General recommendations for drug therapy
Realistic therapy goals for neuropathic pain are:
-
Pain reduction by ≥30%
-
Improvement of sleep quality
-
Improvement of quality of life
-
Preservation of social activity and relationships
-
Maintaining the ability to work
-
Improved functionality
Neuropathic pain is a therapeutic challenge, since often freedom from pain cannot be achieved and, with all drug options, some patients respond poorly or suffer from intolerable side effects. The therapeutic goals must therefore be discussed realistically. Before starting therapy, potential side effects should be clarified to improve compliance. Patients should also be informed that the effect starts only after reaching an effective dose and with a time delay to avoid early discontinuation of potentially effective preparations. It may be useful and more effective to combine several drugs, as this may result in synergistic pain-relieving effects and the individual doses may remain lower [
37].
The approval status of the individual substances must be taken into account, since some substances might be used off-label. To use them, the following off-label use criteria must be met.
2.
Favorable benefit-to-risk profile
3.
Missing alternatives – individual healing attempt
In addition, the attending physician has a special duty to inform the patient of the possible consequences of off-label use (no manufacturer’s liability etc.)
Anticonvulsants with effect on neuronal calcium channels
Gabapentin and pregabalin bind with high affinity to the α2-δ-subunit of the voltage-gated calcium channels on peripheral and central nociceptive neurons, thereby reducing the activating calcium influx. A recent Cochrane meta-analysis of the effect of gabapentin [
38] could demonstrate a significant pain reduction of > 30% only in PHN and painful diabetic neuropathy. Compared to placebo, gabapentin and pregabalin treatment was associated with more side effects, with severe side effects occurring in only 3%. Side effects included drowsiness, dizziness, edema, gait disturbances, and ataxia.
A further systematic review and meta-analysis [
39] showed a combined NNT of 6.3 for gabapentin and 8.3 for delayed release gabapentin or gabapentin-encarbil, with overall good tolerability. There was no evidence of different effects depending on the given dose. The NNT of pregabalin (150–600 mg/day) was 7.7 [
39]. A better response was found at a daily dose of 600 mg compared to 300 mg.
The NeuPSIG recommendations [
39] strongly recommend the use of gabapentin (in a daily dose of 1200–3600 mg, divided into three doses) and pregabalin (in a daily dose of 300–600 mg, divided into two doses). Gabapentin is approved for the treatment of peripheral neuropathic pain, and pregabalin for the treatment of peripheral and central neuropathic pain. It should be noted that the study situation is not sufficient for all neuropathic pain syndromes.
Recommendation: Gabapentin and pregabalin shall be used as first choice drugs for the treatment of chronic neuropathic pain of any etiology.
Antidepressants
Tri−/tetrazyclic antidepressants
Several meta-analyses and a Cochrane analysis confirm the efficacy of tricyclic antidepressants, but emphasize that the evidence is based on several small studies and is therefore of only moderate quality and that the treatment effect has probably been overestimated [
39,
58‐
60]. Tricyclic antidepressants have no direct antinociceptive properties. They are also effective in patients who do not have depression. The effect on neuropathic pain appears to occur earlier and at lower doses than the effect on depression. Tricyclic antidepressants (amitriptyline, imipramine and clomipramine) bind to norepinephrine and serotonin (5-HT) transporters. The reuptake of these neurotransmitters is inhibited, which activates descending noradrenergic inhibitory pathways [
39]. Tricyclic antidepressants also block sodium channels and thus inhibit ectopic discharges.
The number needed to treat (NNT) for a 50% pain reduction is lowest for tricyclic antidepressants. For amitriptyline, imipramine, and clomipramine, which inhibit norepinephrine and serotonin reuptake, a meta-analysis by Finnerup [
39] shows that NNT is 2.1, whereas for pure norepinephrine reuptake inhibitors (nortriptyline and desipramine) it is 2.5. However, these studies were conducted some time ago with smaller patient numbers, with a cross-over design and without direct comparison with other substances. There are only 2 studies on imipramine and diabetic neuropathy, so no further statement on individual substances could be made in that meta-analysis. A distinction must be made between sedating (e.g. amitriptyline) and non-sedating (e.g. clomipramine) TCA. Amitripytline can be particularly helpful for insomnia due to neuropathic pain.
Dosage: Individual titration is required depending on the effect and side effects. Amitriptyline and imipramine have the advantage of being available as drops. Starting dose: 10–25 mg (extended release) at night or - depending on the active ingredient- also in the morning, dose increase very 3–5 days by 10–25 mg. In elderly patients lower doses should be used, especially at the beginning. Prior to treatment, an ECG should be obtained in all patients at cardiac risk and over 65 years of age. The effective and tolerable dosage is usually between 25 and 75 mg/day (sometimes even lower), depending on the active ingredient, either as a single dose or divided into 2–3 daily doses. Higher doses are only necessary it antidepressive effects are desired (> 150 mg/day). Amitriptyline is in Germany approved for the treatment of neuropathic pain in adults, clomipramine and imipramine for long term pain management as part of an overall therapeutic concept, while trimipramine and nortriptyline are off-label in pain management. Important side effects are: Sedation, dry mouth, cognitive decline, weight gain, constipation, dizziness, orthostatic dysregulation, erectile dysfunction, micturition problems, nausea, tremor and cardiac side effects. Relative contraindications for tricyclic antidepressants include glaucoma, prostate hypertrophy, voiding disorders, an increased risk of seizures, thrombosis, thrombophlebitis, cardiac conduction disorders and heart failure as well as an increased risk of falls. If doses above 100 mg/day are used, regular ECG recordings are recommended, especially for older patients. Laboratory checks of transaminases and blood count before and during therapy are recommended.
The CYP-dependent enzymes lead to a variety of interactions. As an example, amitriptyline must not be combined with MAO-inhibitors (risk of serotonergic syndrome), other anticholinergic (increasing side effects) or adrenergic substances (risk of arrhythmia). Carbamazepine and barbiturates can lower the concentration of tricyclic antidepressants and reduce their effectiveness.
Recommendation: Tricyclic antidepressants shall be used as fist choice drugs for the treatment of neuropathic pain of any etiology.
In the risk-benefit assessment, however, the side effects, drug interactions and cardiac toxicity of TCA must be taken into account.
Selective serotonin- and norepinephrine-reuptake inhibitors (SSNRI)
Duloxetine
The analgesia is explained by the presynaptic reuptake inhibition of the monoaminergic neurotransmitters serotonin and norepinephrine and thus an amplification of the descending pain-inhibitory pathway. In patients with painful diabetic neuropathy, the SSNRI duloxetine is effective at doses of 60–120 mg per day [
61‐
65]. A dose increase from 60 mg duloxetine per day (single dose) to 120 mg per day (spread over two daily doses) did not show a significantly stronger pain reduction in patients with diabetic neuropathy in a post-hoc analysis [
66]. The number needed to treat (NNT) for at least 50% pain reduction after 12 weeks of treatment with duloxetine 60 mg vs. placebo is 5.7 and for duloxetine 120 mg 5.7 [
64]. In a randomized, non placebo-controlled head-to-head study [
67], there was no difference in analgesic efficacy between amitriptyline, duloxetine and pregabalin in patients with painful diabetic neuropathy. The intake of pregabalin led to an improvement in sleep continuity, that of duloxetine to a shortened sleep duration and an improvement in mobility. The frequency of side effects was increased with duloxetine compared to pregabalin. In daily practice, in the event of ineffectiveness or partial effectiveness, a substance from a different group of active substances should be used. Doses lower than 60 mg duloxetine per day are not effective in the treatment of painful diabetic neuropathy [
68].
Dosage: It is recommended to start the therapy with a dose of 30 mg in the morning and after 7–14 days increase to the target dose of 60 mg (up to 120 mg) as a single dose in the morning. A maximum dose of 120 mg can be administered. Duloxetine is in Germany approved for the treatment of diabetic neuropathy, depressive disorders and generalized anxiety disorders. All other indications are off-label use.
Serious side effects are rare [
68]; nausea and vomiting may occur, especially in the first few weeks. Increases in blood pressure can occur, therefore regular checks are recommended. A worsening of the diabetes may occur. In addition, fatigue, dizziness, increased sweating, dry mouth, constipation, reduced appetite, insomnia, diarrhea, disturbed consciousness and trembling, as well as an increase in intraocular pressure may occur. Before treatment, an ECG should be taken for all patients. Before and during therapy, regular laboratory tests of liver and kidney values and blood count should be performed [
69]
. Contraindications are liver and severe kidney dysfunction and uncontrolled hypertension.
Interactions: Duloxetine should not be combined with serotonergically active substances, MAO inhibitors or St. Johns’s wort. CYP1A2 inhibitors (e.g. ciprofloxacin) can lead to an increase in the active level of duloxetine. In smokers, the degradation of duloxetine is accelerated due to CPY1A2 induction, they have lower plasma levels and therefore an increase in dose to 120 mg should be considered. Duloxetine inhibits the breakdown of metoprolol and can therefore double its effective level and increase the risk of bleeding through simultaneous anticoagulation (especially warfarin).
Recommendation: Duloxetine shall be used as the first choice drug for treatment of neuropathic pain of any etiology.
Milnacipran
Evidence: There is currently no evidence of a significant effect of the SSNRI milnacipran in neuropathic pain compared to placebo. A Cochrane analysis identified a single study comparing milnacipran 100–200 mg per day with placebo for 6 weeks in patients with chronic back pain radiating to the leg or buttocks and found no evidence of efficacy [
70]. In Germany, milnacipran is only approved for the treatment of major depression.
Recommendation: Milnacipran should not be used to treat neuropathic pain of any etiology.
Venlafaxine
Evidence: In a Cochrane meta-analysis there were indications that venlafaxine has positive effects on neuropathic pain. However, because some studies had methodological weaknesses and there was a risk of bias [
71], the evidence for the efficacy of venlafaxine was insufficient. The effect of venlafaxine in chemotherapy-induced neuropathy was investigated in a randomized, double-blind study [
72]. Venlafaxine was administered before the start of chemotherapy and on days 2–11 afterwards. The venlafaxine group achieved significantly more frequent symptom relief and improvement, but the number of patients examined was small and the duration of the study was short. For the treatment of chemotherapy-induced neuropathy, the S3 guideline “Supportive therapy in oncology patients” therefore recommends, according to expert opinion, that this therapy can be considered in the context of chemotherapy-induced neuropathy.
In patients with painful diabetic neuropathy, a double-blind randomized study showed that venlafaxine is more effective than placebo [
73]. In a further study with cross-over design, whose methodological quality was poorer and whose case numbers were smaller, patients with painful neuropathy of different etiology were treated with venlafaxine 225 mg/day compared to imipramine 150 mg/day or placebo [
74]. The analgesic efficacy of venlafaxine in this study was better than that of placebo and did not differ significantly from imipramine. However, the methodological limitations of the study significantly limit the validity of the effect.
In Germany, venlafaxine is only approved for the treatment of major depression, generalized and social anxiety disorders and panic disorders.
Recommendation: venlafaxine cannot be recommended for the treatment of neuropathic pain due to insufficient data, but may be considered for off-label use in individual cases.
Opioids
Opioids act as agonists mainly at the μ-opioid receptor in the central nervous system. Depending on the intrinsic activity at the receptor, a distinction is made between low-potency (weak) and high potency (strong) opioids. In addition, there are substances which, in addition to their action at the μ-receptor, act on the descending pain inhibitory system via noradrenergic and serotonergic reuptake inhibition.
In a consensus statement of the Canadian Pain Society [
81], opioids are recommended as a second-choice treatment for chronic neuropathic pain. In contrast, a review article by Finnerup et al. [
39] recommends weak opioids as second-line treatment, while strong opioids are only recommended as third-line medication. This graduation is justified by the potential for abuse of strong opioids in chronic use and the increasing mortality due to overdose. A meta-analysis by Sommer et al. [
82], showed that opioids in therapeutic use for chronic neuropathic pain (duration of the study was only 12 weeks) were superior to placebo in terms of efficacy, but inferior in terms of tolerability.
Tramadol is an opiate agonist with weak affinity to the μ-opioid receptor. The relative analgesic potency in relation to morphine is stated as 0.1. Tramadol also acts as a serotonin and norepinephrine reuptake inhibitor. This mechanism of action provides an additional analgesic and pain modulating effect via descending inhibiting pathways in the spinal cord. In a meta-analysis [
83], tramadol showed significant pain relief, although the evidence was limited due to the small number of participants.
Tapentadol also has a dual mechanism of action as a μ opioid receptor agonist (MPR) and norepinephrine reuptake inhibitor. So far, however, the evidence for the evaluation of tapentadol in the treatment of neuropathic pain is insufficient due to the limited data available [
84,
85].
Cooper et al. [
86] found in a Cochrane review insufficient evidence for the efficacy of
morphine and oxycodone in the treatment of various neuropathic pain conditions, NNT 4.3 (95% CI 3.4–5.8) and NNH 11.7 (8.4–19.3) combined for oxycodone (10–120 mg/day) and morphine (90–240 mg/day). The maximum effect was shown at doses of 180 mg morphine or morphine equivalent without additional benefit at higher doses.
For
oxycodone, a Cochrane review [
87] showed an improved outcome (NNTB 5.7) in diabetic neuropathy or postherpetic neuralgia, but the evidence was not considered sufficient for recommendation.
In a systematic review concerning the importance of
hydromorphone in the treatment of neuropathic pain [
88], only one post-hoc analysis out of 4 RCTs could be included with a positive effect. On the basis of the data available, however, the efficacy of hydromorphone cannot be assessed with certainty.
In a systematic review of
buprenorphine [
89], none of 11 published studies met the inclusion criteria, therefore no statement could be made concerning the efficacy of buprenorphine in neuropathic pain.
In a systematic Cochrane review of
methadone [
90], only 3 studies could be included, but their low methodological quality did not allow any statement about the efficacy of methadone in the treatment of neuropathic pain.
For the synthetic opioid
fentanyl only one study on transdermally applied fentanyl was identified in a systematic review [
91]. Due to the low number of participants and the high number of dropouts, the quality of the study is considered low and the results cannot be assessed with certainty.
Opioids have been shown to be more effective than placebo in diabetic neuropathy and post-herpetic neuralgia, and positive data are also available for post-amputation pain, back pain and spinal cord injury pain. Dosage recommendations are only available for morphine. However, there is no convincing evidence that morphine at doses of up to 180 mg/day is effective in the long-term treatment of neuropathic pain (at least 12 weeks and longer). However, this does not exclude the possibility that certain groups of patients may benefit from treatment with morphine. There is limited evidence for therapy with oxycodone, but a moderate benefit is seen in diabetic neuropathy or post herpetic neuralgia. There are too few studies available for hydromorphone to date to assess an effect on neuropathic pain. Weak opioids such as tramadol cause fewer undesirable side effects such as constipation or dizziness, but overall the evidence is insufficient. For buprenorphine, methadone and fentanyl, there is insufficient evidence for neuropathic pain. Due to adverse side effects, treatment with fentanyl led to premature termination of the study in half of the study participants.
Dosage: In short-term treatment doses of morphine above 180 mg/day or equipotential doses of other opioids should not be exceeded. In the case of treatment over longer periods of time, the spectrum of side effects (especially somnolence, sedation, constipation, and nausea) and the development of tolerance limit the analgesic benefit.
Recommendation: Low potency μ opioid receptor agonists and norephrine reuptake inhibitors such as tramadol as well as high potentcy opioids can be used as a third line treatment of neuropathic pain of any etiology. Undesirable side effects, development of tolerance and comorbid additions can limit the application.
Cannabinoids
Cannabinoids are agonists at CB1 receptors in the CNS, spinal cord and peripheral nerves. They act by inhibiting neuronal excitability [
92]. A meta-analysis of 11 studies found a significant, but clinically only small pain reduction by cannabinoids. In another meta-analysis [
93] cannabinoids significantly reduced neuropathic pain, although the individual data were heterogeneous. Cannabis smoked or absorbed through mucous membranes seemed to be more effective than cannabis administered orally. In the meta-analysis by Petzke et al. [
94] cannabinoids also showed a significant reduction in pain, but this effect was not clinically relevant with an NNTB of 14, while the central nervous and psychiatric side effects were significantly and relevantly more frequent with an NNTH (number needed to treat for an additional harm) of 3 and 8 respectively. A meta-analysis on the use of inhaled cannabis found a significantly more frequent 30% pain relief among cannabinoids compared to placebo with an NNTB of 5.6; however, only very short term effects (between 5 h and a maximum of 2 weeks) were investigated and only 5 RCTs were included. The meta-analysis by Iskedjian et al. [
95] also showed a significant, but only slightly pronounced effect of cannabinoids on pain intensity, which was no longer significant after correction for 2 studies that had allowed many other analgesics. A review by Hauser [
96] summarized several meta-analyses and concluded that the data on the efficacy of cannabinoids are inconsistent. Overall, only few data on the long-term effect and long-term safety were available. In the NeuPSIG recommendations [
39], a weak recommendation is given against the use of cannabinoids, as only 2 of 9 studies examined had a positive effect, using the criterion of 50% pain reduction. According to the recommendations of the National Guidelines for Care in diabetic neuropathy (Nationale Versorgungsleitlinie), cannabinoids should not be used in painful diabetic neuropathy. In a recent Cochrane review, the 30% pain reduction was more frequent with cannabinoid use, but the effect was rather small with an NNTB of 11 and significantly more central side effects occurred with an NNTH of 3, so that the small effect of cannabinoids may be antagonized by the side effects [
97]. In an EFIC (European Pain Federation) position paper, cannabinoids should only be considered for neuropathic pain after failure of standard therapies in a multimodal setting [
98].
Overall, several meta-analyses showed a reduction of neuropathic pain, but this effect was rather small and the therapy led significantly more often to central and psychiatric side effects.
In 2017 a new law came into force in Germany (“Cannabisgesetz, Cannabis Act”), which made cannabinoids (cannabis flowers, cannabis extracts, dronabinol, nabilone, nabiximols) reimbursable upon application to health insurance funds. The patient must submit a case-by-case application for the costs to be covered by the statutory health insurance. After approval, these substances can be prescribed by means of narcotic (BTM) prescription. It is still an off-label use, as none of these substances is approved for the indication “pain”. The “Cannabis Act” obliges the prescribing physician to conduct an accompanying survey to record the success of the therapy.
Dosage: Available are dronabinol (semi-synthetically produced tetrahydrocannabinol (THC), dosage 2.5–10 mg/day), nabilone (fully synthetically produced THC, dosage 1–4 mg/day) and a combination of THC and cannabidiol (CBD, nabiximols) as an oromucosal spray [
94]. In addition, cannabis flowers and cannabis extracts can be prescribed, but note that the THC content varies depending on the flower variety and origin. Currently, only the combination (THC/CBD (nabiximols)) is approved as a nasal spray for the treatment of spasticity in multiple sclerosis (MS) at a dosage of 1–12 strokes/d (corresponding 2.7–32.4 mg THC/2.5–30 mg CBD).
Recommendation: Cannabionoids cannot be recommended for the treatment of neuropathic pain of any etiology, because the effect is rather small and the rate of side effects is high. Only in individual cases, in the event of failure of other pain therapies, can the use of cannabinoids as off-label therapy be considered within a multimodal therapy concept.
Alpha lipoid acid
Alpha lipoic acid is a radical scavenger. All studies have only been conducted in patients with diabetic neuropathy. A meta-analysis of 6 RCT showed a significant improvement in the total sum score (TSS), especially after i.v. administration [
99]. A meta-analysis using 4 RCT also found a significant improvement in TSS; however, this effect was unlikely to be clinically relevant for oral administration with less than 30% improvement in TSS, while the effect was greater for i.v. administration (2 studies), so that this was classified as potentially effective. However, long-term data are not available [
100]. A meta analysis from 2004 [
101] found a significant 50% response rate on the improvement in TSS. However, none of the included studies reported the amount of pain reduction or a 30% pain reduction, as only one cumulative score, TSS, was used, which is not very common in other studies [
102]. The most recent meta-analysis with 5 RCTs found a significant effect on the pain subscore of TSS, but due to the short duration of the studies and a high risk of bias, the evidence level was assessed as low [
102]. A long-term study using 600 mg alpha lipoic acid daily vs. placebo for 4 years showed no effect on the primary endpoint (improvement in “composite score” consisting of neuropathy impairment score as a measure of negative symptoms and 7 neurophysiological tests) and the TSS; only the neuropathy impairment score itself was significantly improved and the therapy was well tolerated [
103].
Dosage: 600 mg alpha lipoic acid per day. In Germany the preparation is not reimbursable, but approved for the treatment of paresthesias in diabetic neuropathy.
Recommendation: Alpha lipoic acid cannot be recommended for the treatment of neuropathic pain of any etiology. An effect in diabetic neuropathy cannot be excluded. However, the evidence is not sufficient to generally recommend its use in diabetic neuropathy.
NMDA receptor antagonists
The effect is achieved by inhibition of the N-methyl-d-aspartate (NMDA) receptor and thus reduction of glutamate release, e.g. in the posterior horn of the spinal cord, but also in other parts of the CNS (Central nervous system). In a review article, different NMDA receptor antagonists were examined: Ketamine had a relevant analgesic effect in the intravenous application, memantine had no effect, methadone showed only a slight analgesic effect in 3 of 3 studies; amantadine had a slight effect in 2 of 3 studies, but only when applied intravenously. Overall, the studies were small and a meta-analysis was not feasible due to the heterogeneity of the data, which clearly limits the significance of the results [
104]. In a review of 12 studies with different oral NMDA receptor antagonists (memantine, magnesium and dextromethorphan) only 2 were positive. Overall the NNT was given as 5.0 (3.6–8.1) and the NNH as 9.4 (6.2–25); however, with inconsistent data, it was not possible to issue a NeuPSIG recommendation [
39]. A small, uncontrolled study involving 32 patients showed an effect of ketamine in chronic neuropathic pain with an unacceptable high rate of side effects in both intravenous and oral therapy [
105]. In another randomized study, intravenously administered ketamine was also effective, but with unacceptable side effects [
106].
Recommendation: NMDA receptor antagonists should not be used to treat chronic neuropathic pain of any etiology.
Non-opiod analgesics
Although 40% of patients with neuropathic pain take NSAIDs (non steroid analgesic anti-inflammatory drugs), there is little data on the efficacy of these drugs [
107]. A Cochrane analysis on the use of NSAIDs in neuropathic pain could only include 2 studies of patients with back pain with a neuropathic component and PHN [
108]. These data could not demonstrate a significant pain reduction by NSAIDs. Not a single study could be included in a Cochrane analysis of the use of paracetamol (acetaminophen) in neuropathic pain [
109] and no relevant study could be found for metamizole. These drugs can have dangerous side effects such as kidney damage and bleeding, especially gastrointestinal bleeding, when used over a long period of time. Paracetamol can be hepatotoxic in high doses and metamizole has a risk of agranulozytosis, although rare.
Recommendation: Non-opioid analgesics (NSAIDs, Cox-2 inhibitors, paracetamol, metamizole) should not be used for the treatment of chronic neuropathic pain of any etiology, as there is no evidence of efficacy.
Topical therapies
Lidocaine patch
Lidocaine prevents the development of ectopic action potentials by blocking voltage-dependent sodium channels. In addition, a reduction in epidermal nerve fiber density has been described with prolonged use. The effectiveness of lidocaine patches (5%) in post-herpetic neuralgia (PHN) has been demonstrated in several studies. Besides the local anesthetic effect, it offers protection against mechanical stimulation (mechanical dynamic allodynia), which is a common problem in PHN).
In patients with painful diabetic neuropathy, an open randomized trial showed an effect comparable to pregabalin after 4 weeks [
111]. However, a Cochrane-review could not provide sufficient evidence due to the poor quality of the randomized trials [
112]. There are several reports of a positive effect and the spectrum of side effect is very small, therefore its use is recommended in many guidelines [
39].
Dosage: 1–3 patches (700 mg/patch, 10 × 14 cm) are applied to dry, intact, non-irritated skin in the painful area for 12 h. Between patches an application free interval of at least 12 h must be observed. The patches can be cut to size so that smaller areas can also be treated. A maximum of 3 patches can be applied every 24 h hours. Approval exists only for PHN; all other indications are off-label use.
Possible side effects are local skin reactions such as erythema, itching and very rarely blistering. Due to the low systemic absorption rate, no central side effects or interactions are expected, which is particularly beneficial in older patients [
39]. Overall, treatment with lidocaine patch can be considered safe [
113]. A tolerance development has not been described. Contraindications are intolerances and open skin wounds. The application site should be inspected as part of the follow-up examinations, in case of local skin reaction, the application area should be changed or a therapy break should be taken.
Recommendation: Lidocaine patch can be recommended as second line treatment of localized neuropathic pain. Its efficacy has been shown in particular in PHN. In PHN the primary used should also be considered.
Capsaicin
Capsaicin is the active ingredient of chili pepper and acts as a natural ligand of TRPV1 receptor (TRPV1; transient receptor potential cation channel subfamily V member 1). In a Cochrane review of 8 RCT in 2488 patients, the majority of patients showed a moderate to significant pain relief of the capsaicin 8% patch compared to placebo or patches containing only 0.04% capsaicin. However, the quality of the evidence was moderate to very low and the proportion of the patients who benefited from treatment was small. The effect of the capsaicin 8% patch was found to be similar to other treatment options for neuropathic pain [
114]. In a systematic review and meta-analysis of the treatment of neuropathic pain which examined 229 studies a weak recommendation as a second choice drug war made [
39]. In an early meta-analysis of the Qutenza Clinical Trials Database including 1458 patients in 7 studies, the authors conclude that capsaicin 8% is superior to a lower dose in patients with painful HIV neuropathy and PHN [
115]. In another systematic review of 25 studies with painful diabetic neuropathy, the capsaicin 8% patch was superior to placebo, better than pregabalin and gabapentin, and similar to duloxetine [
116]. Overall, a reduction in neuropathic pain was shown in several meta-analyses. This effect was comparable to effects of oral medications for neuropathic pain with fewer side effects.
Dosage: Capsaicin 8% patch is available in Germany as a formulation containing 179 mg capsaicin. It is applied to the painful area of the body for a maximum of 60 min, with a maximum of 4 patches applied simultaneously. The patches can be cut to a smaller size. The treatment can be repeated every 90 days. Pre-treatment with lidocaine cream or oral analgesics can be performed. The patch is in Germany approved for the treatment of peripheral neuropathic pain in adults.
Recommendation: Capsaicin 8% patch can be recommended for the treatment of neuropathic pain of any etiology as second choice. The effect is comparable to that of established oral medications with good tolerability. Primary use should be considered for localized neuropathic pain.
Botulinumtoxin
Botulinum toxin (BTX) acts at the neuromuscular junction and blocks the release of acetylcholine from its presynaptic vesicles by cleaving the SNARE proteins (soluble N-ethylmaleimide), resulting in muscle paralysis. However, the effect on neuropathic pain appears to be independent of the effect on muscles [
117] and seems to be mediated by a reduction of the release of pro-inflammatory mediators from peripheral nerves and dorsal root ganglia (substance P, CGRP (calcitonin gene-related peptide), glutamate).
A meta-analysis of 2 small studies with only 58 patients on diabetic neuropathy found a significant pain reduction without significant side effects [
118]. A further meta-analysis including 6 RCT on PHN and trigeminal neuralgia [
119], found a significant reduction in pain and a significant rate of patients with 50% pain relief, however, with risk of bias. In NeuPSIG recommendations [
39], NNT is calculated with 1.9 (4 RCT), but with one additional negative study, so that a weak recommendation is made for the use of BTX. A larger RCT in 66 patients with post-traumatic neuralgia, painful neuropathy or PHN found a significant pain reduction (NNT 2.5) [
120].
In summary, the data suggest that BTX is effective with a demonstrable 30% pain reduction, but the number of treated patients in the trials has been very small and in some cases a risk of bias has been described.
Dosage: 50–200 units botulinum toxin A (onabutulinumtoxin A). BTX is not approved for this indication.
Recommendation: Botulinum toxin can be considered for the treatment of neuropathic pain of any etiology, but only as a third choice drug for focal limited pain in specialized centers.
Transcutaneous electrical nerve stimulation (TENS)
The mode of action of TENS is controversially discussed in the literature. The effect depends on the stimulus frequency. Low frequency stimulation (1–10 Hz) excites especially A- and A-delta fibers and high frequency stimulation (about 80–150 Hz) rather A beta fibers. This leads to a modulation of the spinal nociceptive transmission. Low-frequency stimulation induces the release of dynorphin. In addition to these spinal effects, the descending pain modulation is probably also activated by TENS (especially by low frequency stimulation).
In TENS application, peripheral nerves are electrically stimulated via skin electrodes. The electrical impulses of the various battery-powered stimulation devices are variable in stimulus form, amplitude, impulse duration and frequency. Stimulation is either performed directly above the pain area or above the main nerve trunk that innervates the pain area. The stimulus induced paresthesias should always cover the pain area. Sometimes, stimulation is also effective contralateral to the pain area. There are only few controlled studies. In a recent Cochrane meta-analysis, it is stated that the quality of the available studies on the effectiveness of TENS in neuropathic pain is low [
123]. In conclusion, an analgesic effect of active TENS was found in comparison to a sham-stimulation. However, from the perspective of evidence-based medicine, it was not possible to make a reliable statement regarding efficacy [
123].
Therapeutic approach: Despite long experience with TENS, its success in individual cases cannot be predicted. Correspondingly, test stimulation is necessary prior to prescription. A pain reduction is reported in up to 60% of all patients with various pain syndromes. However, it should be avoided to stick the electrodes directly above areas with allodynia. In PHN, TENS helps especially in patients with preserved sensitivity. Even in central pain, occasional effects of TENS were observed. In most cases TENS is applied 2–4 times a day for about 30 min.
Recommendation: TENS (transcutaneous electrical nerve stimulation) cannot be recommended for the treatment of neuropathic pain of any etiology due to the lack of evidence. Since some studies suggest, that it might be effective, its use may be considered in individual cases.
Various therapies
The intravenous administration of lidocaine and the topical application of ambroxol, clonidine, ketamine and acetylsalicylic acid is not discussed due to the lack of data.
Psychotherapeutic interventions
Like other chronic pain disorders, neuropathic pain can only be understood considering the “bio-psycho-social pain model”. Although there are no RCT studies on specific psychological risk factors for development and chronification for most of the neuropathic pain conditions, there is clinical consensus that neuropathic pain is associated with psychological symptoms (depression, anxiety, impulse control disorders etc.) to varying degrees. Pain psychotherapy is therefore an important and a central component of a multidisciplinary therapy concept. Psychotherapeutic interventions are usually of crucial importance for the overall success of pain management, as they can also contribute to improved acceptance, compliance and quality of life of patients.
A Cochrane analysis [
124] found only 2 studies with a total of 105 participants that fulfilled the inclusion criteria: In a multicenter RCT study, the short and long-term effects of cognitive behavioral therapy were compared to a waiting control group with 61 patients with pain after spinal cord injury (SCI) [
125]. The other RCT [
126] tested the efficacy of psychotherapeutic group intervention in 24 patients with burning mouth syndrome compared to 20 patients who received placebo medication only. Both studies could not provide sufficient evidence for the explicit benefit of psychotherapeutic treatment compared, but were also subject to a high bias.
Recommendation: Psychotherapeutic treatment approaches can be used in the treatment of neuropathic pain of any etiology. So far, however, a 30% reduction of pain could not be proven due to the insufficient data available. Nevertheless, pain psychotherapy represents an important therapeutic option, especially in the context of interdisciplinary multimodal treatment.
Multimodal pain therapy
The basis for multimodal pain therapy is a “bio-psycho-social model” of pain development [
127]. In addition to physiotherapy and occupational therapy, psychological support is also important. However, the data regarding multimodal pain therapy for neuropathic pain is very limited. A small but uncontrolled study showed a long-lasting positive effect of multidisciplinary cognitive behavioral therapy [
128]., while another study found no clear pain reduction, but an improvement in coping strategies in an interdisciplinary pain program [
129].
Recommendation: The available data regarding a 30% pain reduction for the use of multimodal pain therapy is not sufficient to be able to derive a general recommendation. Nevertheless, multimodal pain therapy is an important therapeutic option for chronic neuropathic pain that is difficult to treat.