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Clonidine Revisted…Again…

We continuously endorse the use of over-the-counter analgesics (non-opiate multi-modal therapy) such as Advil (Ibuprofen), Aleve (Naproxen), and Tylenol (Acetaminophen) – alone or in combination – for most – if not all dental procedures…including surgery. In fact, we train doctors who participate in our state mandated opiate compliance webinar “Strategies For Acute Pain Management In Dentistry” how to move toward an opiate-free practice to ultimately forego their DEA registration.

There are, however, some exceptions. If, for example, you administer any form of sedation or general anesthesia dropping your DEA registration is a non-starter. But even if you don’t, some dentists may feel they need to retain their DEA permit to afford the ability to prescribe sedative agents like a benzodiazepine for their more anxious patients.

Or do you?

I wrote this brief article and published it on LinkedIn almost 5 years ago. With regard to the need to prescribe sedative agents – without a DEA permit – let me reintroduce all of you to Clonidine – again – for the first time!


10 Reasons An Oral & Maxillofacial Surgeon Should Consider Clonidine A More Routine Premedication For Office Anesthesia

While clinicians should be mindful that many of the peri-operative applications of alpha-2 agonists – like Clonidine – remain off label, there are nevertheless many good reasons to consider it’s prospective use on a more routine basis.

David MH Lambert, DDS – LinkedIn July 10, 2017

Clonidine is an imidazoline alpha-2 adrenergic agonist which was originally approved by the FDA in 1974 (Catapres – BI) as an antihypertensive agent. It’s use was initially limited by reports of Clonidine Withdrawal Syndrome – a symptom complex consisting of hypertension, tachycardia, agitation, and insomnia. However, it’s use has been repurposed resulting in unlabeled uses for ADHD, opiate and alcohol withdrawal, smoking cessation, mania and psychosis, and Tourette Syndrome to name a few. In 2010, extended release Clonidine was approved by the FDA for ADHD. It has also been used as a peri-operative adjuvant for anesthesia.

Here are 10 good reasons to consider the administration of Clonidine more routinely as a premedication for office-based anesthesia:

1) Wide margin of safety

Within the context of peri-operative use of Clonidine, there are few reports of activities consistent with syndromic withdrawal. It is safe and effective with a wide margin-of-safety.

2) Produces anxiolysis & sedation

Activation of alpha-2 receptors in the locus caeruleus – a small neuronal nucleus in the upper part of the brainstem which is responsible for wakefulness – results in sedation and anxiolysis. It is, however, devoid of any the addictive potential so commonly demonstrated by other, more commonly utilized agents, i.e. benzodiazepines.

3) Provides analgesia

Descending neural activity from the locus caeruleus decreases nociceptive input and potentially may produce hyperalgesia in combination with NMDA antagonists (i.e. ketamine) while reducing their untoward neurologic sequelae. 

4) Attenuates sympathoadrenal responses

The native activity of alpha-2 adrenergic agonism is sympatholytic resulting in a blunting of central sympathetic outflow – meaning the “fight-flight” system is down regulated.

6) Prevents shivering

Clonidine is the most widely studied alpha agonist for shivering control. It lowers the threshold for vasoconstriction in a linear dose response and is as effective as meperidine in termination.

7) Effective premedication to address “White Coat Syndrome” in normotensive or otherwise well controlled hypertensive patients.

Because Clonidine produces anxiolysis & sedation in addition to it’s native alpha-2 agonist activities, it is an ideal agent to use for patients with situational anxiety who are otherwise normotensive.

8) Provides another site of action in balanced anesthesia

Balanced anesthesia depends upon the administration of multiple agents with activity at differing loci and mechanisms of action. The advantage of this approach is lower overall dosages of all drugs resulting in greater safety and quicker recovery.

9) Prolongs nerve blockade

A plethora of studies have shown that a2 agonists when employed either alone or in combination with local anesthetics or opiate narcotics are highly effective adjuvants in the treatment of short-term pain.

10) Cardio-protective effects

Alpha-2 agonists have demonstrated efficacy in reducing intra-operative myocardial ischemia and post-operative tachycardia. 

Summary

While clinicians should be mindful that many of the peri-operative applications of alpha-2 agonists – like Clonidine – remain off label, there are many good reasons to consider it’s prospective use on a more routine basis. Though it may occasionally produce hypotension and bradycardia in a younger demographic, these patients often possess enough reserve so as to minimize the cardiovascular impact notwithstanding any appropriate intervention to address same. In an older population, the sedative effects of Clonidine – coupled with it’s native sympatholytic effects – make it the perfect pre-medication for management of situational anxiety in otherwise normotensive patients.

I have used Clonidine – safely – on a routine basis as a pre-medication for office based anesthesia for over 10 years mostly in combination with a weight based dosage of alprazolam. Please feel free to inquire more about the technique.

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Study: Naproxen More Effective Than Hydrocodone-Acetaminophen After Dental Surgery

More evidence that NSAIDs with or without acetaminophen are more effective in alleviating pain in the postoperative dental surgery pain model. A recent study from JBR Clinical research demonstrated some unanticipated findings:

“This study is important because the relative efficacy of these two commonly used pain medications has not been directly compared in a validated acute pain model, furthermore, this study is timely because options for reducing the use of opioids to control postoperative pain are highly desired and can provide clinicians with important alternatives when recommending appropriate analgesics.”

Todd Bertoch MD, CEO JBR Clinical Research

We would love to see a fixed OTC combination of naproxen with acetaminophen – much akin to Advil Dual Action – for the future!

David MH Lambert, DDS

Diplomate, ABOMS

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Arthrotec

Any of you who have ever taken of our safe opiate prescribing compliance courses know that I’m a huge fan of combination drugs – like Advil Dual Action.  The reason is compliance – one of the worst practices is to give a patient 5 or 6 prescriptions after a procedure – the likelihood a patient will follow through with instructions is inversely related to the number of prescriptions given and the frequency of administration.  And then we wonder why our patients aren’t compliant, right?  So, ideally it’s best to use drugs that are 1) safe 2) effective 3) have a long half-life and 4) combine drugs when possible.

I was intrigued to learn about Arthrotec.  I kinda hate to say that because it’s been around for…well…decades.

Better late than never, right?

Arthrotec is a combination of the NSAID diclofenac and the cytoprotective agent misoprostol which is approved for arthritic conditions.  The logic behind the combination is that those with arthridities treated with an NSAID are far more likely long term to develop GI ulceration with possible bleeding.  And so the cytoprotective agent in combination with an NSAID is shown to be clinically effective in preventing adverse GI sequelae.

However, there’s a twist to Arthotec.  A growing body of evidence supports the view that the diclofenac/misoprostol combination provides an improved therapeutic ratio over diclofenac alone, not only by improving gastrointestinal safety but also by enhancing analgesic/antiinflammatory effects.  When using an oral surgery pain model, the combination of diclofenac/misprostol improves pain relief over diclofenac alone and for longer duration.  In other words, this is a true example of pharmacologic synergism.

A growing body of evidence supports the view that the diclofenac/misoprostol combination provides an improved therapeutic ratio over diclofenac alone, not only by improving gastrointestinal safety but also by enhancing analgesic/antiinflammatory effects.

Diclofenac/Misoprostol: novel findings and their clinical potential.
Shield MJ
J Rheumatol Suppl. 1998 May;51:31-41
PMID: 9596552

Another earlier study from Temple University looked at the combination of ibuprofen/misprostol with equivocal results but also noted improved therapeutics with diclofenac/misoprostol.   So, apparently the combination of diclofenac/misoprostol is unique.

This product might be considered in patients with a history of GI disorders and possibly in combination with acetaminophen.  High dose acetaminophen has also been demonstrated to be an excellent analgesic in an oral surgery pain model and Arthrotec might be a useful alternative to an opiate for control of breakthrough pain.

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Analgesia & COVID Vaccination

NSAIDS May Impair Host Defenses

The preference for the use of non-opioid analgesics for pain should now be obvious.   However as the option of public COVID-19 vaccination is now widely available in many states, practitioners should be cautioned about the routine use of NSAIDS for pain relief where their treatment may overlap a patient’s vaccination window.(1)

NSAIDs inhibit cyclooxygenase (COX) which plays a critical role in the prostaglandin mediated inflammatory process.  The COX enzyme system exists as isoforms COX1 and COX2 with COX2 being pro-inflammatory.  COX2 is also responsible for optimal for antibody production from B-lymphocytes.

The implication is that both non-selective inhibitors (COX1/COX2) – like ibuprofen – and selective inhibitors (COX2) – like celecoxib – after infection or any vaccination may impair host defenses – and probably should be avoided in favor of acetaminophen.

1.   Bancos S, Bernard MP, Topham DJ, Phipps RP. Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. Cell Immunol. 2009;258(1):18-28. doi: 10.1016/j.cellimm.2009.03.007. Epub 2009 Apr 5. PMID: 19345936; PMCID: PMC2693360.