Abstract

In response to “Trigeminal neuralgia: drug therapy: The new German guideline”, a 17-year single center experience (Duke University Medical Center) with over 5000 treated patients is shared. Recommendations as in the updated German guidelines are endorsed, however extended by pointing out the critical relevance of very early intervention with as-needed medications that are rapidly absorbed and self-applied by patients in case of impending attack, which in most cases is reliably anticipated by patients thus opening up a time-window to implement such treatments. These treatments are rapid-acting carbazines, clonazepam and other off-label medications, formulated either as liquid, orally-dissolving tablet or nasal spray. In addition, pain-evoked blood pressure peaks deserve attention and possible early intervention using as-needed treatments to prevent a vicious pain-hypertension feedforward. In terms of antineuralgic medical maintenance treatment, the robustly beneficial experience with lacosamide is shared, in particular the combination of lacosamide or other anti-neuralgic medical regimens with low-dose naltrexone.

Recent German guidelines on medical therapy of trigeminal neuralgia are relevant and timely [1-3] because trigeminal nerve pain sufferers endure one of the worst forms of pain humans can suffer. Bad pain readily becomes worse once patients seek urgent medical attention which dials up their stress levels and faciliates a detrimental feed-forward. At one point, patients lose the ability to speak and to communicate rationally because of the impact of their trigeminal pain. In such a situation of acute pain distress, and also in follow-up, patients suffering from trigeminal pain are often times mistreated, means too late, too low of a dose, or not at all. This is so in the US, in Germany and in many other parts of the world, thus spread of well-informed information on trigeminal pain disorders and how to treat them safely and effectively can help address the severe unmet medical need of trigeminal pain.

Importantly, episodic trigeminal nerve pain also shares an element of post-traumatic stress disorder – the next devastating, supra-maximal and destructive pain attack can hit the patient any time, she/he feels absolutely helplessly exposed, a no-option victim at the receiving end of viciou pain to their head and face, and threatened in their existence.

“Off-label” medical therapy in real-world clinical practice is essentially relevant to enhance management of trigeminal nerve pain. This can be in the context of combination therapy where components complement each other, and in the context of personalized medicine approaches.

The translational-medical mandate of trigeminal nerve pain disorders is as compelling as it is timely. A decisive factor for all stakeholders to score a win against this formidable foe is closely coordinated collaboration and alignment between clinical research and development, and basic science.

Here I will share my experience with >5000 patients seen over 17 years (2004-2021) whom I had the privilege to serve in the two pain-focused clinics at Duke University Medical Center (Durham NC) which I founded and directed, while at the same time at the helm of my own basic science research laboratory which focused on fundamental pain and sensory neuroscience mechanisms [4-11].

I have three main points, next, plus additional comments, in form of four Tables.

My main points.

1) Rapid-onset as-needed medications open up perspectives for patient-initiated early intervention

Trigeminal nerve pain attacks typically announce themselves with a prodromal phase characterized by sensory focal symptoms such as tingling or other forms of altered sensations in the respective trigeminal territory. This sets up a critical time window in which to hit the trigeminal sensory system with fast-acting medicines (onset of action within minutes) that will enhance the system’s resilience and render an otherwise inescapable devastating pain attack less likely. Regular analgesic-antineuralgic tablets act too slow (20-30min onset of action after oral administration, possibly extended latency aggravated by the pain attack itself). Once the pain takes hold in the exquisitely sensitive trigeminal sensory system [10], it will amplify itself in pathological feed-forward – pain begets more pain asf.

In order to disrupt a trigeminal pain feed-forward, which is the stereotypical onset of a trigeminal nerve pain attack, the following therapeutic principles have been real-world validated, intended for immediate patient-based self-administration as early during the prodromal phase as possible.

·   rapid-acting carbazines: chewable carbamazepine, liquid oxcarbazepine

·   clonazepam orally-dissolving tablets

·   ketamine nasal spray

·   -gepant orally dissolving tablets and nasal spray

·   oxytocin nasal spray

Critical detail re the rapid-acting self-administered early intervention medicines can be found in Table 1.

The psychological argument in favor of fast-acting as-needed medications for the acute early-intervention treatment directly by patients themselves cannot be underestimated. Patients feel more reassured and safe, less as victim to devastating, life-disrupting pain attacks, and more as equal partner in the therapeutic alliance together with the treating team, when having direct access to these treatments. Patients are encouraged to have these treatments at home within reach and also when traveling. Overall, this will decrease stress levels, which in turn can increase manageability of the trigeminal pain disorder, simply by patients having access to these treatments, where in some cases they actually never or rarely will be using these medicines.

Of course these medications can only work with a competent patient-partner who is receptive to instructions to use the medicines during the early prodromal phase of impending pain attacks.

There has been mention in the new German guidelines of lidocaine nasal spray and jelly for intra-oral applications, also -triptan nasal sprays.

Local anesthetics applied directly to trigeminally-innervated surface epithelia represent a form of rapid acting as-needed medications and will be particularly welcome for those patients in whom epithelial surface hypersensitivity and trigger zones (such as intra-orally or nasally) contribute to attacks.

In my own practice I have not encountered instances of -triptan medications effective against trigeminal nerve pain. They can have high-impact effect against co-morbid migraines, and such migraines can feed into and enhance co-morbid trigeminal nerve pain – in those cases rapid acting -triptans can make a lot of sense.

See also Table 4 “Additional commentary and considerations”.

Last but not least, trigeminal nerve pain attacks or rapid aggravation of neuropathic trigeminal pain often times increase blood pressure, which can feed forward into more pain. This often times overlooked simple issue first needs verification. Patients need to be instructed to measure blood pressure before and during pain attacks, which understandably needs particularly dedicated coaching. It will be worth it, and the vast majority of patients can implement. The rationale is to prevent pain and/or stress-induced increase of blood pressure which will further enhance pain and render it more therapy-refractory.

Helpful antihypertensive co-medications can be applied toward this end, namely captopril, clonidine, and again adjuvant clonazepam orally-dissolving tablets, sometimes also helpful lorazepam orally-dissolving tablets, the latter without analgetic impact on trigeminal pain, yet one of the most potent anti-panic approaches in real-world mental health medicine.

Dosing and additional critical detail can be seen in Table 2.

2) Lacosamide has changed many lives of trigeminal nerve pain patients in my practice

Let’s make it brief: lacosamide has changed many lives – the living reality of many of my trigeminal pain patients has decisively improved because they took lacosamide on regular basis. Lacosamide is a more recent medicine than all carbazines (carbamazepine, oxcarbazepine) showcasing a robustly improved therapeutic window, i.e increased effectiveness of inhibition of pain-relevant voltage-gated sodium channels (pain-Nav’s). Based on preclinical studies, there is additional activity against pain-relevant voltage-gated calcium channels, via adaptor protein CRMP-2 [12-14]. Also, lacosamide is significantly safer and showing a much better side effect profile than all carbazines. These conclusions are based on my own longstanding clinical experiences (also referred to in [4, 5]) and in keeping with experiences of colleagues [15-18]. In detail, my experience with lacosamide readily surpasses hundreds of cases. My robustly positive and favorable view of lacosamide appears to contrast with the recent new German guidelines that list lacosamide under “3rd choice”. Following their own definition of 3rd choice by the authors, this is meeting their definition of “3rd choice”. However, “3rd choice” infers a connotation of inferiority whereas in my lexicon lacosamide is clearly superior. – Lacosamide did change many lives.

Dosing and additional critical detail can be seen in Table 3.

3) Combination therapy with low-dose naltrexone (LdN) has also significantly benefited many of my trigeminal pain patients

Naltrexone is a µ-opioid receptor antagonist, which with normal dosing (50-100 mg/d) will evoke a virtually complete antagonism of receptor function in opioid addiction, also in alcoholism. LdN, similar but different, inhibits µ-opioid receptors on nerve cells moderately and for a brief period of time ((minutes to) hours), which in turn elicits a rebound of receptor function. This enhances likelihood of enhanced production of endogenous opioids, which is beneficial for a multi-pronged analgesic regimen. One can try to maximize LdN’s analgesic effects via a circadian dosing strategy, either before onset of sleep or with dawn-coincident timing, both aimed at eliciting a stronger rebound effect of endogenous opioid production. Beyond effects on µ-opioid receptor-expressing neurons, LdN has glio-tropism, attenuating pain-enhancing neuroinflammation via toll-like receptors (TLRs) on glial-lineage cells, astrocytes and microglia that express TLR4. Both postulated mechanisms of action are in need of further neurobiologic work-up [19, 20].  From the standpoint of treating clinician, it is important to realize that chronic pain disorders can be treated with LdN with convincing safety because in controlled studies LdN’s side effect profile was similar to placebo’s [20, 21]. Any minor practical challenges with sleep (dream activity) and gastro-intestinal function (nausea, motility-diarrhea, constipation) can be overcome by very slow dosing in, over several weeks (LdN with slow onset of action anyway). In more than several hundred cases in my practice I was able to combine LdN with an existing moderately effective polypharmacy, which resulted in robust enhancement of manageability of the trigeminal pain. This effect became apparent typically with protracted effectiveness, it could take up to two months after the beneficial effects of LdN became clear. Particularly helpful, in my practice, was the combination of lacosamide with LdN, which for example permitted dose reduction of lacosamide from 2-3x100mg/d to 2x50mg/d.

Dosing and additional critical detail can be seen in Table 3.

Additional considerations and comments regarding trigeminal nerve pain are listed in Table 4, in response to thoughtful discussions re the new German guidelines  [1-3].

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CoI: The author is a full-time executive employee of Regeneron Pharmaceuticals, Tarrytown NY, a professional relationship which has not impacted the content of this article, which represent the author’s own opinions and position, not that of Regeneron, neither that of Duke University, New York University or the US  Facial Pain Association.