Pharmaceutical companies’ payments to doctors may be influencing them to prescribe more expensive, brand-name versions of the pain drug gabapentin, a team of researchers report in the July 8 issue of JAMA Internal Medicine, and the increasing use of the drug suggests it may be being abused.
“We found that the more physicians receive industry money, the more likely they were to prescribe gabapentin.
But more research is needed to understand how much of that gabapentin goes to drug abuse,” says lead author Greg Rhee, an assistant professor of medicine and public health at UConn Health.
Gabapentin is a fairly old drug, normally prescribed to control seizures and treat nerve pain.
But use of the drug has increased 3-fold in the US between 2002 and 2015, and Rhee and his colleagues wanted to understand why.
It is chemically similar to the brain chemical gamma-aminobutyric acid, known as GABA.
Gabapentin seems to work similarly to GABA by calming overexcited brain cells, which is why it is sometimes used to treat epilepsy.
The way it relieves nerve pain is less well understood.
But because it doesn’t interact dangerously with other drugs nor cause euphoria when taken at therapeutic doses, it is frequently prescribed for chronic pain.
And its use has been increasing: prescriptions of gabapentin and analogs of it rose from 1.2% of US adults in 2002 to 3.9% of US adults in 2015.
Rhee and colleagues from Yale University wondered whether payments from the pharmaceutical industry to doctors might be influencing prescribing.
They looked at the Open Payments and Medicare Part D Prescriber databases for 2014-2016.
Both databases are made available through the Centers for Medicare and Medicaid Services.
Open Payments is a national program that obligates drug manufacturers to disclose payments made to physicians.
Medicare Part D Prescriber database shows all the prescriptions made to people in Medicare Part D plans, and is searchable by doctor and by drug.
Gabapentin manufacturers paid physicians $11.5 million between 2014 and 2016, Rhee and his colleagues found.
The payments went to about 14% of the doctors who prescribed any kind of gabapentin in those years, mostly pain doctors and general practitioners, most of whom were located in the southern and eastern parts of the country.
The researchers found that doctors who received payments from industry were more likely to prescribe a brand name version of gabapentin such as Lyrica, Gralise or Horizant.
These brand name drugs cost several hundred dollars for a one month supply, compared to less than $20 for a one month supply of the generic.
Besides cost, the rise in prescriptions is concerning because gabapentin has the potential to be abused.
Although it is not reported to be intoxicating when used as directed, searching for gabapentin on drug experience websites such as erowid shows that taking it in larger quantities can cause a long lasting high.
Some long-term users who took gabapentin at therapeutic doses for legitimate medical reasons also report it can be addictive.
Rhee and his colleagues are concerned that the three-fold increase in prescriptions over the last decade and a half indicate some gabapentin is being diverted for recreational purposes, but caution that more research needs to be done before that can be determined.
Gabapentin functions as a γ-aminobutyric acid (GABA)-mimetic agent, binding to the alpha-2-delta subunit of the voltage-gated calcium channels, purportedly inferring antinoceptive, anticonvulsant, and anxiolytic properties.1
Gabapentin was originally approved by the US Food and Drug Administration (FDA) in 1993 for epilepsy and later, postherpetic neuralgia.
Owing to the multiple actions of the GABA system, gabapentin has subsequently been used for a wide variety of conditions, with up to 95% of gabapentin today prescribed for off-label indications.2,3
Prescribers are often unaware of gabapentin’s approved indications and their prescribing of gabapentin is largely guided by informal discussion with colleagues or professional meetings, as opposed to prescribers’ evaluation of its merits for a given indication.2
Although gabapentin has been on the market for many years, prescribing in the United States increased 64% from 2012 to 2016.4
Although the root of this increased utilization is multifactorial, a major influence is the current opioid abuse epidemic, which has led clinicians and policymakers to seek new therapeutic approaches to chronic pain management to reduce opioid prescribing.5
Unfortunately, effective pharmacologic alternatives to opioids are limited, though one such option commonly prescribed, particularly for neuropathic pain, is gabapentin.
Likely owing to several factors (cost, familiarity, noncontrolled status at the federal level, relatively benign adverse effect profile), clinicians view gabapentin as a safe alternative.6,7
However, in recent years, reports of recreational gabapentin abuse or intentional misuse have increased at an alarming rate,1 along with reports of associated harm.1,8
The risk of adverse effects appears to be particularly prevalent when combined with other central nervous system depressants, such as opioids.
A recent systematic review described 31 publications documenting gabapentin abuse, and though the likelihood of abuse was relatively low in the general population, annualized data revealed a rapidly rising trend.1
Furthermore, the rate of gabapentin abuse among patients with known substance use disorders was found to be markedly higher, in the range of 15% to 22%.1
A subsequent study of a US commercial insurance claims database found a direct relationship between all-cause and drug-related inpatient hospital and emergency department utilization and increasing degrees of gabapentin overuse.8
Patients with prolonged overuse of concomitant gabapentin and opioids were significantly more likely to experience an all-cause or drug-related inpatient hospital stay and, more specifically, an inpatient hospital stay or emergency department visit for altered mental status or respiratory depression.8
Due to the heightened concern regarding recent trends in the abuse and misuse of gabapentin, the risk profile of gabapentin may be higher than previously realized.
As a result, it is worth reconsidering whether there is sufficient evidence of efficacy to justify the public health risk that might arise from the aforementioned prescribing patterns.
Accordingly, the goal of this review is to examine the history of gabapentin, relevant data on efficacy across nonapproved indications, and ethical considerations that should be considered regarding its use, to assist health care providers in applying a more stringent assessment of the risk-benefit balance of prescribing gabapentin for various off-label indications.
History
In 1993, the FDA approval of Neurontin, the original branded gabapentin, was for use as an adjunctive medication to control partial seizures.9
Over the next several years, the manufacturer, Parke-Davis, a subsidiary of Warner-Lambert, engaged in a large marketing campaign to increase off-label prescribing of Neurontin for pain.4
By the mid-1990s, it was well known that antiseizure medications also improved neuropathic pain not responsive to traditional medications like opioids.
Due to a comparatively favorable safety profile, gabapentin posed limited risks to patients alongside effective pain management; accordingly, by 2001, 83% of gabapentin prescriptions were for nonseizure conditions.10
Although research suggested analgesic effects, evidence was deemed only sufficient enough to justify approval by the FDA for postherpetic neuralgia in 2002.
Indications for neuropathic pain in general are prevalent internationally,11,12but the FDA opted not to grant such a broad indication without evidence supporting efficacy of the drug across all or most etiologies of neuropathic pain, shown to be mitigated by similar disease processes.13
With such a high barrier to approval, the company did not pursue extension of the label.
However, by this time, a number of off-label uses for gabapentin had been reported, including bipolar disorder (BPD), diabetic neuropathy, complex regional pain syndrome, attention deficit disorder, restless legs syndrome (RLS), trigeminal neuralgia, periodic limb movement disorders (PLMDs) of sleep, premenstrual syndrome, migraine headache, and drug and alcohol withdrawal seizures.14,15
Later in 2004, the Neurontin patent expired and gabapentin became available as a generic with multibillion dollars in sales.
Widespread prescribing for gabapentin continues today, particularly for pain; in 2016, gabapentin was the 10th most commonly prescribed medication in the United States with 64 million prescriptions dispensed, an increase from 39 million in 2012.4
Recent guidelines from the Centers for Disease Control and Prevention (CDC) recommend that other medication classes be considered before beginning opioids for chronic noncancer pain, which includes a recommendation of gabapentin as a first-line agent for neuropathic pain.5
Ethical Concerns
Beyond the clinical data, there is additional information regarding gabapentin that should be considered.
Despite the lack of robust data for off-label indications, gabapentin was aggressively and illegally marketed for numerous unapproved uses, including indications that were reviewed and rejected by the FDA.40
This marketing strategy, carried out by Parke-Davis, included targeting physicians who frequently prescribed anticonvulsants, had the potential to influence their peers, and had an influential affiliation with a major academic medical center.40
Residents and trainees were also targeted 2-fold to influence the physicians in which they work under and to establish familiarity with gabapentin as they entered into their own practice.40
Aside from the commercial marketing, gabapentin was promoted via a “seeding” clinical trial called the Dosing to Efficacy with Neurontin: Study of Titration to Effect, Profile of Safety (STEPS) trial.41
Seeding trials ultimately aim to promote medications that are either under FDA review or recently FDA-approved by allowing recruited prescribers to participate as investigators in a clinical trial.42
These trials are typically poorly designed and loosely regulated, with complex inclusion and exclusion criteria that limit external validity.41
Physician participants are usually underqualified with nearly absent oversight on investigation sites.41
The STEPS trial met these criteria which undermined the quality of data and scientific validity.41 In addition, analysis of prescribing rates among trial investigators before and after trial completion was conducted, finding both increased prescribing rates and higher doses prescribed, although the intent to analyze prescribing patterns was not disclosed to investigators.41
Despite the façade as a clinical trial, Parke-Davis repeatedly referenced this as the “best tool” in its marketing strategy to promote gabapentin.41
These marketing tactics came at a settlement price of US $430 million in criminal and civil liability charges in 2004,40,43 but led to a tremendous growth in gabapentin prescriptions for off-label use from the early 1990s to early 2000s,40 a trend that has now shaped modern practice.44
After the settlement, use of gabapentin for off-label indications persisted, albeit to a lesser degree,44 as prescribers were more likely to continue patients on gabapentin rather than de-prescribe as a result of legal scrutiny.45
In addition, prescribers still have access to industry-funded literature that promotes gabapentin for off-label use.43
Furthering gabapentin-related unethical practices, Pfizer, who bought Parke-Davis in 2000, agreed to pay US $190 million in April 2014 as part of a settlement that alleged the company took steps to delay market entry of generic versions of gabapentin.46
After 6 weeks, Pfizer also agreed to pay US $325 million after they were accused of defrauding insurers and health care benefit providers via off-label marketing of gabapentin.47
Journal information: JAMA Internal Medicine
Provided by University of Connecticut
