pregabalin and Heroin-Dependence

The gabapentinoid pregabalin is a rapid-acting anxiolytic and analgesic, possibly suitable in supervised opioid detoxification. However, clinicians have been cautious in using it because of its unknown addictive risk and rising number of mortalities after pregabalin self-medication in opioid abusers. Here, we studied interactions of pregabalin and morphine on reward functions of the dopamine system in mice and the efficacy of pregabalin on withdrawal in opioid addicts. After the treatment of mice with pregabalin and morphine, we used electrophysiology to study neuroplasticity in midbrain slices, self-administration and conditioned place preference tests to investigate the rewarding potential of pregabalin and naloxone-precipitated morphine withdrawal to evaluate opioid withdrawal symptoms. Further, we ran a pilot single-blind, randomized, controlled trial (34 heroin addicts) to evaluate the efficacy and safety of pregabalin in the treatment of opioid withdrawal syndrome. Pregabalin alone did not induce glutamate receptor neuroplasticity of dopamine neurons in the ventral tegmental area, but pre-treatment with pregabalin suppressed morphine-induced neuroplasticity, hyperlocomotion and morphine self-administration. Pregabalin administration after chronic morphine exposure failed to induce any rewarding effects. Instead, pregabalin suppressed withdrawal symptoms in both morphine-treated mice and opioid addicts and was well tolerated. Intriguingly, pregabalin administration after a low dose of morphine strongly facilitated ventral tegmental area neuroplasticity and led to increased conditioned place preference. Pregabalin appears to have the efficacy to counteract both reinforcing and withdrawal effects of opioids, but it also has a potentiating effect when given to mice with existing opioid levels.

Topics: Adult; Analgesics, Opioid; Animals; Conditioning, Psychological; Dopaminergic Neurons; Electrophysiological Phenomena; Female; Heroin Dependence; Humans; Inhibition, Psychological; Locomotion; Male; Mesencephalon; Mice; Morphine; Naloxone; Narcotic Antagonists; Neuronal Plasticity; Pilot Projects; Pregabalin; Receptors, Glutamate; Reinforcement, Psychology; Self Administration; Single-Blind Method; Substance Withdrawal Syndrome; Ventral Tegmental Area

Pregabalin (PGL) is a gabapentinoid used to treat epilepsy, neuropathic pain and generalized anxiety disorder. PGL is also misused by heroin users as it enhances the effects of heroin. While it is thought those who misuse PGL take it in amounts greater than the recommended therapeutic dose, it is unknown whether there is a significant difference between the amounts of PGL used by heroin users compared to non-heroin users. This study hypothesized that the PGL concentrations in postmortem (PM) samples taken from heroin users positive for PGL would be higher than those in non-heroin users. Between 1 January 2016 and 31 December 2016, a routine drug screen and a specific screen for PGL were carried out on femoral-vein bloods from 3,750 PM Coroners' cases. Of the cases screened, 354 were heroin users, of which 264 cases were negative for gabapentinoids and therefore used as the control-heroin-user group. PGL was positive in 229 cases, of which 69 were heroin users and 160 were non-heroin users. On comparing the PGL concentrations, statistically higher concentrations were observed in the heroin users compared to non-heroin users (P = 0.002). There was no correlation between the concentrations of PGL and morphine (from heroin) in the heroin users (P = 0.95), and the amount of heroin (morphine) consumed was not dependant on whether PGL was consumed or not (P = 0.98). The prevalence of anti-depressants, benzodiazepines, methadone and non-heroin-related opioids was seen to be significantly higher in heroin users that were positive for PGL than the control-heroin users (P = < 0.001 for all drugs). This study suggests that heroin users are using greater amounts of PGL compared to non-heroin users; however, the magnitude of the difference in use may not be sufficient to conclude that heroin users are at substantially greater risk of PGL toxicity compared to non-heroin users. Results indicate that heroin users who take PGL are more likely to use multiple depressant drugs, hence increasing the risk of multi-drug toxicity and death in this population.

Topics: Autopsy; Heroin; Heroin Dependence; Humans; Morphine; Pregabalin

Due to the rise in their misuse and associated mortality, the UK government is reclassifying gabapentin (GBP) and pregabalin (PGL) to Class C controlled drugs from April 2019. However, it is impossible to gauge the extent of their use with current post-mortem toxicological screening, where GBP and PGL are only screened for if they are mentioned in the case documents. This study determines the prevalence of GBP and PGL, the potential extent of their under-reporting and poly-drug use in a post-mortem population. Between 1 January 2016 and 31 December 2017, 3,750 deceased from Coroners' cases in London and South East England underwent a routine drugs screen and a specific screen for GBP and PGL. The prevalence of both drugs was determined in the cohort and the subcategories of heroin users and non-heroin-users. The prevalence of both drugs was compared to tramadol (Class C drug). Case documents were reviewed to investigate the under-reporting of GBP and PGL and poly-drug use. Of 3,750 samples analyzed, 118 (3.1%) were positive for GBP, 229 (6.1%) for PGL and 120 (3.2%) were positive for tramadol. If routine analysis without additional screening of GBP and PGL had been performed in this cohort, GBP would have been under-reported by 57.6% (P < 0.0001) and PGL by 53.7% (P < 0.0001) in deaths. The most common drug group observed with GBP and PGL was non-heroin-related opioids at 60.2% and 64.6%, respectively. In total 354 deceased (9.4%) were heroin users. GBP was positive in 23 (6.5%) of these cases and PGL was positive in 69 (19.5%). The prevalence of PGL in heroin users (19.5%) was 4.1 times greater than in non-heroin users (4.7%) (P < 0.0001). GBP and PGL are being significantly under reported in fatalities. Both drugs are extensively used with opioids. The prevalence of PGL in heroin users is highly significant.

Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; England; Female; Forensic Toxicology; Gabapentin; Heroin Dependence; Humans; Incidence; Male; Middle Aged; Pregabalin; Prevalence; Substance-Related Disorders

To examine the risk to heroin users of also using gabapentin or pregabalin (gabapentoids).. Multi-disciplinary study: we (a) examined trends in drug-related deaths and gabapentoid prescription data in England and Wales to test for evidence that any increase in deaths mentioning gabapentin or pregabalin is associated with trends in gabapentoid prescribing and is concomitant with opioid use; (b) interviewed people with a history of heroin use about their polydrug use involving gabapentin and pregabalin; and (c) studied the respiratory depressant effects of pregabalin in the absence and presence of morphine in mice to determine whether concomitant exposure increased the degree of respiratory depression observed.. England and Wales.. Interviews were conducted with 30 participants (19 males, 11 female).. (a) Office of National Statistics drug-related deaths from 1 January 2004 to 31 December 2015 that mention both an opioid and pregabalin or gabapentin; (b) subjective views on the availability, use, interactions and effects of polydrug use involving pregabalin and gabapentin; and (c) rate and depth of respiration.. Pregabalin and gabapentin prescriptions increased approximately 24% per year from 1 million in 2004 to 10.5 million in 2015. The number of deaths involving gabapentoids increased from fewer than one per year prior to 2009 to 137 in 2015; 79% of these deaths also involved opioids. The increase in deaths was correlated highly with the increase in prescribing (correlation coefficient 0.94; 5% increase in deaths per 100 000 increase in prescriptions). Heroin users described pregabalin as easy to obtain. They suggested that the combination of heroin and pregabalin reinforced the effects of heroin but were concerned it induced 'blackouts' and increased the risk of overdose. In mice, a low dose of S-pregabalin (20 mg/kg) that did not itself depress respiration reversed tolerance to morphine depression of respiration (resulting in 35% depression of respiration, P < 0.05), whereas a high dose of S-pregabalin (200 mg/kg) alone depressed respiration and this effect summated with that of morphine.. For heroin users, the combination of opioids with gabapentin or pregabalin potentially increases the risk of acute overdose death through either reversal of tolerance or an additive effect of the drugs to depress respiration.

Topics: Adult; Amines; Analgesics; Animals; Cyclohexanecarboxylic Acids; Disease Models, Animal; Drug Interactions; Drug Overdose; Drug Users; England; Female; Gabapentin; gamma-Aminobutyric Acid; Heroin Dependence; Humans; Male; Mice; Middle Aged; Pregabalin; Risk; Wales; Young Adult

Pregabalin is a substance which modulates monoamine release in "hyper-excited" neurons. It binds potently to the α2-δ subunit of calcium channels. Pilotstudies on alcohol- and benzodiazepine dependent patients reported a reduction of withdrawal symptoms through Pregabalin. To our knowledge, no studies have been conducted so far assessing this effect in opiate dependent patients. We report the case of a 43-year-old patient with Pregabalin intake during opiate withdrawal. Multiple inpatient and outpatient detoxifications from maintenance replacement therapy with Buprenorphine in order to reach complete abstinence did not show success because of extended withdrawal symptoms and repeated drug intake. Finally he disrupted his heroine intake with a simultaneously self administration of 300  mg Pregabaline per day and was able to control the withdrawal symptoms. In this time we did control the Pregabalin level in serum and urine in our outpatient clinic. In the course the patient reported that he could treat further relapse with opiate or opioids with Pregabalin successful. This case shows first details for Pregabalin to relief withdrawal symptoms in opiate withdrawal.

Topics: Adult; Anticonvulsants; Drug Administration Schedule; gamma-Aminobutyric Acid; Heroin Dependence; Humans; Male; Narcotics; Opiate Substitution Treatment; Opioid-Related Disorders; Pregabalin; Secondary Prevention; Substance Withdrawal Syndrome