Gabapentinoids (gabapentin and pregabalin) are agents derived from the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and exert their action via alpha2-delta (α2δ) receptors, mainly at intracellular sites requiring active uptake. Gabapentinoids resemble the amino acid leucine in mechanism of action and depend on facilitated transport across cell membranes via L-amino acid transporters (LATs), resemble leucine in mechanism of action.
Despite their structural similarity to GABA, gabapentin and pregabalin, originally marketed off-label for the treatment of pain, do not bind to GABA receptors but have high affinity for the α2δ-1 subunit of potential-dependent calcium channels (VGCC). They were later approved by the FDA for the treatment of postherpetic neuralgia.
Description and structure of the drug
Pregabalin (Lyrica) is an antiepileptic drug that is available in capsules and oral solution and is approved as an adjunctive treatment for adult partial seizures, fibromyalgia, and pain caused by diabetic peripheral neuropathy or postherpetic neuralgia.
Pregabalin is also believed to have several off-label uses, including generalized anxiety disorder, social anxiety disorder, bipolar disorder, insomnia, and chronic pain conditions. However, in 2012, Pfizer was fined by the U.S. government for «misleading and unlawful advertising of Lyrica for indications not prescribed in the instructions». Gabapentin (Neurontin) was originally approved by the US FDA in 1993 for the adjunctive treatment of partial seizures. The drug was then approved in 2002 for the treatment of postherpetic neuralgia.
Gabapentin was originally developed as an analog of the neurotransmitter γ-aminobutyric acid (GABA), but it was later found to have no agonism toward GABA and no antagonism toward uptake or degradation.
Despite their structural similarity to GABA, gabapentin and pregabalin, originally marketed off-label for the treatment of pain, do not bind to GABA receptors but have high affinity for the α2δ-1 subunit of potential-dependent calcium channels (VGCC). They were later approved by the FDA for the treatment of postherpetic neuralgia.
Description and structure of the drug
Pregabalin (Lyrica) is an antiepileptic drug that is available in capsules and oral solution and is approved as an adjunctive treatment for adult partial seizures, fibromyalgia, and pain caused by diabetic peripheral neuropathy or postherpetic neuralgia.
Pregabalin is also believed to have several off-label uses, including generalized anxiety disorder, social anxiety disorder, bipolar disorder, insomnia, and chronic pain conditions. However, in 2012, Pfizer was fined by the U.S. government for «misleading and unlawful advertising of Lyrica for indications not prescribed in the instructions». Gabapentin (Neurontin) was originally approved by the US FDA in 1993 for the adjunctive treatment of partial seizures. The drug was then approved in 2002 for the treatment of postherpetic neuralgia.
Gabapentin was originally developed as an analog of the neurotransmitter γ-aminobutyric acid (GABA), but it was later found to have no agonism toward GABA and no antagonism toward uptake or degradation.
Gabapentin has also been surrounded by controversy due to off-label indications and selective reporting in industry-sponsored trials. However, unlike pregabalin, there are no additional indications for fibromyalgia and diabetic neuropathy.
Although gabapentin is increasingly used in clinical practice, the available evidence is complicated due to variability in dosing, adjunctive therapy and heterogeneity in the diagnoses in which it has been used. This includes numerous case reports of its use in bipolar disorder, depression, anxiety disorders, post-traumatic stress disorder, alcohol dependence and substance abuse.
Mechanism of action
The main putative mechanism of action of gabapentinoids is their binding to the α2-δ subunit of potential-dependent calcium channels on presynaptic neurons.
This binding reduces calcium influx into presynaptic endings, which subsequently reduces the release of excitatory neurotransmitters such as glutamate, substance P, and norepinephrine.
Although gabapentin is increasingly used in clinical practice, the available evidence is complicated due to variability in dosing, adjunctive therapy and heterogeneity in the diagnoses in which it has been used. This includes numerous case reports of its use in bipolar disorder, depression, anxiety disorders, post-traumatic stress disorder, alcohol dependence and substance abuse.
Mechanism of action
The main putative mechanism of action of gabapentinoids is their binding to the α2-δ subunit of potential-dependent calcium channels on presynaptic neurons.
This binding reduces calcium influx into presynaptic endings, which subsequently reduces the release of excitatory neurotransmitters such as glutamate, substance P, and norepinephrine.
- Potential-dependent Ca2+ channels are heteromeric transmembrane complexes consisting of a pore-forming α1 subunit, an extracellular α2δ subunit, and an intracellular β subunit.
- They are widely distributed in the CNS, and their inherited defects are closely associated with a number of neurologic diseases.
- Their role in the development of seizure disorders is complex, but there is increasing evidence that there are abnormalities in how they mediate the activation of action potentials and the release of neurotransmitters.
However, recent discoveries indicate that the action of gabapentinoids may extend beyond the α 2-δ mechanism. Their analgesic effects are now thought to encompass several mechanisms.
- Inhibition of calcium-mediated neurotransmitter release (substance P, norepinephrine)
- Modulation of NMDA-sensitive glutamate receptors
- Interaction with neurexin-1 and thrombospondins.
- Astrocyte-derived thrombospondins play a role in presynaptic plasticity through interaction with α2δ-1. Gabapentinoids inhibit excitatory synapse formation by blocking thrombospondin binding to α2δ-1.
- The slow process of synaptogenesis does not appear to contribute to the rapid effects of gabapentinoids.
- These recent findings challenge the previous assumption that their therapeutic effect is solely due to a reduction in calcium channel activity.
Pregabalin is a structural derivative of gamma-aminobutyric acid (GABA) that binds with high affinity to the α2δ subunits of potential-dependent calcium channels, mainly in neurons but also in cardiac and skeletal muscle cells. Although pregabalin is a GABA mimetic, it does not bind to GABA A or GABA B receptors, but instead binds selectively to α2δ subunits 1 and 2. Here it is hypothesized that binding to the α2δ-2 subunit reduces calcium-dependent release of pronociceptive neurotransmitters in the spinal cord.
- The α2δ-1 subunit is found in excitatory neurons, whereas the α2δ-2 subunit is mainly found in inhibitory neurons.
- It has been suggested that pregabalin has differential effects on excitatory and inhibitory neurons, by which pregabalin mediates the correction of excitation-inhibition imbalance.
The antinociceptive and anticonvulsant activity of pregabalin is also presumably the result of its interaction with descending noradrenergic and serotonergic pathways that originate in the brainstem. Animal models have demonstrated that inhibition of noradrenaline and serotonin reuptake increases their levels in the spinal cord, thereby inhibiting neuropathic pain.
The therapeutic mechanism of action of gabapentin depends on the physiological state of neurons; in seizures or neuropathic pain, it is hypothesized that rapid transmission and implementation of calcium channels into presynaptic endings are slowly inhibited, leading to a subsequent decrease in synaptic transmission.
Dosage, pharmacokinetics and interactions of pregabalin
The starting dose is 150 mg/day, which can be divided into 2-3 doses and then increased to 300 mg/day after 7 days. The maximum dose is 600 mg/day (this may be increased 7 days after the 300 mg dose) in patients with partial seizures, diabetic peripheral neuropathy, or postherpetic neuralgia. However, in patients with fibromyalgia, the maximum dose is 450 mg/day.
Pregabalin undergoes minor metabolism in the human body: about 90% of unchanged pregabalin is found in the urine. The major metabolite is the N-methylated derivative of pregabalin, but it constitutes only 0.9% of the dose. Finally, animal studies have shown that pregabalin does not bind to plasma proteins, can pass through the placenta, and is detectable in breast milk.
Interaction of gabapentin with other drugs
- Since most pregabalin is excreted unchanged, no interactions with CYP450 enzymes have been observed in humans. In addition, drug interaction studies have shown that pregabalin does not induce CYP1A2 or CYP3A4 activity.
- Drug interaction studies have shown that the pharmacokinetics of pregabalin are independent of another gabapentinoid, gabapentin. Although co-administration of pregabalin with gabapentin had no effect on the extent of absorption, a slight decrease in the rate of absorption was observed.
- Concomitant drugs such as other antiepileptic drugs (e.g. carbamazepine, lamotrigine, phenytoin, topiramate and valproic acid) did not affect the pharmacokinetics of pregabalin and vice versa.
Dosage, pharmacokinetics and interactions of gabapentin
In patients with postherpetic neuralgia, gabapentin therapy should be started with a single dose of 300 mg and gradually increased to 600 mg/day on day 2 and to 900 mg/day on day 3. The maximum recommended dose is 1800 mg/day (3 x 600 mg), and although doses of 2400 mg/day and 3600 mg/day are well tolerated, no additional benefit has been identified.
In patients with postherpetic neuralgia, gabapentin therapy should be started with a single dose of 300 mg and gradually increased to 600 mg/day on day 2 and to 900 mg/day on day 3. The maximum recommended dose is 1800 mg/day (3 x 600 mg), and although doses of 2400 mg/day and 3600 mg/day are well tolerated, no additional benefit has been identified.
In adults with normal renal function, the total clearance of gabapentin is 100 mL/min, which is equivalent to CrCl and therefore does not suggest the involvement of any appreciable tubule reabsorption in renal clearance. Patients with reduced renal function (i.e., the elderly) are likely to experience toxicity. Higher plasma concentrations and longer half-lives have been shown to cause sedation, dizziness, and confusion; therefore, dose reduction is strongly recommended.
Interaction of gabapentin with other drugs
- In vitro studies have shown that gabapentin shows no appreciable interaction with any of the major CYP450 enzymes, including CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Only at doses greater than 15 x 3600 mg, a small degree of CYP2A6 inhibition was observed.
- Meanwhile, in vivo drug interaction studies have shown that gabapentin has no effect on phenytoin, carbamazepine or valproic acid in patients with epilepsy.
- Studies of naproxen and hydrocodone have shown that gabapentin increases absorption by about 15%. However, gabapentin decreases the bioavailability of hydrocodone in a dose-dependent manner.
- Finally, concomitant use with morphine increases the bioavailability of gabapentin, which may increase respiratory depression, somnolence, and sedation; therefore, dose adjustment is strongly recommended.
- However, a study published in N Engl J Med demonstrated that combination therapy with low doses of gabapentin and morphine demonstrated better analgesic effect than each drug alone.
Toxicity and safety profile
Pregabalin is well tolerated and the most common adverse reactions are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and concentration/attention difficulties. There have been reports of patients experiencing hypersensitivity to pregabalin immediately after starting treatment, which has been manifested by dyspnea, wheezing, skin blisters and urticaria.
The instructions for use of pregabalin also contain the following warnings and precautions:
Pregabalin is well tolerated and the most common adverse reactions are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and concentration/attention difficulties. There have been reports of patients experiencing hypersensitivity to pregabalin immediately after starting treatment, which has been manifested by dyspnea, wheezing, skin blisters and urticaria.
The instructions for use of pregabalin also contain the following warnings and precautions:
- Rapid discontinuation of therapy with pregabalin increases the risk of seizure activity.
- Post-registration analysis has shown that some patients have experienced angioedema (swelling of the face, mouth, and neck) with life-threatening respiratory distress.
- Pregabalin may also cause peripheral edema (incidence of 6% in clinical trials), which is not associated with any known heart or peripheral vascular disease.
The most common adverse reactions [Gabapentin] with are dizziness, somnolence, and peripheral edema in patients with postherpetic neuralgia and somnolence, dizziness, ataxia, fatigue, and nystagmus in patients with epilepsy. Other warnings and precautions include:
- Anaphylaxis and angioedema may occur at any time during treatment. Signs and symptoms include difficulty breathing and swelling of the lips, throat, and tongue.
- In patients with epilepsy, gabapentin has been shown in multiple clinical trials to be associated with the occurrence of status epilepticus with a cumulative incidence of 1.5%. However, it is unknown whether treatment was directly associated with this adverse event.
- In addition, pooled analysis of clinical trial data indicated that gabapentin may increase the risk of suicidal thoughts or behaviors with an estimated incidence of 0.43%.
- The development of a life-threatening multi-organ hypersensitivity known as drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with gabapentin use.
In 2019, the FDA issued a cautionary statement regarding the potential occurrence of respiratory depression, stating:
This recommendation was prompted in part by the increasing frequency of gabapentin being detected in toxicology reports of individuals who have been victims of unintentional overdose from opioids, especially fentanyl.
Evidence is accumulating that both pregabalin and gabapentin are susceptible to misuse, abuse and dependence. The available literature suggests significant clinical potential for abuse of pregabalin, and clinicians should pay attention to signs of abuse, especially in patients with a history of substance abuse.
Evidence is accumulating that both pregabalin and gabapentin are susceptible to misuse, abuse and dependence. The available literature suggests significant clinical potential for abuse of pregabalin, and clinicians should pay attention to signs of abuse, especially in patients with a history of substance abuse.
Although gabapentinoid overdose appears relatively safe in its pure form, its lethality is increased, especially in the case of pregabalin, when combined with other psychoactive drugs, particularly opioids and sedatives.
In light of these results, a comparative analysis of the risks of dependence on traditional psychoactive substances indicates that gabapentinoids should be avoided in patients with a history of substance use disorders. If necessary, cautious administration with strict therapeutic and prescription monitoring is recommended.
Similarly, the experience in Germany shows that cases of escalating gabapentinoid abuse and related fatalities occur most frequently in countries struggling with the opioid epidemic. Germany, despite having one of the highest rates of non-medical gabapentinoid use in Western Europe, has not seen a corresponding spike in severe adverse outcomes, including fatalities. This discrepancy in results may be due to the lack of a national opioid epidemic in Germany. As a result, experts in addiction medicine in Germany characterized gabapentinoids as substances associated with a low level of harm.
Conclusion
The gabapentinoids, pregabalin and gabapentin were originally developed for the treatment of seizures but are now predominantly prescribed for acute or chronic pain, with approved indications limited to specific conditions. Their unique mechanism of action involves inhibiting potential-dependent calcium channels, key receptors in the regulation of neuronal excitability. As the use of gabapentinoids in pain disorders continues to grow, concerns have arisen regarding their efficacy and safety.
The gabapentinoids, pregabalin and gabapentin were originally developed for the treatment of seizures but are now predominantly prescribed for acute or chronic pain, with approved indications limited to specific conditions. Their unique mechanism of action involves inhibiting potential-dependent calcium channels, key receptors in the regulation of neuronal excitability. As the use of gabapentinoids in pain disorders continues to grow, concerns have arisen regarding their efficacy and safety.
In the UK, pregabalin and gabapentin were classified as controlled substances in 2019 due to their potential misuse and increased associated fatalities. In the US, pregabalin was placed in Schedule V of the Controlled Substances Act in 2005. The introduction of real-time prescription monitoring in Australia is aimed at combating potential misuse.
It is critical for patients to be aware of the risk of abuse or dependence, and prescribers should exercise caution, particularly in patients with a history of substance use disorders, in monitoring for signs of abuse or misuse. Strategies recommended to prevent abuse and misuse include limiting the number of medications prescribed, gradually reducing the dose of gabapentinoids to prevent withdrawal, and adopting a comprehensive approach to the management of chronic pain.
