The Pharmacological Therapy of Chronic Neuropathic Pain

Background: Chronic neuropathic pain, including painful peripheral polyneuropathy and post-herpetic neuralgia, affects 6.9–10% of the general population.

Methods: In this article, we present current treatment recommendations on the basis of a selective review of the literature.

Results: Neuropathic pain does not respond consistently to classic non-opioid analgesic drugs and is better treated with co-analgesic, antidepressant, and anticonvulsant drugs and topical agents. Under certain conditions, however, neuropathic pain can be treated with opioids, even chronically. It was concluded in a large-scale meta-analysis that tricyclic antidepressants, selective serotonin-norepinephrine reuptake inhibitors, and calcium-channel anticonvulsants are the drugs of first choice, with a number needed to treat (NNT) of 3.5–7.7 for a 50% reduction of pain. An analysis of all studies yielded an estimated publication bias of 10%. Treatment planning must include adequate consideration of the patient’s age and comorbidities, concomitant medication, and potential side effects.

Conclusion: Drugs are now chosen to treat neuropathic pain independently of the cause and symptoms of the pain. Topical agents are used only to treat peripheral neuropathy. The utility of a treatment approach based on the patient’s symptoms and pathological mechanisms was recently demonstrated for the first time in a randomized trial. The goal of current research is to facilitate treatment planning on the basis of the clinical phenotype.

Pain is called neuropathic when it arises as the direct result of a disease or lesion of the central and/or peripheral somatosensory nervous system (1). The classic neuropathic pain syndromes include post-herpetic neuralgia, painful peripheral neuropathy, pain after traumatic nerve lesions, and pain due to damage of the spinal cord or brain (Box 1). Patients with neuropathic pain often complain of spontaneous burning pain, painful sensitivity to touch, and pain attacks. The prevalence of chronic neuropathic pain in the general population is 6.9–10% (2). Up to 34% of persons with diabetes mellitus suffer from painful diabetic peripheral neuropathy (3).

The distinction of neuropathic from nociceptive pain is important, as these two types of pain differ fundamentally in their underlying mechanisms and therefore also in their responses to different drugs (4). Nociceptive pain arises from the “physiological” stimulation of nociceptors in an individual with an intact afferent somatosensory system (4). The causative pathological process lies in the tissue. This type of pain is predominant, for example, in osteoarthritis and rheumatoid arthritis. Aside from neuropathic and nociceptive pain, pain can also be a symptom of psychiatric or psychosomatic disease (5).

In this review, we present the basic principles of chronic neuropathic pain and the drugs used to treat it. We will not discuss trigeminal neuralgia here because of the special pathophysiological, clinical, and therapeutic considerations associated with it. (For more information on this subject, see the relevant guideline of the German Neurological Society [Deutsche Gesellschaft für Neurologie, DGN]).

Learning objectives

This article should enable readers to

• understand why neuropathic pain is treated with antidepressant and anticonvulsant drugs and topical agents,
• know the drugs of first choice, and
• know what algorithm to follow as a guide to treatment.

Methods

This review is based on pertinent articles retrieved by a selective search of the literature on the treatment of chronic neuropathic pain, including national guidelines and current meta-analyses (AWMF search term, “neuropathischer Schmerz”; PubMed search terms, “neuropathic pain,” “treatment,” “therapy,” “review,” “meta-analysis,” “trial”).

The mechanisms of neuropathic pain as targets for pharmacotherapy

Nerve damage has been shown to alter the neuro-physiological properties of afferent neurons (4). Spontaneous ectopic activity arises, damaged axons degenerate and regenerate, and there is heightened sensitivity to afferent stimuli. These phenomena manifest themselves clinically as spontaneous pain, thermal hyperalgesia, and pain attacks (4). Ectopic activity is induced and maintained by a number of factors, including voltage-gated neuronal sodium channels and transient receptor potential (TRP) channels (4). These channels can be modulated with drugs such as carbamazepine, lidocaine, and capsaicin, with resulting relief of pain (6).

The term “central sensitization” refers to neuronal hyperexcitability that is found mainly in the spinal cord (7). Its clinical manifestations are intensified spontaneous pain, mechanical allodynia, and hyperalgesia. Central sensitization can be modulated with drugs including gabapentin, pregabalin, and opioids, with resulting relief of pain (6).

Nociceptive impulse transmission in the spinal cord is physiologically modulated by a descending system (4).

Inhibition of the reuptake of these neurotransmitters from the synaptic cleft through the action of antidepressant drugs leads mainly to an intensification of the analgesic effect (6).

The concept of mixed pain

The presence of a neuropathic pain component does not preclude the simultaneous presence of a nociceptive component (e.g., in diabetes mellitus: a patient can have nociceptive pain from a foot ulcer and, at the same time, painful diabetic peripheral neuropathy or cancer-related pain) (8). An estimated 16–25% of patients with back pain (with or without leg pain) have pain of both nociceptive and neuropathic origin (9). This combination has been termed “mixed pain” (Box 1)—a concept that has not been validated to date by any clinically applicable gold standard. In any patient who might have either or both types of pain, evidence for neuropathic pain should be sought by meticulous history-taking and physical examination, as the proper analgesic treatment will depend on the particular type of pain that is present: opioid and non-opioid analgesics for nociceptive pain, appropriate drugs (cf. treatment recommendations) for neuropathic pain, and, possibly, a combination of both types of medication for mixed pain.

Box 1

Examples of neuropathic pain syndromes

Diagnosis and classification

Clear diagnostic criteria for neuropathic pain were issued in 2008 by the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) (1) on the basis of a revised definition of the entity. According to these criteria, neuropathic pain is definitely present when:

1. the pain has a neuroanatomically plausible distribution (corresponding to a peripheral or central territory of innervation or representation),

2. the history suggests a lesion or underlying disease that can damage the somatosensory system, and

3. both (1) and (2) have been securely demonstrated either clinically or by ancillary testing.

The kinds of tests available for the third criterion above include electrophysiological studies (neurography, evoked potentials) and neuroimaging studies (computed tomography, magnetic resonance imaging). For more detailed information on the diagnostic evaluation of neuropathic pain, see the German guideline on this subject (10). Neuropathic pain is distinguished from nociceptive pain on clinical grounds by the presence of hyperalgesia (increased intensity of pain) and allodynia (pain induced by ordinarily non-painful stimuli) in response to a mechanical and/or thermal stimulus. These positive symptoms are often (11) seen in combination with negative symptoms that reflect a lesion of the somatosensory system, e.g., hypesthesia.

The origin of neuropathic pain can be classified as either peripheral (e.g., peripheral neuropathy) or central types (e.g., stroke or multiple sclerosis) on the basis of the history, physical examination, and further testing if necessary. Some patients have both peripheral and central neuropathic pain. The systemic pharmacotherapy of neuropathic pain is the same regardless of its origin.

A meta-analysis of drug trials performed to date and publication bias

The most comprehensive and up-to-date meta-analysis on the treatment of chronic neuropathic pain to date appeared in Lancet Neurology in early 2015 and included 229 randomized, double-blind, placebo-controlled trials (6). It yielded the following conclusions:

• Wide variations in trial methods, size (patient numbers), and quality make it difficult to compare the utility of older and newer drugs (Table).
• The number needed to treat (NNT) of all first-line drugs, i.e., the number of patients who would need to be treated with a given drug so that one of them, on average, would experience a reduction of pain by at least 50%, lies in the range 3.5–7.7. No recommendation can be given for the preferential use of any particular first-line drug over any other (Table) (6).
• The treatment recommendations are the same regardless of the etiology of the pain (12).

Table

The pharmacotherapy of neuropathic pain: number of trials, number of patients, number needed to treat, evidence levels (GRADE [27]), and common side effects (modified from [6])

It should be pointed out, however, that these conclusions are based in part on assumptions of efficacy across pain syndromes that were made only by analogy. This methodological approach may have put some drugs at a disadvantage in the final assessment. For example, a review of the use of cannabinoids yielded a more positive evaluation than the meta-analysis did, though a need for further trials was mentioned in the review (13). As for some other drugs, such as carbamazepine, there is agreement that the available evidence does not clearly support a general recommendation for their use (14).

The meta-analysis also included a statistical estimate of the effect of publication bias (i.e., the tendency of trials with negative findings to remain unpublished), according to which the therapeutic benefit of drugs against neuropathic pain is likely to have been overstated by 10%. This small effect does not negate the treatment recommendations derived from the meta-analysis.

The fundamentals of treatment

Pain should be treated at once if it impairs the patient’s functioning in everyday life. The treatment options should be discussed clearly with the patient to prevent excessively high expectations and possible disappointment (Box 2). Drugs can lessen neuropathic pain by 30–50% (6). Complete freedom from pain often cannot be achieved. For all types of drug, 20–40% of patients either experience less than  30% pain reduction (so-called “non-responders”) or have intolerable side effects (6). The choice of drug is independent of the etiology of neuropathic pain (12, 15–18), but some drugs have not been tested or approved for pain of some etiologies.

Box 2

Realistic goals for the treatment of neuropathic pain

To improve compliance, patients should also be informed about the following before the treatment is begun:

• The substance classes to be used as analgesic or co-analgesic agents
• The potential side effects and interactions, including impairment of attention, concentration, and ability to drive a motor vehicle
• The temporal course of drug administration until the final dose is reached, and the often delayed onset of the therapeutic effect (e.g., days to weeks for antidepressant and anticonvulsant drugs).

It should be borne in mind in treatment planning that the approval status of the individual active substances may vary from one manufacturer to another. Moreover, drug treatment can be combined at any time with non-pharmacological treatments, and indeed should be if indicated. These treatments include physiotherapy, psychotherapy, and transcutaneous electrical nerve stimulation (TENS) (10).

Substance classes

In the following sections, we list the substance classes and active agents whose use is recommended by the German Neurological Society in its current S1 guideline and by the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) in its meta-analysis. We indicate whenever the recommendations found in these two publications differ. We do not list the scientific evidence for the use of each drug in particular pain syndromes, as the trial data do not show the utility of differential treatment based on the underlying syndrome. We also present results from newer trials that came to our attention through our review of the literature. All of the recommendations given here are based on the findings of randomized, placebo-controlled, double-blind trials. The dosing recommendations may differ from those given in the manufacturers’ informational material for physicians and reflect the authors’ personal experience. We will not discuss the topic of manufacturer-specific approval status for particular active substances; where relevant, this should be checked by the prescribing physician.

Anticonvulsant drugs that act on neuronal calcium channels

Gabapentin

Mechanism of action: Gabapentin is presumed to act on the α2-δ-subunit, thereby lessening the activating calcium influx of central neurons (Figure).

Figure

Pathophysiological mechanisms of neuropathic pain (modified from Baron et al., Lancet Neurol 2010 [4])

Dosing: The initial dose is 100 mg tid. The dose can be raised by 3 × 100 mg every three days until a total of 1200–2400 mg/d in three divided doses is reached. The maximum dose is 3600 mg/d. The dose must be adjusted in patients with impaired renal function.

Recommendation: Gabapentin is recommended in both of the main publications as a first-line drug for the treatment of chronic neuropathic pain.

Pregabalin

Mechanism of action: Pregabalin binds to the α2-δ-subunit of the voltage-dependent calcium channel of peripheral and central nociceptive neurons, lessening the activating calcium influx.

Dosing: The initial dose is 25, 50, or 75 mg once or twice per day and can be escalated by 50–75 mg every three or four days up to a maximum dose of 600 mg/d in two divided doses. The dose must be adjusted in patients with impaired renal function.

Recommendation: Pregabalin is recommended in both of the main publications as a first-line drug for the treatment of chronic neuropathic pain.

Antidepressant drugs

Tricyclic antidepressants (TCA) and selective serotonin-norepinephrine reuptake inhibitors (SSNRI) have both antidepressant and analgesic effects. The doses of TCA that are used to treat pain are generally lower than the effective dose for the treatment of depression.

This is not true of SSNRI, however. Their analgesic effect is derived from a potentiation of the descending nociceptive inhibitory pathways by presynaptic inhibition of the reuptake of serotonin and norepinephrine, two monoaminergic neurotransmitters. TCA also block voltage-dependent sodium channels and have sympatholytic properties.

Tricyclic antidepressants (TCA)

Dosing: Antidepressants must be given in an individually titrated dose depending on their therapeutic effect and side effects. The initial dose is 10 or 12.5 mg, or else 25 mg in a time-release preparation, given either at night (for sedating TCA) or in the morning (for drugs that have a stimulating effect).

Dose escalation: The dose can be raised by 10–25 mg every three to five days, up to a recommended maximum analgesic dose of 75 mg/d. Depending on the active substance, the drug can be given once a day as a time-release preparation or else in two or three divided doses.

Recommendation: TCA are recommended in both of the main publications as first-line drugs for the treatment of chronic neuropathic pain.

Selective serotonin and norepinephrine reuptake inhibitors (SSNRI)—example: duloxetine

Dosing: The initial dose is 30 mg every morning. Dose escalation should take place over a period of 7–14 days. The target dose to be achieved initially should be 60 mg, and the maximal dose is 120 mg once per day in the morning.

Recommendation: Duloxetine is recommended in both of the main publications as a first-line drug for the treatment of chronic neuropathic pain. It has been approved in Germany for the treatment of painful diabetic polyneuropathy. Venlafaxine has not been approved for the treatment of pain in Germany.

The treatment of neuropathic pain with opioids is controversial; cf. the German S3 LONTS guideline on the long-term treatment of pain of non-malignant origin with opioids (19, 20). In the LONTS guideline, the following statements are made:

• Diabetic neuropathy: “Opioid analgesics should be offered as a treatment option for 4 to 12 weeks.”
• Post-herpetic neuralgia: “Opioid analgesics can be offered as a treatment option for 4 to 12 weeks.”
• Phantom pain, radiculopathy, non-diabetic polyneuropathy, and pain after spinal cord injury: “Opioid analgesics should be offered as a treatment option for 4 to 12 weeks.”
• Long-term opiate treatment (for 6 months or more): “Opioid analgesics can be offered as a long-term treatment option to patients with […] chronic neuropathic pain (neuropathies of various causes, post-herpetic neuralgia) who have experienced a clinically relevant reduction of pain and/or subjective physical impairment, with few or no adverse side effects, when treated with such drugs for a limited time (4–12 weeks).”

These recommendations accord with those of the DGN and the NeuPSIG/IASP: both of the latter groups also recommend low- and high-potency opioids for the treatment of chronic neuropathic pain, though only as second-line treatment (low-potency opioids) or third-line treatment (high-potency opioids) under some circumstances.

Opioid analgesics

Mechanisms of action: Opioids act as agonists primarily at the µ opioid receptor. They are classified as either weak (low-potency) or strong (high-potency), depending on their intrinsic activity at the receptor. Tramadol exerts an additional effect on the descending pain-suppressing system by inhibiting the reuptake of norepinephrine and serotonin.

Therapeutic procedure: Current evidence does not support a recommendation to use opioids preferentially. “High-potency opioids are indicated only when there is an interdisciplinary consensus that the pain is resistant to curative approaches or to non-opioid drug treatment, and that low-potency opioids are ineffective or insufficiently effective. Opioids should be given as a long-acting preparation (time-release oral formulations or transdermal systems).” (10) The lowest effective dose must be found by slow titration, starting from a low dose (exception: transdermal systems are not suitable for a dose-finding procedure of this kind). High-potency opioids should not be given to opioid-naive patients as primary treatment. Monitoring for hepatic and renal toxicity with appropriate laboratory tests is recommended despite the low risk. Even under controlled opioid therapy, there is a risk of physical dependency; therefore, a psychiatric and/or psychotherapeutic evaluation is indicated before opioid treatment is begun in any patient with a history of a mental disorder.

Recommendation: Opioids can be used effectively against neuropathic pain when drugs of other types have not been effective or a more rapid onset of pain relief is needed. When opioid therapy is initiated, low-potency opioids should be given first (Box 3).

Box 3

Treatment algorithm for chronic neuropathic pain The following treatment algorithm is based, as regards pharmacotherapy, on the

μ-opioid receptor agonist norepinephrine reuptake inhibitors

Mechanism of action: Drugs in this class (abbreviated MOR-NRI) exert a combined analgesic effect, acting as agonists at the μ receptor while simultaneously inhibiting the reuptake of norepinephrine. They do not inhibit serotonin reuptake to any major extent.

Recommendation: In clinical trials, tapentadol relieved the pain of diabetic neuropathy significantly better than placebo (6, 21). It should be used in the same way as the other morphine agonists among the high-potency opioids.

Topical treatments

Lidocaine patch

Mechanism of action: Lidocaine patches developed especially for the treatment of pain prevent the generation of pathological nerve excitation by blocking sodium channels. Unlike conventional lidocaine patches, they do not cause cutaneous hypesthesia.

Dosing: Initial dose: apply 1–3 patches (700 mg/patch, 10 × 13 cm) to the painful area for 12 hours, with an application-free interval of at least 12 hours thereafter. The patch can be cut to a smaller size if indicated.

Escalation: The maximum dose (3 patches in 24 hours) can be given at the first application. The patch should only be applied to intact skin.

Recommendation: In its S1 guideline, the German Neurological Society designates lidocaine patches as first-line treatment (as either monotherapy or combination therapy) against post-herpetic neuralgia, because of their favorable side-effect profile. According to the meta-analysis, lidocaine patches are a second-line option for the treatment of painful peripheral neuropathy.

High-dose capsaicin patches

Mechanisms of action: Capsaicin is a vanilloid receptor (TRPV1) agonist. A single application of a high-dose patch (8%) leads to reversible degeneration of nociceptive afferent fibers in the skin. Cutaneous innervation with nociceptive afferent fibers renormalizes in approximately 90 days (22).

Dosing: Up to 4 high-dose capsaicin patches (8%) (179 mg/patch, 14 × 20 cm) can be used in a single application for 30 or 60 minutes (on the feet or other parts of the body, respectively). They should be applied directly to the painful area of the skin. According to the manufacturers’ instructions, capsaicin patches cannot be used on the head or face and should only be applied to intact skin. There should be an interval of at least 90 days before any second application.

Recommendation: High-dose capsaicin patches are listed in the German guideline as a first-line treatment for the monotherapy or combination therapy of peripheral neuropathic pain. They are listed in the meta-analysis as a second-line option for the the treatment of peripheral neuropathic pain.

The treatment of neuropathic pain in the elderly

According to the PRISCUS list of potentially inappropriate medications for elderly patients, published in 2010 (24), selective serotonin reuptake inhibitors (SSRI) or mirtazapine should be used in the elderly in preference to tricyclic antidepressants because the latter increase the risk of falls, delirium, and thromboembolic events. Nonetheless, SSRI and mirtazapine are not recommended for the treatment of neuropathic pain, as outlined above.

The concept of individualized, mechanism-oriented treatment

The assignment of different mechanisms to the different clinical manifestations of neuropathic pain has led to the concept of mechanism-oriented treatment (25). It is postulated that a determination of the individual patient’s clinical pain “phenotype” will enable identification of the underlying pathophysiological mechanisms and thus of the drug that is most likely to relieve the symptoms.

Pursuant to this concept, the German Research Network on Neuropathic Pain (Deutsche Forschungsverbund Neuropathischer Schmerzen, DFNS; www.neuropathischer-schmerz.de) has issued the LoGa classification of clinical manifestations (11). “LoGa” stands for loss and gain, i.e., negative and positive symptoms. The classification is based on the physical examination of sensation in the area of the patient’s pain.

The relevance of this classification for individualized symptom- and mechanism-oriented treatment was demonstrated recently in a randomized, placebo-controlled trial (26). Further trials are needed to validate this concept. If it should indeed prove useful, individualized treatment based on the patient’s symptoms will be possible in the near future.

Conflict of interest statement

PD Dr. Binder has served as a paid consultant for Pfizer, Grünenthal, Astellas, and Mundipharma. He has received reimbursement of meeting participation fees and of travel and accommodation expenses from Astellas, Pfizer, and Grünenthal. He has been paid for the preparation of continuing medical education events by Astellas, Pfizer, and Grünenthal. He has received financial support from Grünenthal and Pfizer for a research project that he initiated.

Prof. Baron has served as a paid consultant for Pfizer, Genzyme, Grünenthal, Mundipharma, Allergan, Sanofi Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Novartis, Bristol Myers-Squibb, Biogenidec, AstraZeneca, Merck, Abbvie, Daiichi Sankyo, Glenmark Pharmaceuticals, Seguris, Teva, Genentech, and Galapagos.

He has received payment for authorship and co-authorship of publications on topics related to that of this article from Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Desitin, Teva Pharma, Bayer-Schering MSD, Seguris, Novartis, Bristol Myers-Squibb, Biogenidec, AstraZeneca, Merck, Abbvie, Daiichi Sankyo, and Glenmark Pharmaceuticals.

He has received reimbursement of meeting participation fees and of travel and accommodation expenses, as well as lecture honoraria, from Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Desitin, Teva Pharma, Bayer-Schering, MSD, and bioCSL.

He has received payment for carrying out clinical trials on behalf of Grünenthal and Pfizer. He has received financial support from Pfizer, Genzyme, Grünenthal, and Mundipharma for a research project that he initiated.

Manuscript received on 3 November 2015; revised version accepted on 9 May 2016.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
PD Dr. med. Andreas Binder
Sektion Neurologische Schmerzforschung und Therapie
Klinik für Neurologie
Universitätsklinikum Schleswig-Holstein, Campus Kiel
Haus 41, Arnold-Heller-Str. 3,
24105 Kiel, Germany

@Supplementary material
Case Illustration:
www.aerzteblatt-international.de/16m0616

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