Introduction

Pregabalin is a novel gamma-aminobutyric acid (GABA) analogue that increases neuronal GABA levels by selectively binding to the alpha2delta subunits of voltage-gated calcium channels and inhibiting the release of excitatory neurotransmitters like glutamate, noradrenaline, and substance P. Pregabalin has been approved for the treatment of partial-onset seizures, neuropathic pain, fibromyalgia, and general anxiety disorders [1–4]. The efficacy of pregabalin in chronic pain conditions like diabetic neuropathy, postherpetic neuralgia and central neuropathic pain has been demonstrated by a Cochrane database review of double-blind randomized controlled trials reporting on the analgesic effect of pregabalin [5]. In addition, pilot studies indicated pregabalin to be effective in the treatment of anxiety in schizophrenia [6], and of the alcohol withdrawal syndrome [7]. Pregabalin is widely used in neurology and psychiatry, and ranked within the 30 most prescribed medications in the US in 2011 [8]. Premarketing trials demonstrated a low potential for abuse and a limited dependence liability of the drug if misused [9]. Therefore, pregabalin has been classified as a Schedule V drug (i.e. with a low potential for abuse) in the U.S. Controlled Substances Act [10].

Nevertheless, there is some evidence suggesting that pregabalin might possess a potential for abuse among patients with past or current drug abuse or addiction. Recently, we published a case report of a patient who abused pregabalin in extremely high dosage (up to 7,500 mg per day), thereby developing an addiction as indicated by the occurrence of severe symptoms upon withdrawal of the drug [11]. This patient reported a history of heroin dependence and current abuse of alcohol and cannabis, pointing out that “in the (heroin) scene,” pregabalin is regarded as a new substance used by some addicts who appreciate it for the “kicks” it produces, particularly in combination with alcohol. Furthermore, Schwan et al. reported data from the Swedish National Register of Adverse Drug Reactions (SWEDIS): until the end of 2009, 16 cases of pregabalin abuse were registered, most of them concerning patients with a history of drug abuse and/or addiction [12]. By the same token, a retrospective evaluation of indicators of drug dependence provided by data from the Global Individual Case Safety Reports Database (VigiBase) of the World Health Organization (WHO) has highlighted pregabalin’s dependence potential [13]. Additionally, Dyrkorn et al. published results of a nationwide drug screening in Norway investigating [n = 1,854] urine samples. Pregabalin was detected in 4.5 % of these samples. The authors assumed that pregabalin may be abused as one of several substances not included in the standard test panel for the urinary screening for drugs lending themselves to abuse and addiction [14]. Moreover, in a recent report, the Canadian Agency for Drugs and Technologies in Health published a review of the clinical evidence (until April 2012) available on the abuse potential of pregabalin [15].

On the other hand, in a recent double blind randomized study, Zacny et al. investigated in healthy volunteers whether pregabalin, in the dose of 75 mg or 150 mg alone or in combination with 10 mg oxycodon, would affect parameters indicative of abuse liability. Their results show no difference between pregabalin and placebo [16].

However, the question remains open whether there is a significant abuse of pregabalin—and if so, whether a special group of individuals can be identified as being particularly prone to it. Based on the clinical experience with our pregabalin-addicted patient and his medical history [11] and on the research mentioned above, we hypothesize that subjects with a past or current opiate addiction are liable to abuse pregabalin. To test our hypothesis, we resorted to the patients in our outpatient department undergoing opiate replacement therapy (ORT), and focused on the question of whether pregabalin is abused among these patients. To answer this question, we conducted a pregabalin screening of urine specimens of all patients treated in our outpatient ORT unit. Furthermore, to control the findings gleaned therefrom, we also investigated the illicit use of pregabalin among subjects swayed by addiction to other drugs than opiates. We hence extended the screening to 111 other patients admitted to our department for inpatient detoxification from alcohol, benzodiazepines, cannabis, or amphetamines. To our knowledge, this is the first study set up to trace pregabalin abuse in a defined sample of opiate-dependent patients never exposed to pregabalin for medical reasons.

Methods

Participants

A total of 124 (34 female, 90 male) patients with a mean age of 37.1 ± 8.1 years (range 20–55) were screened for pregabalin. We analyzed only a single urine sample per patient. All patients fulfilled the diagnostic criteria for opiate dependence according to the Statistical Manual of Mental Disorders, fourth edition (American Psychiatric Association, 1994). In order to be included in our outpatient ORT-program, a patient was required to have been an opiate addict for at least 2 years. All participants received an opiate replacement containing either methadone or buprenorphine. About two times per month, the patients’ urine was tested for drugs and substances contraindicated during ORT (heroin, benzodiazepines, cocaine, amphetamines, and barbiturates). Furthermore, alcohol intake was controlled by means of a breathalyzer.

The control group consisted of the above-mentioned 111 patients treated for non-opiate addiction: namely to alcohol (n = 90), cannabis (n = 11), benzodiazepines (n = 3), and amphetamines (n = 1). The remaining six patients were polydrug abusers. Their urine samples were collected on the day of their admission to our department for inpatient detoxification.

Upon admission, all patients being treated in our ORT unit or in our inpatient department have to declare their written informed consent that urine and/or blood samples may be collected before and/or during treatment, and analyzed for substances of abuse or medication for treatment/quality control or safety. Therefore, a separate approval of the local ethical Committee was not necessary to conduct this drug-screening.

Laboratory analysis

The urine samples for pregabalin analysis were collected under staff observation between 9.00 and 11.30 a.m. as part of the routine urine drug monitoring for the opiate-addicted subjects, and on the day of their admission for the control group. Five milliliters of urine were separated, immediately refrigerated to 4 °C, and sent to the local medical laboratory (Limbach Laboratories, Heidelberg, Germany) for mass spectrometer analysis. It has been demonstrated in a large nationwide multicenter screening in the US (n > 57,000) that mass spectrometry is a reliable and sensitive method of detecting pregabalin in human urine specimens [17].

Fifty microliters of each urine sample was pipetted into Eppendorf tubes (Eppendorf, Hamburg, Germany). The sediment or peptides were precipitated by adding 500 μl of a solution of 70 % acetonitrile and 30 % methanol, as well as 25 mg/l droperidol. After 1 min of mixing, the tubes were centrifuged at 14,000 rpm for 5 min. The clear supernatant was then transferred to vials that were placed into the autosampler of a high-performance liquid chromatography (HPLC) system (Merck-Hitatchi, Darmstadt, Germany) equipped with a Halo C18 reversed phase column (MZ Analysetechnik, Mainz, Germany). The run time was 4 min; the retention time for pregabalin was 2.1 min (internal standard = droperidol: 2.6 min). For pregabalin detection, we used a mass spectrometer (Quattro Premier, Eschborn, Germany) in a positive electrospray mode.

The analysis showed a linear correlation of the concentration and the signal between 0.1 and 200 mg/l pregabalin, and further a coefficient of variation ranged from 2.3 % to 6 %. The bias varied from 3 % to 5 %. Samples with a higher pregabalin-concentration were diluted with water and then reanalyzed. For external quality control, we used samples of a German quality assessment scheme (GTFCH). No carryover was detected when a blank sample was injected during the validation process after the standard sample containing 200 mg/l pregabalin. However, all samples that were analyzed directly after a sample that contained a pregabalin-concentration above 100 mg/l were reanalyzed. The detection threshold above which pregabalin concentrations were considered to be positive was defined at 0.2 mg/l.

Statistical methods

For the statistical analysis, SPSS 16.0 (SPSS Inc. Chicago, Ill, USA) was used. Pearson’s correlation coefficient was resorted to for computing associations between the pregabalin urine concentration and a variety of sample variables and clinical parameters. The level of significance was set at α < 0.05. The mean values in our data are presented along with the standard errors of the mean.

Results

ORT sample

At the time of the study, 124 patients (90 men and 34 women) with an opiate dependency were being treated in our ORT unit. The average duration of their addiction amounted to 16.2 ± 7.7 years, with a range from 3 to 40 years. Prior to the actual treatment, the patients had, on average, passed through 3.0 ± 4.2 inpatient detoxifications. The treatment was performed with methadone in 78.2 % of the patients, and with buprenorphine in 21.8 %. In Table 1, the data are presented separately for men and women.

Table 1 Sample characteristics of the opiate-dependent patients
Full size table

Urine analysis

Pregabalin is for the most part excreted unchanged in the urine (> 98 %) [18], with a relatively short half-life of 4.6–6.8 h [19]. Pregabalin (in concentrations above the cutoff point of 0.2 mg/l) was detected in 12.1 % (n = 15) of the urine samples from opiate-addicted subjects. Of our patients, 13.3 % of males and 8.8 % of females had positive test results for pregabalin. The mean concentration of pregabalin came to 45.0 ± 74.4 mg/l, with the concentration range extending from 0.2 to 293.6 mg/l. To our knowledge, none of the positively tested patients suffered from epilepsy, general anxiety, fibromyalgia, neuropathic pain, or any other disease constituting an indication for applying pregabalin on medical grounds. Furthermore, when confronted with the positive results, most of the patients concerned (n = 11 of 15) confirmed that they bought pregabalin from other heroin addicts or from drug dealers, but never received prescriptions of pregabalin from their private physicians or other medical facilities. Four male patients did not believe that their urine contained pregabalin, denying its use. The patients confirming the use of pregabalin reported that they bought pregabalin solely for the sake of kicks, disclaiming self-medication of pain or other symptoms associated with opiate withdrawal. Moreover, all abusers were well aware of the fact that pregabalin was not included in the standard test-panel for drug monitoring applied in our ORT program. Interestingly, a vast majority (78.3 %) of the opiate-dependent patients joining the program reported that pregabalin belonged to many drug dealers’ supplies, on account of its kick and euphoriant effects. Additionally, no significant correlations were found between pregabalin use and variables such as age, gender, age at first opiate use, duration of opiate dependence or duration and dosage of opiate replacement.

Control group

We analyzed the urine of 111 Patients (79 men, 32 women) who had been admitted to our department for inpatient detoxification. Most of these patients were addicted to alcohol (81.1 %), 9.9 % to cannabis, 2.7 % to benzodiazepines, and 0.9 % to amphetamines. The remaining 5.4 % were polydrug users. The age of the control subjects came to an average of 44.7 ± 13.3 years (men 45 ± 1.5 years [range 20–70]; women 43.9 ± 2.4 years [range 20–68]). In the control group, three male alcohol-dependent patients tested positive for pregabalin. They had used it regularly in therapeutic dosages of 150–450 mg/day upon prescription from their physicians; two of them for chronic pain syndromes, the third for general anxiety. All three patients answered the questions about having pregabalin-associated “kick” experiences or feelings of euphoria in the negative. Moreover, they assured us of never having heard of pregabalin being a euphoriant drug or having connections to the drug-scene.

Discussion

The results of the present study revealed that about 12 % of the patients undergoing opiate replacement therapy in our unit were positive for pregabalin. Since there was no medical indication for administering pregabalin to these patients, they were likely to have been using this drug irregularly on their own. So far, the international literature offers only a few reports on the abuse of pregabalin. Filipetto and colleagues (2010) published a case of a female patient from the US with chronic pain due to a prior Guillian-Barré syndrome and with a history of opioid-seeking behavior. Having experienced the rewarding effects of pregabalin, she consulted several doctors within a 3-month period in quest of prescriptions to fulfill her growing need of pregabalin. This patient had abused about 88 g of pregabalin in the course of a few weeks before a medical board disclosed irregularities in her pregabalin prescriptions and referred her to a hospital for detoxification [20]. Recently, we reported a similar case of a former heroin addict [11].

Based on its mechanisms of action as a GABA analogue, there have been concerns about pregabalin’s potential for abuse and addiction since the beginning [9].

Preclinical studies with animals did not reveal any abuse liability [9]. By the same token, a clinical trial with a small sample (n = 15) of alcohol and sedative users demonstrated that pregabalin administered in the therapeutic dose range of 200–450 mg/day is far from producing the response spectrum diazepam is notorious for. Hence, pregabalin failed to show the profile of a prototypic drug of abuse [9]. In premarketing trials, however, euphoria was noted, depending on dosage, as an adverse effect occurring more frequently in pregabalin than in placebo groups (4 % vs. 1 %, respectively) [21].

Notably, it is a well-known weakness of randomized controlled premarketing trials that patients with addiction disorders are excluded. Thus, naturalistic data on newly approved drugs are often lacking. In view of the known but very rare adverse effect of dose-dependent mild euphoria [21], pregabalin may act as a weakly rewarding substance in some subjects who have developed long-term opioid tolerance. That fits in with the outcome of a recent double-blind placebo-controlled study that failed to trace subjective effects associated with abuse-liability, such as a liking for pregabalin, in healthy subjects never afflicted with addiction [16].

All in all, it is impossible to validate these phenomena in standardized premarketing clinical trials for substances whose abuse liability is uncertain. Therefore, documentation of postmarketing clinical experience, surveillance, and naturalistic trials are urgently called for.

On the other hand, although all pregabalin abusers in our sample stated that they intended to get kicks, one might speculate that the illicit use of pregabalin may, at least for some heroin addicts, be due to its alleviating effects on the opiate withdrawal syndrome (OWS). We have not systematically collected data on that issue yet, but some opiate-addicted patients in our outpatient unit have reported anecdotally that in the heroin scene, addicts have been taking pregabalin to control typical opiate withdrawal symptoms such as pain, unrest, and sleeplessness. One of those cases has recently been published by our group [22].

However, data on the application of well-proven anticonvulsants (carbamazepine, topiramate) in the treatment of OWS have suggested their effectiveness in that area of indications [23–25]. That correlates with the outcome of recent research indicating pregabalin to be effective in the treatment of the alcohol withdrawal syndrome during detoxification [7, 26]. Furthermore, in a recent pilot study regarding the maintenance of alcohol abstinence, pregabalin produced similar results in the prevention of relapses as naltrexone [27]. Additionally, pregabalin has been shown to be effective in the withdrawal phase of benzodiazepine detoxification [28]. All in all, with pregabalin a preparation has been coming to the fore and may hold out the prospect of becoming a valuable asset in the pharmacological repertoire of addiction medicine.

Some limitations of the investigation presented here should be mentioned. The screening was conducted in one center only, with the number of participants being small. Additionally, we analyzed only a single urine sample per patient, without integrating pregabalin into the standard test panel. This may have lead to false negatives in our data. Moreover, due to the relatively short half-life of pregabalin, the time frame for detection is brief, which may also have lead to false negatives. Another limitation is that we did not measure urine creatinine.

However, with regard to the lack of naturalistic data on the potential of pregabalin for abuse, systematic research on this topic is urgently needed. In view of the research mentioned above and of our current findings, we conclude that pregabalin displays a potential for abuse among individuals with a history of chronic opiate intake. Thus, we recommend being vigilant and cautious when administering it to these patients, in particular in the polypharmacological management of complex chronic pain and of anxiety disorders.