Gabapentinoids for Pruritus in Older Adults: Dermatological Applications

There is currently no standardized algorithm for the treatment of chronic pruritus (CP), or pruritus lasting more than 6 weeks, in adults ≥ 65 years.

However, the antiepileptic agents gabapentin and pregabalin are gaining popularity in the dermatological community for their effectiveness in the treatment of CP of neuropathic origin. The lack of literature specifically examining the safety and effectiveness of these medications in older adults results in limited guidance for providers on the safe use of gabapentinoids.

In this article we discuss special considerations and recommendations for the treatment of older adults with gabapentin and pregabalin and explore the possibility that these drugs improve CP of multiple etiologies.

Gabapentin and pregabalin were initially developed as antiepileptics, but have since been approved to treat neuropathic pain. Both drugs have several common off-label uses and, in the world of dermatology, are used to treat CP.

Gabapentinoids are analogs of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), but do not affect the binding, absorption, or degradation of GABA. Although the mechanism of action of these drugs has not yet been completely elucidated, both bind with high affinity to the α2δ subunit of voltage-gated calcium channels in the nervous system.

This binding is believed to increase the neuronal excitation threshold, thereby decreasing the release of excitatory neurotransmitters. Research has shown that the α2δ subunit, in particular, is upregulated at the site of peripheral nerve injury, which could help explain its selectivity in the treatment of neuropathic pain.

With respect to chronic pruritus (CP), the efficacy of gabapentin and pregabalin in modulating pruritus may be due to the fact that the voltage-gated calcium channels they affect regulate the release of substance P (SP) and the peptide related to the calcitonin gene (CGRP). SP and CGRP are neuropeptides that cause neurogenic inflammation through local vasodilation and mast cell degranulation, and although SP and CGRP are classically released by histaminergic nerves that are involved in acute itch, SP and one of its receptors, the neurokinin receptor 1 (NK1R) have attracted the attention of the scientific community due to their participation in the PC.

Pregabalin and gabapentin have been shown to reduce the release of SP and CGRP from inflamed spinal tissue in rat models in vitro and in vivo , supporting the hypothesis that the role of gabapentinoids in itch could be due to their modulation of these two key inflammatory neuropeptides.

Research also shows that other pruritic conditions that were not classically considered to be of neuropathic origin could attribute their itching to dysregulated nerves.

Although gabapentin and pregabalin are relatively safe medications with benign side effect profiles in the general population, both medications have several unique properties that should be considered when treating older adults. First, gabapentin and pregabalin are eliminated almost exclusively by the kidneys.

The labels of all brands of gabapentin and pregabalin warn that since older adults are more likely to have decreased kidney function, dose adjustments in this population should be made based on creatinine clearance.

Therefore, prior to initiation of gabapentin administration, patients should be asked if they have compromised renal function and, if so, creatinine clearance should be assessed and the gabapentinoid dose should be adjusted appropriately. Kidney function should then be carefully monitored throughout your gabapentinoid cycle.

Some of the commonly reported side effects for both gabapentinoids were dizziness and drowsiness and these were the most common adverse reactions that led to the discontinuation of gabapentin in clinical trials for postherpetic neuralgia and epilepsy.

Another condition that should be monitored when gabapentinoids are administered is a possible increase in suicidal thoughts and behaviors. This potential adverse event is part of the 2008 FDA class warning for antiepileptic drugs (AEDs).

While studies have since found conflicting evidence about the link between AEDs and suicide, some pooled analyzes of AEDs have found an increased risk of suicidal ideation as early as one week after starting treatment; Consequently, this warning is still listed in the drug information for both gabapentin and pregabalin.

Despite conflicting data, this warning should not be discounted in patients with CP, as even at baseline, studies have suggested that pruritus may be as debilitating as chronic pain, potentially contributing to the strong association that has been found. found between CP and comorbidity. anxiety and depression with high risk of suicidal ideation.

While there has been no evidence to suggest different efficacy of gabapentinoids between older and younger adults, a notable example of differences in safety was observed during clinical trials for the use of gabapentinoids in postherpetic neuralgia.

Older age was associated with a higher incidence of peripheral edema and ataxia; this association was not observed in the pregabalin trials. Peripheral edema has been observed in several randomized control trials for gabapentin, and case reports suggest that this finding may be observed within days to 2 weeks after initiation. Providers should counsel patients about this possible reaction prior to initiation of gabapentin treatment so that patients are not alarmed if peripheral edema develops.

Perhaps, however, the most important consideration when prescribing gabapentinoids to older adults is their interaction with opioids. This was included in the 2019 update to the Beers criteria and was issued as a safety alert by the FDA in December 2019. The Beers criteria state that the use of opioids in competition with gabapentinoids should be avoided (unless transition from opioids to gabapentinoids) due to the increased risk of sedation-related serious adverse events such as respiratory depression.

The FDA warning further details that this risk applies not only to patients taking opioids, but also to those taking other central nervous system (CNS) depressants or who have a history of reduced lung function from conditions such as lung disease. chronic obstructive. Therefore, patients should be closely examined for reduced lung function and use of opioids or CNS depressants; If any of these act as a contraindication to the use of gabapentinoids, other treatments should be considered.

Finally, prescribers should be aware of the abuse potential of gabapentinoids. Pregabalin is a Schedule V controlled substance, and although gabapentin is not listed as a controlled substance, there is a growing body of literature regarding its potential for abuse, especially among patients with a history of substance abuse.

The authors recommend that when considering gabapentinoids for patients with pruritus, screening questions should be asked to verify safety in administration. If adequate screening is performed without contraindications, an elderly patient should be prescribed a low initial dose with close monitoring to ensure tolerance.

While both gabapentin and pregabalin can be used in the treatment of chronic pruritus (CP), gabapentin is more commonly prescribed since pregabalin is a Schedule V controlled substance and, due to its sedative side effects or lack of efficacy, healthcare coverage may be difficult to obtain without evidence of gabapentin failure.

Regarding the use of pregabalin for the treatment of CP, an open-label trial of 22 patients (aged 56 ± 13.65 years) observed a significant decrease in the intensity of pruritus 4 weeks after the start of treatment with a fixed dose of 150 mg. / day; No differences were observed in the intensity of pruritus between 4 and 8 weeks. These results led the authors to conclude that the maximum antipruritic efficacy of pregabalin was at 4 weeks and that it could be used thereafter as maintenance therapy.

After starting gabapentinoids in an elderly patient, it is important to screen for adverse effects. Screening questions should be asked before initiation and 1 to 2 weeks after initiation or dose change, as symptoms of suicide and peripheral edema have been reported. a few days after starting gabapentin. More importantly, any change in mood should be assessed by asking about new or increasing depression or suicidal ideation.

Gabapentin and pregabalin are effective and safe options for the treatment of multifactorial pruritus in older adults.

The goal of this review is to contextualize the nuances of prescribing these medications in this population and advocate for the inclusion of these medications in the limited therapeutic range for chronic pruritus in older adults.

While the field of dermatology continues to evaluate best practices in this population, it is essential that providers are educated and confident in the use of these potential options.