Abstract
Neuropathic pain is caused by a lesion or disease affecting the somatosensory nervous system. This chapter summarizes the evidence behind the current recommendations for the pharmacotherapy of neuropathic pain, published by the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain.
The evidence is based on systematic review of the literature and its meta-analysis, considering the GRADE approach for determining the quality of evidence and the strength of recommendations.
Based on GRADE recommendations for or against the use of particular drugs (or classes of drugs) in neuropathic pain, and taking into consideration the numbers needed to treat (NNT) and numbers needed to harm (NNH) for each drug, the pharmacologic agents are divided to first-, second-, and third-line treatments recommended for neuropathic pain. Drugs, the utility of which is questionable, or not supported by current evidence, are summarized separately. Pharmacologic considerations including dosing regimens, adverse effects, drug-interactions, and key pharmacokinetic parameters are outlined for each drug class.
Keywords
central neuropathic pain, drugs, NeuPSIG, neuropathic pain, neuropathy, peripheral neuropathic pain, pharmacotherapy
Neuropathic Pain—Epidemiology and Assessment
Neuropathic pain (NeuP) is defined by the International Association for the Study of Pain (IASP) as “pain caused by a lesion or disease affecting the somatosensory system.” From a taxonomy standpoint, it is typically divided into central and peripheral NeuP, depending on whether the anatomic location of the nerve lesion or disease affects the central or the peripheral nervous system, respectively. Classic examples of peripheral NeuP include polyneuropathies such as painful diabetic peripheral neuropathy (DPN), chemotherapy-induced peripheral neuropathy (CIPN), and human immunodeficiency virus (HIV)–induced sensory neuropathy as well as focal neuropathies such as in postherpetic neuralgia (PHN), posttraumatic nerve injury, postamputation pain, and entrapment neuropathies. Central NeuP conditions include, but are not limited to, pain after spinal cord injury (SCI), central poststroke pain (CPSP), and multiple sclerosis (MS) pain.
There are various epidemiologic estimates of the prevalence of NeuP. Some estimates suggest a prevalence of about 3%, others point toward 6%–10% in the general population. This substantial discrepancy is derived primarily from NeuP assessment methodology and the criteria used for defining “neuropathic pain” or “pain with neuropathic characteristics.” One of the current limitations in performing reliable population-wide surveys is the lack of a “gold standard” for diagnosing NeuP. Recently, the criteria for identifying NeuP and grading its probability have been revised by the Neuropathic Pain Special Interest Group (NeuPSIG) of the IASP and are intended to allow more consistent and accurate assessment of NeuP in large-scale studies and in clinical practice.
Briefly, the probability of NeuP can be determined based on the three following criteria:
- 1.
Patient’s history of signs, symptoms, and descriptors suggestive of pain related to a neurologic lesion or disease and pain distribution that is consistent with the suspected lesion or disease
- 2.
Presence of sensory disturbances upon examination in the painful area and with a neuroanatomically plausible distribution
- 3.
Diagnostic tests that confirm a lesion or disease of the somatosensory nervous system
Unmet criterion 1 implies unlikely NeuP, whereas the fulfillment of each criterion in this sequence grades NeuP as possible, probable, or definite. Obtaining probable or higher grading of NeuP should be sufficient for initiating treatment per the NeuP guidelines discussed in this chapter.
Interdisciplinary management of chronic pain typically yields higher response rates than individual drug or nondrug approaches; however, pharmacotherapy has been the key approach to NeuP management. Several guidelines and their iterations have been available over the past decade, each using a somewhat different approach for creating the evidence base and the recommendations. This chapter focuses on the process and the contents of the 2015 recommendations for the pharmacotherapy of NeuP based on the work carried out by the IASP NeuPSIG treatment guidelines committee.
Constructing the Evidence Base for Recommendations for Neuropathic Pain Pharmacotherapy
The NeuPSIG treatment guidelines were generated by an international committee representing 17 members from 10 countries; they included experts in neurology, anesthesiology, neuroscience, pain medicine, psychology, pharmacy, biostatistics, and epidemiology.
As the first step, a systematic literature search has been performed in PubMed, Medline, and Embase databases and in the Cochrane Central Register of Controlled Trials for identifying all NeuP treatment articles published since 1966. In addition, a web search was performed on the website of the US Food and Drug Administration (FDA), clinical trial registries such as ClinicalTrials.gov , and the pharmaceutical company websites to identify any unpublished research studies with available results. The details of the web search are available in the appendix of the published guidelines.
It is important to mention that exclusion criteria have been applied, and several studies have been excluded from analyses. Only randomized, double-blind, placebo-controlled studies were included. The included interventions were of systemic or local treatments of at least 3 weeks’ duration or single-administration treatments with follow-up of at least 3 weeks’ duration. Studies of shorter duration were excluded. All conditions meeting the IASP criteria of NeuP were included. Importantly, conditions such as complex regional pain syndrome type 1, low back pain without radicular pain, fibromyalgia, and atypical facial pain were not included because they do not meet the current definition of NeuP.
Studies with enriched-enrollment randomized withdrawal designs were analyzed separately.
The primary outcome of effectiveness was based on NeuP intensity, considering the proportion of responders to active treatment versus responders to placebo. The response of a reduction in pain intensity equal to or greater than 50% (or, if unavailable, ≥30% reduction in pain intensity or at least moderate pain relief) was the primary outcome measure, which was used to calculate the numbers needed to treat (NNT) for each intervention. NNT is the number of patients needed to treat with a drug to achieve a response (i.e., ≥50% reduction in pain intensity) that is not attributable to placebo.
The NNT is the inverse of absolute risk reduction. It was calculated based on the following formula:
NNT = 1 / [ P ( active ) − P ( placebo ) ]
where P is the proportion of responders. For example, if 60 of 100 subjects in the active arm and 27 of the 100 subjects in the placebo arm report a reduction in pain intensity equal to or greater than 50%, the NNT is calculated as follows:
NNT = 1 / [ ( 60 / 100 ) − ( 27 / 100 ) ] = 1 / ( 0.60 − 0.27 ) = 3
Subsequently, of every three patients treated with the drug, one will have an important (≥50%) degree of pain relief not attributable to placebo. In the real clinical scenario, the objective response rate might be somewhat higher, considering that the patients might experience an additional placebo response effect added to the “true” drug effect, although these effects are not necessarily additive.
For determining the balance between the benefit and the potential risks of each intervention, the numbers needed to harm (NNH) were calculated for each drug/drug group. NNH is calculated similarly to NNT (but from the ratios of subjects who withdrew from the study owing to side effects) for active drug versus placebo. Contrary to NNT, a larger NNH implies a safer drug (i.e., a smaller ratio of patients is harmed). It is important to note, though, that although NNH provides a measure of tolerability, it does not, by itself, indicate the seriousness of adverse effects. Rare but serious risks as well as side effects that develop over long periods of treatment are unlikely to be captured by clinical trials of a few weeks’ duration.
All identified studies have been assessed for methodologic quality using the five-point Oxford Quality Scale. Two investigators independently extracted the data from each manuscript, and the findings were compared for any inaccuracies to produce a single extraction dataset from each study for data analyses.
The majority of randomized controlled trials (RCTs) have been performed in DPN and PHN with fewer studies in other NeuP conditions, such as painful radiculopathy, phantom pain, and postsurgical NeuP. There is a considerable overlap in symptoms and signs in different NeuP conditions and there was no evidence for effectiveness of particular drugs in specific disorders. Therefore the NeuPSIG recommendations do not divide NeuP conditions based on etiology or pathophysiology but rather present the evidence on the safety and effectiveness of each drug (or drug class) in a variety of NeuP conditions. Although some differences may exist, there is no current evidence to support that a given drug is more effective in a certain peripheral or central NeuP condition. The main exception is trigeminal neuralgia (TGN), which has quite a different presentation of symptoms and signs. Most TGN studies did not meet NeuPSIG inclusion criteria; therefore TGN treatment recommendations offered here are based on a separate body of work that systematically addressed the evidence of safety and effectiveness of drugs in TGN.
In general, poorer effectiveness of pharmacotherapy in conditions such as painful radiculopathy, CIPN, and HIV sensory neuropathy have also been suggested; however, there is a limited number of studies and no direct comparison studies to confirm this with certainty. In addition, studies in HIV sensory neuropathy in general tend to have higher placebo response rates and may thus not have sufficient assay sensitivity, while studies in CIPN often include patients with nonpainful symptoms, which are less likely to be responsive to analgesic treatments.
To minimize bias in translating evidence into recommendations, the NeuPSIG treatment guidelines committee used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), which is a systematic, transparent approach to making judgments about quality of evidence and strength of recommendation.
Pharmacologic Therapy of Neuropathic Pain—Summary of Evidence
The current NeuP guidelines are based on 229 randomized, placebo-controlled trials of pharmacologic agents in NeuP. Of these, 191 have been published, and 21 have not been published, but results were publicly available.
Table 50.1 presents the results of meta-analyses for drugs that had sufficient data to allow NNT and NNH analysis. Based on these analyses incorporated into GRADE framework, the drugs were categorized to lines of treatment according to the strength of recommendation for or against their use in NeuP.
| Between-Arm Comparisons | Total Number of Participants | Achieved Pain Relief With the Active Drug | Achieved Pain Relief With Placebo | NNT (95% CI) | NNH (95% CI) | |
|---|---|---|---|---|---|---|
| Tricyclic antidepressants | 15 | 948 | 217/473 | 85/475 | 3.6 (3.0–4.4) | 13.4 (9.3–24) |
| Serotonin-norepinephrine reuptake inhibitors | 10 | 2541 | 676/1559 | 278/982 | 6.4 (5.2–8.4) | 11.8 (9.6–15) |
| Pregabalin | 25 | 5940 | 1359/3530 | 578/2410 | 7.7 (6.5–9.4) | 13.9 (12–17) |
| Gabapentin (including ER formulation and gabapentin enacarbil) | 14 | 3503 | 719/2073 | 291/1430 | 7.2 (5.9–9.1) | 25.6 (15–79) |
| Tramadol | 6 | 741 | 176/380 | 96/361 | 4.7 (3.6–6.7) | 12.6 (8.4–25) |
| Strong opioids | 7 | 383 | 211/426 | 108/412 | 4.3 (3.4–5.8) | 11.7 (8.4–19) |
| Capsaicin 8% | 6 | 2073 | 466/1299 | 212/774 | 10.6 (7.4–18.8) | NA (single treatment) |
| Botulinum toxin A | 4 | 137 | 42/70 | 4/67 | 1.9 (1.5–2.4) | NA (single treatment) |
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