Gabapentin Raises Risk of Delirium in Older Surgery Patients

By Pat Anson, PNN Editor

It’s become trendy in recent years for U.S. hospitals to use gabapentin (Neurontin) as a “safer” alternative to opioids for post-operative pain.  But a large new study has found that gabapentin increases the risk of delirium and other adverse health effects in older patients recovering from surgery.

The study, published in JAMA Internal Medicine, looked at nearly a million patients over the age of 65 who had major surgical procedures, including cardiac, orthopedic and gastrointestinal surgeries. About 12% of the patients received gabapentin and other analgesics for perioperative pain management between the day of surgery and two days after surgery.

Researchers found that gabapentin “modestly increased” the risk of delirium, a mental state in which a person becomes confused, disoriented and unable to think or remember clearly. Patients who received gabapentin were also more likely to be prescribed antidepressants and other anti-psychotic drugs, and to develop pneumonia.

“Considering the increasing number of major surgeries performed in older adults, and the negative consequences of perioperative delirium, our findings raise concern about an increasingly adopted clinical practice that involves routine use of gabapentin as part of multimodal analgesia,” wrote lead author Dae Hyun Kim, MD, a geriatrician and epidemiologist at Brigham and Women's Hospital and Assistant Professor of Medicine at Harvard Medical School.

“On the basis of these findings and those of meta-analyses of RCTs (randomized controlled trials) showing a weak opioid-sparing effect of gabapentin, clinicians should reconsider routine use of gabapentin for perioperative pain management among older adults and individualize the treatment decision after assessing the risk of immediate harms vs opioid-sparing benefits of perioperative gabapentin use.”

‘Windfall Medication’

Although gabapentin is an anti-convulsant that was originally developed to treat epilepsy, it is increasingly prescribed “off-label” to treat various types of pain. In 2016, the American Pain Society recommended that gabapentin be used “around the clock” for post-operative pain because it lowered pain scores and reduced the use of opioids. But studies later found the drug was ineffective for post-operative pain and actually increased the risk of an overdose.

An editorial published in JAMA Internal Medicine said the new study demonstrates that the risks of gabapentin outweigh its potential benefits in older patients.

“These results are consistent with what is now a growing body of literature suggesting that gabapentin may not be the windfall medication for perioperative pain management that surgeons hoped it might be for decreasing opioid use. The adverse events reported in this study (delirium, antipsychotic use, and pneumonia) add to similar findings that gabapentin, especially when used concomitantly with opioids, increases the risk of postoperative sedation and dizziness,” wrote lead author Zachary Marcum, PharmD, University of Washington School of Pharmacy.  

“As the use of gabapentin continues to rise, it is critically important clinicians understand its risks, especially for older adults. Poorly controlled postoperative pain is associated with several complications, including cognitive impairment, delirium, depression, decreased mobility, and longer recovery.”

It’s a common misconception that patients often become addicted to opioids after surgery. A 2016 Canadian study found that long term opioid use after surgery is rare, with only 0.4% of older adults still taking opioids a year after major elective surgery. A 2018 study at Harvard Medical School had similar findings. Only 0.6% of patients who were prescribed opioids for post-operative pain were later diagnosed with opioid dependence, abuse or a non-fatal overdose.

Most Americans Believe Opioids Necessary for Pain After Surgery

By Pat Anson, PNN Editor

Nearly 8 out of 10 U.S. adults believe opioids are sometimes necessary to manage pain after a surgery, according to a new survey that found most people are more worried about treating post-operative pain than they are about becoming addicted to opioids.

The online survey of over 2,000 adults was conducted last month by The Harris Poll on behalf of MediaSource and Orlando Health, a large Florida-based healthcare system. The survey comes at a time when many hospitals around the nation have adopted policies that discourage or eliminate the use of opioids after many common surgeries.

A recent study of nearly half a million surgeries performed at U.S. hospitals found that the number of opioid pills prescribed to patients decreased by 50% since 2017. Instead of opioids, hospitals are giving patients acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), gabapentinoids and other non-opioid medications.  

“It's very important for us to keep in mind that people do have pain and people do need pain control. The solution is not to just pull opioids away from people and leave them to fend for themselves,” said Luke Elms, MD, a general surgeon at Orlando Health’s Dr. P. Phillips Hospital. “That is a real problem after surgery that needs to be addressed in a compassionate manner.”

Dr. Elms has implemented a protocol that uses over-the-counter drugs like acetaminophen, ibuprofen and muscle relaxers. He says they are safer medications than opioids and help surgical patients recover faster without side effects such as nausea, dizziness and constipation.

“When I talk to patients and reassure them that we're going to be replacing opioids with a much more effective and safe method, and really talk to them about the risks of opioids that have become much more evident with the research that's come out recently, most patients are very open to the idea,” Elms said in a press release.

But that is not how most U.S. adults feel, according to the survey findings. When asked a series of questions about post-surgical pain, many said they have a strong preference for opioids:

• 78% Believe opioid pain medication after surgery is sometimes necessary

• 67% Expect to receive opioids to manage pain after surgery

• 65% Are more concerned about pain relief after surgery than opioid addiction

• 60% Prefer strong prescription painkillers over OTC pain relievers like ibuprofen

At the same time, over two-thirds of respondents (68%) said they are open to the idea of using non-opioid pain relievers and would be willing to try them. Adults who are employed, have high incomes and those with college degrees are more likely to prefer sticking to opioids.

Opioid addiction is actually quite rare after surgery.  A large 2016 study found that less than one percent of older adults were still taking opioids a year after major surgery.  Another large study in 2018 found less than 1% of patients prescribed opioids for post-operative pain were later diagnosed with opioid dependence, abuse or had a non-fatal overdose.

A recent Mayo Clinic study found that hospital guidelines are useful in reducing the number of opioid pills prescribed after surgery, but sometimes go too far. While most patients were satisfied with their pain control, about 10 percent were not.  

Poorly controlled post-operative pain is associated with increased morbidity, less function and quality-of-life, delayed recovery time, and higher health-care costs. The intensity of acute pain during or after surgery is also predictive of developing of chronic pain.

Did CDC Opioid Guideline Have ‘Unexpected Benefit’ for Surgery Patients?

By Pat Anson, PNN Editor

Since its release in 2016, the CDC’s opioid prescribing guideline has had a sweeping impact on pain management in the United States. Although only intended for primary care physicians treating chronic pain, the guideline’s recommended limits on opioids have been widely adopted by states, insurers, pharmacies, hospitals and doctors treating all types of pain.

A new study published in JAMA Network Open documents how opioid prescribing for post-operative acute pain fell significantly in the first two years after the guideline’s release.      

Researchers looked at prescribing data for over 360,000 patients who had 8 common surgical procedures and found that the amount of opioids initially prescribed after surgery fell by an average of 16 percent. The decline for each patient was the equivalent 11 oxycodone 5mg tablets.  

“This study has important policy and practice implications. Although the primary focus of the 2016 CDC guideline was on opioid prescribing for chronic pain, our findings suggest that the guideline was associated with clinically relevant changes in patterns of opioid prescribing after surgery,” wrote lead author Tori Sutherland, MD, a Professor of Anesthesiology at the Perelman School of Medicine, University of Pennsylvania.

The study didn’t look at what alternatives surgery patients were given for pain management or whether they were satisfied with their pain relief. But because refill rates were unchanged after the guideline’s release, Sutherland and her colleagues concluded that “it is unlikely that guideline misapplication led to significant opioid underprescribing for surgical pain.”

An editorial also published in JAMA Network Open called the decline in opioid prescribing for post-operative pain “a promising trend” and said further cuts were needed to reduce the number of leftover pills.

“The 2016 CDC guideline for chronic pain may have provided an unexpected benefit to surgical patients by accelerating the alignment of opioid prescribing with amounts recommended in surgery-specific prescribing guidelines. Nonetheless, much room for improvement remains,” wrote lead author Mark Bicket, MD, an anesthesiologist at the University of Michigan School of Medicine.

“We have known for a long time that the average patient has been prescribed nearly twice as much opioid as they need, or will use, following surgery,” said Dr. Lynn Webster, a PNN columnist and pain management expert. “This unused medication has been a major source of diverted opioids that have contributed to the national illicit drug use problem. In this regard, their observation does suggest fewer drugs are available for diversion. That is a good thing.

“However, mean data does not take into account an individual’s need. Some patients need more medication than other patients for the same surgical procedure. It is unhelpful to use dose reduction as a measure of improved care. We should focus on using the appropriate amount of opioids for the appropriate length of time to achieve improved prescribing.”

Webster said it was speculative to suggest that the CDC guideline had an “unexpected benefit” for surgery patients. The best measure is whether overdose deaths are decreasing – and by that standard the guideline has been a failure. Five years after its release, opioid prescribing is at 20-year lows while overdose deaths are at record highs, fueled largely by illicit fentanyl and other street drugs.

“Cleary, the decline in opioids prescribed for post-op pain has not improved that outcome which is, arguably, the most important outcome to measure,” said Webster.

Opioid addiction is actually rare after surgery.  A large 2016 study found only 0.4% of older adults were still taking opioids a year after major elective surgery.  Another large study in 2018 found only 0.6% of patients who took opioids for post-operative pain were later diagnosed with opioid dependence, abuse or a non-fatal overdose.

Legal Fight Brews Over Non-Opioid Pain Reliever

By Pat Anson, PNN Editor

Competition between drug companies can get so intense that some resort to bare knuckle tactics to preserve market share. Such is the case for Pacira BioSciences, which filed a lawsuit against the American Society of Anesthesiologists (ASA) last month for “false and misleading conclusions” about the effectiveness of Pacira’s flagship product Exparel, an injectable non-opioid analgesic used for postoperative pain.

In February, the ASA published two research articles and an editorial in its journal Anesthesiology saying Exparel works no better than other bupivacaine products on the market. New Jersey-based Pacira considered that libelous, and filed a complaint in federal court seeking a retraction and damages for lost business.

Now comes word that Pacira’s attorneys withdrew their motion for a retraction after the ASA asked the court for a prompt hearing “to expose flaws in Pacira’s claims.”

“It is vitally important that we defend and stand behind these three works and the integrity and scholarship of those who contributed to them,” said Evan Kharasch, MD, editor-in-chief of Anesthesiology. “These authors are leading physicians and researchers in the fields of anesthesiology and clinical studies. Physicians and patients must have trusted information on which to base clinical decisions and care, and that information needs to be unaffected by commercial interests.”

It is not yet clear if Pacira will withdraw the rest of its libel case. “Our corporate policy is not to comment on pending litigation,” a spokesperson told PNN.

This is not the first time Pacira has used aggressive tactics to promote Exparel or fend off criticism. In 2014, the company filed a lawsuit against the FDA after the agency sent a warning letter to Pacira for off-label marketing of Exparel. The FDA said Pacira promoted Exparel for “surgical procedures other than those for which the drug has been shown safe and effective.”

Pacira won that case in an out-of-court settlement after the FDA backed down, withdrew its warning letter and changed Exparel’s label to say that it can be used for more types of post-operative pain.

In addition to doubts about Exparel’s effectiveness, some have questioned its cost. A 2015 STAT story pointed out that a vial of Exparel cost $285 and provided no better pain relief than a $3 vial of generic bupivacaine. 

In 2016, Pacira funded a report by an expert panel at the Jefferson College of Population Health that called for greater use of non-opioid medication for post-operative pain. One of the non-opioids recommended by the panel was Exparel. Pacira’s funding of the project was only noted at the end of the report.

In 2020, Pacira agreed to pay $3.5 million to resolve federal allegations that it gave kickbacks to doctors in the form of fake research grants that promoted Exparel.

Pacira has also been active politically, spending over $1.7 million on lobbying and campaign donations since 2018, according to OpenSecrets.org.

In 2019, Pacira hired former New Jersey Gov. Chris Christie as a consultant for $800,000 and lucrative stock options. The move was controversial, because Christie had just chaired President Trump’s opioid commission, which recommended that Medicare and Medicaid reimbursement policies be changed to encourage hospitals to use more non-opioid painkillers.

All this suggests that Pacira won’t back down easily from a fight. But it doesn’t sound like the ASA will either.

“Although Pacira started this lawsuit, ASA will not shy away from refuting Pacira’s claims and from exposing the important issues with Pacira’s controversial drug,” the ASA said in a news release.

Zynrelef Approved

Pacira is about to get more competition in the post-operative pain market. San Diego-based Heron Therapeutics says it has received FDA approval for Zynrelef, an extended-release analgesic for use by adults up to 72 hours after a bunionectomy, hernia repair and total knee replacement surgery.

Zynrelef combines bupivacaine with a low dose of the nonsteroidal anti-inflammatory drug (NSAID) meloxicam. In clinical studies, the company says the synergy between the two drugs resulted in patients experiencing significantly less pain with less use of opioids compared to bupivacaine alone.

"The first three days after surgery are when patients experience the most severe postsurgical pain and are most likely to receive opioids to manage that pain. With the impressive reduction in pain and opioid use demonstrated by Zynrelef, we now have an important new option to help many patients achieve an opioid-free recovery," said Roy Soto, MD, an anesthesiologist at Beaumont Health System who consults with Heron. 

The company expects Zynrelef to be available by July. Patients are advised not to take the drug if they are allergic or have side effects from NSAIDs. The most common side effects of Zynrelef are constipation, vomiting and headache.

Hospira Recall

Pfizer’s Hospira division is voluntarily recalling a single lot of bupivacaine and a lot of lidocaine due to mislabeling that caused some of the vials to be incorrectly labeled as the other product. Both drugs are used to treat surgical pain. The mislabeling was identified after a customer complaint.

Hospira assessed the potential risk to patients if the mislabeled products were used to be “moderate to high severity.” If the mislabeled lidocaine was administered to a patient instead of bupivacaine, the patient may not get enough pain relief. If the bupivacaine was administered instead of lidocaine, the outcome could be even worse: an overdose of bupivacaine may occur, which could lead to seizures, respiratory problems, irregular heartbeat and cardiac arrest.

The recalled lots were distributed nationwide to wholesalers and hospitals in the United States, Puerto Rico and Guam from December 29, 2020 to April 15, 2021.

Hospira has not received reports of any adverse events associated with the mislabeling. The company did not respond to a request to explain how the mislabeling occurred or how it went undetected for nearly five months.

Opioid Prescribing Reduced by 50% After Some Surgeries

By Pat Anson, PNN Editor

In recent years, hospitals around the country have adopted policies to reduce the use of opioids for post-operative pain, fueled in part by studies showing that many surgery patients were sent home with more pills than they need. New research shows just how far efforts to reduce “overprescribing” have gone.

In an analysis of nearly half a million common surgeries performed at 87 U.S. hospitals, the Epic Health Research Network found that the number of opioid pills prescribed to patients decreased by 50% since 2017. The surgeries included in the study were low-risk arthroscopic or laparoscopic surgeries in which small incisions are made and patients are sent home from the hospital the same day.

Researchers say outpatients are just as likely to get opioids today after surgery as they were in 2017, but they will get significantly fewer pills. For example, a typical patient recovering from arthroscopic rotator cuff surgery in 2017 was prescribed the equivalent of 60 oxycodone 5mg tablets. By the end of 2020, the average patient received about 30 tablets after that procedure.      

“By reducing the number of pills that go out the door, we reduce the amount of time the patient is on opioids and we reduce their risk of long-term opioid use,” explained David Little, MD, a Physician Liaison with Epic Health.  

“The other thing that happens when someone goes home with 60 tablets of opioids is that they probably end up with 50 of them left sitting in the medicine cabinet. Those 50 pills in the medicine cabinet then become a problem in and of themselves, because patients start taking them later for unrelated stuff and they get addicted. Or the teenage child finds the pills and they start on them or take them out to be sold or give out to their friends.”

While the number of pills prescribed has declined significantly, Little told PNN they need to be reduced even more to meet treatment guidelines established by Johns Hopkins University.  A patient recovering from rotator cuff surgery should only get about 20 oxycodone pills according to that guideline, which recommends that ibuprofen also be used for pain relief.   

The Epic Health study did not look at what other medications were given to patients or if they were satisfied with their pain relief.

A recent Mayo Clinic study found that surgery guidelines are useful in reducing the number of pills prescribed, but sometimes go too far. While most patients were satisfied with their pain control, about 10 percent were not.  

Opioid addiction is actually rare after surgery.  A large 2016 study found only 0.4% of older adults were still taking opioids a year after major surgery.  Another large study in 2018 found only 0.2% of patients who were prescribed opioids for post-operative pain were later diagnosed with opioid dependence, abuse or had a non-fatal overdose.

Opioid Guidelines Leave Some Surgery Patients in Pain

By Pat Anson, PNN Editor

In recent years, many U.S. hospitals have adopted policies that reduce or eliminate the use of opioids during and after surgery.

Patients at Houston Methodist Hospital, for example, are getting acetaminophen (Tylenol) for post-operative pain after hernia repairs and other minimally invasive surgeries. And dozens of hospitals in Michigan have adopted guidelines for post-operative pain that have significantly reduced the use of opioids.

But a new study presented at the annual meeting of the American College of Surgeons suggests that policies that discourage the use of opioids for post-operative pain may be neglecting patients that need opioids for better pain control.

“The key findings of our study are that we were able to successfully reduce how many opioids we were prescribing for patients after operations using evidence-based guidelines,” said lead author Cornelius Thiels, DO, a surgical oncology fellow at Memorial Sloan Kettering Cancer Center and a researcher at the Mayo Clinic.

“However, the other finding of our research is that there’s still additional room to improve in terms of making sure all patients after surgery have their pain well controlled.”

The researchers evaluated 138 patients who had one of 12 elective surgeries after the Mayo Clinic adopted guidelines in 2018 that call for “multimodal pain control,” a combination of opioids with non-opioid pain relievers such as ibuprofen, naproxen and acetaminophen. Those patients were compared with 603 patients who had the same procedures before the guidelines, when opioids were used more widely.

While most patients in the post-guideline group were satisfied with their pain control after discharge, a significant number were not.

In telephone surveys conducted about four weeks after discharge, the percentage of patients in the post-guideline group who were dissatisfied with their pain control was more than double that of the pre-guideline group (9.4% vs. 4.2%). The percentage who said they were not prescribed enough pain medication was also higher (12.5% vs. 4.9%).

“There is a small subset of patients who we’re not optimally managing yet, and this study confirmed that this is a small number,” Thiels said. “However, I think that’s a critically important subset of patients.”

Thiel says about half of patients need opioid medication after major surgeries, and doctors need to do a better job identifying who they are.

“Our goal is to give them the exact right amount so that we limit the number of un-used opioids in our community while also making sure we don’t reduce it down too far and then leave them in pain,” he said. “The right answer may be more non-opioid based pain medications, better patient education and setting of expectations, or in some cases patients may actually require slightly more opioid medications, and that is OK.”  

Opioid addiction is actually rare after surgery.  A large 2016 Canadian study found only 0.4% of older adults were still taking opioids a year after major elective surgery.  Another large study in the British Medical Journal found only 0.2% of patients who were prescribed opioids for post-surgical pain were later diagnosed with opioid dependence, abuse or had a non-fatal overdose.

Genetics Play Significant Role in Post-Surgical Pain

By Pat Anson, Editor

An important new study has confirmed that a patient’s genes really do play a role in determining whether they develop chronic pain after surgery.

Researchers in China collected blood samples from 1,152 surgical patients to look for genetic variations in 54 "pain-related" genes which have been associated with pain sensation. Patients were then contacted a year later to see if they had chronic post-surgical pain.

A surprising number – one out of five patients – still experienced pain at the wound site, and 33 percent of them said their pain was severe.  Patients with pain also reported problems with their overall health, as well as daily activities such as mood, walking, relations with others, sleep, and quality of life.

Aside from genetic factors, the study also found patients younger than 65, males, and those with a prior history of chronic pain were at increased risk. The study is published online in the journal Anesthesiology.

"Our study not only shows there are common genetic variations among people that may help to identify whether they are at high-risk for developing chronic pain after surgery, but it also helps explain why only a fraction of patients ever even experience persistent pain," said lead researcher Matthew T.V. Chan, MD, at the Chinese University of Hong Kong.

"Until now, the genetic variations associated with chronic post-surgical pain have not been well identified."

One genetic variation in particular - a gene found in the nervous-system called brain-derived neurotrophic factor (BDNF) - was found to be most frequently associated with chronic post-surgical pain. Researchers confirmed the finding in a study on laboratory mice.

The researchers also found that genetic variations account for a higher percentage of chronic post-surgical pain (between 7 percent and 12 percent) than other risk factors such as age, sex, smoking history or anesthesia technique (between 3 percent and 6 percent).

Chronic post-surgical pain is one of the most common and serious complications after surgery. Previous studies have found that chronic pain was common after abdominal hysterectomies (25.1%) and heart or lung surgery (37.6%).

“Considering that more than 230 million surgeries are performed each year worldwide, the data would imply that millions of patients will continue to suffer wound pain, months to years after their surgery,” researchers said.

The study comes at a time when many U.S. states have adopted or are enacting laws that would limit the supply of opioid medication to just a few days for acute short-term pain. Minnesota, for example, is close to adopting strict guidelines that would limit the dose and supply of opioids to three days for acute pain and seven days after a major surgery.

Post-Surgical Pain Guidelines Reduce Use of Opioids

By Pat Anson, Editor

The American Pain Society (APS) has released new guidelines for post-surgical pain management that encourage physicians to limit the use of opioids and offer “multimodal therapies” to patients suffering from postoperative pain.

According to studies, more than half of patients who undergo surgery receive inadequate pain relief, which can heighten the risk of developing chronic pain, mood disorders and disability.

The 32 recommendations were developed by a panel of nearly two dozen experts that reviewed over 6,500 scientific studies. Most of the recommendations were adopted unanimously.

“The intent of the guideline is to provide evidence-based recommendations for better management of postoperative pain, and the target audience is all clinicians who manage pain resulting from surgery,” said lead author Roger Chou, MD, a prominent researcher who also co-authored the proposed opioid prescribing guidelines developed by Centers for Disease Control and Prevention.

Like the CDC guidelines, the APS guidelines encourage the use of non-pharmacological therapies and non-opioid medications, such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), gabapentin (Neurotin) and pregabalin (Lyrica). Those treatments would be used along with opioids for post-operative pain.

“Because of the availability of effective non-opioid analgesics and non-pharmacologic therapies for postoperative pain management, the panel suggests that clinicians routinely incorporate around the clock non-opioid analgesics and non-pharmacologic therapies into multimodal analgesia regimens,” the guideline states.

“Systemic opioids might not be required in all patients. One study suggests that it should be avoided when not needed, because limited evidence suggests that perioperative opioid therapy might be associated with increased likelihood of long-term opioid use, with its attendant risks.”

Chou says using multiple approaches to pain management provides better pain relief than a single analgesic.

“Randomized trials have shown that multimodal anesthesia involving simultaneous use of combinations of several medications -- acting on different pain receptors or administered through different techniques -- are associated with superior pain relief and decreased opioid consumption compared with use of a single medication administered by one technique,” Chou said.

The APS panel also recommends that non-pharmacological therapies, such as cognitive behavioral therapy and transcutaneous elective nerve stimulation (TENS), can be used as effective adjuncts to pain medication.

Other recommendations in the APS guidelines include:

• Adults and children can be given acetaminophen and/or NSAIDs for postoperative pain management
• Oral administration of opioids is preferred over intravenous (IV) administration
• Spinal analgesia (epidurals) is appropriate for major thoracic and abdominal procedures
• Use of benzodiazepines, tramadol and ketamine is not recommended for postoperative pain.
• Clinicians should consider giving preoperative doses of celecoxib (Celebrex) to adult patients
• Gabapentin (Neurotin) and pregabalin (Lyrica) can be considered for postoperative pain relief.  The drugs are associated with lower opioid requirements after surgery.

The guidelines recommend the physicians consult with a pain management specialist when a patient has a tolerance for opioids, or a history of substance abuse or addiction.

“Adequate pain treatment should not be withheld from patients with active or previous opioid addiction because of fears of worsening addiction or precipitation of relapse. In addition to the ethical requirement to address postoperative pain, poorly treated pain can be a trigger for relapse,” the guidelines say. “An interdisciplinary approach using pharmacologic and nonpharmacologic interventions might be required to achieve successful postoperative outcomes and should be considered as part of the perioperative management plan in these patients.”

The APS post-operative pain guidelines, which are being published in the Journal of Pain, was endorsed by the American Society for Regional Anesthesia. A link to the guidelines can be found here.