The Diagnosis and Treatment of Neuropathic Pain

Background: The reported prevalence of neuropathic pain in the general population in Germany is from 6.9% to 10%. There are both medical and surgical treatment options.

Methods: This review is based on pertinent publications retrieved by a selective search in PubMed, with consideration of clinical trials, meta-analyses, and guidelines.

Results: Neuropathic pain is diagnosed when pain of the appropriate character is accompanied by further features such as hypesthesia/anesthesia, allodynia, or hyperalgesia. It is generally treated initially with drugs (antidepressant drugs, anticonvulsant drugs, opioids, topical agents, and others); the number needed to treat (NNT) is between 7 and 8 for gabapentin and 3.6 for amitryptiline, as estimated in meta-analyses. For nerve compression and entrapment syndromes, surgical decompression is a treatment directed against the cause of the problem, which can therefore be curative. Microvascular decompression (MVD) is often used to treat supposed compression syndromes of cranial nerves, above all classic trigeminal neuralgia; according to a meta-analysis, MVD brings about a pain-free state in 92.9% [89.1; 96.8] of patients after 5 months to 5 years of follow-up. Ablative surgical procedures are used for symptom control in patients with refractory and/or cancer-related pain. Further symptom-directed treatment options for medically intractable neuropathic pain include neuromodulatory techniques, which involve minimally invasive electrical stimulation of neural structures, and the chronic intrathecal application of drugs such as opioids and ziconotide.

Conclusion: The treatment of neuropathic pain can be either cause-directed or symptom-directed, depending on its origin. Multidisciplinary collaboration can facilitate both the diagnostic evaluation and the selection of the optional modality and timing of treatment.

Neuropathic pain develops as a direct consequence of an injury to or lesion of the somatosensory nervous system (1). The injury can be mechanical, traumatic, metabolic, inflammatory, toxic, or medication related. Neuropathic pain is very common and can lead to a substantially impaired quality of life.

Epidemiology and pathomechanisms

The prevalence of pain with neuropathic characteristics is 6.9–10% (2). Radiculopathies especially in the area of the lumbar spine (prevalence 3–5% of the population) and painful diabetic polyneuropathies (15% of all diabetes patients) are the two most common causes of peripheral neuropathic pain in the general population (3, 4, 5). The pathophysiology is extremely complex and among others includes ectopic activity in injured or neighboring nerves, in the dorsal root ganglion, or in central pathways; it also includes peripheral and central sensitization processes and a multitude of molecular mechanisms (6, 7, 8). A recent publication that studied the structural plasticity or abnormal connectivity and malfunctions of nociceptors during re-innervation after neural lesions showed for the first time that paradoxical sensations, such as allodynia or hyperalgesia, arise as a consequence of malfunctions and abnormal target structures in end organs (9). An understanding of neurochemical, inflammatory, and structural mechanisms is the prerequisite for the symptomatic treatment of neuropathic pain and can be consulted for novel pharmacologic and neuromodulatory therapeutic strategies.

Classification of neuropathic pain

In the current ICD-11 classification, neuropathic pain is for the first time, and depending on the localization of the lesion, classified into peripheral and central neuropathic pain (11) and differentiated by the underlying disease (Box).

Box

Classification of neuropathic pain*

Diagnosis and imaging methods

The ascertainment/detection of neuropathic pain is based on subjectively perceived symptoms such as pain, hypesthesia or anesthesia, allodynia, and hyperalgesia. Patients often describe neuropathic pain as burning, stabbing, including tingling or electrifying, and it can occur spontaneously or evoked in the context of hyperalgesia or allodynia. Hyperalgesia occurs where normal painful stimuli are experienced as vastly more painful, whereas in allodynia, stimuli that are normally not painful—such as touch—become painful. No standardized or specific diagnostic approach or biomarkers exist. Certain neuropathic pain syndromes, such as postherpetic neuralgia, painful diabetic polyneuropathy, or postischemic central pain syndrome enable an easier diagnosis of neuropathy because the presence of an underlying disease determines the existence of a lesion in the nervous system. Other forms of pain—especially mixed forms—may present a diagnostic challenge. In addition to the clinical presentation, laboratory tests, electrophysiology, diagnostic imaging, and—if required—skin biopsies can be used to make a diagnosis.

Clinically provable functional impairments of afferent pathways often entail a combination of “minus” symptoms (sensory deficits, such as hypesthesia and hypalgesia) and “plus” symptoms (burning pain, pain attacks, allodynia, hyperalgesia) (10). Diverse questionnaires and scales are intended to make such symptoms quantitatively and qualitatively standardizable or evaluable. Strong recommendations for use in the diagnosis of possible neuropathic pain have been formulated for the screening questionnaires DN4 (Douleur Neuropathique en 4 Questions), I-DN4 (self-administered DN4), and LANSS (Leeds Assessment of Neuropathic Symptoms and Signs), and weak ones for the S-LANSS (self-administered LANSS) and the PainDETECT (11).

To evaluate the diagnosis, an assessment system to differentiate possible, probable, and confirmed neuropathic pain is helpful (12) (Figure 1).

Figure 1

Flow chart to assess the diagnosis of neuropathic pain

Diagnostic imaging

Imaging modalities in neuropathic pain include neurosonography and MR-neurography as a complementary diagnostic option for the clinical examination, as well as electrophysiology, especially if the former are inconclusive. Neurosonography is characterized by high spatial resolution and wide availability, but it is examiner-dependent and can be used only for nerves lying close to the surface. MR-neurography is a specially developed MR technology with dedicated surface spools and sequencing techniques to yield a high-resolution exposure of peripheral nerves. It allows for exposure of surface as well as deep-seated neural structures. In addition to the exposure of the anatomical conditions in T1 weighted images, a decisive diagnostic role is covered by T2 weighted images with fat suppression. Normal nerves display an isointensive signal to the surrounding muscles, whereas in neuropathies, the signal is stronger in the affected nerve sections. This is highly sensitive but not very specific for the underlying pathophysiology (for example, inflammation, compression, or metabolic disorder). In addition to nerve morphology, MR-neurography increasingly uses functional and quantitative approaches (for example, nerve perfusion and diffusion) (13). Its limited availability is a limitation, as is the expense involved in terms of time and equipment. The primary area of application of imaging modalities is the exposure or exclusion of symptomatic nerve lesions in neuropathic pain—for example, nerve tumors, neuritides, compression neuropathies, or traumatic nerve lesions, such as neuromas (Figure 2).

Figure 2

62-year-old (female) patient with stabbing pain in her right thumb and index finger. The Hoffman-Tinel sign on the inside of the elbow was positive

Figure 3

56-year-old male patient with long-term type 2 diabetes and painful neuropathy.

Therapeutic options

Neuropathic pain may present a vast therapeutic challenge. Before starting conservative and symptom-oriented treatment for neuropathic pain, using medication or non-medication measures, the guideline on the diagnosis and non-interventional therapy of neuropathic pain of the German Society of Neurology(14) requires the definition of realistic therapeutic objectives. These include a reduction in pain of ≥30 % as well as improvements in pain-associated functions. The therapeutic measures are therefore multimodal and in combination are intended to work synergistically, adapted to the pain entity and the individual experience.

Medication-based measures

As monotherapy using antidepressants and anticonvulsants often fails to achieve the desired effect or adverse effects of the drugs prompt a dose-limiting effect, affected patients receive combinations of drugs. For combinations of opioid-antidepressants, opioid-gabapentinoids, and gabapentinoid-antidepressants, however, meta-analyses have not shown superiority compared with monotherapy (15, 16, 17, 18, 19, 20, 21, 22, 23). Table 1 summarizes clinically important effective substances and their pharmacologic mechanisms in the treatment of neuropathic pain.

Table 1

Clinically important active ingredients in drug-based treatment for neuropathic pain

Non-medication-based measures

Psychotherapeutische Interventionen

Psychotherapeutic treatment approaches can be used in the therapy of neuropathic pain of any cause because learning to take personal responsibility and to cope with pain contribute to better acceptance, better adherence, and better quality of life among affected persons and can therefore be of crucial importance for the overall success of medical pain treatment. The resultant participation in social and professional life is again a formulated objective in the guideline (14). Studies of the effectiveness and safety of psychological interventions in chronic neuropathic pain did not show superiority over the control group as regards the parameters under study, which means that no general recommendation can be formulated because of insufficient data (23).

Surgical treatment

The decompression of neuronal structures in bottleneck syndromes of peripheral nerves, spinal compression syndromes, tumors, or neuro-vascular conflict of the cranial nerves constitutes causal and thus curative treatment for neuropathic pain. In the oncology setting too, decompression as a result of tumor resection can have a therapeutic role. These procedures can as a rule be used for all peripheral neuropathic pain in case of confirmed compression or failure of conservative treatment. In sustained pain or incipient functional sensorimotor impairment or unreasonable adverse effects of the medication, prompt surgical care should be considered. In this scenario, individual benefits and risks of decompression should be considered and discussed with the patient. Causal treatment can thus prevent the pain from becoming chronic as well as prevent functional impairments, which are difficult to treat, and restore the function (Table 2).

Table 2

Surgical methods with examples: very high success rates have been reported for all three treatment groups (> 90 %)*

Janetta decompression, also known as microvascular decompression (MVD), is the main technique used for cranial decompression. It can be deployed in case of therapy refractory classic trigeminal neuralgia, neuralgias affecting other cranial nerves, or in compression of cranial nerves VII with consequent hemifacial spasm (24, 25). The most common indication is the classic trigeminal neuralgia (prevalence of TGN as a result of neurovascular conflict=3.4%, 95% confidence interval: [2.5; 4.3], p < 0.01, I2=67.9%). In such cases, compression of the trigeminal nerve by the vertebrobasilar arteries is the most common cause and can be eliminated by microvascular decompression. A meta-analysis of n=9 studies showed that immediate freedom from pain after MVD was achieved in 96% of patients ([94.3; 99.5], p<0.01, I2=2%). Over the longer term ((5 months up to 5 years), it was 92.9% ([89.1; 96.8] p<0.01, I2=0%) (26). The most common specific complications after MVD are facial paresthesias, (13.8% [8; 18]), hearing loss (5%), and cerebellar ataxia (3% [2; 8]) (26).

Radiculopathies and spinal canal stenoses as the main degenerative disorders of the spine, but also trauma and tumors in the spinal region can trigger acute or chronic neuropathic pain.

The indication for surgical decompression with stabilizing measures if required is defined to relieve nerve structures. Pain and neurologic deficits can be treated in this way (27).

In case of bottleneck syndromes with compression of the peripheral nerves, similar recommendations for the revaluation of the individual indication for surgery are documented in the current guidelines (28).

Ablation surgery serves as symptomatic pain treatment as a result of the destruction of neural structures. Such procedures can treat neuropathic pain effectively in spite of their possible potential intrinsic potential of causing neuropathies. Their use is recommended in treating tumor pain (29), neuroma removal (30), for peripheral sensory nerves (31) or ganglion-related problems—for example, in trigeminal pain syndromes (28). To this end, operations to resect/transect, mechanical and thermic or physical methods—such as radiofrequency, laser, or radiosurgery—can be used. These usually have high response rates over the short term, with the long term effect varying by disorder and method. A meta-analysis of the use of radiofrequency for the treatment of facial pain showed that this treatment is highly effective in immediate pain control (up to 100%) but also during long-term follow-up (absence of pain 83.3%-92.3% after 2 years) \(32, 33). Radiofrequency ablation of the intervertebral joints can yield excellent results in selected indications. To improve outcomes by carrying out standardized procedures and indications, the current guideline includes the relevant recommendations (31). The main complication of ablation is the predictable functional impairment of the nerve target, or sensitivity deficits in the region innervated by the trigeminal branches after thermocoagulation in the Gasserian ganglion (29, 30, 31, 32, 33).

Neuromodulatory approaches to electrically stimulate the spinal cord, the peripheral nerves, and the vegetative nervous system can treat chronic, treatment refractory pain in a minimally invasive, sparing, and reversible manner. This modulates pain transmission and processing and thus yields the subjective reduction in pain. For the invasive form of the treatment, neurostimulator implants are required. A preliminary testing phase preceding permanent implantation is recommended. Pain reduction of at least 50% is the prerequisite for a positive evaluation of the test. Further developments to the implants in recent years have been able to vary stimulation parameters and stimulation fields, aim for new targets—such as the spinal ganglion and occipital nerves—and thereby widen the range of indications for these treatments. In this setting, the methods of spinal neuromodulation in the sense of epidural spinal cord stimulation (SCS) (34) and stimulation of the spinal ganglion (DRGS) (35), as well as stimulation of peripheral nerves (PNS) (36) have become well established. The respective method is decided on the basis of localization, extent, and etiology of the pain. In a recent meta-analysis, an average of 71% of patients with persistent leg and back pain who were treated with SCS experienced a substantial alleviation in pain after 24 months as a result of the treatment (34). DRGS is particularly suitable in chronic painful lesions of the peripheral nerves or circumscribed, distally located neuropathic pain after knee or groin surgery, also pain after amputation. PNS is recommended for smaller areas of pain that is caused by lesions of individual peripheral nerves as well as other pain syndromes, even when they occur bilaterally and affect large areas, and can—depending on the underlying disease or method applied—yield up to >80% responders (>50% reduction in pain (37). Serious complications with neurologic deficits are rare in this setting, at 0.1–0.25% (35).

For the painful central neuropathies, no large prospective controlled studies exist to date. As a last resort, however, satisfactory results have repeatedly been shown in smaller case series for motor cortex stimulation (MCS) in postischemic pain and facial anesthesia dolorosa (38, 39).

Because of the prohibitive costs, invasive neuromodulation is still considered a reserve method for use in therapy-refractory pain. To define and justify the indication, select and implement the approaches/methods, and for follow-up of these implants, specialized centers are recommended.

Intrathecal drug delivery (IDD) using morphine and ziconotide can have a crucial role in the optimal medication therapy and reduction of adverse events in the treatment of neuropathic and tumor related pain (40). In spite of decades of experience with this approach, the method is not practiced in a standardized manner in terms of technique and application; for this reason, hardly any valid data for its effectiveness exist. A catheter and a pump are placed intrathecally and are at regular intervals percutaneously filled with the medication while the dosage is adjusted. This type of drug delivery is almost always the therapeutic option of last resort and because of its variable application and results has to always be weighed up—and the indication defined—individually. The reported incidence of complications associated with IDD is 15–40% (40).

Non-invasive neuromodulatory procedures

Transcutaneous electrical nerve stimulation

The mechanism of action of transcutaneous electrical nerve stimulation (TENS) that is under discussion relates especially to the modulation of the spinal nociceptive transmission as a result of stimulating the C- and A-delta fibers (when low-frequency stimulation is used, at 1–10 Hz) and the A-beta fibers (when using high-frequency stimulation, at 80–150 Hz). In addition to the spinal effects, the descending pain inhibition is also suspected to be activated by TENS (14, e1). Insufficient data are available for TENS; a recommendation for its use in neuropathic pain in adults can therefore not be drawn (e1). Because of individual indications of effectiveness and the low rate of adverse effects, its use can be weighed up in the individual case (e2).

Transcranial neurostimulation=non-invasive electrical and magnetic stimulation of the brain

The latest research insights are opening up new strategies in the modulation and influence on cortical networks by using targeted non-invasive electrical and magnetic stimulation. Examples include transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). In repetitive TMS (rTMS), a magnetic field is applied to the cortex to enable the electromagnetic induction of an electrical current. In the setting of chronic neuropathic pain, the target is usually the primary motor cortex (M1) (e3). Indications exist that rTMS has short-term analgesic effectiveness in neuropathic pain, but the quality of the evidence to date is poor (e3).

Conclusions

A multidisciplinary approach is essential for the optimal diagnostic evaluation and the selection of the type and timing of the treatments. Interventional therapies are considered for patients with neuropathic pain who have not responded satisfactorily to pharmacologic treatment alone and should be considered as a component of the multidisciplinary approach and according to patients’ individual needs. The individual, general, and special risks of an intervention should be weighed up, just like the chances and options of the therapy. Patients should therefore be educated appropriately and thoroughly about all therapeutic options, based on individual criteria, so they are in a position to jointly decide whether and when the treatments should be added to or widened. This can primarily be realized in a multidisciplinary context.

Conflict of interest statement
RA received financial contributions for lectures from Boston Scientific und Curronix. She is the spokesperson of the Section of Functional Neurosurgery in the German Society of Neurosurgery and the secretary of the German Neuromodulation Society.

All remaining authors declare that no conflict of interest exists.

Manuscript received on 9 March 2024, revised version accepted on 10 October 2024.

Translated from the original German by Birte Twisselmann, PhD.

Corresponding author
Prof. Dr. med. Rezvan Ahmadi

Sektion „Operative Schmerztherapie“

Medizinische Fakultät Heidelberg

Klinik für Neurochirurgie
Im Neuenheimer Feld 672
69120 Heidelberg

Cite this as
Ahmadi R, Kuner R, Weidner N, Keßler J, Bendszus M, Krieg SM: The diagnosis and treatment of neuropathic pain. Dtsch Arztebl Int 2024; 121: 825–32. DOI: 10.3238/arztebl.m2024.0215

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