Genes May Explain Why Gabapentin Works for Some Pain Patients

By Pat Anson

Over the years, gabapentin (Neurontin) has been prescribed for dozens of health conditions, from epilepsy and fibromyalgia to depression and post-operative pain. It’s even been used to treat bipolar disorder. Gabapentin has been marketed for so many different conditions – at times illegally -- that a pharmaceutical company executive infamously referred to the drug as “snake oil.”

Even though it’s been approved for medical use for over 30 years, the UK’s National Health Service admits it’s still “not clear exactly how gabapentin works.”

A new study may finally help explain why gabapentin is an effective pain medication for some patients and an addictive drug with unwelcome side effects for many others.

It could be all in the genes.

Researchers at the University of Edinburgh took another look at a previous study of women with chronic pelvic pain to see why gabapentin worked no better than a placebo for most, but was a moderately effective pain reliever for about 40% of them.

Researchers took saliva samples from 71 women who participated in the study -- 29 who responded to gabapentin and 42 who had no improvement -- and found that the responders were more likely to have a variation of the gene Neuregulin 3 (NRG3). The gene is primarily expressed in the brain, spinal cord and central nervous system, and helps regulate pain sensation and transmission.

The findings, recently published in the journal iScience, may explain why gabapentin works for some women with chronic pelvic pain.

"A genetic factor that can predict how well gabapentin will work in patients offers the prospect of tailored treatment, and provides invaluable insights into understanding chronic pain. We hope eventually to use this genetic marker to optimize personalized treatment decisions and minimize adverse effects for women with chronic pelvic pain," wrote lead author Scott Mackenzie, MD, from the University of Edinburgh's Centre for Reproductive Health.

The study also has implications for other chronic pain conditions. Further research is needed to confirm the findings, but researchers say a genetic test for NRG3 could help limit the use of gabapentin to people who actually benefit from the drug.

"Isolating this single genetic marker is an important discovery that could ultimately help refine treatments for millions of women worldwide who suffer from chronic pelvic pain, as well as increasing our understanding of its role in other pain conditions. We believe this is an exciting opportunity for collaboration with a commercial partner who can help translate the research into a clinical setting," said Susan Bodie, PhD, Head of Business Development for the College of Medicine and Veterinary Medicine at the University of Edinburgh.

Gabapentin and other nerve drugs like pregabalin (Lyrica) have come under increased scrutiny in the UK because they are increasingly involved in overdose deaths.  

A recent analysis of drug tests suggests that gabapentin is also being misused in the U.S. Gabapentin was found in in over 13% of urine samples that tested positive for fentanyl -- about twice the number of drug tests in which prescription opioids were found.

Despite the risks of side effects and addiction, gabapentin is increasingly prescribed “off-label” for conditions it is not approved to treat, such as dental pain. A 2019 study found little evidence that gabapentin and pregabalin should be used for pain and said their effectiveness was often exaggerated by prescribing guidelines.

The CDC’s revised opioid guideline says gabapentin and pregabalin can have “small to moderate improvements” on pain, but with a moderate risk of side effects.

UK Crisis Grows Over Pregabalin Misuse

By Pat Anson, PNN Editor

Nearly 3,400 people in the UK have died from overdoses involving pregabalin in the last five years, according to an investigation by The Sunday Times.

One of them was a young man named Alex Cottam, who spiraled into drug abuse, addiction and a fatal overdose after he started taking pregabalin for anxiety and depression.   

“It’s hard to imagine somebody’s whole life revolved around a pill, but it did,” said Cottam’s mother, Michelle. “It completely changed him, like it was an obsession.”

The Sunday Times’ story about Cottam and other pregabalin users sparked a frenzy in British tabloids about the growing misuse of the drug.

“Our Pregabalin nightmare” was the headline in the Daily Mail, which shared the story of a woman with arthritis who said she “felt like I was losing my mind” after taking the drug for six months. Another woman told the tabloid she began seeing “dead people” within 30 minutes of her first dose.  

In a first-person account published in The Telegraph, Miranda Levy wrote about the severe withdrawal she experienced when she stopped taking pregabalin for depression.

“First came the pins and needles, closely followed by the sweating,” said Levy. “Add to this the progression of unremitting nausea, retching, diarrhea, jitteriness, dizziness so bad you can’t stand up and the feeling you’re about to die.”

Pregabalin – commonly known as the brand name Lyrica -- was never intended to treat anxiety, depression or arthritis. It was originally developed as an anticonvulsant that was first approved by the FDA in 2004 as a treatment for epilepsy. Since then it has been prescribed for dozens of painful conditions such as fibromyalgia and diabetic neuropathy, and is sometimes hailed as a “wonder drug” that is safer than opioids.

Pregabalin has helped some pain patients, but for many it’s also had severe side effects such as fatigue, insomnia and cognitive decline. Margaret Heath started taking pregabalin two years ago for Complex Regional Pain Syndrome (CRPS) and says it ruined her life.

"I've been on every type of morphine you can be put on... this is by far and away the worse drug to be on. It's worse than fentanyl. There is absolutely no comparison with the viciousness of the withdrawal of pregabalin," Heath told LBC News. "There would be days where I would not be able to do anything except lie there... it was debilitating."

Nearly nine million prescriptions for pregabalin were written in the US in 2021, the last year for which data is available. A similar number were written in England and Wales the following year, despite growing concerns in the UK that pregabalin is being misused to boost the euphoric effects of other drugs.

Pregabalin has become so popular with illicit drug users that it frequently appears in overdose toxicology reports. The number of fatal overdoses in the UK involving pregabalin has risen by nearly 11,000% since 2011, followed by a 3,275% increase in gabapentin-related drug deaths.    

UK Drugs With Biggest % Increase in Deaths (2011-2022)

DAILY MAIL GRAPHIC

Pregabalin and gabapentin (Neurontin) belong in a class of nerve medication known as gabapentinoids. Their mechanism of action – how they affect the brain and central nervous system – is still unclear two decades after their medical use was approved.

The UK drug statistics are mirrored in a recent analysis of drug tests in the US, which found gabapentin in over 13% of urine samples that tested positive for fentanyl. That’s about twice the number of drug tests in which prescription opioids were found.

Just because a drug is “involved” in an overdose or appears in a drug test doesn’t necessarily mean that drug caused the overdose or is a red flag for addiction. But experts say its long past time for doctors to be more careful about prescribing pregabalin, and to warn patients about potential side effects and the risk of withdrawal.

“How can there be rising deaths from pregabalin and a huge explosion of prescriptions, with all these troubles, and yet doctors are using this drug to treat anxiety?” asks Dr. Mark Horowitz, a clinical research fellow at the UK’s National Health Service.

“Doctors are selling cars without brakes,” Horowitz told The Sunday Times. “It boggles the mind when a drug is showing all these dangers to then use it on a wider variety of people.”

Gabapentinoids Still Overprescribed Despite Warnings

By Pat Anson, PNN Editor

Despite warnings that they are overprescribed for conditions they were never intended to treat, the use of gabapentinoids continues to grow in the United States.

Pregabalin (Lyrica) and gabapentin (Neurontin) are both gabapentinoids, a class of nerve medication initially developed to treat epileptic seizures. Sales of Lyrica and Neurontin tripled a decade ago, when they were touted as safer alternatives to opioids and prescribed off-label for a variety of pain conditions.

In 2018, Michael Johansen, MD, a researcher and family medicine physician, was one of the first to warn that gabapentinoids were being overprescribed, despite little of evidence of their safety and efficacy for pain conditions. Johansen was particularly concerned the drugs were being given to older adults who were long-time users of opioids and benzodiazepines, a class of anti-anxiety medication.

Not much has changed, according to a new research study by Johansen. Using data from a large national survey, Johansen found that 4.7% of U.S. adults were prescribed a gabapentinoid in 2021, up from 4% in 2015 – a statistically significant increase of 17.5% in six years. The growth was primarily driven by gabapentin, as there was little change in pregabalin’s use.

As Johansen found in his earlier study, gabapetinoid use was much more likely in patients who were co-prescribed opioids, muscle relaxants, benzodiazepines or anti-depressants for chronic pain or mental health conditions. The likelihood of a patient being prescribed a gabapentinoid also rises sharply after age 50.

“Gabapentinoids continue to be commonly used in conjunction with other sedating medications, which is concerning in light of the US Food and Drug Administration’s 2019 warning about co-prescribing of gabapentinoids with other central nervous system depressants,” Johansen reported in the Annals of Family Medicine. “Gabapentinoids are likely used for an array of conditions, with the majority being off-label uses for chronic pain with minimal evidence supporting use.”

Despite those warnings, gabapentinoids — gabapentin in particular — are still being promoted as a treatment for all sorts of things, from dental pain to alcoholism to improving your sex life. Gabapentin has been pitched for so many different conditions that a drug company executive infamously called it “snake oil.”

Gabapentin is FDA-approved for epilepsy and neuropathic pain caused by shingles, but is often prescribed off-label for depression, ADHD, migraine, fibromyalgia, bipolar disorder and postoperative pain.  Pregabalin is approved for diabetic nerve pain, fibromyalgia, post-herpetic neuralgia caused by shingles and spinal cord injuries, but is also prescribed off-label for other types of pain.

Many patients report side-effects from gabapentinoids, such as weight gain, blurred vision, dizziness, sedation and cognitive issues. There are also an increasing number of reports that the drugs are being abused and sold on the street to boost the potency of illicit drugs.

“Reports of gabapentinoid abuse alone, and with opioids, have emerged and there are serious consequences of this co-use, including respiratory depression and increased risk of opioid overdose death,” Douglas Throckmorton, MD, a top FDA official said when the agency released  its 2019 warning.  

A 2019 study found little evidence that gabapentinoids should be used off-label to treat pain and said their effectiveness was often exaggerated by prescribing guidelines. The CDC’s 2016 opioid guideline recommended gabapentin and pregabalin dozens of times as alternatives to opioids, without saying a word about their abuse or side effects.

The CDC’s 2022 revised opioid guideline takes a more cautious approach, saying gabapentin and pregabalin can have “small to moderate improvements” on pain, but were associated with a moderate risk of adverse events. Evidence on their long-term use was also lacking, according to the CDC.  

Fibromyalgia Treatment Is a Real Gas

By Pat Anson, PNN Editor

Immersing fibromyalgia patients in high levels of oxygen is more effective at treating their pain and other symptoms than two medications commonly prescribed for the disorder, according to a new study.

Researchers at Tel Aviv University have been studying hyperbaric oxygen therapy (HBOT) for years as a possible treatment for fibromyalgia, a poorly understood condition characterized by widespread body pain, headaches, fatigue, depression and insomnia.  

Hyperbaric medicine is a form of treatment in which patients stay in a pressurized chamber and breathe 100% oxygen to help them heal faster. HBOT has long been used to treat infections, severe burns, carbon monoxide poisoning, and even scuba divers recovering from decompression sickness. The higher air pressure allows lungs to gather more oxygen than they would normally, and promotes the growth of new blood vessels and neurons in the brain.

In a 2015 study, researchers found that HBOT can also induce neuroplasticity in the brain and significantly reduce fibromyalgia pain.

"Until 15 to 20 years ago, there were doctors who believed that it was a psychosomatic illness and recommended that patients with chronic pain seek mental health care¸” said Shai Efrati, MD, of the Sagol Center for Hyperbaric Medicine and Research at Shamir Medical Center. “Today we know that it is a biological illness, which damages the brain's processing of the signals received from the body. When this processing is malfunctioning, you feel pain without any real damage in related locations.”

Efrati and his colleagues recruited 64 adults who suffer from fibromyalgia as a result of a traumatic head injury, and randomly assigned them to two groups.

One group was exposed to 100% pure oxygen in a hyperbaric chamber for 90 minutes, five times a week for three months; while the second group received either pregabalin (Lyrica) or duloxetine (Cymbalta), two FDA-approved medications for fibromyalgia.

The study findings, published in PLOS One, show that HBOT induced significant improvement in pain levels, quality of life, and emotional and social function. The clinical changes were correlated with increased brain activity in the frontal and parietal regions of the brain, which are associated with function and emotional processing.

A HYPERBARIC oxygen CHAMBER. 

"The results were dramatic," said Efrati. "At the end of the treatment, 2 out of 5 patients in the hyperbaric treatment group showed such a significant improvement that they no longer met the criteria for fibromyalgia. In the drug treatment group, this did not happen to any patient.

"In the group that received hyperbaric treatment, you could see the repair of the brain tissue, while in the control group there was only an attempt to relieve the pain -- without treating the damaged tissue -- and of course the medication group experienced the side effects associated with drug treatment.”

Duloxetine is an anti-depressant and pregabalin is an anti-seizure medication. Neither drug was initially developed to treat fibromyalgia, but were later repurposed as pain treatments.

"These drugs are not very effective,” said lead author Jacob Ablin, MD, from the Tel Aviv Sourasky Medical Center. "As a whole, existing treatments are not good enough. It is a chronic disease that significantly affects the quality of life, including young people, and hyperbaric medicine meets an acute need of these patients.”

Ablin says other non-pharmacological treatments are also beneficial for fibromyalgia, such as aerobic activity, hydrotherapy, cognitive-behavioral therapy and Tai Chi. He said quite a few patients request treatment with medical cannabis.

The studies are preliminary, and researchers say more long-term studies are needed to gauge the effects of HBOT after one, two and three years. But they’re encouraged by what they’re finding.

"This is a difference in approach: to cure instead of just treating the symptoms,” says Efrati. “Our goal as doctors is not only to treat the symptoms but to treat as much as possible the source of the problem, thus improving the quality of life of fibromyalgia patients."

Gabapentin and Pregabalin Only ‘Modestly Effective’ for Pain

By Pat Anson, PNN Editor

A new review of clinical studies on the use of gabapentin (Neurontin) and pregabalin (Lyrica) in pain management found the drugs are only “modestly effective” and could be risky for some pain patients.

Gabapentin and pregabalin belong to a class of nerve medication called gabapentinoids, which were originally developed as anticonvulsants to treat epileptic seizures. In recent years, however, they have been increasingly prescribed off-label as an alternative to opioids in managing pain. About one in five U.S. adults with chronic pain are prescribed a gabapentinoid.  

"Treating pain has been problematic for a long time, and we're still dealing with the fallout from opioid overuse," says lead author Craig Williams, PharmD, a clinical professor at Oregon State University College of Pharmacy. "Gabapentinoids are modestly effective for certain patients; they are rarely extremely effective, and they are not effective at all for some patients because the mechanisms of the pain don't match up with the mechanisms of the drug.

"Doctors who prescribe gabapentinoids for pain should do so with their eyes wide open and be prepared to stop them if they are ineffective or cause too many side effects."

The study findings, published in the journal Drugs, found that many of the clinical trials for gabapentin and pregabalin were of short duration, had a small number of participants, and performed only slightly better than placebos in reducing pain. Many patients who take the medications also report side effects such as dizziness, confusion, drowsiness, mood swings and weight gain.

"Treating pain is about making patients more functional so they can live their lives better, and if they have to deal with adverse effects for a little pain relief, their lives may not be improving," said Williams.

Pregabalin has been approved by the Food and Drug Administration for four pain conditions: post-herpetic neuralgia (shingles), diabetic peripheral neuropathy, spinal cord injury, and fibromyalgia. Gabapentin has only been approved by the FDA for post-herpetic neuralgia.

Despite the limits on their uses, many doctors legally prescribe the drugs “off-label” for pain conditions such as migraines, back pain, post-operative pain and even dental pain. Gabapentin was once derisively referred to as “snake oil” by a pharmaceutical executive because it is so widely prescribed for so many different pain conditions, despite weak evidence.

"In addition, we found that the trials used by the FDA to approve gabepentinoids for pain indications had a couple of key structural weaknesses," Williams said. "The trials tended to be short, typically lasting one to three months, and the trials typically excluded the simultaneous use of other medications that affect the central nervous system. That's important because patients taking gabepentinoids are rarely taking them exclusively; they're often prescribed in conjunction with opioids, muscle relaxants or other epilepsy drugs."

Gabapentin can cause euphoria and feelings of intoxication, and make the effect of opioids and other drugs seem stronger. A 2019 study linked gabapentin to a growing number of attempted suicides.

That same year, the FDA warned that gabapentin and pregabalin may cause serious breathing problems and respiratory depression, especially in older adults. A recent study found that gabapentin raises the risk of delirium in older adults recovering from surgery.

UK Warns Pregnant Women About Taking Pregabalin

By Pat Anson, PNN Editor

Health officials in the UK are warning women of childbearing age that pregabalin (Lyrica), a drug commonly prescribed for pain, anxiety and epilepsy, raises the risk of major birth defects.

A recent study in four Nordic countries of over 2,700 pregnancies found that 5.6% of babies born to women who took pregabalin in the first three months of pregnancy had birth abnormalities. That compares to 4.1% of babies whose mothers did not use pregabalin.  

“The study showed that taking pregabalin during early pregnancy was associated with a slightly increased chance of having a baby who is born with a physical birth abnormality. It is important to note that this study could not show that pregabalin was the cause of the physical birth abnormalities,” the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) said in a new safety alert.

The birth defects associated with pregabalin primarily involved the nervous system, eyes, face, urinary system and genitals. The MHRA – which regulates drugs in the UK – cautioned pregnant women not to stop taking pregabalin without talking to a doctor first.

“If you think you may be pregnant and are currently taking pregabalin, you should set up an appointment with your GP, specialist or nurse at your earliest opportunity, to discuss any concerns you may have. However, do continue to take pregabalin as prescribed until you can speak to them,” the MHRA alert said. “Untreated epilepsy, pain, or anxiety could be harmful to you and your unborn baby. It is important that you talk to your healthcare professional before stopping pregabalin or making any changes to your usual medicines.”

An international study in 2016 also linked pregabalin to birth defects. Women taking pregabalin were found to be six times more likely to have a baby with a major birth defect, including abnormalities in the heart, central nervous system (CNS) and other organs.

Pregabalin Concerns

In recent years, pregabalin has come under increased scrutiny in the UK.  In 2021, the MHRA said pregabalin was associated with serious breathing problems in people over age 65 and in patients with compromised respiratory systems.

Doctors in Northern Ireland were also told last year not to prescribe pregabalin for neuropathic pain due to a “significant increase” in drug-related deaths involving the drug.

In 2019, pregabalin and gabapentin (Neurontin) were both rescheduled as Class C drugs in the UK due to a rising number of overdose deaths. Health experts said the medications cause “an elevated mood in users” and could have serious side effects when combined with other drugs.

Lyrica and Neurontin are two of Pfizer’s top selling drugs and generate billions of dollars in annual sales. They belong to a class of nerve medication called gabapentinoids that were originally developed to treat seizures, but are now widely prescribed as an alternative to opioid painkillers. A 2019 study found little evidence that gabapentinoids should be used to treat pain and said their effectiveness was often exaggerated by prescribing guidelines.

In the United States, where Lyrica is approved for fibromyalgia, neuropathic pain, seizures and postherpetic neuralgia, the FDA’s lengthy warning label states that “there are no adequate and well-controlled studies with Lyrica in pregnant women,” but at the same time cautions that “Lyrica may harm your unborn baby.”  

An earlier warning label said it was “not known if Lyrica will harm your unborn baby.”

Gabapentinoids Riskier for Surgery Patients

By Pat Anson, PNN Editor

Another study is casting doubt on the use of gabapentinoids such as Lyrica (pregabalin) and Neurontin (gabapentin) for pain relief during and after surgery.

Gabapentioids are a class of nerve medication originally developed to treat convulsions, but the drugs are increasingly being used as a trendy alternative to opioids for acute and chronic pain. Some U.S. hospitals are even using gabapentinoids for surgical pain and have phased out or reduced the use of opioids.

In an analysis of over 5 million adults admitted for major surgery in the U.S. from 2007 to 2017, researchers at Harvard Medical School found that using gabapentinoids with opioids increases the risk of overdose, respiratory depression and other adverse events. Researchers say the additional risk was “extremely low” and would result in one additional overdose for every 16,000 patients.

“Our findings add to the growing evidence that gabapentinoids can potentiate the respiratory depressant effects of opioids,” researchers reported in JAMA Network Open. “The events were rare… (but) patients receiving multimodal pain management therapy that includes gabapentinoids should be closely monitored for possible respiratory depression.”

The study did not examine whether gabapentiniods were effective in treating surgical pain or if they improved the analgesic effect of opioids.

In an editorial also published in JAMA Network Open, a pain management expert said more studies were needed to see if gabapentiniods were worth the additional risk.

“The evidence in support of the analgesic benefit of gabapentinoids combined with opioids for postoperative analgesia is equivocal; there is no real support that adding gabapentinoids to opioid pain relievers offers additive, much less synergistic, enhancements to pain control,” wrote Joseph Pergolizzi, Jr, MD, Chief Operating Officer of NEMA Research.  

“Considering that combination analgesic regimens generally reduce overall opioid consumption, this study is important because it shows that this may not necessarily translate to reducing opioid-associated adverse events. As combination analgesia gains traction for in-hospital acute painful conditions, such as postsurgical pain, it is important to be guided by evidence rather than intuition.”

No Significant Analgesic Effect

A recent study by Canadian researchers also found little evidence to support the use of gabapentinoids for surgical pain.

“No clinically significant analgesic effect for the perioperative use of gabapentinoids was observed. There was also no effect on the prevention of postoperative chronic pain and a greater risk of adverse events,” wrote lead author Michael Verret, MD, a resident at Laval University in Quebec City.  

These and other findings contradict guidelines published by the American Pain Society in 2016, which advocate “around the clock” use of gabapentin, pregabalin and other non-opioid drugs both before and after surgery.

The risk of becoming addicted or dependent on opioids after surgery is actually quite low. A 2016 study found that only 0.4% of elderly patients who were prescribed opioids for post-operative pain were still using them a year after their surgeries. Another study by Harvard researchers found that only 0.2% of surgery patients prescribed opioids were later diagnosed with opioid dependence, abuse or a non-fatal overdose.

Study Finds ‘Evidence Lacking’ for Most Fibromyalgia Treatments

By Pat Anson, PNN Editor

A new analysis has found little evidence to support the long-term use of any medication or therapy to treat fibromyalgia, a poorly understood disorder characterized by widespread body pain, fatigue, poor sleep and depression.

An international team of researchers from Brazil and Australia reviewed 224 clinical trials of fibromyalgia treatments and found many of them small and of poor quality. High quality evidence was found for cognitive behavioral therapy (CBT), anti-depressants, and central nervous system (CNS) depressants as short and medium-term treatments for fibromyalgia. No treatment was found to be effective long term.

“In this systematic review, the effectiveness of most therapies for fibromyalgia was not supported. Strong evidence supported only cognitive behavioral therapy for pain, as well as antidepressants and central nervous system depressants for pain and quality of life, but these associations were small,” wrote lead author Vinícius Cunha Oliveira, PhD, an adjunct professor at Federal University of the Valleys of Jequitinhonha and Mucuri in Brazil.

“Some therapies may be associated with small reductions in pain and improvements in quality of life in people with fibromyalgia; however, current evidence is lacking for most therapies.”

The study findings, published in JAMA Internal Medicine, reflect what many fibromyalgia sufferers already know; many treatments are ineffective in improving their symptoms.

The Food and Drug Administration has approved only three drugs for fibromyalgia; the antidepressants duloxetine (Cymbalta) and milnacipran (Savella), and the anti-seizure medication pregabalin (Lyrica). All three drugs were originally developed for other medical conditions and are being repurposed as treatments for fibromyalgia.

A large 2014 survey of fibromyalgia patients by the National Pain Foundation found that most people who tried the three FDA-approved drugs did not feel they were effective.

Exercise, acupuncture, massage, electrotherapy, myofascial release, and several other non-pharmaceutical treatments are also commonly recommended for fibromyalgia pain. Researchers found only “moderate” evidence to support their short-term use. High quality evidence was only found for CBT, a form of meditation in which a therapist works with a patient to reduce unhelpful thinking and behavior.

“Clinicians should be aware that current evidence for most of the available therapies for the management of fibromyalgia is limited to small trials of low methodological quality,” researchers concluded. “Clinicians and patients should choose therapies by considering other important outcomes in addition to those presented in this review, such as adverse effects, out-of-pocket costs, and patient preferences.”

The National Institutes of Health estimates about 5 million Americans have fibromyalgia. Most people diagnosed with fibromyalgia are women, although men and children also can be affected.

Study Finds Most Drugs Ineffective for Neuropathic Pain

By Pat Anson, PNN Editor

A first of its kind study that compared four medications widely used to treat neuropathy found that all four were usually ineffective in treating pain and many patients stopped taking them due to side effects.    

Over 20 million people in the U.S. suffer from neuropathic pain, a tingling, burning or stinging sensation in the hands and feet caused by nerve damage. Neuropathy is often caused by diabetes, chemotherapy or trauma, but in about 25% of cases the cause is unknown and classified as cryptogenic sensory polyneuropathy (CSPN).

There is little guidance for physicians and patients on what drugs to take for CSPN, so researchers at the University of Missouri School of Medicine conducted a “real world” study in which 402 patients with CSPN took one of the four neuropathy medications.

The four drugs studied were nortriptyline (Aventyl), a tricyclic antidepressant; duloxetine (Cymbalta), a serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant; pregabalin (Lyrica), an anti-seizure drug; and mexiletine (Mexitil), an anti-arrhythmic medication used to treat irregular heartbeats.

Nortriptyline, duloxetine and pregabalin are approved by the FDA for treating neuropathy, while mexiletine is used off-label. None of the drugs were originally developed to treat neuropathic pain.

"As the first study of its kind, we compared these four drugs in a real-life setting to provide physicians with a body of evidence to support the effective management of peripheral neuropathy and to support the need for newer and more effective drugs for neuropathic pain," said lead researcher Richard Barohn, MD, executive vice chancellor for health affairs at the University of Missouri.

After 12 weeks of use, any drug that reduced pain for a patient by at least a 50% was considered effective, a recognized industry standard to define therapy success.. Researchers also kept track of patients who stopped taking a drug and dropped out of the study due to adverse effects.

The study findings, published in JAMA Neurology, can best be described as underwhelming. Patients were far more likely to stop taking a drug than they were to stay on a medication that was helping them.    

Of the four drugs, only nortriptyline was an effective pain reliever for at least 25% of patients. It also had the second-lowest drop-out rate (38%), giving it the highest level of overall utility. Duloxetine had the second-highest efficacy rate (23%) and the lowest drop-out rate (37%).

Pregbalin had the lowest efficacy rate (15%) and the second highest drop-out rate (42%), while mexiletine had the highest drop-out rate (58%) and an efficacy rate of 20 percent.

EFFICACY RATE OF NEUROPATHY DRUGS

SOURCE: JAMA NEUROLOGY

"There was no clearly superior performing drug in the study," Barohn said. "However, of the four medications, nortriptyline and duloxetine performed better when efficacy and dropouts were both considered. Therefore, we recommend that either nortriptyline or duloxetine be considered before the other medications we tested."

While nortriptyline had the highest efficacy rate, it also had the highest rate of adverse events, with over half of patients (56%) reporting side effects such as dry mouth, drowsiness, fatigue and bloating.  

Previous studies have found that duloxetine and pregabalin had higher efficacy rates for neuropathic pain, but Barohn and his colleagues say their research more accurately reflects what patients experience in real life and what physicians encounter in their practice.

“Our findings could affect how these 4 drugs are used by all physicians who treat patients with neuropathy. Findings support duloxetine and nortriptyline as better-performing drug choices in this population with neuropathic pain, suggesting that they should be prescribed before pregabalin or mexiletine are considered. However, this study also supports a finding that all 4 drugs helped improve pain in at least some patients, so each could be tried if others failed,” they concluded.     

There are several other drugs used to treat neuropathy, including gabapentin, venlafaxine and sodium channel inhibitors. Barohn says additional comparative studies should be performed on those drugs. His goal is to build effectiveness data on nearly a dozen drugs for CSPN.

Gabapentinoids Involved in a Third of Overdoses in Scotland

By Pat Anson, PNN Editor

A new study in Scotland is shining more light on the risks of overprescribing gabapentin (Neurontin) and pregabalin (Lyrica). The two drugs belong to a class of nerve medication called gabapentinoids, which are increasingly prescribed in Western nations to treat chronic pain.

In 2018, there were 1,187 accidental drug-related deaths (DRDs) in Scotland – the highest overdose rate in the European Union — and gabapentinoids were involved in about a third of them.

According to research published in the British Journal of Anaesthesia, gabapentin was implicated in 15.2% of fatal overdoses in Scotland, while pregabalin was linked to 16.5% of drug deaths. That’s up from 3% and 1% of fatal overdoses, respectively, in 2012.

Researchers say deaths involving gabapentinoids are rising because they are frequently co-prescribed with opioids and other medications that depress the central nervous system and raise the risk of overdose. Drug diversion also plays a role.

“Gabapentinoid prescribing has increased dramatically since 2006, as have dangerous co-prescribing and death. Older people, women, and those living in deprived areas were particularly likely to receive prescriptions. Their contribution to DRDs may be more related to illegal use with diversion of prescribed medication,” wrote lead author Nicola Torrance, PhD, Senior Research Fellow at the School of Nursing & Midwifery, Robert Gordon University, in Aberdeen, Scotland.

From 2006 to 2016, the number of pregabalin prescriptions in Scotland rose by an astounding 1,600 percent, while prescriptions for gabapentin quadrupled. About 60% of the time, gabapentin was co-prescribed with an opioid, benzodiazepines or both.  

Gabapentinoids are also showing up in Scotland’s illicit drug supply. Drug users have found they can heighten the effects of heroin, marijuana, cocaine and other substances. In the Scottish region of Tayside, gabapentinoids were involved in 39% of drug deaths. About three out of four of those overdose victims did not have a prescription for the drug.

In addition to overdoses, gabapentinoids have also been associated with increased risk of suicidal behavior, accidental injuries, traffic accidents and violent crime. UK health officials were so alarmed by misuse of the drugs and the rising number of deaths that gabapentin and pregabalin were reclassified as controlled substances in 2019.

Gabapentin is not currently scheduled as a federally controlled substance in the United States, but pregabalin is classified as a Schedule V controlled substance, meaning it has low potential for addiction and abuse.  

A 2019 clinical review found little evidence that gabapentinoids should be used off-label to treat pain and that prescribing guidelines often exaggerate their effectiveness. The U.S. Food and Drug Administration also recently warned that serious breathing problems can occur in patients who take gabapentin or pregabalin with opioids or other drugs that depress the central nervous system.

Gabapentinoids Ineffective for Pain Relief After Surgery

By Pat Anson, PNN Editor

Would you want to take Lyrica (pregabalin) or Neurontin (gabapentin) for pain relief after a major surgery? Both drugs belong to a class of nerve medication called gabapentinoids that are increasingly being prescribed to patients perioperatively (after surgery) as an alternative to opioid medication.

But gabapentinoids also have risks and there is little evidence to support their use for postoperative pain relief, according to a large new study by a team of Canadian researchers.  

“No clinically significant analgesic effect for the perioperative use of gabapentinoids was observed. There was also no effect on the prevention of postoperative chronic pain and a greater risk of adverse events. These results do not support the routine use of pregabalin or gabapentin for the management of postoperative pain in adult patients,” wrote lead author Michael Verret, MD, a resident at Laval University in Quebec City.  

Verret and his colleagues conducted a meta-analysis of 281 clinical trials involving nearly 25,000 patients undergoing a wide range of surgeries, including orthopedic, spinal and abdominal operations.

Their findings, recently published in the journal Anesthesiology, indicate that the analgesic benefits of pregabalin and gabapentin after surgery are negligible, regardless of the dose or type of operation. Gabapentinoids were also ineffective in preventing chronic pain from developing after surgery, one of the primary justifications for using the drugs postoperatively.

“Gabapentinoids were also associated with a greater incidence of adverse events, namely dizziness and visual disturbance, while other major adverse events such as respiratory depression and addiction are not reported or are underreported,” said Verret.

The findings contradict guidelines published by the American Pain Society (APS) in 2016,  which advocate “around the clock” use of gabapentin, pregabalin and other nonopioid drugs both before and after surgery.

“The panel recommends use of gabapentin or pregabalin as part of a multimodal regimen in patients who undergo surgery. Both medications are associated with reduced opioid requirements after major or minor surgical procedures, and some studies reported lower postoperative pain scores,” the APS guideline states.

“The panel suggests that clinicians consider a preoperative dose of gabapentin or pregabalin, particularly in patients who undergo major surgery or other surgeries associated with substantial pain, or as part of multimodal therapy for highly opioid-tolerant patients.”

‘Evidence of Harm’

Although opioid addiction is relatively rare after surgery, dozens of U.S. hospitals followed the lead of the APS and other medical guidelines by stopping the use of opioids for certain surgeries.

Cleveland Clinic Akron General Hospital, for example, adopted a policy of only using gabapentin and other non-opioid analgesics for colorectal operations.

“It is now clear that over the past two decades, evidence of benefit from routine perioperative administration of gabapentinoids has diminished, while evidence of harm has increased.”

— Dr. Evan Kharasch

Critics say gabapentinoids have become a trendy alternative for post-surgical pain relief, even though evidence supporting their use is minimal.

“It is now clear that over the past two decades, evidence of benefit from routine perioperative administration of gabapentinoids has diminished, while evidence of harm has increased. If any potential benefits exist in ‘special populations,’ published reports have yet to identify the benefits or the populations,” lead author Evan Kharasch, MD, Editor-in-Chief of Anesthesiology, wrote in an editorial.

“The good intentions that led to routine gabapentinoid use should be redirected to lead the way out. The French Society of Anesthesia and Intensive Care Medicine now states that gabapentinoids should not be used systematically or in outpatient surgery. Other societies should follow. As the weight of evidence has shifted and the risk–benefit balance tilted away from benefit, evidence-based practice impels revising if not eliminating the routine use of perioperative gabapentinoids in adults.”

It's too late for the APS to change its guideline. The organization filed for bankruptcy in 2019, ironically because of the high cost of legal fees in defending itself against opioid litigation.

While the CDC’s controversial opioid guideline does not advocate using gabapentinoids for post-surgical pain, it does recommend their use in treating chronic pain -- with little to no mention of their side effects.

One of the co-authors of the CDC guideline, Dr. Roger Chou, also played a significant role in drafting the APS guideline. Chou is currently heading much of the research being conducted by the CDC as it prepares to update and possibly expand its 2016 guideline.

Study Finds Limited Evidence to Support Use of Non-Opioid Drugs for Chronic Pain

By Pat Anson, PNN Editor

A new study by federal researchers has found limited evidence to support the use of non-opioid medications in treating chronic pain conditions such as fibromyalgia, neuropathy, rheumatoid arthritis and low back pain.

Only small improvements in pain and function were found in the use of anti-convulsants and non-steroidal anti-inflammatory drugs (NSAIDs), while moderate improvement was found in the use of some antidepressants.

Researchers noted that evidence was “too limited to draw conclusions” on long-term use of non-opioid drugs, and “no treatment achieved a large improvement in pain or function.” They also cautioned that “careful consideration of patient characteristics is needed in selecting nonopioid drug treatments” because of the risk of side effects.

The report was prepared for the Agency for Healthcare Research and Quality (AHRQ) by the Pacific Northwest Evidence-based Practice Center (EPC) at Oregon Health & Science University. The EPC has recently finalized two other studies on the use of opioids and nonpharmacological treatments for chronic pain.

Unlike their report on opioids, EPC researchers did not consult with technical experts and peer reviewers associated with Physicians for Responsible Opioid Prescribing (PROP), an anti-opioid activist group.

The researchers analyzed nearly 200 clinical studies and systematic reviews of non-opioid medication. Only 25 of the studies were rated as good quality and only 8 lasted a year or more. The pharamceutical industry funded 82 percent of them.

The EPC report is more cautious than other federal studies on the use of non-opioids such as pregabalin (Lyrica) and gabapentin (Neurontin).  Side effects from those drugs were often so severe that some patients stopped taking them and dropped out of clinical studies.

“Large increases in risk of adverse events were seen with pregabalin (blurred vision, cognitive effects, dizziness, peripheral edema, sedation, and weight gain), gabapentin (blurred vision, cognitive effects, sedation, weight gain), and cannabis (nausea, dizziness),” EPC researchers found. “Dose reductions reduced the risk of some adverse events with SNRI antidepressants. In the short term small increases in risk of major coronary events and moderate increases in serious gastrointestinal events (both short and long term) were found with NSAIDs.”

The EPC study is in marked contrast to the 2016 CDC opioid guideline, which recommends pregabalin, gabapentin and NSAIDs as alternatives to opioids with little to no mention of their side effects.

Other researchers have also warned that the effectiveness of gabapentin and pregabalin, which belong to a class of anti-convulsant drugs known as gabapentinoids, is often exaggerated in prescribing guidelines.

“Gabapentinoids have become frequent first-line alternatives in patients with chronic pain from whom opioids are being withheld or withdrawn, as well as in patients with acute pain who traditionally received short courses of low-dose opioid,” researchers at the University of South Carolina School of Medicine warned in a 2019 study.

“The evidence to support off-label gabapentinoid use for most painful clinical conditions is limited. For some conditions, no well-performed controlled trials exist.”

The EPC’s trio of studies on opioids, non-opioid drugs and non-pharmacological treatments are expected to help guide the CDC as it prepares an update and expansion of its 2016 opioid guideline, which is expected in late 2021. The update is likely to include new guidelines for treating short term, acute pain.  

How will CDC interpret the EPC findings on opioids and non-opioids? One outcome is suggested in the opioid study.

“Findings support the recommendation in the 2016 CDC guideline that opioids are not first-line therapy and to preferentially use nonopioid alternatives,” researchers said.

FDA Warns of Serious Breathing Problems Caused by Gabapentinoids

By Pat Anson, PNN Editor

The U.S. Food and Drug Administration is warning that serious breathing problems can occur in patients who use gabapentin or pregabalin with opioids or other drugs that depress the central nervous system. The elderly and patients with lung problems are at higher risk when they use the drugs, according to an FDA drug safety communication.

The advisory is the latest in a series of warnings about gabapentinoids, a class of nerve medication increasingly prescribed as an alternative to opioid painkillers. There are growing reports of gabapentinoids being abused or raising the risk of overdose and suicide.

“Reports of gabapentinoid abuse alone, and with opioids, have emerged and there are serious consequences of this co-use, including respiratory depression and increased risk of opioid overdose death,” Douglas Throckmorton, MD, deputy director for Regulatory Programs in the FDA’s Center for Drug Evaluation and Research, said in a statement.

“In response to these concerns, we are requiring updates to labeling of gabapentinoids to include new warnings of potential respiratory depressant effects. We are also requiring the drug manufacturers to conduct clinical trials to further evaluate the abuse potential of gabapentinoids, particularly in combination with opioids, with special attention being given to assessing the respiratory depressant effects.”

Gabapentinoid products include gabapentin, which is marketed under the brand name Neurontin, and pregabalin, which is marketed as Lyrica. Generic versions of the drugs are also available.

Gabapentinoids were originally developed to prevent seizures, but their use has tripled over the past 15 years. The drugs are approved to treat a variety of chronic pain conditions, such as fibromyalgia, neuropathy and shingles. They are also widely prescribed off-label.

According to the FDA, over 13 million people filled a prescription for gabapentin in 2016, while over 2 million patients were prescribed pregabalin. Nearly one in five of those patients were also taking opioids.

“Pairing an opioid with any CNS depressant – a gabapentinoid, benzodiazepine, sedating antidepressant, sedating antipsychotic, antihistamine, or other product – will increase the risk of respiratory depression. Shifting treatment from one CNS depressant to another may pose similar risks,” the FDA said.

A Dozen Deaths

The agency said it received 49 case reports of serious breathing problems in patients taking gabapentinoids, including 12 people who died from respiratory depression. It’s advising doctors, caregivers and patients taking gabapentinoids to be alert for signs of confusion, disorientation, dizziness, sleepiness, slow or shallow breathing, unresponsiveness, or bluish-colored lips, fingers and toes.

A 2018 study by Australian researchers found that gabapentinoids often had side effects such as drowsiness, dizziness and nausea. Another study found that combining gabapentin with opioids significantly raises the risk of dying from an overdose. And a recent analysis of calls to U.S. poison control centers found a significant increase in suicide attempts involving gabapentin.

There have also been increasing reports of gabapentin and pregabalin being abused by illicit drug users, who have learned they can use the medications to heighten the high from heroin, marijuana, cocaine and other substances.

A recent study published in JAMA Internal Medicine found little evidence that gabapentinoids should be used off-label to treat pain and said their effectiveness was often exaggerated by prescribing guidelines. The CDC’s 2016 opioid guideline recommends gabapentin and pregabalin dozens of times as alternatives to opioids, without saying a word about their abuse or side effects.

“Our goal in issuing today’s new safety labeling change requirements is to ensure health care professionals and the public understand the risks associated with gabapentinoids when taken with central nervous system depressants like opioids or by patients with underlying respiratory impairment. However, we do not want to unintentionally increase opioid use by turning prescribers away from this class of pain medications,” Throckmorton said.

One in Four Adults in England Take Addictive Meds

By Pat Anson, PNN Editor

Nearly 12 million people – about one in four adults in England -- are taking addictive prescription drugs to treat depression, anxiety, insomnia or chronic pain, according to a new review by Public Health England (PHE).

The review takes a cautionary view on the use of five drug classes – opioids, antidepressants, benzodiazepines, gabapentinoids, and so-called “z-drugs” such as zolpidem, zopiclone and zaleplon.

“The medicines we looked at help to make millions of people every year feel better and recover from their illness. Doctors can prescribe them because there is good evidence that they work, but they do have some risks,” the PHE report found.

Benzodiazepines, z-drugs, opioids and gabapentinoids are associated with dependence and withdrawal, while there’s a risk of withdrawal with antidepressants. When the drugs are taken in combination or in high doses, there is also risk of respiratory depression and overdose.  

About half the patients prescribed the drugs in England had been taking them for at least a year — a sign of dependence. But the report cautions doctors not to abruptly discontinue the drugs and to taper them gradually, if at all.

“There is a view that a sub-population of chronic pain patients can be prescribed long-term opioids at relatively stable doses so that their analgesia and functioning can be maintained with good adherence and tolerable side-effects,” the report found.

“We do not want to put anyone off safely using medicines that could help them. Stopping or limiting the use of medicines could also cause harm, including increasing the risk of suicide or making people try to get medicines or illegal alternatives from less safe sources, such as illegal websites or drug dealers.”

Increasing Use of Antidepressants and Gabapentinoids

Antidepressants were prescribed to about 7.3 million people in England or 17% of the adult population. Opioids were prescribed to 5.6 million patients, followed by gabapentinoids (1.5 million), benzodiazepines (1.4 million) and z-drugs (1 million). Prescriptions for opioids, benzodiazepines and z-drugs are dropping, while the use of antidepressants and gabapentinoids is growing. 

Gabapentinoids such as pregabalin (Lyrica) and gabapentin (Neurontin) were originally developed to treat epilepsy, but the drugs are increasingly prescribed in the UK to treat neuropathy and other types of chronic pain. PHE researchers found only marginal evidence that they are effective for pain and alarming signs that they are being misused. 

“Gabapentinoids have come to be used for a wider range of indications than is supported by the evidence or their licensing, and they have sometimes been prescribed in place of opioids or benzodiazepines in the likely-mistaken belief that they are less liable to misuse or dependence, and lack of awareness of the withdrawal problems that can arise when prescribing is stopped,” the report said. 

Prescriptions for opioids and gabapentinoids were 1.6 times higher in parts of England with more poverty. People in poor areas are also more likely to be prescribed medicines for longer periods. Prescription rates for women are about 1.5 times higher than for men. Prescription rates also increased with age.

Are You Paying Too Much for Pregabalin?

By Pat Anson, PNN Editor

It didn’t take long for cheaper generic versions of pregabalin to take a bite out of Pfizer’s monopoly of Lyrica, a drug widely used to treat fibromyalgia, diabetic neuropathy and other types of chronic pain.

Last month the U.S. Food and Drug Administration gave approval to rival drug makers to begin selling generic pregabalin after Pfizer’s patent on Lyrica expired. According to FiercePharma, Pfizer lost about a third of the market for pregabalin to 16 competitors by the end of July.  

It’s not hard to see why. According to Healthcare Bluebook, a 60-day supply of 75mg Lyrica sells for a “fair price” of $472. That compares to generic versions that sell for about $28.

“The price that most patients pay is set by insurers. The cost difference for patients between brand-name Lyrica and generic pregabalin may vary depending on the patients’ insurance plan, the state in which their prescription is filled, or the pharmacy where they pick up their prescription,” said Steven Danehy, a Pfizer spokesman.

As of August 9, Lyrica still had about 43% of the market for pregabalin, but that’s likely to change as patients, doctors and insurers became more aware of the significant difference in price.

Pregabalin is approved by the FDA for the treatment of pain associated with shingles, spinal cord injury, fibromyalgia, and diabetic peripheral neuropathy. It is also commonly prescribed "off label" for other types of chronic pain.

Pregabalin is a Schedule V controlled substance, which means it has a low potential for abuse. In recent years, however, there is growing concern that pregabalin and its sister drug gabapentin (Neurontin) are being abused and overprescribed.

The drugs, which belong to a class of nerve medication called gabapentinoids, were originally developed to treat epilepsy, not pain. Prescriptions for gabapentinoids have tripled over the past 15 years as more doctors prescribed them as “safer” alternatives to opioids.

Deaths involving gabapentinoids have increased in the UK, Australia and Canada, where some addicts have learned the drugs can heighten the euphoric effect of heroin and other opioids. The drugs were recently classified as controlled substances in the UK.