Diabetic neuropathic pain, what treatments are effective?

Toulouse, France – How to effectively manage diabetic neuropathic pain in 2024? At the congress of the Francophone Diabetes Society ^[1], Prs Agnès Hartemann, Nadine Attal AND Denis Fontaine provided a comprehensive overview of the treatment of these very specific pain conditions, the prevalence of which is increasing worldwide, particularly lamenting the underuse of spinal cord stimulation.

Treatment of diabetic neuropathic pain begins with improving diabetes control. But be careful not to tell the patient lies, warns Professor Agnès Hartemann, head of the department of diabetology at the Pitié-Salpêtrière Hospital (APHP, Paris): “Balancing diabetes will not affect the pain experienced.” Also, beware of the risk of “insulin” neuritis, that rapid balance of diabetes historically described with insulin. This can happen today with crash diets, GLP-1 analogues, semi-closed cycling, etc. “In particular, a rapid drop in blood sugar can lead to diffuse hyperexcitability and dysfunction of small fibers and fibers of the autonomic nervous system. ^[2].

What to do against increased excitability in addition to specific treatment?

Treatments for diabetic neuropathy (DN), such as alpha lipoic acid, are not reimbursed in France, making them difficult to access (commonly prescribed in Italy, for example). However, “saw minimal effect on pain.” ^[3], they do not provide symptomatic treatment,” explains Professor Nadine Attal, neurologist in charge of the Center for the Study and Treatment of Pain at the Ambroise-Paré Hospital in Boulogne-Billancourt. Consequently, we often turn to purely symptomatic multimodal treatment, using not only pharmacological but also psychological means, all with better consideration of the patients’ phenotypes. »

As for pharmacological treatment, traditional analgesics (aspirin, NSAIDs, paracetamol, weak opioids such as codeine, lamalin, opium powder) are ineffective, DN do not involve classical pain mechanisms (ectopic discharge, etc.).

Centrally acting treatments with proven effectiveness that are more commonly used include antidepressants (duloxetine, a serotonin (5-HT) and norepinephrine reuptake inhibitor marketed for diabetics DN) and some antiepileptic drugs such as pregabalin, amitriptyline, clomipramine (AMM DN ). , with central rather than peripheral action, without effect on small fibers or excitability) and gabapentin (AMM DN peripheral)^[4].

Therapeutic combinations may be very interesting, in particular the combination of gabapentinoids and antidepressants in moderate doses.

“Opioids should never be prescribed as first or second line,” warns Nadine Attal, with the possible exception of tramadol, but after discussion with specialists. Moreover, and this is a fairly recent concept, “therapeutic combinations can be very interesting,” she adds, especially the combination of gabapentinoids and antidepressants in moderate doses. This may be as effective as increasing doses of monotherapy. ^[5,6]. »

Local treatment of focal pain

Local treatment is especially useful in cases of focal DN. Patches with a very high concentration of capsaicin (8%) are approved in peripheral DNs. ^[7]. Use in HDJ allows you to get a lasting effect for 3 months. Capsaicin acts on small fibers, especially sensitized C-fibers. “It puts them to rest for about three months, thereby reducing pain,” explains Professor Attal. Additionally, due to its effects on damaged C fibers, it can potentially have a “disease-modifying” effect, as in post-chemotherapy neuropathy, where the painful area shrinks with its use.

Another solution prescribed in pain centers, 5% lidocaine patches do not have marketing approval for this indication, although with some effectiveness despite a significant placebo effect when the pain is very distal and localized.

Finally, botulinum toxin (BTX-A), regardless of the effect on the muscle, has an analgesic effect. “We have shown that when injected subcutaneously into a painful area, botulinum toxin can have a lasting effect on DN, in particular in diabetics. ^[8] “, points out Nadine Attal. At this stage, injections are being administered off-label at several CETDs in the area.

Neuromodulation included in international recommendations

Pharmacological treatment can be combined with techniques such as non-invasive neurostimulation, including transcutaneous electrical stimulation (TENS) or direct current stimulation (dDC). If TENS is already an old technique, compensated according to the prescription of the pain center, then in the field of DN, methods of cerebral neurostimulation appear, although they have been known in psychiatry for a long time. This is exactly the case with repetitive transcranial magnetic stimulation (rTMS). It has been tested at the level of the motor cortex in the Ambroise Pare pain center with a positive effect for at least six months in DN, especially in diabetes, with an excellent tolerability profile. ^[9]. “This is a promising technique,” ​​comments Professor Attal. Several meta-analyses have been published on the treatment of diabetic DN, with a good response rate of one in two, one in four, or even six or seven. ^[10]. »

Therapeutic algorithm International Association for the Study of Pain (IASP) dates back to 2015. Currently under review, an updated version is expected in 2024 or even early 2025 and will include neuromodulation techniques. Diabetes guidelines are distinguished by their emphasis on therapeutic combinations. ^[11]. For their part, representatives French Society for the Study and Treatment of Pain (SFETD) published in 2020 ^[4] have the ability to distinguish between widespread and localized pain. The risks associated with pregabalin somewhat put it off initial use.^time therapeutic line.

However, since the number of patients who do not respond to the pharmacopoeia is large, research needs to be continued. For example, oxcarbazepine showed a preferential effect specifically in patients with diabetic DN suffering from burns and painful paroxysms. ^[12]. Because the goal now is to individualize care according to phenotype. Moving away from the empiricism of research, new drugs are being developed, particularly some new sodium channel blockers, including a molecule that was recently abandoned despite promising research. ^[13]. For cannabis, the data show a significant placebo effect and very modest or even non-significant effectiveness in a meta-analysis consisting of conflicting studies. ^[14].

Pain from diabetic polyneuropathy can be treated with spinal cord stimulation.

Professor Denis Fontaine

Chronic electrical stimulation of the spinal cord via a posterior epidural electrode aims to enhance inhibitory physiological control of pain. This neuromodulation technique is a symptomatic treatment for severe neuropathic pain. The reversible effect causes noticeable paresthesia in the painful area. Modes other than tonic stimulation, which are newer, most often allow one to overcome paresthesia.

“In France, between 1,600 and 2,000 procedures are performed annually (44 centers in France). The technique has been known for 50 years, with recent improvements and miniaturization of technology (3-4 years of autonomy of the stimulator) and without any serious complications (2% of infections in the literature).

Pain in diabetic polyneuropathy (DPN) fully corresponds to the indications for spinal cord stimulation, in 3^e technological line (see diagram) ^[15]very little used in France in this context,” clarifies Professor Denis Fontaine, Department of Neurosurgery (University Hospital of Nice) and Federation of University Hospitals INOVPAIN (innovative solutions in the treatment of refractory chronic pain).

However, three randomized controlled trials confirm the greater effectiveness of IPA: 60% of patients experience an improvement of more than 50%, and the effect is maintained over a long period of time. ^[16,17,18]. The intensity of day and night pain, functional and emotional impact, and quality of life improve.

“But real-world data is lacking, and technical questions remain (stimulation sites and methods, patient selection, etc.). Potentially 30,000 to 60,000 people with diabetes in France could benefit from this, compared with fewer than 20 operated on each year. This gap is mainly due to the lack of familiarity with the technique among diabetologists and those treating DN, the saturation of pain centers, the fact that specialized surgeons end up not seeing diabetic patients, etc. In 2024, too few patients will receive spinal cord neurostimulation, which could potentially benefit them a big relief,” concludes Professor Fontaine.

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