Neural Prolotherapy

Neural prolotherapy is a broad term used for treatments that have evolved from traditional prolotherapy (using concentrated Dextrose to stimulate healing) but to focussing on trying to calm chronically irritated and painful nerves. Over time these nerves may become swollen and entrapped with compromised blood supply. This chronic nerve irritation +/- reduced blood supply creates a vicious cycle where the more unhappy the nerve is, the more it fires. The more it fires, the more prone it is to further stimulation at a lower threshold, which makes it fire more. And the cycle continues.

Nerves with a chronically compromised blood supply from compression and/or swelling create conditions that are acidotic (low pH), hypoxic (low O2) and hygoglycaemic (low glucose). A study by MacIver and Tanellan in 1992 looked into the effects of these 3 conditions on neuronal (nerve cell) firing. As you can see it the image below, hypoglycaemia to a nerve (in this study by induced by changing the infiltration of D-glucose form of glucose which our nerve cells utilise, to L-glucose that our body cannot utilise) created a significant increase in nerve cell firing after 10 minutes. This increased cell firing rate quickly returned to baseline with the D-glucose infusion was re-established. The effect of hypoxia (induced by changing the environment to having Nitrogen instead of Oxygen) also produced an effect on increased nerve cell firing, although only about 40% as much as hypoglycaemia. Interestingly, acidotic conditions (lower pH) had no effect on nerve cell firing.

MacIver & Tanellan (1992)

So, it appears that at least part of the issue of irritated nerves over firing comes from the fact that they do not have enough glucose and that by providing them with more glucose, in the form of D5W injections, this can correct the hypoglycaemic state and let them return back to a more normal firing state. Whereas prior to treatment, this energy deficit situation means that because the nerve cell can’t get back to its usual resting state, it fires more. But by firing more it makes it even harder to get back to its resting state and hence more likely to fire more. And the cycle continues.

This can not only cause persistent pain that is triggered with ever reducing stimulus threshold (for example pain being set off by a simple movement or exercise that under normal conditions it should not). But recent evidence also suggests that our pain nerve fibres (predominantly type C fibres) also have an important role in healing and tissue homeostasis. Meaning that the fact that they are chronically overactivated can by itself cause a situation where an existing injury won’t heal properly and/or the supplied tissue can degenerate causing further injury and pain.

It was shown that the non-irritating solution of 5% Dextrose in water (D5W) had the same benefit on nerve pain as the traditional, irritating, hypertonic solutions of 15-25% Dextrose. Therefore, we tend to treat this nerve irritation and pain with the D5W solution as it is not irritating or painful to inject and is readily available D5W intravenous fluid bags.

There are a couple of different ways to treat irritated nerves with 5% Dextrose.

Superficial D5W injections (under the skin)

Around the nerves under direct vision with an ultrasound

Firstly, the technique of superficial D5W injections under the skin is commonly referred to as Perineural Injection Treatment (PIT). This technique was pioneered by Dr John Lyftogt who was the first to discover this link of Dextrose alleviating nerve pains. Lyftogt’s PIT method involves a assessing a patient by palpating over tender areas of skin that will tend to correlate with areas of underlying nerve. Every nerve will have certain points where it is more prone to “friction” or irritation. These are anatomical regions where compression and irritation of underlying nerves is more likely to occur. The method starts by simply palpating the skin and noting which areas are more tender than then surrounding areas. These more tender areas are then injected with a very small amount (0.5-1mL) of using a very fine needle. This process is continued until all of the tender areas have improved. This technique is as simple as it is effective. The pain relief in the tender area is pretty much instantaneous and even seems to have a therapeutic effect to the much deeper nerve, despite only injecting around its superficial branches under the skin.

The second technique, most commonly referred to as Dextrose Hydrodissection involves finding the painful, irritated region of the nerve (often at the same “friction points” mentioned above) and then under ultrasound guidance infiltrating the D5W solution around the nerve. This method has 2 potential benefits over the superficial PIT method mentioned above. Firstly, with each injection a much larger volume of D5W can be infiltrated around the irritated nerve (commonly 5-10mL+, rather than 0.5-1mL at a time) soaking a larger area of the nerve in the therapeutic D5W solution. The other potential benefit is that nerves run through the fascial layers between muscles. Fascia is the interconnected connective tissue throughout our entire body. It appears that within these fascial layers the fascia can become thickened and almost scarred. This change likely causes more friction and causing the nerves to become stuck to the fascia. Using the D5W solution can help free up these sticky/scarred fascial layers allowing the muscles and nerves to glide much more easily resulting in less nerve entrapment and irritation. The only downside to this technique is that identifying and treating these nerves under ultrasound requires a much greater level of skill and training than the simple PIT method. However, with Dan’s background in Anaesthetics and Pain medicine he is no stranger to treating nerves and in fact it is his passion area and he has spent countless hours developing his craft. This means that he has done extensive extra training and has a wealth of experience in treating nerves using this method, a technique that only a small group of practitioners worldwide are experienced at.

How does it work?

We are still studying and trying to elucidate the exact mechanism by which D5W can calm chronically irritated nerves.

To date there is evidence of 4 potential mechanisms

1. Increased extracellular dextrose concentration may depolarise (inhibit firing) of C fibres

Increasing extracellular dextrose from 0.1% (blood level) to 0.5% in intestinal lumen results in hyperpolarisation of enteric cell membranes by activating sodium glucose cotransporter SGLT1, which is also present in peripheral nerves (Chen et al, 2016)

Clinically this appears true as the pain relief (reduced firing) after injection is almost immediate and this is the only mechanism that would explain this.

2. Correcting energy-deficient state in neuropathic nerves

As mentioned above the over-firing, low energy state causing further propensity to fire which worsens the energy state and the cycle continuing seems to be a factor. A decrease in blood dextrose of 25% will initiate histopathological changes in the peripheral nervous system (low energy state may be alarm system). (Jensen et al, 2014)

3. Inhibition and down-regulation of TRPV1 receptors on C fibres

Chronic neuropathic pain is associated with upregulation of the TRPV1 (Capsaicin) receptor (Malek et al, 2015). Mannitol (an analog of Dextrose) both reduces pain induced by Capsaicin which activates the TRPV1 receptor (Bertrand et al, 2015)

4. Modulating the activation of acid-sensing ion channel 1a (ASIC1a) and the release of substance P from muscle afferents

Induced nerve constriction injury in ASIC1a and substance P knockout mice, D5W has no effect on hyperalgesia/allodynia vs “normal” mice (Han et al 2022)

Glucose injection about entrapped peripheral nerves may have several favourable biochemical actions that enhance neuronal cell function

Glucose helps improve function in inflamed, damaged and apoptotic neurons via reactive oxygen species scavenging enhancement of MAPK family and Akt pathways (Cherng etc al, 2023)

What to expect?

Another great thing about the Dextrose Hydrodissection techniques is that as injections go, they tend to be much less painful. There is still a small sting as the fine needle penetrates the skin (but much less than a blood test) but the injectate itself (D5W) does not sting while going in, although can sometimes feel a little cold. Sometimes afterward one can feel a bit of pressure from the injected fluid, but as worst this is mildly uncomfortable and brief. This is opposed to traditional methods using strong local anaesthetic and steroid, both of which will produce significant pain when injected. In fact, usually most of the pain that one associates with injections they have had for pain, the bulk of the pain is most from the injectate (local anaesthetic and steroid) than the actual needle itself.

Everyone’s experience and progress are a little bit different. However, as a general guide initial treatment should produce a noticeable improvement in pain levels by the end of the treatment. However, often after the first couple of treatments the duration of benefit can be on the short side, for example a few hours or so. So although this in itself is not particularly impressive, the great thing about the D5W treatments is that with each subsequent treatment this duration of benefit should increase more and more every time. As a rough ballpark figure, we tend to see about a doubling or tripling of the last effect with each treatment.

So, for example, if a patient has their first treatment and feels an improvement in their pain that then wears off after a few hours. If we repeat the treatment after a couple of weeks their next duration of improvement should increase to about 8-12 hours. Then if we repeat again a fortnight later, this should increase to 1-2 days. Then 3-5 days, then 1-2 week, then 2-4 weeks, then 4-8 weeks and so on. I personally find that the PIT method is a little slower and a little more treatment is required. However, both methods have their benefits and your doctor will provide a thorough review and discuss the pros and cons of each option with you if appropriate.

So, as you can see despite a slow start it eventually builds up to very significant prolonged benefit periods. And to make things even better generally this is also helping with background healing of the tissues and the long-term goal is always for someone to heal completely and not need to return!

As a ballpark most patients will requite 4-8 treatments to get this prolonged effect. Some are faster than this and 1-4 treatments gives prolonged relief. While others take a while to get going and their progress is slower. An excellent example of the progression I see over a group of patients was published by Lam et al in 2017, one of the pioneers and world leaders in Dextrose hydrodissection. As you can see in the graph below, of 26 treated patients using this method, some reduced their pain score from 7.5-9 to 2/10 or less in 1-4 treatments, while others took longer (5-7 treatments).

Lam et al, 2017

Generally speaking the longer the pain has been present and the more severe it is, the slower it will be to respond. With pains present only a couple of months or so, most will see significant improvement within a few treatments. Because some patients who end up doing very well are slower responders I usually like to perform 3-4 treatments before calling it a failure. The reason for this is that its not uncommon that in the first couple of treatments there is benefit but the benefit is so minor that it is hard to appreciate. Due to the every increasing effect with more treatments its not uncommon for patients to require 3-4 treatments before they really notice the change. If we get to 3-4 treatments without significant benefit then I don’t continue with this method of treatment as we should be seeing a response by then so I like to reassess to see if we can find if there is a reason the response is not going to plan and consider alternative treatments.