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We
neurologists have used gabapentin for many years as a very useful
anticonvulsant. But, over the past couple decades, gabapentin and gabapentinoids have been far more often used in management
of pain. At the beginning, they were used primarily for neuropathic pain. But
now we see them used for almost any sort of pain.
Over
the past 5 years, we’ve seen more and more examples of the downside of gabapentinoids (see our prior columns listed below). There
were several reports of increased risk of respiratory depression when gabapentinoids were used in conjunction with opioids.
In our February 25, 2020 Patient Safety Tip
of the Week “More
on Perioperative Gabapentinoids” we
described 2 studies (Ohnuma
2019, Yan
2019) that showed gabapentinoids
were associated with more post-operative respiratory depression and no
significant reduction in opioid use. Also, a systematic review and
meta-analysis on perioperative use of gabapentinoids
(Verret
2019) found no clinically significant analgesic
effect for the perioperative use of gabapentinoids,
with low level of evidence, and an increased risk of adverse events with
moderate level of evidence. The authors concluded that their results do not
support the use of gabapentinoids for the management
postoperative acute pain in adult patients.
Now
another study has looked at perioperative gabapentin use among older patients
undergoing major surgery. Park et al. (Park 2022) looked at almost 1 million patients aged 65
and older who underwent major surgery and were not on gabapentin prior to
admission. The rate of perioperative gabapentin use was 12.3% in these
patients. They used propensity score matching to reduce confounding when
comparing events in those who received gabapentin compared to those who did
not. Compared with nonusers, gabapentin users had increased risk of delirium
(3.4% vs 2.6%), new antipsychotic use (0.8% vs 0.7%), and pneumonia (1.3% vs
1.2%). There was no significant difference in in-hospital death (0.3% vs 0.2%)
between the groups. Risk of delirium among gabapentin users was greater in
subgroups with high comorbidity burden than in those with low comorbidity
burden.
The
Park study and the two studies mentioned above were not randomized, controlled
trials. Nevertheless, the evidence is growing that patients receiving
perioperative gabapentinoids have an increased risk
of complications, particularly postoperative opioid-related respiratory
depression and delirium.
In
the editorial accompanying the Park study, Bongiovanni et al. (Bongiovanni 2022) question whether the use of gabapentinoids as part of multimodal pain management is
wise in older patients. They note that most studies showing a reduction in
opioid use when gabapentinoids are used were done in
patients of all ages. So, perhaps they are useful in younger patients
undergoing surgery but should be used with caution in older patients. They also
note that in the Park study 80% of gabapentin users received gabapentin on the day
of surgery, suggesting that it was started prior to any patient report of pain.
They suggest this might represent an opportunity to de-escalate gabapentin use
for some patients.
One
thing we were struck by was the low incidence of delirium in the Park study.
76.4% of the patients in that study had orthopedic surgery. Yet the incidence
of delirium was only 3.4% and 2.6%, respectively, in the two groups. That
incidence is far below what we’d expect in elderly patients undergoing major
orthopedic surgery. The authors acknowledge that as well. They note that the claims-based
algorithm used for delirium detection in this patient population had high
specificity but low sensitivity. They further speculate that the delirium
identification algorithm was better at identifying hyperactive delirium than
hypoactive or normoactive delirium and that this might lead to their risk
difference estimates even being underestimated.
Our January 2020 What's New in the Patient
Safety World column “FDA
Warning on Gabapentinoids”
summarized some of our previous concerns about gabapentinoids
and discussed a new warning on gabapentinoids from
the FDA (FDA 2019). The
FDA warns that “serious breathing difficulties may occur in patients using
gabapentin (Neurontin, Gralise, Horizant)
or pregabalin (Lyrica, Lyrica CR) who have respiratory risk factors. These
include the use of opioid pain medicines and other drugs that depress the
central nervous system, and conditions such as chronic obstructive pulmonary
disease (COPD) that reduce lung function. The elderly are also at higher risk.”
The FDA notes that gabapentinoids
are often being combined with CNS depressants (including opioids, anti-anxiety
medicines, antidepressants, and antihistamines), which increases the risk of
respiratory depression. It acknowledges that there is less evidence supporting
the risk of serious breathing difficulties in healthy individuals taking gabapentinoids alone.
Note that the American
Geriatrics Society Beers Criteria® now lists
gabapentin as a potentially inappropriate medication (PIM) in the elderly because
of its risk of sedation and respiratory depression, especially when used in
combination with opioids.
We
think it is pretty unlikely that a randomized, controlled trial of gabapentin
or gabapentinoids will ever be done on elderly
patients undergoing major surgery. But the evidence from the observational and
cohort studies and meta-analyses certainly suggests that caution should be used
in such patients, particularly when opioids are also used. We concur with
Bongiovanni et al. that multimodal pain management pathways for older adults
should be reconsidered, keeping in mind both pain reduction and complications.
Some
of our prior columns on safety issues with gabapentinoids:
References:
Verret
M, Lauzier F, Zarychanski
R, et al. Perioperative Use of Gabapentinoids for the
Management of Postoperative Acute Pain: A Systematic Review and Meta-analysis.
2019 annual meeting of the American Society of Anesthesiologists (ASA; abstract
A2096).
http://www.asaabstracts.com/strands/asaabstracts/abstract.htm?year=2019&index=18&absnum=1927
OhnumaT, Raghunathan K, Ellis A, et al. Abstract S-344 Effects
of Acetaminophen, NSAID’s, Gabapentinoids and Their
Combinations on the Day of Surgery in Total Hip and Knee Arthroplasties. Anesthesia
& Analgesia 2019; 128(5): 741
https://iars.app.box.com/v/AM19AbstractSupplement
Yan
R, Ohnuma T, Krishnamoorthy V, et al. Abstract S-353 Gabapentinoids on the Day of Colorectal Surgery Are
Associated with Adverse Postoperative Respiratory Outcomes. Anesthesia &
Analgesia 2019; 128(5): 760
https://iars.app.box.com/v/AM19AbstractSupplement
Park
CM, Inouye SK, Marcantonio ER, et al. Perioperative Gabapentin Use and In-Hospital
Adverse Clinical Events Among Older Adults After Major Surgery. JAMA Intern Med
2022; Published online September 19, 2022
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2796501
Bongiovanni
T, Anderson TS, Marcum ZA. Perioperative Gabapentin Use in Older Adults:
Revisiting Multimodal Pain Management. JAMA Intern Med 2022; Published online
September 19, 2022
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2796503
FDA
(US Food and Drug Administration). FDA warns about serious breathing problems
with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin
(Lyrica, Lyrica CR)When used with CNS depressants or in patients with lung
problems. FDA 2019; 12-19-2019
https://www.fda.gov/media/133681/download
American
Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially
Inappropriate Medication Use in Older Adults. J Am Geriatr
Soc 2019; 67: 674-694 First published: 29 January 2019
https://agsjournals.onlinelibrary.wiley.com/doi/abs/10.1111/jgs.15767
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