By Ashley Hattle

People living with neuropathic pain face an uphill battle in their efforts to achieve symptom relief, often requiring a combination of therapies when medication options are not as effective as patients and doctors would hope. Prescription medications are a common treatment for chronic pain and can provide marked pain relief when prescribed wisely. However, side effects are common and can deter some individuals from taking the appropriate dose, and the desired pain reduction sometimes falls short of expectations.

“No one pain management treatment uniformly helps in the same way that I can say to you, ‘If you take the prescribed antibiotic for your strep throat, you will be cured of your strep throat in a defined number of days,’” says Charles Argoff, MD, neurology professor and director of the Comprehensive Pain Program at Albany Medical Center. “This underlies the challenge of pain management.”

First-line treatments

Guidelines published in the International Journal of Immunopathology and Pharmacology in 2019 list gabapentinoids (gabapentin, pregabalin, or gabapentin enacarbil) as first-line treatment for neuropathic pain. Yet these medications can cause many side effects, including cognitive changes, weight gain, vertigo, blurred vision, and lethargy. There are barriers to access, too: pregabalin is a controlled substance according to the United States Drug Enforcement Administration (DEA), and gabapentin is considered a controlled substance in some states. In those states, some physicians are reluctant to prescribe it in general, or in conjunction with other central nervous system depressants.

The side effects of these medications are dose specific, which leaves many patients and their physicians weighing the benefits of effective treatment. The average patient on gabapentin takes less than half of the recommended dosage. The reasons may include side effects as well as underdosing by the prescriber.

“I had a brain surgery 20 years ago and was put on gabapentin for a couple of years to avoid seizures,” says Michael Schatman, PhD, a clinical psychologist who has worked in multidisciplinary chronic pain management for almost four decades. He is the editor-in-chief of the Journal of Pain Research. He also currently serves on the faculty of the Department of Anesthesiology, Perioperative Care, and Pain Medicine and the faculty of the Department of Population Health’s Division of Medical Ethics at New York University Grossman School of Medicine. Schatman notes that he experienced cognitive deficits as a side effect of the medication, adding, “I can certainly empathize with my patients who’ve been on gabapentin.”

Another form, gabapentin enacarbil, offers pain relief with fewer side effects. Although the amount of gabapentin that enters the body with this medication may be higher, individuals take the medication less often at lower dosages, which allows for relief without the same likelihood of side effects as other gabapentinoids. Unfortunately, access to this medication is not always possible for a variety of reasons, including cost, Medicare Part D rules, and lack of prescriber knowledge regarding its availability.

Amitriptyline, a tricyclic antidepressant, is another first-line treatment for neuropathic pain, along with serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine and venlafaxine. However, both SNRIs are linked to cardiac and blood pressure concerns. Age is an important factor in amitriptyline use, as side effects and iatrogenic complications increase with age.

Certain anticonvulsants such as carbamazepine are FDA-approved for neuropathic pain, while others may be used off-label, with varying degrees of efficacy.

When the side effects outweigh the therapeutic benefit, the treatment plan should be adapted to ensure a good quality of life with at least some pain relief. Combining gabapentinoids with tricyclic antidepressants or opioids at smaller doses shows more promise than monotherapy or a one-medication approach. However, combining gabapentin with opioids has a warning label for respiratory depression.

“The gold standard medications are very tarnished gold standards,” says Schatman. “Relatively very few people can tolerate the side effects.”

Second- and third-line treatments

The next line of recommended medications includes topical 5% lidocaine patches or gel and 8% capsaicin patches. Their side-effect profiles are lower, and include itching, rash, pain, and rare cases of high blood pressure. Third-line guidelines include subcutaneous botulinum toxin injection (BTX-A, or Botox), which may work well for individuals with peripheral neuropathic pain and allodynia—pain caused by sensations that typically do not cause pain, such as touching the skin. Opioids are sometimes used for neuropathic pain management; one of them, tapentadol, is FDA-approved for the condition.

“[Opioids] are effective and a very viable option for some conditions; neuropathic pain is not one of them,” says Schatman. The data and patient history of treatment with opioids just simply does not show the promise and efficacy of first- and second-line treatments for neuropathic pain, he says.

Schatman believes cannabis could be another viable option for neuropathic pain management. THC can help people experience less pain, but trying to find the right dose and strain can be challenging.

These treatments can have a catch or a trade-off, and patients must weigh the benefits and risks to determine whether their treatment plan is providing them with the best improvement possible.

“It’s very frustrating for the person in pain, and very often in my experience as well as for the provider, because treatment guidelines don’t provide a true roadmap or a reality-based approach,” says Argoff.

For instance, Argoff says, the treatment guidelines for diabetic neuropathy published by the American Academy of Neurology (AAN) in 2022 found limited evidence that any medications and treatments worked. However, this guideline made recommendations solely on the basis of published studies, rather than basing them on any practical experience combined with studies. This guideline also did not recommend nor even comment on high-frequency spinal stimulation, which was FDA approved for painful diabetic neuropathy in 2021, or the 8% capsaicin patch, which also was approved in 2021 for this condition.

Another challenge in treating neuropathic pain is that it overlaps with many other medical concerns, explains Argoff. Diabetes, back injury, multiple sclerosis, migraine disease, HIV, and other diseases can lead to neuropathic pain—all while needing to be managed and treated, too. It’s also common to experience multiple types of pain, such as a person who has diabetic neuropathy and osteoarthritis.

“I think that we too often talk about these conditions as if they were just discrete ‘buckets,’ or individual problems to control,” says Argoff. “When in fact, there’s certainly plenty of evidence to support that a single person may be experiencing multiple pain types at the same time.”

New options on the horizon

Clinical trials have studied and continue to study the effectiveness and safety of different molecules to treat neuropathic pain.

A few interesting areas being studied include ketamine and cannabis-based medications. One in particular is Sativex, a THC- and CBD-derived medication. Dozens of research studies have been and continue to be conducted on this particular drug that is showing promise for its impact on neuropathic pain, sleep issues, and multiple sclerosis-related pain. While these are not currently FDA-approved for neuropathic pain, they offer hope for better pain relief in the future. Argoff and Schatman agree the area of neuropathic pain management is sorely in need of more research and medical interventions to provide patients with a better quality of life free from constant pain.

Finding a doctor you trust to manage neuropathic pain

Primary care physicians are often the first doctors to treat neuropathic pain, and they may not make a referral to a pain specialist until asked. Effective pain management often requires a combination approach of medications, devices, physical rehabilitation therapies, self-management, and other methods to reach a baseline that allows individuals to experience manageable levels of pain throughout their day. If you live with neuropathic pain, building a team of providers to manage your condition(s) with experience in various treatments is key.

“It really behooves you to work with someone who is knowledgeable and creative and can help you to navigate your journey with a combination of therapies,” says Argoff. “If you’re a provider, become knowledgeable about the different domains of treatment and the overlap of treating something with traditional and complementary approaches.”    

I think that we too often talk about these conditions as if they were just discrete ‘buckets,’ or individual problems to control. When in fact, there’s certainly plenty of evidence to support that a single person may be experiencing multiple pain types at the same time.”