Accurate Education – Alpha-2 Adrenergic Agonists

Alpha-2 Adrenergic Agonists

  1. Catapres (clonidine)
  2. Lucemyra (lofexidine)
  3. Zanaflex (tizanidine)

 

The a-2 adrenergic agonists are a class of drugs used to treat multiple, distinctively different, conditions. They are used to treat pain, opioid, benzodiazepine and alcohol withdrawal, symptoms of cigarette craving,  high blood pressure, attention-deficit/hyperactivity disorder and panic disorder.

 

Common a-2 adrenergic receptor agonists include clonidine (Catapres) and lofexidine (Lucemyra) and also tizanidine (Zanaflex), a medication commonly used as a muscle relaxer.

 

See also:

Medications for Pain

Complementary and Alternative Medicine Alternatives for Pain

Opioid Withdrawal

 

 Definitions and Terms Related to Pain

Key to Links:

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“Pain is temporary. It may last a minute, or an hour, or a day, or a year, but eventually it will subside and something else will take its place. If I quit, however, it lasts forever.”
– Lance Armstrong

Alpha-2 (α2) Adrenergic Agonists

Alpha-2 adrenoreceptors (ATARs) are found as a network in the body and function as an adaptive system, a link between the sympathoadrenergic system (nervous and adrenaline hormone system) and multiple organs and other systems. Alpha-2 agonists activate this ATAR network and triggers transformations in cellular biology and in function of organs and systems. These reactions and responses increase resistance to stress/tissue damage and protect the homeostasis (balance) of the nervous system. Clonidine, a prototype α-2 agonist, enhances adaptation to stress and is therefore considered an “adaptogen,” in a new clonidine-ATAR-adaptation concept.  This concept explains the successful use of clonidine in diverse applications.

See clonidine-ATAR adaptogen below

 

Clonidine (Catapres)

For example, a 2015 publication describes how the use of transdermal clonidine leads to favorable changes in the metabolic profiles of patients with type 2 diabetes mellitus, including a reduction in fasting glucose levels, reduction in insulin resistance, and enhanced glucose utilization. Furthermore, it described oral clonidine as providing improved symptoms of bloating, nausea, vomiting and gastric emptying time in a group of patients with diabetic autonomic neuropathy and gastroparesis.

 

Clonidine has also been reported to provide relief of symptoms (stool frequency, consistency, and ease of passage) in patients with diarrhea-predominant irritable bowel syndrome.  Oral clonidine also reportedly may decrease the volume of diarrhea in patients with severe diabetic autonomic neuropathy. The decrease in sympathetic activity by transdermal clonidine may reduce symptoms in patients with ulcerative colitis.

 

Clonidine, initially prescribed as a nasal decongestant, is now used most frequently to treat high blood pressure. However, it has been shown to be an effective supplemental agent for managing neuropathic pain. Additionally, it is sedating and can be useful for sleep, it reduces anxiety and it suppresses many of the symptoms of drug withdrawal, including opioids, benzodiazepines, cocaine, tobacco and alcohol.

 

Clonidine for Pain

Chronic Pain

There is increasing evidence from animal and human studies that clonidine may be effective in the prevention and management of chronic pain, including neuropathic pain, trigger points/myofascial pain, osteoarthritis,  and complex regional pain syndrome (CRPS). There are also mixed results in the use of transdermal clonidine in the treatment of cluster headaches. In one study, the frequency, duration, and intensity of headaches were reduced, whereas in another study, only some patients experienced relief of symptoms.

 

Clinical studies evaluating the effect of clonidine in chronic pain remain limited and focus largely on the use of topical clonidine and epidural clonidine with fewer studies evaluating oral clonidine. However, transdermal clonidine and oral clonidine have demonstrated comparable pharmacodynamics and therefore the therapeutic potential of transdermal clonidine likely matches that of oral clonidine, but with less side effects.

 

To clarify the terms “transdermal” and “topical,” transdermal products are designed to distribute a drug through the skin and into the blood stream in order to be distributed systemically, throughout the body. Topical preparations are designed to deliver the drug only to local tissues where the product is applied to the skin.

    

Peripheral Neuropathy

Peripheral neuropathy is a chronic painful condition resulting from multiple etiologies but most commonly afflicting more than 50% of diabetics. It is associated with pain in the distal extremities affecting feet and less often, the hands in a stocking or glove-like distribution, and is characterized by tingling, sharp and stabbing pain akin to “walking on broked glass” in more severe cases. In the case of diabetic peripheral neuropathy (DPN), the progression of the disease may lead to complete destruction of the small nerves in the hands and/or feet (denervation) resulting in numbness. Ttreatment of painful DPN can be effective with use of topical and transdermal clonidine. Unfortunately, for those patients with DPN who have progressed to complete denervation and numbness, topical therapy may be ineffective.

 

Transdermal Clonidine in Peripheral Neuropathy

An early 1995 clinical trial of transdermal clonidine in DPN patients using  transdermal clonidine patches (titrated from 0.1 to 0.3 mg/day) showed pain benefit, especially in patients who described their pain as sharp and shooting.

 

Topical 0.1% Clonidine in Peripheral Neuropathy

Another 2o12 study evaluating topical 0.1% clonidine applied three times/day to the feet in DPN patients demonstrated that treatment with topical clonidine reduces pain from diabetic neuropathy and, furthermore, indicated that analgesic effectiveness depends on the relative level of functionality of nociceptors (nerve receptors) in the skin. In this study, the blood levels of clonidine were below the level of detection (10 pg/ml), indicating that the analgesic effects were almost certainly peripherally-mediated directly from the topical application, not due to systemic absorption of the clonidine.

 

Post-Operative Pain

With the use of peri-operative systemic clonidine, there is evidence of a decrease in pain intensity and nausea post-operatively at 24 hours as well as a sparing effect for the use of opioids for acute post-operative pain at 24 hours. There appear to be no studies evaluating the benefit of clonidine for  prevention of chronic post-surgical pain.

 

For reducing post-surgical pain and opioid dosing as well as reducing potential withdrawal in opioid dependent patients, clonidine has been recommended as a premedication orally or continuously i.v. post-operatively at 0.1-0.3 μg/kg/hour. A 2012 study performed in Iran with 66 adult patients ages 20-55 comparatively evaluated pre-operative doses of 0.2 mg clonidine or 900 mg gabapentin orally 2 hours before thyroidectomy surgery and their impact on post-operative pain. The study concluded that  oral premedication with both gabapentin or clonidine significantly decreases post-operative pain, while only gabapentin reduces post-operative morphine consumption also. The clonidine group experienced more nausea & vomiting compared to the gabapentin group.

 

In other studies, oral clonidine doses between 0.1 to 0.3 mg have been used as a pre-medication to reduce post-surgical pain. In one study, 0.15 mg oral clonidine had the best effect on prolongation of spinal anesthesia. Other studies used 0.1 and 0.2 mg oral clonidine for post-operative pain reduction, but 0.1 mg clonidine was not successful in the reduction of post-operative morphine consumption.

 

A 2005 study assessed the effect of oral clonidine on anxiety, analgesia, and hemodynamic stability in patients undergoing abdominal hysterectomy. A total of 61 patients were evaluated, who were randomly assigned to receive either oral clonidine 0.1 mg or placebo before surgery and 24 h after surgery. The use of clonidine reduced anxiety and pain for up to 72 hours after surgery.

 

A recent 2017 study evaluated pre-operative use of clonidine in preventing or reducing post-surgical right shoulder tip pain, a common problem after laparoscopic cholecystectomy (removal of gall bladder). The use of the laparoscopic procedure is now a standard treatment for gallstone disease because it leads to less post-operative pain than open cholecystectomy. However, post-laparoscopic shoulder pain (PLSP) is commonly reported and is believed to result from residual air left in the abdomen after surgery that irritates the diaphragm which triggers referred pain to the right shoulder.

 

While various medications have been tried to control PLSP including non-steroidal anti-inflammatory (NSAIDs), pain management for this condition remains an unresolved problem. The finding of this study was that premedicating with 0.2 mg oral clonidine while not effective in preventing PLSP, it is however safe and effective for reducing PLSP intensity in the first postoperative hours.

 

Of unusual interest, the placebo group in this study received  a “placebo” dose of 100 mg of Vitamin C with outcme of the study comparing this placebo group with the clonidine group. In fact, there is growing research that suggests that Vitamin C is in itself therapeutic in reducing post-operative pain.

Post-Operative Pain and Bleeding in Endoscopic Surgery

Clonidine has also been studied in endoscopic surgery where it is used to help maintain less bleeding which lowers the risk of surgical complications. Studies found post-operative pain is lower in patients who receive clonidine premedication, showing up to a 45% reduction in requirements for analgesics during the intraoperative period. Clonidine administration in perioperative settings is safe and serious complications are very rare. Pre-operative use of clonidine also has a beneficial effect on reduction of hemodynamic response associated with laryngoscopy and endotracheal intubation. Additionally, clonidine is not associated with risk of respiratory depression.

 

Post-Mastectomy Pain

An interesting study published in 2013 investigated the analgesic benefit of adding clonidine to topical bupivacaine for acute post-mastectomy pain. Bupivacaine 0.5%  in combination with two different dosages of clonidine (0.150 mg and 0.250 mg) were infiltrated into the surgical site following mastectomy to assess their effects on post-mastectomy neuropathic pain. The study found that both dosages of clonidine-bupivacaine combination were associated with significantly less neuropathic pain over 48 hours post-operatively than placebo and there was no difference in effect between the two doses.

 

Clonidine and Obstructive Sleep Apnea (OSA)

During surgery it has been noted that patients who received clonidine are less prone to require supplemental oxygen. Clonidine has also been shown to have a positive effect on the overall oxygen saturation in patients with obstructive sleep apnea (OSA). Clonidine has been studied as a surgical premedication in patients with OSA and has been shown to improve oxygen saturation. Clonidine is also known to reduce the decrease in ventilation in response to increasing carbon dioxide (CO2), which is a protective mechanism against sleep apnea related to high levels of CO2 during non-REM sleep. In addition, there is some evidence to support the benefit of clonidine for central sleep apnea as well.

  

Clonidine for Opioid Detoxification/Withdrawal

“Detoxification” is a supervised withdrawal from a drug of dependence to minimize withdrawal symptoms, and is a prelude to abstinence-based treatment. In the case of opioid detoxification, different methods have been tried, but none are perfect.  Clonidine, an α2-adrenergic receptor agonist and imidazoline receptor agonist, has been use for opioid detoxification for more than 40 years. Clonidine provides an anticraving effect for opioids as well as reducing symptoms of withdrawal.

 

A 2018 study comparing the use of clonidine vs. buprenorphine (Suboxone) found them to be equally effective for opioid detoxification when comparing clonidine with very low dose buprenorphine (0.6–1.2 mg/day), but a higher dose of buprenorphine (1.4–2.4 mg/day) was more effective than clonidine. The usual standard dose for buprenorphine in opioid detoxification is 8-16 mg/day. Because clonidine and buprenorphine have different mechanisms of action, they can be used together and potentially provide enhanced benefit compared with either medication alone.

 

Clonidine Dosing for Opioid Withdrawal

Clonidine at oral doses of 0.2–0.4 mg/day have been shown to be as effective as higher doses of 0.5–0.8 mg/day in controlling the withdrawal symptoms, with less side effects. Transdermal clonidine patches have also been shown to be effective.

 

Clonidine Formulations

Oral Clonidine

Clonidine is available in 0.1 mg, 0.2 mg and 0.3 mg tablets

 

Transdermal Clonidine Patches

Transdermal clonidine patches are designed to deliver clonidine systemically via absorption into the blood stream to be distributed to the whole body for treating high blood pressure, opioid withdrawal and Tourette’s Syndrome.. Clonidine transdermal patches also effectively ease pain in migraine, face pain and complex regional pain syndrome. Transdermal clonidine, though generally well-tolerated, may be associated with systemic side effects such as low blood pressure, sedation, and dry mouth.

 

Transdermal clonidine is available in patches that deliver 0.1 mg/24 hours, 0.2 mg/24 hours and 0.3 mg/24 hours and are designed to deliver clonidine for one week and then they need to be replaced. The maximum dose recommended for treating either high blood pressure or Tourette’s Syndrome is 0.6 mg/24 hours (use of two 0.3 mg patches simultaneously).

 

Topical Clonidine

Topical applications have been the most studied formulation for management of neuropathic pain. Topical administration of clonidine effectively reduces pain intensity in painful diabetic polyneuropathy, postherpetic neuralgia and hyperaesthesia of the skin in trigeminal neuralgia. 

 

A 2011 study showed that use of a clonidine patch delivering 30 mcg/cm2/day, either 7 cm2 or 10.5 cm2 in size for 7 days provided good pain relief with hyperalgesia, even after removal of the patch. Other studies have shown that use of topical clonidine patches provide significant pain relief in diabetic peripheral neuropathy (DPN).  Unfortunately, topical patches of this nature are not commercially available in the U.S.

 

The effectiveness of 0.1% topical clonidine cream formulations has been supported in cases of DPN, offering an alternatine means for pain relief with no systemic absorption and therefore no likelihood of systemic side effects. Topical cream formulations can be made up by a compounding pharmacist.

 

Intrathecal and Epidural Clonidine

Many clinical trials have evaluated intrathecal and/or epidural clonidine with or without other drugs including opioids, baclofen and ketamine for prevention or management of different cancer and non-cancer painful conditions with varying degree of success. Intrathecal clonidine has been found to be effective in both cancer and non-cancer pain. Intrathecal drug delivery can be delivered episodically or  accomplished by implanting a refillable pump under the skin that distributes a drug via catheter into the spinal fluid where the drug impacts the spinal cord and brain. Long-term use of intrathecal clonidine has been reported with the use of an implantable pump. One study reported that a combination of clonidine and morphine is superior to either drug alone in post-spinal cord injury related pain.

 

With an epidural route, clonidine has been used in a wide range of dosage ranging from 90 mcg to 700 mcg. It has been found to be effective in reflex sympathetic dystrophy, chronic low back pain, post-thoracotomy pain and neuropathic pain not responding to conventional management. Epidural  clonidine may have a role in prevention of the chronic post-surgical pain when used along with local anesthetics.

 

Benefits have been noted in many of the studies; however these interventional methods will not be explored here. Referral to interventional pain specialists is advised for further information.

 

Pharmacology of Clonidine

Clonidine has an affinity predilection of 200:1 for α-2 vs α-1 receptors, respectively (see below). It  lowers systemic blood pressure through adrenergic stimulation in the central brainstem . Clonidine is rapidly and almost completely absorbed after oral administration. Transdermal clonidine patches that deliver from 0.1 mg to 0.4 mg of clonidine a day provide therapeutic plasma levels of clonidine, about 2.0 ng/mL.  The steady-state plasma levels of clonidine achieved with transdermal clonidine patches is close to the trough levels achieved with equivalent daily amounts of oral clonidine with absence of peak-to-trough variability. The oral half-life is 12–16 hours while the transdermal patches half-life is 14–26 hours.  Clonidine is about 50% metabolized by the liver (Cyp 2D6 isoenzymes metabolize 60%–70%) and about 50% excreted unchanged in urine and feces. In plasma, only 20% of clonidine is protein-bound.

 

Clonidine is also an imidazoline-receptor agonist, located peripherally on peripheral nerve endings. The activation of I2-imidazoline receptors may be responsible for additional mechanisms of the analgesic activity, especially with topical clonidine applications.

 

Side Effects of Clonidine

Clonidine is generally well tolerated but it can cause side effects such as sedation and low blood pressure, rebound hypertension and heart arrythmias imcluding atrioventricular block, and bradycardia. Dryness of mouth, however, is one of the most common side effects reported.

 

Clonidine as an Adaptogen

 

The acute adaptive response to external stressors, often referred to as the “fight or flight” reaction, is a complex of coordinated physiological processes in multiple organ systems. The locus coeruleus region of the brain is activated and activity in the descending and in the ascending adrenergic pathways is substantially increased.  Brain areas are integrated, the level of vigilance is heightened, input of information is filtered, while working memory and executive function are maximized.  Sympathetic tone is increased, blood pressure and heart rate are raised, increase in secretion of growth hormone and suppression of insulin release promote higher serum glucose level. Pain is suppressed. Parasympathetic “rest and digest” reflexes are turned off. The adaptive response is carried out by the sympathetic nervous system, connecting with the ATAR network and effector organs.

 

An adaptation engages damage repair and symptom control and increases resistance to physical, chemical and biological stressors when the stressor is a threat to homeostasis or balance. Adaptogens are agents that facilitate adaptation and it has been proposed that clonidine is an adaptogen along with many plant-based adaptogens called phytoadaptogens.

 

Dexmedetomidine

In 2016, a Cochrane systematic review of dexmedetomidine use perioperatively for acute pain after abdominal surgery concluded that while it has some opioid-sparing effect, in general it has no important improvement in postoperative pain when compared with placebo. However the quality of the evidence is very low due to a relatively small number of studies and the authors concluded that larger studies with longer periods of follow-up are needed.

 

Lofexidine (Lucemyra)

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Tizanidine (Zanaflex)

Tizanidine is similar to clonidine, but with important differences. Like clonidine, it is sedating and has anxiety-relieving and pain-relieving properties, but it has a shorter duration of action and less effect on heart rate and blood pressure.

 

Tizanidine for Pain and Muscle Spasm

Tizanidine is frequently used to treat myofascial pain in the head and neck. It reduces painful muscle spasms in the neck and shoulder and can reduce spasticity by increasing the presynaptic inhibition of motor neurons in the brain and spinal cord. In an early 2002 study evaluating its effectiveness in the treatment of myofascial pain, tizanidine was shown to significantly reduce pain and muscle tenderness and was rated as “good to excellent” in relieving pain by 89% of the patients studied. It was also noted to improve the quality of sleep. Additionally, tizanidine may be useful in cerebral palsy and other spastic disorders.

 

Dosing of Tizanidine

Tizanidine comes in 2-mg and 4-mg tablets and in 2-mg, 4-mg, and 6-mg capsules.  It is important to note that the capsules and tablets are bioequivalent under fasting conditions, but not when taken with meals. The quantity absorbed from the capsule under fed conditions is approximately 80% compared to the tablet formulation. The maximum recommended dosing is 3x/day, up to 36 mg/day. Tizanidine has a “narrow therapeutic margin,” meaning that it is easy to go from a dose that is too low and ineffective to a dose that is too high and associated with side effects. For this reason it is recommended to start at a low dose of 2-4 mg one to three times per day and then slowly increase the dose as needed by 2-4 mg per dose, every 2-4 days.

 

Tizanidine may be taken with food or on an empty stomach.

 

Pharmacology of Tizanidine

Tizanidine is metabolized extensively by the liver CYP450 1A2 enzymes, with a half-life of 2.5 hours. Tizanidine is centrally acting at both the brain and the spinal cord levels, reducing muscle spasm and spasticity by increasing pre-synaptic inhibition of motor neurons, with no direct effect on skeletal muscle fibers.

 

Drug Interactions with Tizanidine

Due to hepatic metabolism through the CYP1A2 pathway, concentrations of tizanidine are increased with concomitant use of inhibitors of this cytochrome P450 such as ciprofloxacin, fluvoxamine, cimetidine, famotidine, anti-arrhythmics, and oral contraceptives.

 

Side Effects of Tizanidine

Common side effects of tizanidine include dry mouth (2%), sleepiness (14%), nausea and other GI symptoms (2%), weakness, and dizziness (1%). Serious side effects may include low blood pressure, liver problems and psychosis. A recent study showed that prolonged use of tizanidine can induce QT prolongation, especially in patients predisposed to arrhythmias and patients with impaired drug elimination. QT prolongation involves a slowing of electrical conduction throught the heart.  Tizanidine should be used with caution in patients taking other commonly used medications that cause QT prolongation, especially methadone.

 

Asymptomatic elevations ofliver enzymes have been noted in patients taking tizanidine, so monitoring of liver enzymes is warranted. Abrupt discontinuation may induce a hyperadrenergic syndrome that can include reflex tachycardia and hypertension, tremor, anxiety, and hypertonicity. A recent case report showed that abrupt discontinuation of tizanidine given concomitantly with baclofen led to the development of delirium, extrapyramidal symptoms, and autonomic dysfunction in a patient with impaired renal function.

It is unclear if use in pregnancy and breastfeeding is safe.

 

Tapentadol (Nucynta)

Tapentadol is a newer synthetic opioid that has multiple modes of action: it functions as “traditional” opioids (pure mu-opioid receptor (MOR) agonists such as morphine, hydrocodone, oxycodone etc.) do, so it provides the same pain-relieving benefits and side effects as these medications. But tapentadol is also a norepinephrine reuptake inhibitor (NRI) which means that it enhances the pain inhibiting effects of the descending pathways (see Neurobiology of Pain) by enhancing the effects of the neurotransmitter norepinehphrine. This secondary NRI function makes it more effective for nerve pain than usual opioids (see Neuropathic Pain). This NRI reuptake inhibition is what makes duloxetine (Cymbalta) effective for pain.

However, in addition, tapentadol is also believed to provide additional pain suppression as an alpha-2-adrenergic agonist in the spinal cord and brain. Studies have shown that naloxone, a MOR antagonist, only partially inhibits tapentadol-mediated analgesia; however, the addition of the alpha-2-antagonist, yohimbine, eliminates all analgesic effects, suggesting that tapentadol’s activation of alpha-2-adrenergic receptors is also a signifcant contributor to tapentadol’s analgesic benefit.

See: Tapentadol (Nucynta)

Alpha-2 Agonists – Mechanisms of Action

Alpha-2 agonists produce their effects within both the central and peripheral nervous systems. Centrally within the locus ceruleus of the midbrain, for example, a-2 agonists provide pain benefit and produce sedation. It is here also that they reduce acute opioid withdrawal symptoms. Additionally, they can also act on the dorsal horn of the spinal cord,  where they also reduce pain. Neuropathic peripheral nerves are also sensitive to inhibition of pain signalling by adrenergic agonists. 

 

Alpha-2 (α2) Adrenergic Receptors

There are 2 subtypes of adrenergic receptors , α and β. Each has both excitatory and inhibitory effects based upon where that receptor is located. The α adrenergic receptors are divided into α-1 and α-2 while the β adrenergic receptors are divided into β-1, β-2 and β-3.  This page is limited to exploration of only the  α-2 adrenergic receptors and agonists.

 

The physiologic functions of the α-2 adrenergic receptors include:

A. Inhibition of norepinephrine release from presynaptic neurons

B. Centrally induced sedation via locus ceruleus

C. Centrally mediated pain modification via dorsal horn

D. Inhibition of insulin release from pancreatic B cells

 

The a- 2 receptors represent a family of G-protein–coupled receptors with 3 pharmacological subtypes, α-2A, α-2B, and α-2C. Endogenous agonists, such as norepinephrine and epinephrine, have similar affinities for all 3 subtypes. The α-2A and α-2C subtypes are found mainly in the central nervous system. Stimulation of these receptor subtypes leads to sedation, analgesia, and sympatholytic effects whereas the α-2B receptors are found in vascular smooth muscle where they mediate blood pressure effects. All 3 subtypes have been shown to inhibit adenyl cyclase, leading to a suppression of neural firing. This suppression inhibits norepinephrine release and reduces activity of the ascending noradrenergic pathways, resulting in hypnosis and sedation.

 

Alpha-2 receptors (ATARs) are present in the dorsal horns of the spinal cord, where the first and second nociceptive neurons synapse and are also part of the descending inhibitory monoaminergic pathway which originates in the brainstem serotonergic raphe nuclei, locus coeruleus and reticular formation in the lateral medulla.. Stimulation of presynaptic ATARs inhibit release of substance P from axons of the first afferent neurons and stimulation of postsynaptic ATAR inhibits firing of the second neuron in the dorsal horn; these activities provide most of the α-2 agonist drugs’ analgesic action.

 

Although there is some evidence for supraspinal and peripheral sites of action, stimulation of presynaptic α-2 receptors inhibits nociceptive neurons in the dorsal horn of the spinal cord and reduces the release of substance P which provides most of the α-2 agonist drugs’ analgesic action.

 

The analgesic effect is probably a result of the absorption of the drug, and it is associated with a presynaptic decrease of noradrenaline release from endings of the sympathetic nervous system and with an increase in the release of endogenous opioids (enkephalins).

 

 Clonidine

Clonidine is a presynaptic alpha-2-adrenergic receptor agonist and an agonist of imidazoline receptors. Activation of alpha-2 receptors leads to release of an inhibitory G-protein, which down-regulates adenylate cyclase and other second messengers responsible for initiating and maintaining the abnormal excitability of nociceptors. Activation of the I2-imidazoline subclass of receptors located on peripheral nerve endings may be responsible for additional mechanisms of analgesic activity of clonidine.

  

 

 

References

 

Alpha-2 Adrenergic Receptor Agonists

  1. Alpha-2 Adrenergic Receptor Agonists – A Review of Current Clinical Applications – 2015

 

Clonidine (Catapres) – Chronic Fatigue Syndrome

  1. Clonidine May Help in Chronic Fatigue Syndrome (CFS) and Fibromyalgia Because – 2013

 

Clonidine (Catapres) – Opioid Withdrawal

  1. Efficacy of buprenorphine and clonidine in opioid detoxification: A hospital- based study – 2018

Clonidine (Catapres) – Pain

  1. Idiopathic Peripheral Neuropathy Responsive to Sympathetic Nerve Blockade and Oral Clonidine – 2012
  2. Clonidine for management of chronic pain – A brief review of the current evidences – 2014
  3. Clonidine – clinical pharmacology and therapeutic use in pain management 2011
  4. Transdermal and Topical Drug Administration in the Treatment of Pain A Comprehensive Algorithm for Management of Neuropathic Pain – 2019
  5. Therapeutic alternatives in painful diabetic neuropathy – a meta-analysis of randomized controlled trials – 2018
  6. Effect of the addition of clonidine to locally administered bupivacaine on acute and chronic postmastectomy pain. – PubMed – NCBI – 2013
  7. Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy – 2012
  8. Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage ‘enriched enrollment’ design. – PubMed – NCBI – 1995
  9. Analgesic synergy between opioid and α2-adrenoceptors – 2014
  10. Clonidine May Help in Chronic Fatigue Syndrome (CFS) and Fibromyalgia Because – 2013
  11. Pharmacologic Treatments for Neuropathic Pain

   

  

Clonidine (Catapres) – Post-Operative Pain

  1. Effect of perioperative systemic α2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of rando… – PubMed – NCBI – 2012
  2. Chronic pain patient and anaesthesia – 2019
  3. Special indications for Opioid Free Anaesthesia and Analgesia, patient and procedure related: Including obesity, sleep apnoea, chronic obstructive … – PubMed – NCBI – 2017
  4. Alternative approaches to treatment of Central Sleep Apnea – 2014
  5. Effects of Clonidine on Breathing during Sleep and Susceptibility to Central Apnoea – 2013
  6. ORAL CLONIDINE IN CHILDREN – EFFICACY AS PREMEDICANT AND POSTOPERATIVE ANALGESIC AS COMPARED TO DIAZEPAM – 2006
  7. oral-clonidine-premedication-reduces-postoperative-pain-in-children
  8. The Effect of Pre-operative Oral Clonidine or Gabapentin on Post-operative Pain intensity, Morphine Consumption and Post-operative Nausea and Vomiting in Patients Who Undergone Thyroidectomy – 2012
  9. The clinical effect of small oral clonidine doses on perioperative outcomes in patients undergoing abdominal hysterectomy. – PubMed – NCBI – 2006
  10. Clonidine or remifentanil for adequate surgical conditions in patients undergoing endoscopic sinus surgery – a randomized study – 2017
  11. Comparison of Clonidine and Midazolam Premedication Before Endoscopic Sinus Surgery – Results of Clinical Trial – 2014
  12. Effect of Oral Clonidine on Shoulder Tip Pain and Hemodynamic Response After Laparoscopic Cholecystectomy – A Randomized Double Blind Study – 2017
  13. Designing the ideal perioperative pain management plan starts with multimodal analgesia – 2018

Clonidine (Catapres) – Sleep Apnea

  1. Special indications for Opioid Free Anaesthesia and Analgesia, patient and procedure related: Including obesity, sleep apnoea, chronic obstructive … – PubMed – NCBI – 2017
  2. Alternative approaches to treatment of Central Sleep Apnea – 2014
  3. Effects of Clonidine on Breathing during Sleep and Susceptibility to Central Apnoea – 2013

 

Clonidine (Catapres) – Topical

  1. Topical Treatments for Localized Neuropathic Pain – 2017
  2. Topical treatments for diabetic neuropathic pain – 2019
  3. Topical analgesics for acute and chronic pain in adults ‐ an overview of Cochrane Reviews – 2027
  4. Topical clonidine for neuropathic pain – 2015
  5. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. – PubMed – NCBI – 1991
  6. The Role of Topical Agents in Podiatric Medicine – 2013
  7. Emerging therapeutic potential of transdermal clonidine – a prospective as an adaptogen – 2015

 

Dexmedetomidine

  1. Effect of perioperative systemic α2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of rando… – PubMed – NCBI – 2012
  2. Perioperative dexmedetomidine for acute pain after abdominal surgery in adults. – PubMed – NCBI – 2016

  

Tapentadol (Nucynta)

  1. The switch from buprenorphine to tapentadol – is it worth? – 2016

 

Tizanidine (Zanaflex)

  1. Tizanidine is effective in the treatment of myofascial pain syndrome. – 2002
  2. Considerations for the Appropriate Use of Skeletal Muscle Relaxants for the Management Of Acute Low Back Pain – 2014
  3. Role of Muscle Relaxant (Tizanidine) in Painful Muscle Spasm – 2010

Emphasis on Education

 

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