Introduction
Nerve pain encompasses a broad spectrum of conditions resulting from damage or diseases affecting the somatosensory system, either at the peripheral or central levels. It is often severe, challenging to treat, and leads to a chronic state that impairs patients’ overall well-being, imposing a significant economic burden on individuals and society. To address this, numerous clinical practice guidelines have been published over the past 15 years to aid clinicians in selecting appropriate medications for managing neuropathic pain.
While there is consensus on first-line drugs for neuropathic pain, the debate continues regarding second and third-line options, particularly weak and strong opioids. Opioids, though effective for nerve pain, are not the initial choice due to adverse effects and concerns about misuse and addiction. First-line medications include antidepressants and anticonvulsants acting on calcium channel blockers.
What Is Nerve Pain?
Nerve pain or neuropathic pain is a term used when pain results directly from a disease or injury to the central and/or peripheral somatosensory nervous system. Common neuropathic pain conditions include post-herpetic neuralgia, painful peripheral neuropathy, pain following traumatic nerve injuries, and pain arising from damage to the spinal cord or brain. Individuals with neuropathic pain often describe experiencing spontaneous burning sensations, heightened sensitivity to touch, and episodes of intense pain. The prevalence of chronic neuropathic pain in the general population ranges from 6.9 to 10 percent. Additionally, as many as 34 percent of individuals with diabetes mellitus experience painful diabetic peripheral neuropathy.
What Are the Medications Prescribed to Treat Nerve Pain?
The medications prescribed to treat nerve pain can be:
1. First-Line Analgesics: These include medication from the gabapentinoid class of anticonvulsants, tricyclic antidepressants (TACs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). These drugs have shown effectiveness in various neuropathic pain conditions such as diabetic neuropathy and postherpetic neuralgia. Tricyclic antidepressants, which include secondary amines like Nortriptyline and Desipramine, are well-studied, cost-effective, and can be taken daily. They work by inhibiting the reuptake of serotonin and norepinephrine. It is important to consider potential side effects and tailor dosing to minimize adverse reactions, especially in elderly individuals.
Gabapentin and Pregabalin, reduce the influx of calcium in nerve cells, and they require dose adjustments in cases of renal insufficiency. Common side effects include dizziness, somnolence, weight gain, and edema. SNRIs, like Duloxetine and Venlafaxine, inhibit the reuptake of serotonin and norepinephrine at nerve junctions and are known to be effective, although nausea can be a common side effect. It is also important to evaluate not just the pain intensity but also patients’ overall function, sleep patterns, and social interactions when assessing the success of treatment.
2. Second-Line Analgesics: These include Tramadol, which has shown beneficial effects in diabetic neuropathy and mixed neuropathic pain syndromes. Tramadol is a weak opioid receptor agonist and a weak SNRI. it is recommended as a second-line agent by the Neuropathic Pain Special Interest Group (NeuPSIG). Tramadol may have fewer side effects like constipation and nausea compared to other weak analgesics, but it can lower the seizure threshold and increase the risk of serotonin syndrome when used with serotonergic drugs.
Opioids have been found to be more effective than placebos for pain relief in chronic neuropathic pain; however, due to their potential side effects, medical complications, risks of overdose, diversion, addiction, withdrawal, and the need for specialized follow-up and monitoring, opioid are considered second-line agents for neuropathic pain.
Some common side effects of opioids are:
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Nausea.
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Constipation.
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Drowsiness.
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Dizziness.
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Vomiting.
While some tolerance to these side effects may develop, constipation tends to persist with prolonged opioid use.
3. Third-Line Analgesics: Third-line analgesics for neuropathic pain include cannabinoids. The strongest evidence for cannabinoid use is in cases of neuropathic pain resulting from conditions like:
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HIV (human immunodeficiency virus).
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Diabetic neuropathy.
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Posttraumatic or post-surgical neuropathic pain.
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Mixed central and peripheral neuropathic state.
Common side effects of cannabinoids are:
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Somnolence.
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Feeling “high.”
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Confusion.
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Dizziness.
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Tachycardia.
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Hypotension.
Cannabinoid formulations are Nabilone, Nabiximols, and dried Cannabis. Dosing for dried cannabis is highly individualized and relies on titration, considering complex pharmacology, genetic differences, and prior exposure. Monitoring is essential to assess potential misuse, abuse, and efficacy, and cannabis therapy should be discontinued if it offers no benefit or causes harm.
Interventional therapies, such as epidural injections, pulsed radiofrequency, adhesiolysis sympathetic blockade, and radiofrequency denervation, may be considered in specialized pain clinics for cases where other treatments have failed. The effectiveness of these interventions varies, and the choice of procedure depends on the specific neuropathic pain condition and patient response. Careful monitoring and evaluation are necessary, and multiple procedures may be required.
4. Fourth-Line Analgesics: Fourth-line analgesics for nerve pain include serotonin reuptake inhibitors (SSRIs), which have demonstrated some analgesic effectiveness in conditions like diabetic neuropathy and painful polyneuropathy, except for Fluoxetine. It is important to be cautious about the risk of serotonin syndrome when combining SSRIs with medications that elevate serotonin levels.
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Topical Lidocaine, a local anesthetic, is useful in managing peripheral neuropathic pain, particularly for postherpetic neuralgia. It has been considered a second-line agent for this specific condition. Topical Lidocaine is generally safe, with minimal systemic absorption and few systemic effects when used topically.
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Capsaicin is another topical agent with evidence of effectiveness at high concentrations (8%) in postherpetic neuralgia and painful HIV neuropathy for up to 12 weeks following a single application.
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Methadone, a synthetic opioid with unique properties affecting N-methyl-D-aspartate receptors and serotonin-norepinephrine reuptake inhibitors, has shown potential efficacy in mixed neuropathic pain conditions in small trials.
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Tapentadol, a newer opioid, acts as mu-receptors and inhibits monoamine reuptake, with minimal impact on serotonin reuptake. It has shown efficacy in treating painful diabetic neuropathy. Common side effects include nausea, vomiting, somnolence, and dizziness, but they occur at a lower incidence compared to Oxycodone. Tapentadol is considered a fourth-line agent because its efficacy has been studied in a single neuropathic pain model.
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Additional anticonvulsants explored in neuropathic pain management include Lamotrigine, Lacosamide, Topiramate, and Valproic acid. Lamotrigine had mixed results in various neuropathic pain conditions, with positive outcomes in small studies for specific cases. Lacosamide has been primarily studied in the context of painful diabetic neuropathy, offering modest benefits. Topiramate and Valproic acid showed mixed results in neuropathic pain trials.
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Botulinum toxin injections represent a novel treatment for neuropathic pain with positive results observed in diabetic neuropathy and focal painful neuropathy. However, studies are limited due to small sample sizes, and more evidence is needed to confirm their efficacy.
5. Combined Pharmacotherapy: A recent review on the use of combination pharmacotherapy for neuropathic pain has explored different combinations such as opioids with Gabapentin, Pregabalin, or tricyclic antidepressants, and combination of Gabapentin and Nortriptyline, and various topical medications. A meta-analysis found that combining Gabapentin with an opioid provided better pain relief compared to using Gabapentin alone, but it also resulted in more discontinuations due to side effects.
Conclusion
Prescription medications play a vital role in the treatment of nerve pain. Various options, including opioids, gabapentinoids, tricyclic antidepressants, and combinations thereof, have been explored. While these medications can provide relief, it is essential to carefully consider their benefits and potential side effects, along with individual needs and responses.
