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 Table of Contents  
Year : 2020  |  Volume : 41  |  Issue : 1  |  Page : 14-18

Cognitive impairment and pregabalin dependence

1 Psychiatry Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
2 Neurlogy Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

Date of Submission14-Oct-2019
Date of Decision01-Nov-2019
Date of Acceptance03-Nov-2019
Date of Web Publication22-Jan-2020

Correspondence Address:
MD, Lecturer of Psychiatry Abouzed Mohamed
Psychiatry Department, Faculty of Medicine, Al-Azhar University, Cairo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ejpsy.ejpsy_34_19

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Background One of the major consequences of substance misuse is its effect on patient cognition. Pregabalin is a new-generation antiepileptic which is believed to have an addictive effect.
Objective This cross-sectional study is aimed to estimate the prevalence of cognition impairment among patients with pregabalin misuse. This study includes 300 patients and 100 controls with matched age, sex, and education. The drug abuse patients were divided into two groups: the first group patients used pregabalin alone and the second was a polysubstance group; each group was formed of 150 patients matched in sex, age, and educational level to the pregabalin group. For the diagnosis we used urine screening for drugs. We used the Montreal cognitive assessment test in Arabic edition to evaluate the cognitive function of the patient.
Result Cognitive impairment was more in pregabalin misuse patients (M=25.4, SD=3.3) than in the control group (M=27.5, SD=3.7) according to the Montreal cognitive assessment test, P value less than 0.001. The most affected domains were visuoconstruction, digit span, verbal fluency, and recall, with dose (M=625, SD=400). There was no association between cognitive impairment and dose of pregabalin or duration of substance abuse.
Conclusion This study concluded that pregabalin misuse patients were likely to have cognitive impairment due to the drug effect and their cognitive impairment was less than the polysubstance misuse group.

Keywords: cognitive impairment, polysubstance abuse, pregabalin

How to cite this article:
Mohamed A, Emam. Cognitive impairment and pregabalin dependence. Egypt J Psychiatr 2020;41:14-8

How to cite this URL:
Mohamed A, Emam. Cognitive impairment and pregabalin dependence. Egypt J Psychiatr [serial online] 2020 [cited 2024 Mar 3];41:14-8. Available from: https://new.ejpsy.eg.net//text.asp?2020/41/1/14/276396

  Background Top

Pregabalin is one of the newest antiepileptic drugs that essentially acts as a gamma-aminobutyric acid analog. Pregabalin is used in neurology and psychiatry and, in 2011, it became the 30th most prescribed medication in the United States (Fornasari, 2017). It is used for the treatment of epilepsy, neuropathic pain, some anxiety disorders, fibromyalgia, and for alcohol withdrawal. Its off-label indications include hypnotic-dependent insomnia (Montgomery et al., 2013), and its mechanism of action is similar to that of gabapentin. Pregabalin has inhibitory action on the brain and causes presynaptic inhibition of excitatory neurotransmitters. This antiglutamatergic effect resembles the effect of benzodiazepines and may be responsible for its addictive properties. It may also make alcohol-addicted or benzodiazepine-addicted patients more vulnerable to cross −tolerance (Bonnet and Scherbaum, 2017).

The prevalence of cognitive impairment in polysubstance abusers varies widely and may be as high as 80%(Hagen, 2016). Cognitive impairment includes deficits in cognitive flexibility and attention in cannabis users, deficits in cognitive flexibility in cocaine and opioid users, deficits in attention and impulse control in amphetamine users, and deficits in working memory and declarative learning in tobacco smokers. Alcoholics may develop permanent cognitive deficits, such as Wernicke–Korsakoff syndrome and impairment of psychomotor abilities reported in patients taking stable doses of opioids (Gould, 2010).

Cognitive deficits have an impact on treatment outcomes, including patient insight and judgment, compliance, and relapse prevention (Gupta et al., 2018). Cognitive impairment may affect an individual’s ability to benefit from counseling and/or abstinence-sustaining strategies (Fernandez-Serrano et al., 2011). The cognition deficit may persist even after several months of abstinence. Even during opioid-substitution therapy, some patients have been reported to experience problems with cognitive function(Copersino et al., 2012).

Few studies have examined the effects of pregabalin on cognition. Salinsky et al. (2010) reported that titration of pregabalin to 600 mg for 12 weeks induced mild cognitive deficits and complaints of neurotoxicity in healthy volunteers.

The objectives of the present study were to assess the prevalence and clinical correlates of cognitive impairment in patients with pregabalin abuse and to compare the levels of cognitive impairment among pregabalin and polysubstance abusers and healthy controls.

  Patients and methods Top


A total of 150 patients from psychiatry, addiction, and neurology outpatient clinics, who asked for pregabalin prescription and diagnosed with pregabalin misuse disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria (American Psychiatric Association, 2013), and an equal number of age-matched, sex-matched, and education-matched polysubstance abusers were included in the present study. One hundred controls without a history of substance misuse were selected from the relatives of the patients and matched for age, sex, and education level.

Patients aged less than 18 years and those aged more than 50 years; those with major physical problems (e.g. heart failure, hepatic failure, renal failure, brain insult, dementia); and those with comorbid mental illness (intellectual disability, acute psychosis, or dual diagnosis) were excluded.


Sociodemographic and clinical data were collected from all patients, diagnoses of polysubstance misuse were based on the Structured Clinical Interview from Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Additionally, a routine urine test was performed to screen for substance and pregabalin abuse, which is not a routine investigation. The Montreal cognitive assessment (MoCA) test was used to assess cognitive function of the patients (Rahman and El Gaafary, 2009). The controls comprised relatives of the patients and they also underwent the MoCA and urine tests to exclude the possibility of any substance misuse.

Ethical considerations

The protocol is approved by Al-Azhar Faculty of Medicine Ethics Committee. Written informed consent was obtained from all participants, and the study was performed in accordance with the ethical standards of the Helsinki Declaration of 2004.

Statistical analysis

SPSS, version 11.0.1 (SPSS Inc., Chicago, Illinois, USA) was used for statistical analysis. Quantitative data are expressed as mean and SD, and the Student’s t test was used for comparisons. Fisher’s exact test and the χ2 test were used for qualitative data; P value less than or less than 0.05 was considered to be statistically significant. Comparisons between the polysubstance, pregabalin, and control groups were performed using analysis of variance adjusted for other variables (age and education).

  Results Top

Sociodemographic information

Most of the patients diagnosed with a substance-use disorder (pregabalin or polysubstance) were men (94%). There were no significant differences between the controls and patients in terms of sex, age, education, and marital status. Fifty-four percent (n=81) of the patients took more than or equal to six tablets (900 mg) (M=1050, SD=122 per day). The initiation age of polysubstance misuse (M=16.27, SD=8.9 years) is less than the pregabalin misuse group (M=24.1, SD=6.94). The dose of pregabalin was M=625, SD=400.01 mg/day, and the duration of abuse was M=9.17, SD=7.72 years. The sociodemographic characteristics of the patients in the three groups (i.e. pregabalin alone, polysubstance, and control) were comparable.

Cognitive impairment

The total MoCA scores revealed that patients who abused polysubstance (M=24.9, SD=3.6) exhibited greater cognitive impairment than the controls (M=27.5, SD=3.7), t=5.53, P=0.0001. All cognitive function domains, except naming, t=0.019, P=0.98, were significantly impaired in polysubstance abusers ([Table 1]). On the contrary, patients who abused pregabalin exhibited impairment in all cognitive domains, but the impairment was significant in visuoconstruction t=3.22, P=0.0014, digit span t=2.65, P=0.0084, verbal fluency t=2.01, P=0.045, and recall domains t=3.15, P=0.0018. The total MoCA score was significantly impaired in pregabalin misuse group (M=25.4, SD=3.3) more than the control group (M=27.5, SD=3.7), t=4.69, P=0.0001 ([Table 2]). Sociodemographic data including age, sex, education level, occupation, and marital status demonstrated no association with cognitive impairment. Polysubstance abusers were more likely to experience cognitive impairment (M=24.9, SD=3.6) than those who abused pregabalin alone (M=25.4, SD=3.3) but not significant t=1.25, P=0.21. All cognitive domains were more impaired in the polysubstance abuse group than in the pregabalin abuse group. Differences were significant in verbal fluency and t=3.84, P=0.0001, abstraction t=5.04, P=0.0001, and orientation t=9.14, P=0.0001 ([Table 3],[Table 4],[Table 5]).
Table 1 Cognitive difference between the polysubstance abuse group and the control group

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Table 2 Cognitive difference between the pregabalin abuse group and the control group

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Table 3 Cognitive difference between the polysubstance abuse group and the pregabalin group

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Table 4 Analysis of variance test to compare between polysubstance, pregabalin, and control groups

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Table 5 Tukey honestly significant difference post-hoc test

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A one-way analysis of variance was conducted to compare the effect of addiction on cognition (MoCA test) in polysubstance, pregabalin, and control groups. There was significant difference at F(2, 397)=29.72, P value less than 0.001 between the three groups. Post-hoc analyses using Tukey’s honestly significant difference indicated a significant difference between the polysubstance group (M=24.9, SD=3.6) and the control group (M=27.5, SD=3.7) P value less than 0.001. Also there was significant difference between the control group (M=27.5, SD=3.7) and the pregabalin group (M=25.4, SD=3.3) P value less than 0.001. However, the polysubstance group (M=24.9, SD=3.6) did not significantly differ P=0.453 from the pregabalin group (M=25.4, SD=3.3). Taken together, these results suggest that both polysubstance misuse and pregabalin misuse have a bad effect on cognition.

  Discussion Top

Only a few studies have addressed cognitive impairment with regard to pregabalin; however, these studies involved patients with epilepsy or medically ill patients. Moreover, even in investigations that included healthy volunteers, the study period was short (a few weeks), and doses of pregabalin were limited and did not exceed 500 mg (Salinsky et al., 2010). However, in the present study, the sample used a large amount of pregabalin [mean, 625 mg (range, 200–1200 mg)] over a long period [mean, 9.17±7.72 years (range, 1–18 years)].

Cognitive impairment is important to study patients taking pregabalin due to its nature of use in epilepsy and polyneuropathy, which tend to be chronic and high dose in patients already prone to cognitive impairment because of other physiological and pathological causes. Secondary causes of impairment include novel misuse as an addictive substance, which can also involve large doses over long durations (Landi et al., 2019).

In the present study, four of 10 cognitive domains (visuoconstructional, digit span, verbal fluency, and recall) demonstrated significantly worse scores in patients who abused pregabalin compared with healthy controls. These negative effects were, however, less severe than the cognitive impairment exhibited by polysubstance abusers, in whom nine of 10 cognitive domains were significantly impaired (all except for naming). A previous study that evaluated the cognitive side effects of pregabalin in healthy volunteers after 3 days of treatment (450 mg/day) reported no cognitive side effects (Zacny et al., 2012). In contrast, a double-blinded study involving healthy volunteers who underwent 12 weeks of treatment at 600 mg/day reported more negative effects on cognitive measures (digit symbol, stroop, controlled oral word association task) (Salinsky et al., 2010). In a study comparing the cognitive effects of pregabalin (75 mg dose) versus duloxetine in postoperative pain management, there was a significant decrease in mean MoCA scores in the pregabalin group (1.83±1.31 points) (Myhre et al., 2019). Gabapentin, which has many properties similar to pregabalin, induces mild cognitive side effects; however, this difference may be due selective binding of pregabalin to the alpha-2 delta subunits of voltage-gated calcium channels (Altiparmak et al., 2018). Long-term potentiation in N-type Ca2+ channel deficiency was associated with chronic memory impairment (Nagase et al., 2003). N-type Ca2+ channels are present in the hippocampus and are responsible for hippocampus-dependent memory and learning (Hagen et al., 2007). Pregabalin inhibits depolarization-dependent calcium influx, resulting in decreased neurotransmitter release, mainly in the hippocampus and the cerebellum, thus leading to cognitive impairment (Verma et al., 2014).Cognitive deficits in substance abusers reflect drug-induced impairment, which depend on the type of drug, its mechanism of action, drug–drug interactions, onset of use, duration, and dose (Fowler et al., 2007; Mackey and Paulus, 2013; Battistella et al., 2014).[22]

  Conclusion Top

Patients who abused pregabalin are more likely to exhibit cognitive impairment, although cognitive impairment in this group is less severe than in those with polysubstance abuse.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Reference  Back to cited text no. 1
Altiparmak B, Güzel Ç, Gümüş Demirbilek SClin (2018). Comparison of preoperative administration of pregabalin and duloxetine on cognitive functions and pain management after spinal surgery: a randomized, double-blind, placebo-controlled study. J Pain 34:1114–1120.  Back to cited text no. 2
American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing.  Back to cited text no. 3
Battistella G, Fornari E, Annoni JM, Chtioui H, Dao K, Fabritius M et al. (2014). Long-term effects of cannabis on brain structure. Neuropsychopharmacology 39:2041–2048.  Back to cited text no. 4
Bonnet U, Scherbaum N (2017). How addictive are gabapentin and pregabalin? A systematic review. Eur Neuropsychopharmacol 27:1185–1215.  Back to cited text no. 5
Copersino ML, Schretlen DJ, Fitzmaurice GM, Lukas SE, Faberman J, Sokoloff J, Weiss RD (2012). Effects of cognitive impairment on substance abuse treatment attendance: predictive validation of a brief cognitive screening measure. Am J Drug Alcohol Abuse 38:246–250.  Back to cited text no. 6
Fernandez-Serrano MJ, Perez-Garcia M, Verdejo-Garcia A (2011). What are the specific vs. generalized effects of drugs of abuse on neuropsychological performance? Neurosci Biobehav Rev 35:377–406.  Back to cited text no. 7
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Fowler JS, Volkow ND, Kassed CA, Chang L (2007). Imaging the addicted human brain. Sci Pract Perspect 3:4–16.  Back to cited text no. 9
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Hagen E (2016). Assessment of executive function in patients with substance use disorder: a comparison of inventory- and performance-based assessment. J Sub Abuse Treat 66:1–8.  Back to cited text no. 12
Hagen E, Erga AH, Hagen KP, Nesvåg SM, McKay JR, Lundervold AJ et al. (2007). Impaired long-term memory and long-term potentiation in N-type Ca2+ channel-deficient mice. Genes Brain Behav 4:375–388.  Back to cited text no. 13
Landi S, Petrucco L, Sicca F, Ratto GM (2019). Transient cognitive impairment in epilepsy. Front Mol Neurosci 11:458.  Back to cited text no. 14
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Montgomery S, Emir B, Haswell H, Prieto R (2013). Long-term treatment of anxiety disorders with pregabalin: a 1 year open-label study of safety and tolerability. Curr Med Res Opin 29:1223–1230.  Back to cited text no. 16
Myhre M, Jacobsen HB, Andersson S, Stubhaug A (2019). Cognitive effects of perioperative pregabalin: secondary exploratory analysis of a randomized placebo-controlled study. Anesthesiology 130:63–71.  Back to cited text no. 17
Nagase T, Ito KI, Kato K, Kaneko K, Kohda K, Matsumoto M et al. (2003). Long-term potentiation and long-term depression in hippocampal CA1 neurons of mice lacking the IP(3) type 1 receptor. Neuroscience 117:821–830.  Back to cited text no. 18
Rahman TT, El Gaafary MM (2009). Montreal cognitive assessment Arabic version: reliability and validity prevalence of mild cognitive impairment among elderly attending geriatric clubs in Cairo. Geriatr Gerontol Int 1:54–61.  Back to cited text no. 19
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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