Tuesday, 11 July 2017

Dammit! Find A Drug For Neuropathy That Works!

Today's post from painmedicinenews.com (see link below) is yet another damning report on the efficiency (or lack of) of drugs currently used to treat neuropathic symptoms. Once again it confirms what all neuropathy patients know and that is that if something works for them, that's the result of luck rather than anything else. The article deplores the state of affairs which as been pretty much unchanged for 50 years and calls for the development of new drugs to tackle the problem. However, we all know that the pharma companies are throwing money at research in the race to be the first to come up with an evidence-based successful drug for nerve problems but up to now, all promising leads have led to a dead end. Meanwhile, millions of sufferers across the world have to put up with whatever they're prescribed and now also have to face the stigma of being part of a drug problem that was not their making. Perhaps the most astonishing fact is that if you ask ten people on the street what neuropathy is, they haven't a clue! It leaves you almost speechless but that's the reality of having severe neuropathy in 2017.

Evidence Lacking for Current Pharmacologic Treatment of Neuropathic Pain
—Chase Doyle MAY 19, 2017

Successful management of neuropathic pain remains elusive despite the variety of pharmacologic classes prescribed to treat it, new research suggests. Furthermore, the actual evidence supporting drugs used on an everyday basis is remarkably deficient, according to Richard W. Rosenquist, MD, the study’s author and chairman of the Department of Pain Management at the Cleveland Clinic, in Ohio.

“We’d like better evidence, but we don’t really have it,” Dr. Rosenquist said. “There is marginal evidence for the use of a broad range of oral agents to treat neuropathic pain.”

He surveyed the literature on current pharmacologic management of neuropathic pain and shared the “frustrating, surprising and maybe even appalling” results at the 2016 annual meeting of the American Society of Regional Anesthesia and Pain Medicine (ASRA).

Anticonvulsant Drugs

A review of gabapentin use for chronic neuropathic pain patients demonstrated no first-tier evidence for analgesic efficacy in chronic neuropathic pain and fibromyalgia (Cochrane Database Syst Rev 2014;4:CD007938). The research, which is an update of a review published in 2011 (Cochrane Database Syst Rev 2011;3:CD007938), included data from 37 studies and 5,633 participants looking at oral gabapentin at daily doses of 1,200 mg or higher to treat 12 chronic pain conditions. Second-tier evidence for an outcome of at least 50% pain intensity reduction showed that gabapentin was not significantly better than placebo for treating postherpetic neuralgia.

“You needed to treat at least eight people to get some effect with gabapentin, and only a small number of people experienced significant relief of pain,” Dr. Rosenquist said. “You’ve got to treat a lot of people with gabapentin to get a meaningful reduction in pain.”

A separate analysis composed of data pooled from 18 randomized controlled trials comparing the therapeutic response to pregabalin in patients with neuropathic pain showed no significant differences between patients who had recceived gabapentin and those who did not, in extent of pain relief and relief of pain-related sleep interference for any dose (Pain Pract 2016 Sept 9. [Epub ahead of print]).

Dr. Rosenquist said these findings highlight the importance of tailoring treatment of neuropathic pain based on individual patient response to different treatments, including the trial of multiple agents within the same mechanistic class. “Even if you’ve failed gabapentin, it’s worth trying pregabalin because they don’t behave the same. We think about these drugs as though they’re interchangeable, but they’re probably not.”


Although a variety of antidepressants commonly are used to treat chronic neuropathic pain, amitriptyline is often recommended as first-line therapy, according to researchers. However, an updated version of a 2012 review follows the “same disturbing trend” as anticonvulsants, Dr. Rosenquist said. Researchers found no first- or second-tier evidence for amitriptyline in treating any neuropathic pain condition; only third-tier evidence was available (Cochrane Database Syst Rev 2015;7:CD008242).

Even though these findings were disappointing, the authors pointed out that “a lack of supportive, unbiased evidence for a beneficial effect should be balanced against decades of successful treatment in many people with neuropathic pain.”

They recommended that amitriptyline should continue to be used as part of the treatment of neuropathic pain, “but only a minority of people will achieve satisfactory pain relief.”

In a separate study, duloxetine was shown to be noninferior to pregabalin for the treatment of pain in patients with diabetic peripheral neuropathy who had an inadequate response to gabapentin (Mayo Clin Proc 2011;86:615-626).

“These agents are out there,” Dr. Rosenquist said, “and if we fail one, the evidence says you need to try something else. You shouldn’t be quitting after a single drug.”

Benzodiazepines and Opioids

Benzodiazepines commonly are not used to treat neuropathic pain, and with the FDA’s recent black box warning about mixing benzodiazepines and opioids, many clinicians are revisiting their use of these agents.

Valium and clonazepam increase the inhibitory effectiveness of the neurotransmitter GABA in the spinal cord dorsal horn to suppress incoming nociceptive activity, but this is based on a limited number of studies. One review found no evidence of sufficient quality to support clonazepam for chronic neuropathic pain or fibromyalgia (Cochrane Database Syst Rev 2012;5:CD009486).

“This drug is not widely used, and there is not good evidence for widespread use, but there are subsets of patients that have challenges with spinal cord injury pain and transitional zone pain [for which it is effective],” Dr. Rosenquist said.

Opioids are in the headlines every day and mostly in a negative way, Dr. Rosenquist noted. A Cochrane review on fentanyl use for neuropathic pain in adults—at any dose and by any route of administration—showed insufficient evidence to support or refute the suggestion that fentanyl works in any neuropathic pain condition (Cochrane Database Syst Rev 2016;10:CD011605).

“Reading the evidence for drugs that we’ve been using on a day-to-day basis can be very frustrating,” Dr. Rosenquist said.

At least one glimmer of hope, however, can be found in the first study to compare the effects of methadone with fentanyl in cancer patients with a neuropathic pain component (Eur J Cancer 2016;65:121-129).

“Based on the results,” Dr. Rosenquist said, “methadone should be considered in the treatment of oncologic pain with a neuropathic component. … There may be a role for using methadone in this subset of patients.”

Oxycodone, in contrast, demonstrated very low-quality evidence for the treatment of painful diabetic neuropathy or postherpetic neuralgia, with no evidence for other neuropathic pain conditions (Cochrane Database Syst Rev 2016;7:CD010692).


Another glimmer of hope may come from a small short-term, placebo-controlled trial of inhaled cannabis that demonstrated a dose-dependent reduction in diabetic peripheral neuropathy pain in patients with treatment-refractory pain (J Pain 2015;16:616-627). This finding adds preliminary evidence to support further research on the efficacy of the cannabinoids in neuropathic pain, the study authors noted.

“It did help with pain,” Dr. Rosenquist said, “but it also interfered with subjects’ thinking. … Maybe we’re doing something about your pain, or maybe you just don’t care? Whether that’s a bad thing or not, we can leave open for debate.”

New Drugs Needed

“When we examine the published recommendations on neuropathic pain, we end up with a consensus statement without a strong evidentiary basis,” Dr. Rosenquist summarized. “Further guidance regarding appropriate patient selection and drug and dose strategies is needed to improve management with current drugs. If we’re really going to make a difference for our patients going forward, new drug development to treat these conditions with greater reliability and a smaller side-effect profile is urgently needed.”

Kevin Vorenkamp, MD, director of the pain medicine fellowship at Virginia Mason Medical Center, in Seattle, said this survey of the literature underscores the challenges of a very difficult patient population.

“I think we continue to have excellent targets, and even in animal models many of them have played out, but the challenge of treating the patient is that we’re treating more than just a simple nerve pain condition. There are other variables that are brought out: patients with multiple pain generators, patients with other comorbidities like anxiety and depression, etc.,” he said. “Hopefully, some medicines in development will prove clinically useful.”

Dr. Rosenquist writes educational materials for UpToDate, “an evidence-based, physician-authored clinical decision support resource.” Dr. Vorenkamp reported no relevant financial disclosures.


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