Recent years have seen a dramatic escalation in unapproved prescriptions for gabapentin and pregabalin (gabapentinoids), partly because generic versions of each have been launched over the past two decades, but also partly in response to increasing orders. of non-opioid pain management strategies.
In this context, several recent articles have been published alleging widespread abuse, with speculation about the underappreciated addictive potential of the gabapentinoid class of drugs.
Reports of a population-level prevalence of abuse of 1% come from a single Internet survey in the United Kingdom, and extremely small adverse event results do not support such frequency.
In this targeted narrative review, we aim to disabuse pain physicians and other physicians, pharmacists, and policymakers about the positive and negative myths related to gabapentinoid medications.
| Results |
Gabapentinoids inhibit the joint action of α2δ subunits of the voltage-gated calcium channel (VGCC) together with the n-methyl-D-aspartate (NMDA) receptor, with subsequent downregulation of VGCC expression and release. of excitatory neurotransmitters, and possibly also synaptogenesis, through actions on thrombospondins. These activities reduce the likelihood of central sensitization, which partly explains the effectiveness of gabapentinoids in the treatment of neuropathic pain.
Gabapentinoids also facilitate slow-wave sleep, a relatively rare phenomenon among agents acting on the central nervous system, which is also believed to explain some of the therapeutic benefits of this class in conditions such as fibromyalgia. The number needed to treat to see benefit overlaps that of non-steroidal anti-inflammatory drugs, but with a considerably improved safety profile.
In this regard, in the context of more than 50 million prescriptions per year in the US alone, gabapentinoids pose remarkably low risk, including risks of misuse, abuse, and dependence.
Furthermore, the neurobiology of these agents does not lend plausibility to the accusations, as they have never been shown to elicit dopaminergic activity within the nucleus accumbens, and furthermore likely confer a "negative feedback loop" for habituation and dependence by serving as antagonists. of NMDA, possibly through its actions on thrombospondins.
Clinical and epidemiological studies of addiction corroborate the absence of significant addictive potential of gabapentinoids, and these drugs are increasingly used in the treatment of addiction to other substances, with excellent results and without evidence of cross-addiction. However, among people with other substance use disorders and, in particular, opioid use disorder, there is consistent data showing gabapentinoid misuse in up to 20% of this population.
Although there are accusations of use of gabapentinoids to amplify the hedonic effects of opioids, the vast majority of cases of misuse appear to occur in an attempt to improve opioid withdrawal symptoms. Additionally, rare but potentially serious respiratory depression may occur, again amplified in the context of opioid or other sedative use.
Careful risk : Evaluation and stratification of benefits is warranted when prescribing a gabapentinoid is being considered, particularly among people who use opioids.
| Myth: universal utility |
Gabapentinoid prescribing has tripled in the US over the past 15 years, in part due to the patent expiration of the original drug, gabapentin. The majority of these prescriptions are written for “off-label” indications (not approved by the Food and Drug Administration [FDA]), and this phenomenon may be due to increased awareness of the need for non-opioid drugs.
However, recent criticism of this practice has highlighted the number of gabapentinoids needed to treat (NNT) to benefit as ranging from 3 to 8, assuming a limit of at least 50% improvement in reported pain, which by Of course it is a subjective result.
It should be noted that this figure overlaps that of (but has a much higher safety profile compared to) non-steroidal anti-inflammatory drugs (NSAIDs), and is one to two orders of magnitude smaller than needed to see a benefit in asthma in treatment with long-acting beta-agonists plus inhaled corticosteroids (NNT 73) and in the prevention of stroke and myocardial infarction by treatment with statins (NNT 200-300).
However, it is clear that agents do not benefit everyone, and stratification based on pathophysiology and symptom profile is logical, as is the prerequisite for understanding the mechanism of action of gabapentinoids.
| Conclusion-benefit: risk stratification or patient selection |
There appears to be a patient population at increased risk for gabapentinoid misuse. Various data sources and publications suggest that opioid users are more likely to abuse and misuse gabapentinoids.
While the (disproportionately publicized) self-report of some of these individuals alleges concomitant administration to potentiate an altered state of consciousness or euphoria, more intellectual and methodologically rigorous studies generally favor the theory that opioid users self-administer α2δ ligands in an attempt to decrease withdrawal symptoms and, conversely, also to improve (probably mediated by NMDAR) tolerance to the drug of choice.
The situation is likely to be much more complex and possibly even reciprocal. There is extensive preclinical evidence that NMDAR blockade appears to increase opioid seeking/use in certain circumstances which seems to indicate that this antagonism may cause a compensatory increase in opioid use to compensate for reduced reward and reinforcement.
As such, it is possible that in the opioid-dependent population, α2δ ligands, which serve as functional NMDA antagonists (by reducing trafficking and expression of the CCα2δ - NMDAR heteromer) may mitigate undesirable tolerance and withdrawal phenomena. while driving the increasing use of opioids.
Furthermore, the rare but potentially serious risk of hypoventilation observed in some animal models and also in some perioperative clinical studies is magnified, as expected, in the context of coadministration of sedatives or opioids.
Regardless of the ultimate mechanisms involved, it appears that opioid abusers included a high-risk group for gabapentinoid misuse and, as with any prescription medication or therapy, appropriate risk stratification along with ongoing monitoring is recommended when the treating physician is considering treating this group with gabapentinoids for any reason.
| Conclusions |
Gabapentinoids remain a vital tool in the pain clinician’s multimodal arsenal, but these drugs may not be effective in all clinical situations.
People with central sensitization and pain associated with slow-wave sleep deficits and potentially people with comorbid addictions may benefit the most.
Gabapentinoids appear to possess no addictive potential on their own, based on laboratory and clinical data, but may be abused by people with opioid use disorders; therefore, cautious risk stratification should be performed.
Summary Key Points
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