by Sarah Shafer

As promised in my last post, where I discussed the utility of naloxone in clonidine overdose, we’re going to spend some time today talking about clonidine in opioid withdrawal. Is it a useful therapy for treating opioid withdrawal, or like Claudius in Hamlet, a gaslighting distractor?

Before we dive in, let me make one point of clarification. When I use the term clonidine in this post, I am using it as a stand-in for the entire class of alpha-2 agonists. Whether we’re discussing clonidine, guanfacine, lofexidine, or even dexmedetomidine, we’re still discussing the same central mechanism of action. As a toxicologist, nothing brings me as much joy as getting into the nitty-gritty of the differences between individual drugs within a class. But talking about a drug class as an entity allows us to get to the pharmacologic heart of the matter.

As a recap, clonidine is an imidazoline compound that agonizes both alpha-2 and imidazoline-1 receptors. Its pharmacologic effect comes from a decrease in sympathetic outflow, leading to hypotension, bradycardia, and sedation. The exact relationship between alpha-2 receptors and imidazoline receptors is unclear. Both work to limit sympathetic outflow, but the primary hypotensive effect of clonidine comes from imidazoline-1 agonism.1

Further complicating the interplay between these two receptors is the co-dependency between opioid and catecholamine signaling. First of all, they are colocalized on neurons,2 which means that they like to hang out in all the same places. There is synergy between opioid and catecholamine effects,3 likely related to shared signaling cascades.4 Catecholamines can bind to specialized sites on the mu-opioid receptor.5 Catecholamines and endogenous opioids even get packaged together in the neuron, so when they get released, it’s like getting onion rings and curly fries in the same order.6–8 Catecholamine receptors and opioid receptors are like two roommates who share a lot of the same stuff. Essentially, if you get one, you get a bit of the other.

The use of clonidine for opioid withdrawal began in the 1970s after monkey studies showed that activation of the locus ceruleus resulted in symptoms of opioid withdrawal and that both clonidine and morphine blocked locus ceruleus activation in a similar way.9 This data led to human studies comparing clonidine to methadone in treating opioid withdrawal with favorable results.10 Favorable meaning that there was finally a “non-opioid” that could rapidly bridge patients to naltrexone and get them off of methadone for good.11

How does clonidine treat opioid withdrawal? Because of the interplay between opioid and adrenergic signaling, we have a plausible biochemical mechanism: clonidine treats opioid withdrawal by secondary activation of the opioid system in the locus ceruleus. Of course, it’s not as simple as this since clonidine is not an opioid. Does clonidine have enough of an opioid-like effect to blunt withdrawal symptoms, but not enough to provide the analgesia or euphoria associated with opioids? Maybe the mechanism is much simpler. When patients are in opioid withdrawal, they have a large release of norepinephrine in the locus ceruleus, causing agitation, tachycardia, hypertension, and other classic signs of opioid withdrawal.12 Clonidine prevents norepinephrine release, so its main mechanism might not have anything to do with opioid receptors at all.

In either case, it doesn’t matter, because clonidine is an inferior therapy for opioid withdrawal. Certainly, clonidine is better than nothing, as found when it was compared to placebo,13 but when you put clonidine head to head with real therapies, it turns out that dog has no teeth.14–16 This should come as no surprise to us. If clonidine works to mitigate opioid withdrawal by kind-of activating opioid signaling, it makes sense that true opioid agonists work better. If clonidine works for opioid withdrawal by blunting the signs and symptoms of withdrawal, what’s the point? Why would we give beta-blockers to the patient with ethanol withdrawal instead of a GABA-agonist? If we know the mechanism of withdrawal, we should be directly addressing the problem, which generally requires augmenting the missing stimulus. In the case of opioid withdrawal, this means opioid agonism.

So @RyanMarino, you can Venmo me @WhoseYourToxMomma. Please hurry with the payment as Sephora-habits have a tendency to be problematic. And kids who are at home listening, let me leave you with the only meme that matters today:

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┻┳| •.•) Masking signs of withdrawal is not

┳┻|⊂ﾉ treating withdrawal.

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$100 by Pepi Stojanovski

1. Clin Toxicol (Phila). 2014;52(5):454-469. PubMed] Lowry J, Brown J. Significance of the imidazoline receptors in toxicology.. 2014;52(5):454-469. 2. Synapse. 2002;43(3):208-218. PubMed] Glass M, Pickel V. Alpha(2A)-adrenergic receptors are present in mu-opioid receptor containing neurons in rat medial nucleus tractus solitarius.. 2002;43(3):208-218. 3. Br J Pharmacol. 2015;172(2):388-402. PubMed] Chabot-Doré A, Schuster D, Stone L, Wilcox G. Analgesic synergy between opioid and α2 -adrenoceptors.. 2015;172(2):388-402. 4. Mol Pharmacol. 2003;64(6):1317-1324. PubMed] Jordan B, Gomes I, Rios C, Filipovska J, Devi L. Functional interactions between mu opioid and alpha 2A-adrenergic receptors.. 2003;64(6):1317-1324. 5. Int J Mol Sci. 2018;19(1). PubMed] Root-Bernstein R, Turke M, Subhramanyam U, Churchill B, Labahn J. Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to “Biased Opioids”?. 2018;19(1). 6. J Chem Neuroanat. 1992;5(1):1-10. PubMed] Zhuo H, Fung S, Reddy V, Barnes C. Immunohistochemical evidence for coexistence of methionine-enkephalin and tyrosine hydroxylase in neurons of the locus coeruleus complex projecting to the spinal cord of the cat.. 1992;5(1):1-10. 7. J Neurosci. 1982;2(8):1150-1156. PubMed] Wilson S, Chang K, Viveros O. Proportional secretion of opioid peptides and catecholamines from adrenal chromaffin cells in culture.. 1982;2(8):1150-1156. 8. Mol Cell Neurosci. 2015;68:177-185. PubMed] Podvin S, Bundey R, Toneff T, Ziegler M, Hook V. Profiles of secreted neuropeptides and catecholamines illustrate similarities and differences in response to stimulation by distinct secretagogues.. 2015;68:177-185. 9. Lancet. 1978;1(8070):929-930. PubMed] Gold M, Redmond D, Kleber H. Clonidine in opiate withdrawal.. 1978;1(8070):929-930. 10. Lancet. 1978;2(8090):599-602. PubMed] Gold M, Redmond D, Kleber H. Clonidine blocks acute opiate-withdrawal symptoms.. 1978;2(8090):599-602. 11. Not at all the evidence-based approach to opioid withdrawal and addiction today. . . . 12. Brain Res. 2010;1314:162-174. PubMed] Van B, Reyes B, Valentino R. The locus coeruleus: A key nucleus where stress and opioids intersect to mediate vulnerability to opiate abuse.. 2010;1314:162-174. 13. Cochrane Database Syst Rev. 2016;(5):CD002024. PubMed] Gowing L, Farrell M, Ali R, White J. Alpha₂-adrenergic agonists for the management of opioid withdrawal.. 2016;(5):CD002024. 14. Cochrane Database Syst Rev. 2017;5:CD002021. PubMed] Gowing L, Ali R, White J. Opioid antagonists with minimal sedation for opioid withdrawal.. 2017;5:CD002021. 15. Cochrane Database Syst Rev. 2018;6:CD007522. PubMed] Rahimi-Movaghar A, Gholami J, Amato L, Hoseinie L, Yousefi-Nooraie R, Amin-Esmaeili M. Pharmacological therapies for management of opium withdrawal.. 2018;6:CD007522. 16. Cochrane Database Syst Rev. 2017;2:CD002025. PubMed] Gowing L, Ali R, White J, Mbewe D. Buprenorphine for managing opioid withdrawal.. 2017;2:CD002025.