DOI: 10.14744/DAJPNS.2019.00013 Dusunen Adam The Journal of Psychiatry and Neurological Sciences 2019;32:81-6 EDITORIAL Heightened misuse risk and addictive potential of gabapentinoids: the fate of effective anxiolytics Cuneyt Evren1 , Vahap Karabulut1 1Bakirkoy Training and Research Hospital for Psychiatry Neurology and Neurosurgery, Research, Treatment and Training Center for Alcohol and Substance Dependence (AMATEM), Istanbul - Turkey Gabapentin and pregabalin, two pharmacologically percent of all gabapentin use, accounting for over 90% very closely related substances, are classed as of sales (5). A diagnosis of non-neuropathic pains gabapentinoids (1). Gabapentin was synthesized in accounts for 80.4% of gabapentin and 58.3% of 1977 to create a structural analogue to gamma- pregabalin off-label prescription (6). In Turkey, aminobutyric acid (GABA) with a higher degree of gabapentin has been licensed for the treatment of lipophilia than the original neurotransmitter. In 1993, epilepsy and neuropathic pain, and pregabalin for its use in the treatment of epilepsy began. Pregabalin, epilepsy, neuropathic pain, generalized anxiety another structural analogue of GABA, was synthesized disorder, and fibromyalgia. Drugs containing in 1991; in 2004, it was introduced for the treatment of pregabalin and gabapentin as active ingredients neuropathic pain and in 2005 for the therapy of belonged to the category of controlled drugs distributed refractory epilepsy. A third member of this drug family, with a regular prescription; however, in April 2019 mirogabalin, is currently undergoing clinical trials for pregabalin was included in the category of green- the treatment of diabetic neuropathy, fibromyalgia, and colored (controlled medication) prescription (7). postherpetic neuralgia (2). The mechanism of action of gabapentinoids is not Gabapentinoids are commonly used in neurology, fully understood. A generally accepted opinion states psychiatry, and primary healthcare. In Europe, that they bind to a subunit of voltage-gated calcium pregabalin is used in the treatment of epilepsy (partial channels in neurons, the alpha-2-delta (α2-δ) protein, seizures), neuropathic pain, and generalized anxiety reducing central neuronal excitability. By binding to disorder. In the U.S.A., while it is not licensed for calcium channels, these drugs reduce the calcium influx anxiety, it also has been licensed for fibromyalgia and into the neuron and subsequently the release of postherpetic neuralgia. In addition, the molecule is neurotransmitters, which is believed to contribute to often prescribed off-label for a number of clinical their antinociceptive, anticonvulsant, and anxiolytic conditions, including post-traumatic stress disorder, properties (8-10). While gabapentinoids are structural somatoform disorders, bipolar disorder, alcohol or analogues of the primary inhibitory neurotransmitter substance withdrawal processes, attention-deficit GABA, they do not bind directly to GABA receptors, but hyperactivity disorder (ADHD), insomnia, restless leg they are assumed to possess GABA-mimetic properties syndrome, borderline personality disorder, menopausal (4,11). Therapeutic doses of gabapentinoids cause a slight problems, chronic prostatitis, vertigo, itching disorder, increase in the extracellular GABA concentration in the migraine, trigeminal neuralgia, postoperative pain, and human brain cortex. Accordingly, they show weak non-neuropathic pain disorders (3-5). It is estimated GABA-mimetic properties at the beginning of treatment that off-label use of gabapentin makes up 83-95% and at higher doses, triggering relaxation and euphoria How to cite this article: Evren C. Gabapentinoids. Dusunen Adam The Journal of Psychiatry and Neurological Sciences 2019;32:81-6. Correspondence: Cuneyt Evren, Bakirkoy Training and Research Hospital for Psychiatry Neurology and Neurosurgery, Research, Treatment and Training Center for Alcohol and Substance Dependence (AMATEM), Istanbul - Turkey Phone: +90 212 543 65 65/21 19 E-mail: [email protected] 82 Evren et al. Dusunen Adam The Journal of Psychiatry and Neurological Sciences 2019;32:81-6 (12). In addition, pregabalin reduces the release of that pregabalin enhances the cognitive and motor various neurotransmitters, including glutamate, effects of oxycodone, ethanol, and lorazepam (2). norepinephrine, substance P, and calcitonin gene-related Factors encouraging the use of pregabalin in peptide (13,14). A recent study shows that gabapentin is psychiatry and addiction include its unequivocal, fast, simultaneously a strong activator for voltage-gated and well documented efficacy in a number of psychiatric potassium channels. Pregabalin has been shown not to disorders characterized by anxiety as a fundamental activate these channels; at higher concentrations (≥10 symptom; a daily dose of at least 600 mg is safe and well µM), it actually inhibits them (15). tolerated, drug interactions are few, cytochrome P450 Pregabalin and gabapentin share a number of similar enzymes are not inhibited, and side effects are usually pharmacokinetic and pharmacodynamic properties such light and temporary (19). Studies researching the role of as a similar metabolic profile, negligible protein binding, pregabalin in alcohol and benzodiazepine dependency renal excretion, and minimal drug-drug interaction. At found contradictory results in the treatment of the same time, the two drugs show significant differences withdrawal symptoms; however, they provided in absorption. The bioavailability of oral gabapentin is evidence for its efficacy in the prevention of relapses dose-dependent. The maximum plasma concentrations (20-22). Similarly, study data confirm the safety and of pregabalin after oral administration increase with the efficacy of gabapentin as a new treatment for alcohol dose linearly (10). Gabapentin absorption falls from 68% use disorder (23,24). after a 300 mg dose to 36% after a 1600 mg dose due to In contrast to the important place of both drugs in saturation absorption, while pregabalin reaches a clinical use, a potential for misuse and addiction has bioavailability of 90% despite increasing doses (16). also been found. Generally, when administered in Gabapentin reaches the highest plasma concentrations 3 therapeutic doses to patients with no history of hours after oral intake, but these concentrations are dose- substance abuse, the misuse risk of gabapentinoids limited and can vary between individuals due to appears to be lower than that of other prescription absorption processes (10). The peak blood concentrations drugs such as benzodiazepines (e.g., opioids and of pregabalin, compared to gabapentin, are achieved fast, stimulants) or alcohol and illegal substances (25,26). A within 1 hour (17). Neither of the two drugs binds to study in England that was carried out in the age group plasma proteins. The level of hepatic metabolism is 16-59 years found a lifelong prevalence of gabapentin negligible and the drugs are mainly eliminated through and pregabalin in the general population of 1.1 and renal excretion. Gabapentinoids have a fairly short half- 0.5%, respectively (27). However, in patients with a life of around 6 hours and are excreted with the urine substance use disorder, especially those with opioid almost unchanged (98%) (10). While pregabalin interacts abuse, the misuse of gabapentinoid is more common. with the same binding area as gabapentin and has a Studies focusing on patients with opioid use disorder similar pharmacological profile, its affinity and strength found a misuse rate of 15-22% for gabapentin and of in binding to the α2-δ subunit are higher than those of 3-68% for pregabalin (16). A study analyzing both drugs gabapentin (4). Given that pregabalin has a 2.5 to 6 times in a post-mortem population demonstrated a higher potency, faster absorption, and higher widespread use of these substances together with bioavailability, its misuse risk is higher than that of opioids. Particularly in heroin users, pregabalin use is gabapentine (18). quite significant. The prevalence of pregabalin in heroin Gabapentin is safely tolerated in a very wide range users (19.5%) is 4.1 times higher than in patients not of doses between ca. 800 and 1800 mg/day (5). using heroin (4.7%) (28). It has been shown that Irrespective of clinical indications, the daily amount is pregabalin can be used to increase the effects of heroin administered in three doses per day. The daily dose of or in some individuals to reduce heroin use (29). pregabalin can vary significantly, between 75 and 600 For pregabalin as well as gabapentin, reports of their mg (13), which can be divided into 2 or 3 portions per abuse potential increasingly emerge. In 2011, pregabalin day. The recommended maximum intake for pregabalin was among the 30 most frequently prescribed drugs in and gabapentin, administered in more than one dose, is the U.S.A. (30). In England, within only 5 years the 600 and 3600 mg/day, respectively (16). As the main prescription of pregabalin and gabapentin increased by drug-related adverse reactions to gabapentinoids are 350% and 150%, respectively (31). In parallel, dizziness and drowsiness, simultaneous use of other gabapentinoids are found more readily on the black drugs that share their CNS-depressing effects can be market, hence not requiring prescription. More expected to increase these effects. It has been shown importantly, mortality databases in England have shown Evren et al. Heightened misuse risk and addictive potential of gabapentinoids: