“Gabapentinoid” differences hidden in plain view
The exposition of this epidemiologic survey of “gabapentinoids,” by an elite research collaboration that includes groups at the University of Oxford and Sweden’s Karolinska Institute (Yasmina Molero and colleagues, British Medical Journal 365: 12147, 2019 (published online on June 12, 2019)), seems to have hidden in plain view what may prove critical differences between pregabalin (Lyrica) and gabapentin (Neurontin) with respect to adverse effects neither rare nor trivial.
Prompted by heretofore inconsistent bodies of evidence about diverse psychiatric and behavioral adverse effects of antiepileptics, including emergence or worsening of suicidality, unintentional overdoses, impaired coordination conducing to injurious accidents, and aggressive behavior, the authors surveyed from the national Swedish Prescribed Drug Register 191,973 persons who had filled at least two consecutive monthly prescriptions of pregabalin and/or gabapentin from 2006 through 2013, and identified (from Swedish national prescription, patient, death and crime registers) persons who had histories of “suicidal behavior, unintentional overdoses, head/body injuries, road traffic incidents and offenses, and arrests for violent crime.” Then using each person as his or her own control, they calculated and compared the “hazard rates” of each adverse event category during the two months or longer when the person had been taking pregabalin or gabapentin and during two months or longer when they had not.
Among the authors’ 191,973 subjects, 120,664 had at least one trial of pregabalin; 85,360 at least one trial of gabapentin, and 14,051 at least one trial of each..
Nearly 90 percent (88.2 percent)) of the authors’ gabapentinoid-treated sample were thirty-five or older at the beginning of study, yet a preponderance (81.9 percent) of the intraindividual comparisons of pregabalin were found to have been made in persons between fifteen and twenty-five, who represented just under five percent of the total sample.
For reasons unspecified, the authors analyzed a pooled data set of “gabapentinoid”-treated patients (intraindividual comparisons during treatment with either drug and during treatment with neither). While taking (and not) pregabalin and/or gabapentin, 5.2 percent of the subjects had been treated for suicidal behavior or had commited suicide; 8.9 percent had taken an accidental overdose (of drug(s) unspecified); 6.3 percent a traffic accident or traffic citation; 36.7 percent had suffered injuries to the head and body; and 4.1 percent had been arrested for a violent crime.
Age-adjusted hazard rates of the authors’ adverse event categories during intervals of pregabalin or gabapentin treatment compared with those of intervals of treatment with neither are described by the authors as “increased” (although no p values are reported): They were calculated to be 1.26 for suicide or suicidal behavior; 1.24 for accidental overdosage; 1.13 for traffic accidents or traffic citations; 1.22 for injury to head and/or body, and (explicitly lacking statistical significance) 1.04 for arrest for a violent crime.
Hazard rates of all adverse outcomes were increased in persons between fifteen and twenty-five, who represented less than five percent of the entire sample, but more than 70 percent of whose comparisons were of intervals taking (and not) pregabalin. The hazard rate of suicide and suicidal behavior (1.26 for the entire sample) during pregabalin and/or gabapentin treatment) was 1.67 in the fifteen- to twenty-five-year-olds (suggesting that suicide or suicidal behavior was 67-percent more likely to have occurred while they were taking pregabalin or gabapentin than while they were taking neither) .
When the authors analyzed pregabalin and gabapentin separately, they observed no statistically significant adversity of gabapentin in any assessment category. Moreover, gabapentin was associated with a 30-percent reduction of the hazard rate of traffic accidents and citations for traffic violations. Contrariwise, when they compared durations of pregabalin treatment with those of no pregabalin exposure, they observed increased hazard rates in every one of their adverse outcome categories (except arrest for a crime, which they threw out).
The authors’ overall conclusion posits an association of “gabapentinoids” (presently comprising two prescribable drugs—pregabalin and gabapentin) with suicidality, unintentional overdosage, traffic accidents, and injuries of the head and/or body. They do not advert attention to, nor do they speculate about the distinctly different (and arguably opposite) directionality of their findings pertaining to pregabalin and gabapentin, or the potentially greater adversity that treatment with pregabalin may convey.
(Obiter: Pregabalin has greater milligram-potency than gabapentin, which has been conjectured to devolve from its greater affinity for the putative site of action of both drugs—the alpha-2-delta subunit of voltage-dependent membrane calcium channels, which effectuate glutamate release and mediate energy-dependent membrane transport of other neurotransmitter and neuroendocrine molecules. Pregabalin also is absorbed more rapidly and reaches peak blood concentrations sooner than gabapentin. Potency, rate of absorption, and peak blood concentrations have been reported markers of abusability of drugs that have ‘likeable and seekable’ acute effects, as both pregabalin and gabapentin may. Both drugs also have been reported to eventuate in withdrawal effects after abrupt discontinuation of repeated dosing. Suicidality has been associated with diverse drug withdrawal phenomena (including those of some short-acting SSRIs and SNRIs and most recently, a source of speculation about that of ketamine.)
More than a decade of lawsuits and countersuits filed by more than a dozen pharmaceutical manufacturers on either side of an ongoing battle about “second use patents,” in this case, arising from a dispute about whether a “use” of pregabalin (as Lyrica) for pain can, like a product, be patented. The Patent Court of England initially ruled that it could, and ordered Britain’s National Health Service to notify doctors and pharmacists to prescribe and dispense only Lyrica for pain. This, it did (at a cost of over $500 million dollars). Massively and fiercely protesting, doctors and pharmacists turned things around, and at the appeal of the ruling some months later, the Patent Court threw out the manufacturer’s case as “invalid.” NHS is expected to sue the manufacturer for its outlay, and Lyrica and pregabalin once again are the same molecule. “Gabapentinoids” (just an “oids” away from gabapentin, a generic gabaergic structural (only) analogue once patented as Neurontin and still a strong competitor of pregabalin (as Lyrica), may be a portmanteau designation in a negative marketing campaign devolving from the legal tiff, and the authors embrace it. They profess no commercial ties or conflict of interest in their paper (which relegates to the “fine print” sharp differences in their comparison of each with the other that favor gabapentin, and instead offers a principal conclusion from pooled analysis of opposite findings, giving an impression that the drugs, both “gabapentinoids,” convey similar adversities). Yet, independent sources state that the research contractors of Lyrica’s European manufacturer/distributor are from the University of Oxford and the Karolinska Institute in Stockholm (the institutions at which