Gabapentinoids Raise Risk of Hip Fracture in Older Adults

By Pat Anson

Many patients have learned – the hard way – that nerve medications known as gabapentinoids have over a dozen potential side effects, from brain fog and sleepiness to weight gain and mood changes.

You can now add hip fractures to the list.

A study at Australia’s Monash University found that gabapentinoids such as Lyrica (pregabalin) and Neurontin (gabapentin) significantly raise the risk of hip fractures, especially in older adults who are frail or have kidney disease.

The study, recently published in JAMA Network Open, tracked nearly 3,000 patients aged 50 and older who were hospitalized for hip fractures in Victoria, Australia from 2013 to 2018. Among those 80 and older, nearly 60% were prescribed a gabapentinoid before being admitted, with most of them using pregabalin (94%).  

After adjusting for comorbidities and the use of other medications, researchers estimate that people over age 50 have a 30% higher risk of hip fractures within 60 days of gabapentinoid dispensing. The risk is even higher for patients with chronic kidney disease (141%) and those with high scores for frailty (75%).

“Our results showed patients had 30 per cent increased odds of suffering a hip fracture within two months of being dispensed a gabapentinoid medication,” said co-author Simon Bell, PhD, Professor and Director of the Centre for Medicine Use and Safety at the Monash Institute of Pharmaceutical Sciences. 

“The link between gabapentinoids and hip fractures existed across different age groups but the odds of hip fracture was higher among patients who were frailer or had chronic kidney disease, so these should be important considerations when deciding when to prescribe gabapentinoids.” 

Bell and his colleagues did not establish why gabapentinoids raise the risk of hip fractures, but they suspect the medications increase the risk of falling in older adults, similar to other psychotropic drugs such as anti-depressants, benzodiazepines and opioids.

“Our findings highlight the importance of assessing each patient’s risk before prescribing gabapentinoids,” said lead author Miriam Leung, PhD, a Teaching Associate at the Centre for Medicine Use and Safety at Monash University.

Despite limited evidence of their effectiveness as pain relievers, gabapentinoid use has risen significantly in recent years for neuropathy, fibromyalgia and other chronic pain conditions. The drugs are also increasingly used for acute pain, such as postoperative pain and even 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.

In the United States, nearly 5% of the adult population uses a gabapentinoid, while in Australia 1 in 7 people aged 80 and older is prescribed the nerve medication.

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.  

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.

Should Gabapentin Be Used for Dental Pain?

By Pat Anson, PNN Editor

Since it was first approved as an anti-seizure medication in the 1990’s, gabapentin (Neurontin) has become one of the most widely studied and prescribed drugs in world.  Although gabapentin is only approved by the FDA for epilepsy and postherpetic neuralgia (shingles), it is widely prescribed off-label for fibromyalgia, neuropathy and many other types of pain.

Hundreds of clinical trials have been conducted to find new uses for gabapentin -- for everything from asthma and obesity to alcoholism and improving your sex life. Gabapentin has been pitched for so many different conditions that a drug company executive infamously called it “snake oil.”

Now gabapentin is being touted as a “promising alternative” to opioids for dental pain. In a new study at the University of Rochester Medical Center’s Eastman Institute for Oral Health (EIOH), researchers found that gabapentin, when combined with ibuprofen or acetaminophen, was more effective than opioids in relieving pain after tooth extractions.  

“We hypothesized that using a combination of the non-opioid pain medications and adding gabapentin to the mix for pain would be an effective strategy to minimize or eliminate opioids for dental pain,” said Yanfang Ren, DDS, a dentistry professor at EIOH.   

Ren and his colleagues treated over 7,000 patients at an urgent dental care clinic with different combinations of opioids, ibuprofen, acetaminophen and gabapentin after tooth extractions. The “failure rates” of the medications were determined by how often patients returned to the clinic for additional pain relief.

The study findings, published in JAMA Network Open, found that non-opioid medications, including those with gabapentin, had failure rates significantly lower than opioids.      

Dental Pain Failure Rates

• 0.9% Acetaminophen/ibuprofen

• 3.4% Gabapentin/acetaminophen

• 5.3% Gabapentin/ibuprofen

• 9.2% Codeine/acetaminophen

• 19.4% Hydrocodone/acetaminophen

• 31.3% Other opioid combinations

Providers at the dental clinic have already put their findings into practice by sharply reducing the use of opioids. Prior to that, about 1,800 patients at the clinic were treated each year with opioids. Researchers estimate the reduced opioid prescribing may have prevented 105 of those patients from developing a problem with “persistent opioid use.”

“This study represents continued efforts by our team and other dentists to minimize the use of opioids for dental pain,” said Eli Eliav, DMD, the director of EIOH. “Additional studies, preferably randomized controlled clinical trials, are needed to confirm the safety and effectiveness of this approach. It is our duty to continuously seek safe and effective treatment for our patients in pain.”

Gabapentin has issues of its own. Patients prescribed gabapentin often complain of mood swings, depression, dizziness, fatigue and drowsiness, and a 2019 review found little evidence gabapentin should be used off-label to treat pain. There are also many reports that gabapentin is being abused and sold on the streets because it can heighten the effects of other drugs.

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.

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.