as a result of alpha-2A receptor agonism.
When alpha-2A receptors are stimulated, the diameter of intracranial blood vessels is altered. As a result, corresponding blood flow through those blood vessels changes such that migraines become less likely. Migraines may also be prevented during withdrawal as a result of alpha-2A receptor-mediated inhibition of substance P release. When alpha-2A receptors are agonized, nociceptive neurons in certain regions of the brain secrete less substance P.
Since substance P is a potent vasodilator, inhibiting its secretion may be highly effective for migraine prophylaxis during withdrawal. High concentrations of substance P are associated with anxiety, depression, pain, inflammation, and vomiting. By limiting substance P secretion via alpha-2A receptor agonism, neuropsychiatric and physical symptoms of opiate detoxification should be easier for patients to manage.
Moreover, central agonism of alpha-2A receptors is thought to facilitate an analgesic and antinociceptive effect, possibly lessening the severity of bodily aches and muscle pains experienced during detox. Also worth underscoring is the fact that clonidine's alpha-2A agonism can ameliorate cognitive deficits. Clonidine agonizes postsynaptic alpha-2A adrenergic receptors and upregulates norepinephrine input from the locus coeruleus to enhance noradrenergic tone throughout the prefrontal cortex.
As a result, if administered at an optimal dose, the alpha-2A receptor agonism facilitated by clonidine should improve prefrontal noradrenergic tone to eradicate signs of cognitive dysfunction (e.g. attentional deficits, brain fog, memory impairment, etc.) that can occur during opiate withdrawal. Everything considered, clonidine's alpha-2A receptor agonism can substantially attenuate many opiate withdrawal symptoms. Anyone who finds clonidine useful during opiate detox can likely attribute most of the therapeutic benefit to its action as an alpha-2A receptor agonist.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/364997/
I1 receptor agonist: Historical documentation suggests that clonidine was engineered to mimic the structure of imidazoline-derived decongestants. Although clonidine was initially thought to act predominantly as an alpha-2A adrenergic receptor agonist, research by Bousquet et al. (1984) revealed that clonidine also interacted with imidazoline binding sites (IBSs). Imidazoline binding sites can be distinguished from alpha adrenergic receptors because they are not activated by catecholamines.
It is now understood that clonidine exhibits high binding affinity for I1 imidazoline receptors as an agonist. Clonidine's agonism of I1 receptors inhibits the excitatory activity of neurons localized in the rostral ventrolateral medulla (RVLM) which induces sympathoinhibition and yields a predictable antihypertensive effect. Research by Prichard and Graham (2000) suggests that clonidine lowers blood pressure principally through its action upon I1 receptors rather than upon alpha-2 adrenergic receptors.
What's more, investigations by Bousquet et al. reveal correlations between the significance of a drug's antihypertensive effect and its affinity for imidazoline receptors – not its affinity for alpha-2 adrenergic receptors. During opiate withdrawal, a subset of individuals will experience symptoms such as hypertension, rapid heart rate, and palpitations – each of which may be caused by excessive excitatory transmission. Agonism of I1 receptors can counteract excessive sympathetic activity to attenuate a subset of unwanted cardiovascular symptoms that emerge during opiate detoxification.
Due to the paucity of research investigating the effects of I1 receptor activation, it remains unclear as to whether this action of clonidine ameliorates symptoms of opiate withdrawal beyond those of cardiovascular origin. Preliminary research by Nikolic and Agbaba (2012) indicates that imidazoline receptors can influence anxiety/stress, inflammation, mood, and pain. Perhaps the I1 agonism [and corresponding sympathoinhibition] facilitated by clonidine yields anxiolytic, antidepressant, analgesic, and/or anti-inflammatory effects to help with the management of opiate withdrawal.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/6146707
- Source: https://www.ncbi.nlm.nih.gov/pubmed/9374795
- Source: https://www.ncbi.nlm.nih.gov/pubmed/10984201
- Source: https://www.ncbi.nlm.nih.gov/pubmed/21884004
Other mechanisms by which Clonidine may help manage opiate withdrawal
Although a majority of clonidine's therapeutic effect is attributable to its agonism of alpha-2A adrenergic and I1 imidazoline receptors, evidence suggests that it acts upon other pharmacological targets. At moderate-to-high doses, it is possible that clonidine users derive therapeutic benefit from its action upon secondary and tertiary targets. Examples of such targets, listed in order of clonidine's binding affinity, include: alpha-2B, alpha-1D, alpha-2C, alpha-1A, and alpha-1B receptors.
- Alpha-2B agonist: Clonidine exhibits approximately 2.48-fold lower binding affinity for alpha-2B receptors than alpha-2A receptors. That said, it's agonism of alpha-2B adrenergic receptors may play a role in attenuating symptoms of opiate withdrawal. Animal model data suggests that agonism of the alpha-2B receptor may generate antinociceptive and/or analgesic effects. If similar effects occur in humans as a result of alpha-2B agonism, this mechanism could attenuate the severity of bodily aches and muscle pains during opiate withdrawal. Moreover, since activation of alpha-2B receptors is thought to influence cardiovascular function, it's plausible that this mechanism of action could ameliorate cardiac irregularities associated with opiate discontinuation.
- Alpha-1D agonist: Clonidine exhibits approximately 2.93-fold lower binding affinity for alpha-1D receptors than alpha-2A receptors. Since the physiological effects of alpha-1D receptor agonism aren't well-researched in humans, it remains unclear as to whether this mechanism of clonidine's action is of therapeutic value during opiate withdrawal. Preliminarily, it is suspected that agonism of alpha-1D receptors affects physiological processes such as urinary tract function and, to a lesser extent, cardiovascular function. Based preliminary speculation, one might hypothesize that clonidine's action as an alpha-1D receptor agonist could improve symptoms such as frequent urination and/or [certain] cardiac abnormalities associated with opiate withdrawal.
- Alpha-2C agonist: Clonidine exhibits approximately 5.43-fold lower binding affinity for alpha-2C adrenergic receptors than its primary target of alpha-2A. At low doses, the physiological effects stemming from clonidine's agonism of alpha-2C receptors are likely negligible or nonexistent. Nonetheless, during opiate withdrawal individuals may administer moderate-to-high doses of clonidine whereby alpha-2C receptors receive adequate stimulation, potentially yielding therapeutic effects during opiate detoxification. Research suggests that alpha-2C receptor stimulation induces analgesia, antinociception, sedation, and sympathoinhibition. If this is the case, alpha-2C agonism is likely to attenuate a host of opiate withdrawal symptoms such as: anxiety, muscle tension, pain, palpitations, and rapid heart rate. Since alpha-2C receptors also modulate central norepinephrine release and blood vessel diameter, agonism of these receptors may also ameliorate withdrawal-related cognitive deficits and/or headaches.
- Alpha-1A agonist: Binding assays suggest that clonidine exhibits approximately 7.37-fold lower affinity for alpha-1A receptors than alpha-2A receptors. Among individuals using low doses of clonidine, no substantial therapeutic effects are attributable to its agonism of alpha-1A receptors. If someone were taking high doses of clonidine, perhaps alpha-1A receptors would receive enough stimulation to yield physiological changes that augment the favorable physiological effects derived from clonidine's agonism of other alpha-adrenergic receptors. Research indicates that alpha-1A receptors influence cardiac, urinary tract, and prostate function. Additionally, some hypothesize that alpha-1A receptor activity may affect mood. It's possible that alpha-1A receptor agonism derived from clonidine modestly attenuates opiate withdrawal symptoms associated with cardiac, urinary, and/or neurophysiological function.
- Alpha-1B agonist: Clonidine exhibits an identical binding affinity for alpha-1B receptors as it does for alpha-1A receptors (~7.37-fold less than its affinity for alpha-2A receptors). Because of its low affinity for alpha-1B receptors, any therapeutically-relevant effects derived from clonidine during opiate withdrawal are unlikely attributable to its alpha-1B agonism. That said, in the event that someone uses high-dose clonidine, alpha-1B receptors may receive some stimulation whereby they exert a favorable physiology-altering effect that attenuates various symptoms of opiate withdrawal. In animals, alpha-1B receptors can influence learning, mood, exploratory behaviors, cardiac processes, and prostate function. Perhaps the negligible effect of clonidine upon alpha-1B receptors helps counterbalance opiate withdrawal symptoms such as: cardiac irregularities, cognitive dysfunction, and/or emotional dysregulation.
Note: As with any drug, the significance of clonidine's action at various receptor sites will be contingent upon the dosage administered. If administered at a low dosage, we can expect clonidine to occupy fewer total receptors and act primarily via agonism of alpha-2A and I1 receptors. If administered at a high dosage, secondary actions of clonidine such as alpha-2B agonism may generate and/or contribute to its therapeutic effect.
Moreover, there may be other mechanisms of clonidine's action that play a role in the attenuate opiate withdrawal symptoms. According to the literature, clonidine facilitates an anti-inflammatory and anti-oxidative effect, each of which could directly ameliorate a host of unwanted opiate withdrawal symptoms. Although these actions may be indirect or downstream effects of clonidine's alpha-adrenergic receptor agonism, they may also be distinct mechanisms of clonidine's action, and regardless, are worth mentioning.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/11927164
- Source: https://www.ncbi.nlm.nih.gov/pubmed/11752127
- Source: https://www.ncbi.nlm.nih.gov/pubmed/7477883
- Source: https://www.ncbi.nlm.nih.gov/pubmed/9952154
Benefits of Using Clonidine for Opiate Withdrawal (Possibilities)
There are many potential benefits to be derived from utilizing clonidine during opiate withdrawal. Perhaps the most substantial benefit to be attained from using clonidine during detox is that its usage is supported by evidence from studies dating back to the late 1970s. Other benefits associated with clonidine include its: ability to treat comorbidities, adjunct potential, low cost, and non-opioidergic/non-addictive mechanism of action. Moreover, clonidine can be used as a rapid detox intervention or as a long-term therapy in post-acute stages of withdrawal.
- Adjunct option: In some cases, low doses of clonidine can be safely administered as an adjunct to other pharmacological interventions during opiate withdrawal. As an adjunct, clonidine may address opiate withdrawal symptoms that first-line interventions are unable to, or inadequately, treat. Furthermore, clonidine may act synergistically with certain medications to provide greater symptomatic relief than if each intervention were administered as a monotherapy. For example, a randomized controlled trial in which clonidine was administered as an adjunct to buprenorphine discovered that it significantly attenuated stress-induced cravings and increased time of abstinence – compared to an adjunct placebo. Clonidine has also been noted as effective when co-administered with drugs like amantadine and naltrexone during opiate withdrawal.
- As-needed: Another benefit associated with using clonidine during opiate withdrawal is that occasionally, medical professionals may allow patients to administer it on an "as-needed" (P.R.N.) basis. While certainly not everyone will benefit from "as-needed" usage of clonidine, individuals who are using clonidine as an adjunct may only wish to take it when specific withdrawal symptoms flare up. As a hypothetical example, let's assume a person experiences sedation from clonidine. Due to the sedative effect, this particular individual may find clonidine useful for the management of withdrawal-related insomnia. If allowed to administer clonidine on an "as-needed" basis, the individual can use clonidine on nights when insomnia occurs, yet avert its usage and corresponding sedation when unnecessary (e.g. mornings, afternoons, nights without insomnia). Moreover, an "as-needed" administration protocol may be perceived as beneficial by patients who dislike being under the influence of clonidine and/or dealing with its side effects 24/7.
- Cognitive enhancement: While most individuals inevitably take some time off from cognitively-demanding academic and/or occupational pursuits during opiate detoxification, some may wish to get back into a productive routine as soon as possible. One significant benefit associated with the usage of clonidine during opiate withdrawal is that, unlike most pharmacological interventions, clonidine may enhance cognitive faculties. Its ability to enhance cognition is related to agonism of postsynaptic alpha-2A [and possibly also alpha-2C] adrenergic receptors. The agonism effect upon these receptors increases noradrenergic activity in the prefrontal cortex to improve aspects of executive function (e.g. attention, memory, etc.). Improvement in executive function is thought to explain the efficacy of clonidine for ADHD. Anyone who experiences a cognitive boost from clonidine during opiate withdrawal is likely to perceive it as favorable.
- Effective detox protocols: Although clonidine is sometimes utilized for an extended duration after opiate cessation, it may be used as part of a short-term detoxification protocol. Most clonidine-based detoxification protocols involve the administration of clonidine at a low "test dose" to ensure tolerability among patients. After tolerability is confirmed, the dose is titrated upwards and administered over a 10-day duration. Thereafter, the dosage is titrated downward over an additional 3-day period and patients cease clonidine and initiate naltrexone monotherapy for the maintenance of abstinence. Some research suggests that clonidine drastically expedites the duration of detoxification for most patients compared to other medications.
- Evidence-based: Dating back to the 1970s, clonidine has been evaluated in trials for the treatment of opiate withdrawal symptoms. From the 1970s to present, nearly every published trial and case study in which clonidine was administered to patients undergoing opiate detox reported substantial therapeutic benefit in regards to the attenuation of withdrawal symptoms; the data are consistent – not mixed. Some of these trials implemented randomized and/or controlled designs, indicating that the results are relatively trustworthy. Although conducting additional randomized controlled trials with large sample sizes could further solidify clonidine's therapeutic efficacy for the treatment of opiate withdrawal symptoms, clonidine is already more evidence-based than most medications utilized in opiate withdrawal.
- Formats: Another favorable aspect of utilizing clonidine to manage symptoms of opiate withdrawal is that it is manufactured in various formats including: pills, patches, and a liquid solution. The pills are intended for oral administration, and are sold as "IR" (immediate-release) and "ER" (extended-release). The immediate-release pills deliver an effect for up to 4 hours, whereas the extended-release pills deliver an effect for a full 24-hour period. The patches are administered transdermally and deliver an effect for a full 7-day period. The liquid solution of clonidine is administered via epidural and reserved for persons with severe cancer pain. Individuals who use clonidine during opiate withdrawal will likely receive the drug in pill (IR / ER) format, but transdermal patches are a possibility. Many formats of clonidine are helpful in that treatment can be tailored to meet individualized needs of patients. For example, one patient may require a consistent dose of clonidine over a full week, and to simplify things, patches may seem like the best option. In a different situation, a patient may only wish to take clonidine when certain symptoms become debilitating, in which case the immediate-release (IR) format may be an ideal option.
- Low abuse/addiction potential: Pharmacological assays indicate that clonidine acts predominantly upon alpha-adrenergic receptors as an agonist to induce sympathoinhibitory effects such as sedation and relaxation. Agonism of alpha-adrenergic receptors yields neither psychologically-pleasurable nor rewarding effects for clonidine users. For this reason, clonidine is considered to have a low potential for abuse/addiction and is predictably not classified as a controlled substance in the United States. Knowing that many individuals detoxifying from opiates have histories of drug abuse, it may be best to prescribe an agent like clonidine [virtually devoid of abuse potential] over more addictive drugs with abuse potential like methadone and buprenorphine.
- Long-term effects: Not everyone who uses clonidine during opiate withdrawal ends up using it for a short 10-day detox. Some individuals will continue clonidine treatment for a longer-term to manage PAWS (Post Acute Withdrawal Syndrome) and to help maintain opiate abstinence. Although dependence and tolerance to clonidine can accrue over time, data suggests that it is unlikely to cause adverse long-term effects. For reference, a study by Ferder, Inserra, and Medina (1987) analyzed the effect of long-term antihypertensive therapy among 128 patients (male and female) over a 10-year duration. Each of the patients had been taking between 0.15 mg and 1.2 grams of clonidine (b.i.d.). After a decade of clonidine treatment, there were no noticeable changes in renal or liver function, nor in serum electrolytes or lipids of the patients. It was concluded that long-term clonidine administration regulates blood pressure with minimum side effects and no adverse health effects.
- Low cost: Not everyone detoxifying from opiates has comprehensive health insurance coverage that cover the costs of prescription medications utilized during opiate withdrawal. Various medications prescribed during detoxification remain under patent, and sometimes retail at hundreds of dollars for a single month's supply – making them an unaffordable option for many patients. Assuming you have poor or minimalistic health insurance coverage and incur out-of-pocket expenses for your prescriptions, clonidine will seem like a bargain. Most pharmacies sell 60 pills of clonidine (at dosages of 0.1 mg, 0.2 mg, 0.3 mg) within the range of $6 to $10, equating to approximately $0.17 per pill – a very affordable price. Even if compared to other generic medication used during opiate withdrawal (e.g. buprenorphine/naloxone retailing for $30 to $70 for a month's supply), clonidine is still a better deal.
- Medical conditions: Research suggests that individuals diagnosed with opiate dependence commonly exhibit additional [or comorbid] medical conditions, some of which might remain untreated at the time of detox. It is known that clonidine is approved by the FDA for the treatment of hypertension and ADHD. Moreover, there's evidence to suggest that clonidine can help treat conditions such as: anxiety, chronic pain, hot flashes, and migraine. Assuming an individual with an untreated medical condition for which clonidine is approved to treat were undergoing opiate detoxification, he/she may be pleasantly surprised to find that clonidine simultaneously manages detox-related symptoms plus the medical comorbidity.
- Monotherapy: A majority of the research in which clonidine was found to be effective for the treatment of opiate withdrawal symptoms administered it as a monotherapy. Assuming patients tolerate clonidine without adverse effects, it has been show to alleviate detox-related symptoms when administered for 7 to 10 days post-opiate cessation [followed by a 3-day taper]. Although adjunct interventions can be utilized in conjunction with clonidine, many individuals derive sufficient symptomatic relief from standalone clonidine. Using clonidine as a monotherapy may be preferred over other multi-drug interventions due to lower risk of interactions, contraindications, and side effects. Moreover, prescribing a single medication simplifies things for patients, possibly increasing likelihood of adherence to treatment in outpatient settings.
- Non-opioid: Although opioid-replacement therapies such as buprenorphine and methadone can be useful during detoxification, they are sometimes poor choices for individuals with a history of drug abuse and/or addiction. Both buprenorphine and methadone act upon the mu-opioid receptor in the brain similar to most opiates/opioids, thereby delivering an opioidergic effect. Some argue that these replacement therapies, especially if permitted for a long-term, simply prolong recovery from opioid dependence. Furthermore, each of these interventions can be addictive and drugs of abuse. By comparison, clonidine exerts no effect upon opioidergic transmission, is non-addictive, and not a drug of abuse. This non-opioidergic mechanism of clonidine may be especially favorable in that it allows neurochemical imbalances within the opioid system (e.g. upregulated mu-receptors) to revert back to homeostasis at a faster rate.
- Superior to other options: Based on various criteria, it's easy to argue that clonidine is superior to many other pharmacological therapies utilized during opiate detoxification. Clonidine's efficacy for the treatment of opiate withdrawal symptoms is substantiated by many studies from the 1970s throughout the 2000s. Additionally, since clonidine is non-opioidergic, it has lower potential for abuse and may allow imbalanced neurochemistry associated with opioid dependence to normalize at a faster rate. Clonidine can be used as a monotherapy or adjunct, and is extremely low cost. As of current, the overall profile of clonidine seems to be superior to benzodiazepines, baclofen, gabapentin, and kratom.
- Tolerability: For many individuals, clonidine is a tolerable drug that doesn't provoke unwanted side effects or adverse reactions during detoxification from opiates. The most common side effects of clonidine are hypotension, fatigue, dizziness, dry mouth, and somnolence. Compared to symptoms of opiate withdrawal, these side effects are mild or negligible. Assuming hypotension isn't extreme, clonidine is may be equally as tolerable as other opiate withdrawal medications.
Drawbacks of Using Clonidine for Opiate Withdrawal (Possibilities)
Although clonidine is regarded as a highly-useful medication during opiate withdrawal, it is not devoid of drawbacks. Perhaps the biggest drawback associated with clonidine is that it may be ineffective (or suboptimally effective) in the management of detoxification symptoms among heavy opiate users with a high tolerance. Other notable drawbacks associated with the usage of clonidine include: side effects (especially hypotension), interactions/contraindications, and the fact that there may be superior interventions.
- Adverse reactions: A small percentage of clonidine users can experience adverse reactions whereby the drug endangers their health and/or is intolerable. Examples of adverse reactions that can occur in a rare subset of clonidine users during opiate withdrawal include: atrioventricular block, delusions, depression, gynecomastia, hallucinations (e.g. hearing voices), hyperglycemia, intestinal pseudo-obstruction nightmares, and skin rashes. It's also possible that someone might be allergic to clonidine, possibly leading to an allergic reaction such as facial swelling, irregular heartbeat, severe dizziness, and difficulty breathing. Obviously since clonidine is not universally tolerable, this is a drawback.
- Contraindications: In addition to potential adverse reactions, some individuals will be unable to use clonidine due to contraindications. According to medical documentation, conditions such as: abnormal arterial blood flow, blood vessel disorders, depression, eye disorders, heart conditions, hypotension, kidney disease, paresthesia, and sinus bradycardia – are contraindicated with clonidine. Moreover, clonidine is contraindicated among pregnant/nursing mothers, as well as persons who've recently undergone surgery. Anyone diagnosed with a medical condition that is contraindicated with clonidine may perceive its contraindications as a drawback.
- Ineffective: Although clonidine has a longstanding history of efficacy in the management of opiate withdrawal symptoms, it is not effective for every individual. A subset of persons who receive clonidine during detox may find that it's downright useless or ineffective for the management of debilitating withdrawal symptoms. Others may find that it only provides partial symptomatic relief during opiate withdrawal. If individuals who don't sufficiently respond to clonidine receive it as a monotherapy, they will likely be at high risk of relapse. Moreover, despite the fact that clonidine is more of an evidence-based intervention during opiate withdrawal than various other medications, the quality of evidence might be considered questionable based on small sample sizes and/or suboptimal designs (e.g. non-randomized and/or uncontrolled).
- Inferior option: While some may claim that clonidine is the best medication for treating opiate withdrawal symptoms, others may believe it is an inferior intervention to others. Among persons with a long-term history of opiate abuse and a high tolerance, perhaps clonidine is a suboptimal choice compared to methadone and/or buprenorphine-based therapies. In fact, a study by Nigam, Ray, and Tripathi (1993) discovered that buprenorphine was more effective than clonidine in alleviating most subjective and objective opiate withdrawal symptoms during a 10-day detox. For a long-term high-dose opioid user who's accustomed to receiving significant mu-receptor stimulation on a daily basis, transitioning to standalone clonidine (devoid of opioidergic effect) may provide inadequate relief during withdrawal – as compared to a drug like buprenorphine. Additionally, results from preliminary head-to-head comparison studies suggest that other medications (e.g. baclofen, topamax, etc.) may be more effective than clonidine as monotherapies during withdrawal. Moreover, evidence suggests that lofexidine, a similarly-acting drug to clonidine, is more effective than clonidine in an accelerated 3-day detox setting for alleviation of withdrawal symptoms and is less likely to induce hypotension (making it more suitable for outpatients).
- Inpatient-only: Because clonidine is known to induce hypotension and may provoke adverse physiologic reactions in a subset of the population, some professionals believe its usage during opiate detoxification should be restricted to inpatients. Inpatients are under the supervision of medical professionals which allows for quick dosing adjustments and/or interventions to counteract clonidine-induced adverse reactions. Without professional supervision, outpatient clonidine users may end up with extreme hypotension, possibly leading to fainting and/or injury. Moreover, if outpatients mistakenly administer the wrong dose of clonidine and/or co-administer a CNS depressant, they may experience respiratory depression and various interaction effects. While clonidine can be safely utilized by outpatients, it may be perceived as higher risk due to potential hypotension.
- Interactions: During opiate withdrawal, the last thing anyone wants to experience is a serious interaction effect resulting from the co-administration of clonidine and another substance. Like any medication, clonidine can interact with co-administered substances, including: beverages, dietary supplements, pharmaceutical medications, and illicit drugs. Interactions between clonidine and another substance could induce reactions such as: depersonalization, difficulty breathing, dizziness, fainting, hypotension, irregular heart rate, rash, respiratory depression – and in some cases – death. In most cases, interactions between clonidine and another drug are due to an overlap of drug-induced physiologic effect. Knowing that clonidine is sympathoinhibitory, any co-administered substance that downregulates CNS activity (e.g. alcohol, barbiturates, benzodiazepines, nonbenzodiazepines, etc.) might induce an interaction effect. Medical documentation suggests that various antidepressants, antipsychotics/neuroleptics, beta blockers, and calcium channel blockers cause interactions when taken with clonidine. It is also possible that certain drugs will induce interactions via an overlap in pharmacokinetics. A small amount of clonidine undergoes biotransformation via hepatic enzymes such as CYP2D6, CYP1A2, CYP3A4, CYP1A1, and CYP3A5 to form 4-hydroxyclonidine. If a co-administered substance either induces and/or inhibits any of the aforestated hepatic enzymes, it's possible that an interaction effect may occur. Although medical professionals will work with patients to minimize likelihood of interaction effects, the fact that clonidine interacts with many CNS depressants may be perceived as a substantial drawback during opiate detox.
- Off-label: Since clonidine is not approved by the FDA for the treatment of opiate withdrawal symptoms, some medical professionals may consider it to be an unconventional detox intervention. Because treating opiate withdrawal is technically an off-label use for clonidine, certain medical professionals will [perhaps rightfully] believe it's smarter to utilize methadone or buprenorphine-based medications for management of withdrawal symptoms. Although most patients will tolerate methadone and buprenorphine well, a subset of individuals may be better suited for a non-opioidergic medication like clonidine to accelerate recovery. Anyone who's serious about overcoming opioid dependence may be disappointed to learn that their doctor will only prescribe opioidergic medications (e.g. partial mu-receptor agonists) instead of clonidine during withdrawal, possibly prolonging recovery.
- Side effects: Although clonidine may be extremely helpful for the management of certain symptoms that arise during opiate withdrawal, it may cause unwanted side effects. Examples of very common side effects resulting from clonidine include: dizziness, dry mouth, fatigue, headache, hypotension, orthostatic hypotension, sedation, skin reactions (transdermal formats). Other clonidine side effects that are relatively common include: anxiety, constipation, erectile dysfunction, nausea, vomiting, and weight change. In some cases, the side effects of clonidine may be so significant that they outweigh any therapeutic benefit that users attain during detoxification. For example, if clonidine slightly reduces anxiety, but induces severe dizziness and hypotension – it may be smart to use another medication. While clonidine is tolerable for most users, some individuals will need to discontinue the drug due to intolerability.
- Potential abuse/dependence: Compared to most medications, clonidine has a low potential for abuse and dependence, hence its status as an uncontrolled prescription drug. That said, a subset of individuals may abuse clonidine during opiate detoxification and become dependent upon its effect. In 1992, Lauzon reported upon multiple cases in which clonidine was abused by patients receiving methadone maintenance. Another report published in 2001 by Dennison revealed that a majority of individuals in treatment for opiate dependence were aware of clonidine abuse. It was said that clonidine may potentiate the effects of opiates (e.g. heroin) and prolong the duration of an opiate's effect. Any abuse and/or misuse of clonidine can yield serious adverse reactions, and corresponding dependence may be dangerous – especially if discontinued abruptly.
- Unknown long-term efficacy: Research suggests that clonidine is an effective intervention when administered over a short-term for opiate detoxification. Additional evidence indicates that clonidine can be administered over a longer-term to maintain abstinence (i.e. prevent relapse). When used regularly for weeks in the aftermath of opiate discontinuation, clonidine seems to provide consistent therapeutic benefit. That said, it's possible that clonidine's therapeutically-relevant effect diminishes over time. Patients who plan on using clonidine over a long-term (e.g. months) to minimize likelihood of relapse or prevent protracted withdrawal symptoms may become tolerant to high dosages of clonidine and the previously-beneficial effects are barely noticeable.
- Withdrawal symptoms: Anyone that uses clonidine to help manage symptoms of opiate withdrawal will eventually discontinue treatment. Some individuals may discontinue clonidine after a short-term (e.g. 10 days), whereas others may cease usage after a longer duration (e.g. several months). In any regard, a drawback associated with using clonidine is that precaution needs to be taken during discontinuation to ensure safety of patients. Precaution generally involves the gradual downward titration of dosing (i.e. "weaning") over a reasonable timespan. If precaution isn't taken during withdrawal and/or patients abruptly discontinue clonidine, adverse effects such as rebound hypertension and rapid heart rate may occur. Moreover, even if clonidine is safely discontinued, individuals may still endure lingering clonidine withdrawal symptoms such as: anxiety, blood pressure fluctuations, difficulty concentrating, dizziness, headache, and others.
Clonidine for Opiate Withdrawal (Review of Research)
To understand whether clonidine is therapeutically beneficial during opiate withdrawal, it is necessary to examine relevant medical literature in which its usefulness was examined among patients subject to opiate/opioid detoxification. Research of clonidine as an intervention for the management of opiate/opioid detoxification syndrome commenced in the late 1970s and steadily increased in the 1980s. Results from nearly every preliminary trial and case study suggested that clonidine effectively attenuated symptoms of opiate/opiate withdrawal among persons diagnosed with addiction/dependence.
However, since most early trials of clonidine failed to implement randomized controlled designs, many questioned the accuracy of the findings. Although research investigating the usefulness of clonidine for opiate withdrawal diminished in the 1990s, it regained traction in the 2000s, with some of the newer trials implementing randomized and/or controlled designs. As of current, nearly all findings from well-designed trials conducted throughout the 2000s indicate that clonidine effectively mitigates opiate/opioid withdrawal symptoms and/or improves outcomes among persons attempting to maintain abstinence.
While additional randomized controlled trials with larger sample sizes are needed to strengthen evidence suggesting that clonidine is effective during opiate/opioid withdrawal, clonidine has been subject to a greater number of trials than most pharmaceutical interventions utilized for the management of detoxification. Included below are summaries of all published trials and reports in which clonidine was evaluated and/or discussed as a treatment for opiate/opioid withdrawal symptoms.
2015: Clonidine Maintenance Prolongs Opioid Abstinence and Decouples Stress From Craving in Daily Life: A Randomized Controlled Trial With Ecological Momentary Assessment.
Kowalczyk, Phillips, Jobes, et al. (2015) organized a study to evaluate whether clonidine could effectively attenuate stress-induced cravings for opiates like heroin. The study implemented a randomized, double-blind, placebo-controlled design and included an initial sample of 208 opioid-dependent patients, each of whom had been attending an outpatient buprenorphine-based treatment facility in attempt to cease opiates/opioid usage. Of the initial 208-patient sample, 118 patients remained abstinent from opiates/opioids for 5 to 6 weeks while receiving buprenorphine, an opioid-replacement therapy.
Among the 118 patients who had successfully refrained from opiates/opioid usage for 5 to 6 weeks, 61 patients were assigned to receive adjunct clonidine, and 57 patients were assigned to receive an adjunct placebo – for a duration of 14 weeks. To determine whether patients had reverted back to opiate usage (i.e. relapsed), drug testing was conducted three times per week via collection and analysis of urine samples. The therapeutic usefulness of clonidine among opiate/opioid-dependent patients was measured based upon the number of "lapses" and "relapses" exhibited by patients.
A "lapse" was defined as either: a positive urine test OR a missed urine test, and a "relapse" was considered 2 or more consecutive lapses. Researchers also tracked the time-to-lapse and time-to-relapse, or the duration of time between trial commencement and respective lapses and relapses. Results of the trial indicated that clonidine recipients maintained abstinence from opiates/opioids for an average of 34.8 days, whereas placebo recipients maintained abstinence from opiates/opioids for an average of 25.5 days.
Although there were no differences between clonidine and placebo recipients in time-to-relapse, the time-to-lapse was significantly greater among clonidine recipients than those who received the placebo. Additionally, an ecological momentary assessment revealed that daily life stressors of participants were less likely to induce opiate cravings among clonidine recipients than persons taking the placebo. This finding supports the hypothesis of researchers that one of clonidine's major benefits is in reducing stress-induced opiate cravings during abstinence.
Based on the aforestated findings, researchers concluded that clonidine is not only efficacious for the management of opiate withdrawal symptoms, but also as an adjunct to buprenorphine for increasing average duration of opiate abstinence. The fact that clonidine appears to decouple (or separate) life stressors from induction of opiate cravings may partially explain its usefulness in the maintenance of abstinence. Lastly, while this study didn't evaluate the efficacy of clonidine as a primary treatment of opiate withdrawal symptoms, the results support clonidine's therapeutic potential during the post-acute stages of opiate withdrawal.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/25783757
2012: Comparison of the efficacy of buprenorphine and clonidine in detoxification of opioid-dependents.
Ziaaddini, Nasirian, and Nakhaee (2012) noted that the number of worldwide opioid users continues to increase. Should an individual seek medical guidance in effort to detoxify from opioids, it is imperative that medical professionals prescribe medications that effectively attenuate detoxification-induced reactions. Debilitating physical and/or psychological reactions to opioid detoxification significantly increases likelihood of relapse, or reversion to opioid administration as a means of averting an uncomfortable withdrawal.
If unwanted reactions to opiate detoxification are minimized, odds of relapse can be reduced. Although many pharmaceutical medications are capable of attenuating symptoms of opioid detoxification, it is unknown as to whether certain medications are more efficacious than others. For this reason, researchers organized a double-blind trial comparing the therapeutic efficacy of commonly-administered opioid detoxification interventions, buprenorphine and clonidine, among hospitalized patients undergoing detox.
The study recruited 35 participants and divided them into random groups such that 14 individuals received buprenorphine [plus a clonidine placebo] and 21 individuals received clonidine [plus a buprenorphine placebo]. Persons who received legitimate buprenorphine were classified as being in "Group 1," whereas those receiving legitimate clonidine were classified as being in "Group 2." Individuals in Group 1 administered buprenorphine from Day 1 to Day 5 at daily doses of 2 mg, 4 mg, 6 mg, 4 mg, and 2 mg – respectively.
Individuals in Group 2 administered clonidine from Day 1 to Day 5 at daily doses of 0.2 mg (b.i.d.), 0.2 mg (t.i.d.), 0.2 mg (t.i.d.), 0.2 mg, and 0.2 mg – respectively. To determine relapse rates in each group, participants' urine samples were collected during acute detox and analyzed for opioid metabolites using thin layer chromatography. Efficacies of each intervention were determined based upon: clinical opiate withdrawal scale (COWS) scores [on Day 5 of detox], success rate with naltrexone [2 days after buprenorphine/clonidine cessation], rate of adherence to naltrexone (25 mg/day) for 6 months post-detox, and prevalence of opioid metabolites within urine samples collected for 6 months post-detox.
Results indicated that recipients of buprenorphine (Group 1) and clonidine (Group 2) exhibited substantial reductions in detoxification-related symptoms as evidenced by low COWS scores on Day 5 post-detox. Additionally, overt and subjectively-reported symptoms of opioid withdrawal significantly decreased during detoxification in both Group 1 (buprenorphine users) and Group 2 (clonidine users). It was further noted that adherence to naltrexone treatment over the 6-month post-detoxification period didn't differ between the groups, nor did relapse rates.
Researchers concluded that both buprenorphine and clonidine effectively attenuate symptoms of opiate detoxification, thereby minimizing likelihood of relapse. It was recommended that professionals select either buprenorphine OR clonidine based on patient-related factors such as: potential contraindications, affordability, and/or preference. Although the results generated within this study may be accurate, it's important to emphasize that this was a small-scale trial with potentially-suboptimal medication dosing of buprenorphine and/or clonidine.
With a larger sample, we'd know with greater accuracy as to whether buprenorphine and clonidine are legitimately of equal efficacy in terms of attenuating opiate detoxification symptoms. Some might also argue that the duration over which buprenorphine and clonidine were administered was too short and should've been extended to 10 days – rather than 5. Nonetheless, this study supports the idea that clonidine is an effective non-opioidergic medication for the management of opiate withdrawal.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/24494140
2007: Clonidine attenuates morphine withdrawal and subsequent drug sensitization in rhesus monkeys.
Chen, Zhai, Cui, et al. (2007) conducted a study to determine whether clonidine could alleviate opiate withdrawal symptoms and/or modify the neurophysiologic effects of subsequent illicit drug use. The study incorporated a group of adult male rhesus monkeys who initially received morphine for a 90-day duration to induce opiate dependence. After induction of opiate dependence, the rhesus monkeys underwent detoxification whereby morphine was abruptly discontinued.
A subset of the rhesus monkeys received clonidine for a 1-week duration to help with detox, whereas others had to endure unassisted detox. Researchers monitored the rhesus monkeys and documented all overt withdrawal symptoms. To investigate whether clonidine would influence neurophysiologic effects of subsequent illicit drug usage, rhesus monkeys would later receive challenge injections of morphine or cocaine.
Results of the trial indicated that, on average, rhesus monkeys experience severe withdrawal symptoms that persist for 2 weeks post-morphine discontinuation. Additionally, subsequent administration of morphine and cocaine yields sensitized responses. That said, if clonidine is administered post-morphine discontinuation for a 1-week duration, withdrawal symptoms are significantly reduced and sensitization to subsequent drug use is minimized. It was concluded that clonidine not only is useful in the acute management of opiate withdrawal symptoms, but also in attenuating effects of subsequent drug abuse after detox.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/17376286
2004: Topiramate in opiate withdrawal – comparison with clonidine and with carbamazepine/mianserin.
Zullino, Krenz, Zimmerman, et al. (2004) suggested that anticonvulsant agents functioning as AMPA/kainate glutamate receptor blockers may prove therapeutically useful during opiate detoxification. Preclinical studies had indicated that AMPA/kainate glutamate receptor blockade appeared to attenuate both physical and psychological aspects of opioid withdrawal. For this reason, researchers organized a study in which the therapeutic value of the anticonvulsant drug topiramate was compared to clonidine and a combination of carbamazepine/mianserin – among patients undergoing opiate withdrawal.
The study included a total of 30 patients who sought medical care for opiate detoxification. Of the 30 patients admitted for medical detox: the first 10 patients were assigned to receive topiramate, the subsequent 10 patients were assigned to receive clonidine, and the final 10 patients were assigned to receive a combination of carbamazepine/mianserin. Various adjunct medications were also administered on an "as-needed" basis throughout the study for unremitting withdrawal symptoms, including: analgesics, antiemetics, anxiolytics, hypnotics, and myorelaxants.
Additionally, a subset of patients received antidepressants or antipsychotics to treat comorbid neuropsychiatric conditions. Among the 10 topiramate recipients, 4 received antidepressants and 1 received an antipsychotic. Of the 10 clonidine recipients, 4 received antidepressants, 1 received an antipsychotic, and 1 a proton-pump inhibitor (PPI). Within the group of 10 carbamazepine/mianserin users, 3 received antidepressants and 1 received an antipsychotic.
Throughout the study, researchers assessed the frequency at which "as-needed" adjunct medications were utilized by patients. It was implied that increased usage of "as-needed" adjunct medications indicated poorer efficacy of the first-line detoxification interventions – topiramate, clonidine, and carbamazepine/mianserin. After the study, an analysis was conducted whereby the total number of "as-needed" adjunct medication administrations among patients were divided by the total number of days in hospitalization.
Results indicated that topiramate recipients utilized significantly fewer "as-needed" myorelaxants than recipients of clonidine OR carbamazepine/mianserin. Moreover, individuals receiving topiramate OR clonidine utilized significantly fewer "as-needed" analgesics than recipients of carbamazepine/mianserin. Researchers also reflected upon dosage reductions throughout the study and corresponding rationales for those reductions.
It was reported that topiramate dosage reductions mostly occurred as a result of a successful detox – rather than to avoid side effects. On the other hand, dosage reductions among clonidine and/or carbamazepine/mianserin recipients were said to have resulted from unwanted side effects such as hypotension and nausea/vomiting, respectively. Based on the results of this study, one might conclude that usefulness of each medication during opiate withdrawal is hierarchal such that: topiramate is most useful, clonidine is less useful than topiramate, and carbamazepine/mianserin is least useful.
Despite these findings, there are some notable limitations associated with this study including: the lack of randomization, double-blinding, and a placebo control; the small sample size (of just 30 participants); and the allowance of numerous adjunct medications – many of which may have affected the results. Furthermore, the duration of the clonidine protocol (7 days) was shorter than the topiramate protocol (9 days), possibly influencing study outcomes. In sum, this study further solidifies the effectiveness of clonidine for the attenuation of opiate withdrawal symptoms, while simultaneously bringing attention to the usefulness of topiramate.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/16172090
2001: Alpha 2 adrenergic agonists for the management of opioid withdrawal.
Gowing, Farrell, Ali, and White (2001) emphasized that individuals who detoxify from opioids generally endure a challenging withdrawal phase prior to their successful maintenance of abstinence. In many cases, the withdrawal phase is so debilitating that patients commonly relapse or reinstate opioid usage to avert the disconcerting physical and/or psychological symptoms. To effectively manage the onset of detoxification-related symptoms, most individuals work with a medical professional and utilize prescription medications.
Although many medications can attenuate symptoms of opioid detoxification, more research is needed to determine the most effective interventions. Preliminary data suggests that a group of medications classified as "alpha-2 adrenergic agonists" may effectively manage opioid withdrawal symptoms. Based on this preliminary evidence, researchers conducted a review of evidence to determine the effectiveness of alpha-2 adrenergic agonists in the acute phases of opioid detoxification.
Researchers searched throughout multiple electronic databases and extracted randomized or quasi-randomized controlled trials that compared the efficacy of alpha-2 adrenergic agonists to that of an active control or placebo – for the management of opioid withdrawal symptoms among patients with opioid dependence. A total of 24 trials encompassing 1,956 participants met inclusion criteria for the review. Of the 24 trials included in this review, 19 implemented randomized controlled designs.
Additionally, 10 trials compared the efficacy of an alpha-2 adrenergic agonist to the opioid replacement medication methadone for the treatment of detoxification symptoms. Although quantitative analysis was limited by the diversity of study designs and outcomes, results indicated that alpha-2 adrenergic agonists attenuated the severity of opioid withdrawal with similar efficacy to the drug methadone. Reviewers concluded that alpha-2 adrenergic agonists such as clonidine and lofexidine can attenuate symptoms in the acute stages of opioid detoxification as effectively as methadone.
That said, side effects associated with clonidine such as hypotension, dizziness, dry mouth, and fatigue might be more problematic than those associated with other alpha-2 adrenergic agonists (e.g. lofexidine) and opioid replacement therapies such as methadone. Nonetheless, this review provides additional support for the usage of clonidine to manage opioid withdrawal symptoms. Assuming patients are able to tolerate clonidine, it seems to be an effective intervention for the management of opioid detoxification.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/11279747
2000: Double-blind randomized controlled trial of baclofen vs. clonidine in the treatment of opiates withdrawal.
Akhondzadeh, Ahmadi-Abhari, Assadi, et al. (2000) discussed the fact that an array of medications and corresponding protocols are employed for the management of opiate detoxification symptoms. That said, since not every patient undergoing opiate detoxification responds well to currently-recommended medications, there is a need for novel evidence-based interventions. One such novel intervention may be baclofen, a GABA(B) receptor agonist that has demonstrated efficacy in animal models of opiate detoxification.
Since baclofen had never been formally evaluated in humans, researchers organized a double-blind, randomized, controlled trial in which the therapeutic effect of baclofen was compared to clonidine (a longstanding evidence-based intervention for the management of opiate detoxification) among persons discontinuing opiates. A total of 62 individuals diagnosed with opioid dependence [in accordance with DSM criteria] participated in the trial and were assigned at random to receive baclofen OR clonidine for a 2-week duration following opioid cessation. The maximum daily dose of baclofen was 40 mg, and the maximum daily dose of clonidine was 0.8 mg.
To assess the therapeutic usefulness of each medication, researchers tracked the severity of opiate withdrawal symptoms via the Short Opiate Withdrawal Scale (SOWS) at baseline (prior to the trial) and on Days 1, 2, 3, 4, 7, and 14 of the trial. Analysis of the changes in SOWS scores revealed that baclofen and clonidine were equally efficacious in managing physical symptoms of opiate detoxification, however, baclofen was substantially more effective in managing psychological symptoms. Researchers concluded that baclofen might prove to be a novel, underexplored intervention for the management of opiate withdrawal.
It was acknowledged that a larger study is needed to confirm the results of this study suggesting that baclofen may be superior to clonidine for the management of opiate detoxification. Although baclofen appeared more useful than clonidine in the management of psychological symptoms of opiate detoxification, clonidine still facilitated a therapeutic effect. Moreover, this study substantiates the usefulness of clonidine during opiate withdrawal, especially in regards to mitigating physical symptoms. (Read more: "Baclofen for Opiate Withdrawal").
- Source: https://www.ncbi.nlm.nih.gov/pubmed/11123486
1995: Clonidine and opiate receptor antagonists in the treatment of heroin addiction.
Gerra, Marcato, Caccavari, et al. (1995) observed a trend of favorable clinical responses among patients with opiate dependence who received a combination of clonidine plus opiate receptor antagonists. Based on this observation, researchers decided to investigate the combined efficacy of clonidine plus opiate receptor antagonists for the treatment of opiate dependence. Researchers assessed outcomes in a total of 152 patients with heroin dependence who received: clonidine-only, clonidine plus naltrexone, clonidine plus naloxone, or placebo – to treat opiate dependence.
Outcomes of patients were evaluated in accordance with: treatment results, emotional/behavioral changes, and involvement in psychosocial programs – after a 6-month period. Results indicated that patients who received clonidine plus naltrexone (an opiate antagonist) exhibited the lowest percentage of opioid metabolites in urine (suggestive of continued abstinence) and significant improvements in both mood and relationships. What's more, the greater the duration of a patient's naltrexone treatment, the more likely the patient was to be involved in psychosocial programs.
Based on the results of the study, one might speculate that naltrexone facilitates a bulk of the therapeutic benefit in the treatment of opiate dependence whereby concurrent clonidine usage may have been unnecessary. That said, clonidine is a well-established intervention for the management of opiate withdrawal symptoms and recovery from dependence. It's possible that clonidine acted synergistically with naltrexone such that the benefit derived from this combination treatment yields better outcomes than either would as a standalone.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/7752296
1988: Clonidine and the treatment of the opiate withdrawal syndrome.
A report by Gossop (1988) assessed the usage of clonidine, a centrally-acting alpha adrenergic agonist, among individuals detoxifying from opioids. In the report, Gossop discussed the fact that clonidine had been extensively tested in controlled trials for the management of opiate withdrawal syndrome. Available data regarding clonidine's standalone efficacy and side effect profile as compared to other medications (e.g. methadone) were also discussed.
Upon assessment of the data, Gossop concluded that clonidine is capable of effectively attenuating symptoms of opiate withdrawal. Despite its ability to significantly reduce debilitating detoxification symptoms, clonidine is unable to fully eliminate them – an outcome to be expected. It was also mentioned that withdrawal patterns differ among clonidine users from methadone users, which is also not surprising given the fact that clonidine exhibits a distinct pharmacological profile from methadone.
Moreover, among persons rapidly detoxifying from opioids, the combined administration of clonidine plus naltrexone was implied to be useful. While this report from Gossop may have been limited to data from studies published throughout the early-to-mid 1980s, the evidence suggested that clonidine delivers a therapeutically-relevant benefit to patients undergoing opioid detoxification. The only major drawback associated with clonidine usage was the fact that some users experienced undesirable side effects during detoxification such as hypotension.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/3048954
1985: Clonidine in morphine withdrawal. Differential effects on signs and symptoms.
Jasinski, Johnson, and Kocher (1985) reflected upon the fact that most non-opioidergic medications appear ineffective for the management of opioid withdrawal symptoms, however, the drug clonidine seems to be an outlier. At the time, preliminary data indicated that the non-opioidergic drug clonidine exhibits anti-withdrawal properties in patients when administered following opioid discontinuation. For this reason, researchers sought to test the efficacy of clonidine for the treatment of morphine withdrawal symptoms among patients with opiate dependence.
A study was organized in which volunteer patients with opiate dependence received subcutaneous morphine sulfate at a dosage of 15 mg – four times per day. Thereafter, patients were discontinued from morphine sulfate maintenance and were assigned to receive either: clonidine, morphine sulfate, or a placebo – during withdrawal. Severity of the participants' withdrawal symptoms were monitored and compared.
Results of the study indicated that clonidine was efficacious in attenuating symptoms of opiate withdrawal. Comparatively, clonidine was more effective than morphine in treating autonomic (involuntary or unconscious) symptoms of withdrawal, likely due to its sympathoinhibitory action. That said, clonidine was less effective than morphine in treating participant-reported withdrawal symptoms and overall discomfort. Nonetheless, it was concluded that clonidine can be an effective non-opioidergic medication for the treatment of opiate withdrawal symptoms.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/2413818
1984: New insights and treatments: opiate withdrawal and cocaine addiction.
Gold and Dackis (1984) proposed a theory in which the abnormal opioidergic and noradrenergic transmission are implicated in the neurobiology of opiate withdrawal. Specifically, the researchers believed that noradrenergic neurons became hyperactive and endogenous opioid peptides were imbalanced. When considering these possible neurobiological abnormalities, researchers hypothesized that clonidine, an alpha adrenergic receptor agonist, may ameliorate symptoms of opiate withdrawal.
In the paper, Gold and Dackis noted that clonidine has many advantages over methadone in opiate detoxification, one of which is that it is non-addictive, and another of which is that it can be administered and/or prescribed by general practitioners without the approval of a specialist. The researchers also mention that utilization of clonidine to manage acute opiate detoxification allows for the immediate, subsequent usage of naltrexone to support rehabilitation in the post-acute withdrawal period. Moreover, researchers believe that clonidine may be an efficacious intervention among persons detoxifying from other drugs including cocaine.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/6394130
1983: Clonidine for the treatment of heroin withdrawal syndrome.
An open-label trial conducted by Schanda, Presslich, and Hermann (1983) tested the efficacy of clonidine for the management of heroin withdrawal symptoms. The trial recruited 50 patients with heroin dependence who intended to detoxify and refrain from further opiate use. All patients received clonidine (orally) on an "as-needed" basis for 5 to 7 days following heroin discontinuation.
The average daily dose of clonidine ranged from 0.112 mg to 0.468 mg and intake peaked by the second day of detoxification. It was noted that clonidine failed to treat detox-related insomnia, and as a result, patients received adjunctive medications such as: doxepin (100 mg per day) and/or nitrazepam (10 mg per day). Furthermore, there was no significant decrease in blood pressure that occurred among the nitrazepam recipients, possibly due to doxepin blocking onset of peripheral hypotension induced by clonidine.
A total of 9 individuals dropped out of treatment, 5 of which failed to derive sufficient benefit from clonidine, indicating that clonidine may be ineffective for up to 10% of persons detoxifying from heroin or opiates. In any regard, the results from this trial suggest that orally-administered clonidine effectively treats acute symptoms of heroin detoxification. That said, this trial is limited by a lack of randomization, controlling, and the fact that individuals received adjunct medications (some of which may have yielded as much or more benefit than the clonidine).
- Source: https://www.ncbi.nlm.nih.gov/pubmed/6649643
1982: Clonidine therapy for narcotic withdrawal.
Devenyi, Mitwalli, and Graham (1982) note that, in order to effectively treat narcotic dependence, persons with dependence must fully commit to the detoxification process. What's troubling is that most patients with narcotic dependence are reluctant to commit to follow through with detoxification due to the harshness of withdrawal symptoms. Although narcotic detoxification is typically not life-threatening, individuals with dependence may do whatever it takes to avert harsh physical and/or psychological symptoms of withdrawal.
To avoid facing withdrawal, a subset of individuals may engage in manipulative and/or uncooperative behavior, as well as do whatever it takes to attain narcotics and reinstate usage. Since cold turkey, unassisted detoxification is generally considered inhumane and unrealistic, medications are often prescribed to attenuate the severity of narcotic withdrawal symptoms. Most commonly, a fixed-dose of methadone is administered as a narcotic replacement therapy, and over time, the recipient is tapered off of methadone.
However, since methadone is a potent opioidergic medication itself, its usage to treat opioid dependence is not preferred. While most non-opioidergic medications are unable to manage symptoms of opioid discontinuation, the antihypertensive drug clonidine appears to be an exception. Devenyi, Mitwalli, and Graham presented a series of case reports in which clonidine was successfully utilized to treat symptoms of narcotic withdrawal in 4 narcotic-dependent individuals. Authors noted that, in each of the cases, the Yale protocol for opiate withdrawal [through usage of clonidine], first developed in 1978 by Gold et al., was implemented.
Case #1: The first case presented by authors discussed a 27-year-old male who developed oxycodone dependence after a thoracic spine fracture. The man received oxycodone to treat pain associated with his fracture, however, he derived such significant pleasure from the oxycodone, that he increased his usage to 24 tablets per day, many of which were attained through illicit suppliers. Approximately 3 years after the onset of his oxycodone addiction, the man was admitted to an addiction center and treated with methadone.
He remained abstinent from illicit narcotics for around 4 months, however, he reinstated oxycodone usage plus began using hydromorphone and, on occasion, used intravenous morphine. Eventually his supply of narcotics dwindled and he experienced debilitating opioid withdrawal symptoms, so he sought medical attention. To attenuate opioid withdrawal symptoms, he received clonidine for 10 days in divided doses as is suggested by the Yale protocol.
Although the patient's blood pressure dropped slightly from baseline while taking clonidine, the usage of clonidine completely eliminated all opioid withdrawal symptoms, thereby making detoxification very manageable for the patient. A follow-up with the patient was conducted over 2 months since discharge from the clonidine-assisted detox, and he had remained drug free. While it would be nice to have longer-term follow-up data, this case supports the efficacy of clonidine in managing acute symptoms of opioid withdrawal.
Case #2: The second case presented by authors involved a 28-year-old individual who was voluntarily admitted to a medical facility for detoxification from narcotics. It was reported that this individual a longstanding history of drug abuse. He first abused many types of illicit drugs as a teenager, and at the age of 17, he developed dependence to opiates through regular intake of cough syrup, followed by intravenously-administered heroin. Thereafter, the patient ended up in jail for armed robbery and underwent a methadone-assisted opiate detoxification.
Upon completion of his jail term, the patient reverted back to abusing opiates such as hydromorphone and hydrocodone. At the time of his voluntary admission, the patient was experiencing moderate withdrawal symptoms and received clonidine as an intervention. In days following the initial test-dose of clonidine (to verify tolerability), the patient's withdrawal symptoms were completely controlled and, the entire time, his blood pressure remained within a healthy/normal range.
On Day 10 of hospitalization, the patient received news that his father died and he signed himself out of the facility. Professionals implied that the patient seemed to be doing well upon discharge. That said, it is unknown as to whether the patient refrained from future opiate usage, especially in the aftermath of an emotionally-taxing event such as the death of a first-degree relative.
Case #3: The third case presented by authors involved a 33-year-old male physician who initially started using opioids to manage postoperative knee pain. For a duration of 6 years after the knee surgery, this individual administered a combination of meperidine and oxycodone to attenuate knee-related pain. Because the individual derived such significant pleasure from the aforementioned opioid medications, he resorted to injecting meperidine intravenously for a more potent effect.
In addition to administering meperidine intravenously (2-4 mg/day), the individual occasionally crushed oxycodone tablets for injection. After his 6-year term of opioid use and abuse, the individual found himself in trouble with drug control authorities at his medical practice. Thereafter, he was admitted to the hospital for detoxification whereby he experienced opioid withdrawal symptoms such as: agitation, diarrhea, runny nose, and shivers.
To assist with his detoxification, the patient received clonidine. An initial test dose of clonidine rapidly attenuated the patient's symptoms of opioid withdrawal without tolerability issues, and was continued in accordance with the Yale protocol. Although the patient reported dizziness throughout detoxification, it is unknown as to whether this was a side effect of clonidine, a symptom of opioid withdrawal, or an overlapping of both. Approximately a week into clonidine treatment, the patient experienced a postural drop in blood pressure to 70/55 mm Hg plus an increase in heart rate by 20 BPM.
To ensure safety of the patient, tapering of clonidine was instated after 7 days rather than 10 days. Following the 3-day taper period, the patient experienced no further symptoms of opioid withdrawal and appeared to remain well. This case clearly supports the usage of clonidine to manage opioid detoxification symptoms. That said, it also indicates that professionals and/or clonidine recipients remain cognizant of potential adverse reactions as related to blood pressure or heart rate.
Case #4: The fourth case presented by authors was somewhat related to the third case because it involved the wife of the physician discussed in Case #3. Upon deriving pleasurable intoxication from the intravenous administration meperidine and oxycodone, a physician convinced his wife, a 31-year-old woman to share the experience. The woman had been injecting meperidine for years at daily dosages between 600 mg and 1000 mg and simultaneously abusing other substances such as: benzodiazepines, beta blockers, laxatives, and dietary supplements.
She rationalized her opioid abuse as a way of limiting her husband's usage. After checking into a medical facility for detoxification along with her husband, the woman received clonidine to attenuate acute symptoms of opioid withdrawal. Unlike her husband, this woman experienced no significant side effects from clonidine and maintained normative blood pressure and heart rate.
That said, because the woman's husband experienced adverse reactions to clonidine (e.g. low blood pressure and increased heart rate) he necessitated an earlier-than-usual taper. Since the couple wanted to be discharged at the same time, the woman's tapering off of clonidine was initiated after 7 days in accordance with her husband's. In this case, the clonidine-assisted detox fully eliminated the woman's opioid withdrawal symptoms.
Based on the series of case reports summarized above, it appears as though clonidine is an effective non-opioidergic medication for the treatment of opioid withdrawal. The only problem with these case reports is that there were no long-term follow-ups with each of the patients to confirm their [implied] abstinence from opioids in the subsequent months after discharge. Moreover, while evidence from these case reports supports the efficacy of clonidine in managing symptoms of opioid detoxification, these case reports should not be perceived as a substitute for large-scale randomized controlled trials.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/7139433
1982: Effects of clonidine on opiate withdrawal symptoms.
Girard, Escande, Granier, and Gardes (1982) tested the effect of clonidine on opiate withdrawal symptoms in 19 patients with chronic opiate addiction. The patients were reportedly addicted to morphine, heroin, and/or dextromoramide – and had checked into a medical facility for a professionally-assisted opiate detoxification. All patients received clonidine to help attenuate symptoms of opiate detoxification.
Researchers noted that clonidine appeared to significantly reduce the severity of opiate withdrawal symptoms, and that its therapeutic effect is sometimes rapid. That said, clonidine does not fully mitigate all opiate withdrawal symptoms. It was concluded that clonidine has an anti-withdrawal effect among patients detoxifying from opiates, possibly generated via alpha-2 adrenergic agonism. Though this trial of clonidine was neither randomized nor controlled, the results supported its usefulness during detoxification and were consistent with previous research.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/6284474
1981: Clonidine in opiate withdrawal: review and appraisal of clinical findings.
Washton and Resnick (1981) reviewed the clinical investigations in which clonidine was utilized to manage symptoms of opiate withdrawal. Researchers reported that clonidine is able to treat opiate withdrawal symptoms in humans, as well as in animal models. A multitude of inpatient and outpatient trials in which clonidine was administered to patients with opiate addictions revealed that it was safe and effective for detoxification.
This review of clinical data mentioned that clonidine appears most effective when administered to help patients manage acute symptoms of opiate detoxification. Once the acute detoxification symptoms are under control, clonidine can be discontinued and naltrexone, an opioid receptor antagonist, can be introduced. Initial treatment with clonidine followed by naltrexone and psychotherapy is thought to be extremely effective among persons attempting to overcome opiate addiction.
It was noted that clonidine dosages should be customized for each patient based upon side effects, as well as the severity of opiate detoxification symptoms. Furthermore, all clonidine users should be monitored for hypotension and sedation. The reviewers concluded that clonidine is an important intervention for the treatment of opiate addiction, especially among individuals for whom using methadone is suboptimal.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/6765486
1980: The use of clonidine in detoxification from opiates.
Kleber, Gold, and Riordan (1980) reported that clonidine has demonstrated therapeutic usefulness as an intervention during opiate withdrawal. Authors reflected upon the fact that clonidine is non-opioidergic, yet appears capable of reducing many symptoms of opiate withdrawal. Furthermore, the onset of clonidine's therapeutic effect for the management of opiate withdrawal is often rapid, providing patients with immediate relief.
In addition to its usage as a treatment for symptoms of opiate withdrawal, reports suggest that clonidine is likely useful among persons withdrawing from opioid replacement therapies such as methadone. Some evidence suggests that clonidine attenuates symptoms of withdrawal in patients using up to 75 mg of methadone per day. Not only can clonidine reduce withdrawal symptoms that emerge after methadone discontinuation, it can significantly expedite the methadone withdrawal process.
Most patients who withdraw from methadone require around of 3 to 6 months of tapering before complete cessation. If clonidine is properly utilized to manage detoxification symptoms, the 3 to 6-month tapering process of methadone could be condensed to just 2 weeks. From the perspective of this report, clonidine seems to be among the most useful medications for the treatment of opiate withdrawal symptoms.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/6907020
1980: Efficacy of clonidine in opiate withdrawal: a study of thirty patients.
Gold, Pottash, Sweeney, and Kleber (1980) were among the first to investigate the effectiveness of clonidine for the treatment of opiate withdrawal symptoms. A total of 30 individuals who had been hospitalized for opiate addiction were recruited by researchers to participate in a double-blind, placebo-controlled, crossover trial in which clonidine was administered as an intervention for opiate detoxification. The administration of clonidine significantly reduced signs of opiate withdrawal and increased odds of successful detoxification.
Although this study wasn't large, it supports the therapeutic effect of clonidine during opiate detoxification. Researchers speculate that chronic opiate administration inhibits noradrenergic transmission, and upon cessation of opiates, noradrenergic transmission becomes hyperactive. The administration of clonidine, an alpha-2 adrenergic agonist, is thought to normalize noradrenergic activity whereby it addresses neurochemical imbalances implicated in withdrawal.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/7023893
1978: Clonidine blocks acute opiate-withdrawal symptoms.
Gold, Redmond Jr, and Kleber (1978) were among the first to test the efficacy of clonidine for the treatment of opiate withdrawal symptoms. At the time, the researchers developed a protocol for clonidine administration designed to maximize patient safety and simultaneously attenuate opiate withdrawal symptoms. The protocol involved administering clonidine at a test dose of 6 mcg/kg to gauge tolerability and rule out potential adverse reactions (e.g. hypotension).
Assuming the test dose was well-tolerated by the patient, the dose was increased to 17 mcg/kg per day, administered in divided doses of 7 mcg/kg (at 8 AM, 3 PM, and 10 PM) – for a total duration of 10 days. Blood pressure is continuously assessed to ensure health of the patient. If diastolic pressure drops below 60 mm Hg, the dose is discontinued. After the 10th day, the dosage of clonidine is rapidly reduced to 8 mcg/kg, then 4 mcg/kg, and finally 2 mcg/kg.
It is known that tapering of clonidine is necessary to avoid rebound hypertension following cessation. Once the protocol had been devised, researchers sought to evaluate its efficacy in a double-blind, placebo-controlled, crossover trial with a group of 11 individuals who had been hospitalized for opiate addiction. In this trial, it was discovered that a single dose of clonidine eliminated all objective and subjective symptoms of opiate withdrawal for a duration of 4 to 6 hours.
Results indicated that administration of clonidine for 1-week following opiate cessation significantly reduced opiate withdrawal symptoms and minimized likelihood of relapse. A follow-up with each of the participants conducted 6+ weeks after the trial revealed that 4 patients were using methadone, 1 was using tricyclic antidepressants, and 7 were abstinent from all opiates. Researchers concluded that clonidine appears efficacious in the treatment of opiate withdrawal symptoms, and as a result, hypothesized that opiate withdrawal may be influenced by activity in the locus coeruleus.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/80526
Limitations associated with research of Clonidine for opiate withdrawal
The research of clonidine for the treatment of opiate withdrawal symptoms dates from the late 1970s to present, and findings have been consistent. Results of nearly every trial in which clonidine was tested as an intervention for the management of opiate withdrawal indicate that it effectively attenuates opiate withdrawal symptoms. Despite the consistency with which clonidine has been shown to attenuate opiate withdrawal symptoms in trials, there are a few limitations associated with the available research. The most notable limitation is that clonidine has never been tested in a single large-scale randomized controlled trial (RCT) among humans.
- Few quality trials: The most significant limitation associated with research of clonidine as a treatment for opiate withdrawal is that few quality trials been conducted to test its efficacy. In fact, some might argue that zero trials have been conducted in which clonidine was tested during opiate detox. A majority of trials testing clonidine for the treatment of opiate withdrawal utilized small samples OR poor designs devoid of randomization and/or controlling. While the findings from lower-quality trials may be accurate, our confidence in those findings will be low. Low confidence in findings due to small samples and/or poor designs makes the results less relevant in clinical settings. To improve upon the quality of data generated from studies testing clonidine for the treatment of opiate withdrawal, it is necessary to conduct randomized controlled trials with large sample sizes.
- Lack of incentive: Another limitation associated with the research of clonidine for opiate withdrawal is that there's an overall lack of incentive to conduct further trials that generate higher quality data. Since the patent for clonidine has long-expired and the drug is sold at a low cost, no pharmaceutical companies stand to gain anything by funding higher-quality trials that prove its efficacy for the treatment of opiate withdrawal. Furthermore, the lack of high-quality data likely won't stop most medical professionals from prescribing clonidine to certain patients during opiate withdrawal. Clonidine remains among the most evidence-supported non-opioidergic intervention for the treatment of opiate withdrawal symptoms and will remain a popular intervention after opiate cessation – regardless of additional research. Moreover, most researchers likely won't want to allocate funds to the testing of clonidine during opiate withdrawal when novel [potentially profitable] compounds warrant testing.
- Replacement therapy: Clonidine has been evaluated as a medication for rapid opiate/opioid-detox, however, it has never been tested as an opioid-replacement therapy. Current research suggests that clonidine can reduce stress-induced opioid cravings when administered for weeks after the acute stage of opiate withdrawal. Furthermore, clonidine has been shown to minimize sensitization to subsequent opioid administration after extended abstinence. A study in which clonidine was administered regularly for a 10-year duration reported zero adverse health effects, indicating that it is safe for most over a long-term. Assuming patients tolerate clonidine well, there's reason to suspect that it might work as well as conventional opioid-replacement therapies such as buprenorphine and/or methadone for long-term maintenance of opiate abstinence – especially with co-administered naltrexone. Studies are needed to evaluate the hypothesized long-term efficacy of clonidine as an opioid-replacement therapy.
Verdict: Clonidine is likely effective for the management of opiate withdrawal symptoms
All research conducted among patients detoxifying from opiates suggests that clonidine effectively attenuates opiate withdrawal symptoms. Although there are some limitations associated with the research such as small sample sizes and/or suboptimal designs (e.g. non-randomized / uncontrolled), results are historically consistent in suggesting that clonidine is therapeutically beneficial for patients during opiate withdrawal. Furthermore, an analysis of the literature reveals that clonidine has been evaluated in several moderately-sized randomized controlled trials.
For example, a trial by Jasinski, Johnson, and Kocher (1985) compared the efficacy of clonidine to an active control (morphine sulfate) and a placebo for the management of opiate withdrawal symptoms. The results indicated that clonidine effectively attenuated opiate withdrawal symptoms to a greater extent than the placebo. Interestingly, clonidine was of superior efficacy to morphine in the attenuation of autonomic withdrawal symptoms.
Another randomized controlled study with 152 participants was conducted by Gerra, Marcato, Caccavari, et al. (1995) to determine effective long-term interventions for heroin dependence. Compared to a placebo and other combination therapies, it was discovered that the administration of clonidine plus naltrexone yielded the best clinical outcomes among patients. The efficacy of clonidine was also tested by Akhondzadeh, Ahmadi-Abhari, Assadi, et al. (2000) in a head-to-head, double-blind, randomized trial for the treatment of opiate withdrawal symptoms.
Results from the 62-participant trial indicated that clonidine effectively attenuated the physical symptoms of opiate withdrawal over a 2-week duration. In an animal model study with morphine-dependent rhesus monkeys, clonidine was more effective than no treatment in alleviating opiate withdrawal symptoms when administered for a 1-week duration post-opiate cessation. Data from a 35-participant randomized controlled trial by Ziaaddini, Nasirian, and Nakhaee (2012) also supports the usage of clonidine during detoxification.
This trial discovered that clonidine plus a placebo was as effective as buprenorphine plus a placebo for the treatment of opiate withdrawal symptoms and 6-month outcomes post-detox. Lastly, a randomized, double-blind, placebo-controlled trial by Kowalczyk, Phillips, Jobes, et al. (2015) discovered that recipients of buprenorphine plus clonidine exhibited greater duration of opiate abstinence and fewer stress-induced cravings after detoxification than recipients of buprenorphine plus a placebo. Additionally, there are case reports from clinical practice in which 7-to-10-day clonidine-assisted opiate/opioid detoxification protocols significantly attenuated withdrawal symptoms.
Based on data from clinical trials and reports from medical professionals, it appears as though clonidine effectively treats opiate withdrawal symptoms in a subset of the population. There are many reasons as to why clonidine may work well during opiate withdrawal. Some believe that clonidine's action as an alpha-adrenergic receptor agonist is able to counterbalance the hyperactivity of noradrenergic neurons and the corresponding neurophysiological symptoms.
From a macro perspective, we know that the general effect of clonidine is sympathoinhibition. It downregulates activation of the sympathetic nervous system, thereby mitigating withdrawal symptoms such as: agitation, anger, anxiety, headaches, insomnia, irritability, restlessness or RLS, and tension – during withdrawal. Moreover, we know that centrally, clonidine can enhance noradrenergic tone in the prefrontal cortex such that it may also ameliorate cognitive dysfunction during withdrawal.
That said, it is important to emphasize that not every individual who receives clonidine will find it tolerable or beneficial during opiate withdrawal; research estimates that approximately 10% of recipients will derive inadequate benefit from its administration. Even among those who respond well to clonidine, it may only provide partial benefit whereby adjunctive therapies are warranted. Nonetheless, randomized controlled trials, clinical case reports, and anecdotes all indicate that clonidine is highly therapeutic for a subset of individuals undergoing opiate withdrawal.
How to Use Clonidine for Opiate Withdrawal (Possible Protocols)
Before clonidine can be administered for the management of opiate withdrawal symptoms, medical professionals must confirm that it's safe for each specific patient. Some patients may be unable to take clonidine due to your: medical history, preexisting medical conditions, and/or daily regimen of pharmaceutical medications or dietary supplements. Assuming you don't have a condition with which clonidine is contraindicated and aren't using a substance with which clonidine is likely to interact, it may be prescribed by a doctor during opiate withdrawal.
There are many possible ways in which clonidine might be administered to a patient after opiate discontinuation. Examples of administration strategies or protocols include: short-term clonidine-assisted detox, clonidine-to-naltrexone, buprenorphine-to-clonidine, clonidine plus buprenorphine, long-term clonidine maintenance, and clonidine plus naltrexone. Below is a brief description of each strategy.
- Clonidine-assisted detox: A clonidine-assisted detox is generally reserved for inpatients who are detoxifying from high-dose opiates/opioids. In most cases, clonidine-assisted detoxes are performed in over a short-term of 7 to 10 days. One protocol exists in which professionals initiate the opiate/opioid detox by administering a small "test" dose of clonidine at ~17 mcg/kg for the first day. If the test dose is well-tolerated, the patient continues treatment by receiving 7 mcg/kg administered three times per day with 7-hour between-dose intervals. The patients' blood pressure and heart rate are constantly monitored to ensure that they remain within a safe and/or healthy range. Pending no tolerability issues, thrice-a-day clonidine administrations are continued at 7 mcg/kg for a 10-day duration. When the 10-day period is up, the patients' dosages are titrated downward over an additional 3-day period to avert rebound effects at 8 mcg/kg (Day 11), 4 mcg/kg (Day 12), and 2 mcg/kg (Day 13). Thereafter the patient is discharged from the inpatient detox facility, usually with minimal discomfort.
- Clonidine-to-naltrexone: This is essentially the same as a standard clonidine-assisted detox except, immediately after the detoxification process, treatment is initiated with the drug naltrexone. Although some patients respond well to clonidine followed by the discontinuation of all medications [including clonidine] after an initial detox, others may have an easier time with some sort of continued treatment. One option for patients is to administer naltrexone, a mu-opioid receptor antagonist that reverse the neurochemical effects of opioids and helps former users maintain abstinence.
- Clonidine plus naltrexone: Another viable intervention post-opiate discontinuation is the co-administration of clonidine plus naltrexone. Although naltrexone is not generally recommended during the early stages of opiate withdrawal due to the fact that its mu-opioid receptor antagonism can exacerbate certain withdrawal symptoms, when administered with clonidine it becomes tolerable. Clonidine doesn't appear to interact with naltrexone, and the combination of clonidine plus naltrexone can be administered for a long-term to minimize lingering withdrawal symptoms, facilitate neurochemical recovery (after opiate abuse), and prevent relapse.
- Buprenorphine-to-clonidine: Sometimes, individuals won't derive adequate benefit from standalone clonidine during opiate detoxification. In cases of severe opiate dependence, an opioid-replacement therapy such as buprenorphine may be a necessary intermediary to ease the transition from regular full mu-opioid receptor agonism (provided by opiates) to zero mu-opioid receptor agonism (following cessation). Once an individual has stabilized in buprenorphine, the dosage can be gradually titrated downward and, to prevent severe buprenorphine withdrawal, clonidine can be utilized. Although using buprenorphine followed by clonidine may require more time than standalone clonidine, it may be more tolerable for a subset of patients.
- Buprenorphine plus clonidine: Another possible treatment during opiate detoxification is the combined administration of buprenorphine plus clonidine. This combination may provide synergistic benefit that exceeds relief attained from buprenorphine or clonidine as standalone interventions. Anyone who derives inadequate relief from buprenorphine or clonidine monotherapy during withdrawal may benefit from their combination. Eventually, an individual on buprenorphine plus clonidine can work with a doctor to gradually discontinue buprenorphine while maintaining clonidine. Thereafter, clonidine can be gradually discontinued and the former opiate user can decide whether to pursue naltrexone maintenance.
- Clonidine maintenance: While clonidine is effective for opiate detoxification, it might also be helpful as a long-term therapy in the maintenance of abstinence from opiates. There's evidence suggesting that clonidine attenuates opiate withdrawal symptoms, inhibits stress-induced opiate cravings, and some speculate that it can minimize likelihood of PAWS (post acute withdrawal syndrome). Moreover, according to some research, clonidine can be safely administered for a long-term without inducing any serious adverse health effects, and may enhance the neuropsychiatric status in select patients (especially those with ADHD). Theoretically, a subset of patients may benefit from an initial clonidine-assisted detox followed by indefinite clonidine maintenance therapy.
Note: Some of these strategies may be better suited for inpatients than outpatients. Furthermore, cognitive behavioral therapy (CBT) is generally recommended for most patients following detoxification.
Have you tried Clonidine for opiate withdrawal?
If you've taken clonidine during opiate withdrawal, feel free to share your experience in the comments section below. In terms of managing opiate withdrawal symptoms, did you find clonidine to be highly-effective, slightly effective, or downright useless – for the management of opiate withdrawal symptoms? On a scale of 1 to 10 (with "1" being least therapeutic and "10" being most therapeutic), what number would you assign to clonidine during opiate withdrawal?
Assuming you found clonidine to be of therapeutic value during your detox, which specific withdrawal symptoms (e.g. anxiety, agitation, restlessness, etc.) did it most effectively reduce? To help others get a better understanding of your detox or withdrawal, provide some additional details such as: the dosage of clonidine you were given (e.g. 0.1 mg), the frequency of your clonidine usage (e.g. 3 times per day), and the cumulative duration over which clonidine was administered (e.g. 3 months post-detox). Also note whether you used clonidine as a standalone intervention or as part of a multi-drug regimen.
If you used clonidine along with other medications, how can you be sure that the benefit you're attributing to clonidine is not more attributable to the other medication(s)? Did you experience any unwanted side effects (e.g. hypotension) from taking clonidine or endure any withdrawal symptoms following its discontinuation? As of current, have you been able to maintain abstinence since your detox?
In summary, while clonidine is not a universally-effective intervention during detox, it can be of significant therapeutic benefit for individuals struggling to endure opiate withdrawal symptoms. Most evidence and clinical reports support its usage in detox settings, especially followed by naltrexone and psychotherapy. Should you have any questions regarding the usage of clonidine during opiate withdrawal, do not hesitate to contact a medical doctor.