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. 2017 Sep;112(9):1580-1589.
doi: 10.1111/add.13843. Epub 2017 May 15.

Risk to Heroin Users of Polydrug Use of Pregabalin or Gabapentin

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Free PMC article

Risk to Heroin Users of Polydrug Use of Pregabalin or Gabapentin

Abigail Lyndon et al. Addiction. .
Free PMC article

Abstract

Aim: To examine the risk to heroin users of also using gabapentin or pregabalin (gabapentoids).

Design: 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.

Setting: England and Wales.

Participants: Interviews were conducted with 30 participants (19 males, 11 female).

Measurements: (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.

Results: 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.

Conclusions: 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.

Keywords: Gabapentin; heroin; opioids; overdose; pregabalin; respiration.

Conflict of interest statement

Declaration of competing interests:

The authors declare no competing interests

Figures

Figure 1
Figure 1. Number of pregabalin and gabapentin prescriptions and number of deaths per annum in which pregabalin and gabapentin were mentioned on the death certificate from 2004 – 2015
A. The number of community care prescriptions per annum for pregabalin and gabapentin in the England and Wales are shown in red. Data were obtained from the Health and Social Care Information Centre (HSCIC, UK). The number of registered deaths per annum in England and Wales in which pregabalin or gabapentin were mentioned on the death certificate is shown in green. The number of deaths in which pregabalin and gabapentin as well as an opioid drug were mentioned are shown in purple. Data obtained from the Office for National Statistics (ONS, UK). B. Scatter plot of gabapentoid prescriptions (per 100,000) in England and Wales (2004 to 2015) versus overdose deaths (on a logarithmic scale) in which gabapentoids were mentioned in the coroner’s report. Data are replotted from that used in A. The blue line shows line of best fit (correlation coefficient 0.965): 5% increase in overdose deaths per 100,000 increase in prescriptions.
Figure 2
Figure 2. Depression of respiration by pregabalin and morphine in the mouse
A. Inhibition of respiration by S-pregabalin (200 mg/kg ip). Data are shown as minute volume before and following drug injection. N = 6. In some instances error bars are smaller than the symbol. B. Comparison of inhibition of respiration by S-pregabalin (200 mg/kg ip) and morphine (10mg/kg ip). For each drug treatment then for each animal data are normalised to minute volume before drug injection. Data for S-pregabalin were derived from that illustrated in part A. N = 6 for both drug treatments. C. Raw respiration traces from an untreated mouse and one injected with S/R-pregabalin (400 mg/kg ip) recorded at the height of drug action. The horizontal blue line indicates the point of pressure inflection. In the respiration traces expiration is upwards.
Figure 3
Figure 3. Interactions between S/R-pregabalin and morphine on mouse respiration
A. Pretreatment with naloxone (1 mg/kg ip; nal) for 10 min abolished the depression of respiration induced by morphine (10 mg/kg ip; mor) but not that induced by S/R-pregabalin (400 mg/kg ip, pregab). The area under the curve (AUC) for the percentage change in minute volume induced by each drug treatment has been calculated [see ref 18] and then the mean value determined. N = 6 in each case; * indicates P<0.05, unpaired, two tailed Student’s t test comparing morphine and morphine + naloxone. There was no statistical difference between pregabalin and pregabalin + naloxone. B. Depression of respiration induced by morphine (10 mg/kg ip, filled squares) or saline (filled circles) in mice that had been pretreated with S/R-pregabalin (400 mg/kg ip). C. Comparison of the depression of respiration induced by morphine in naïve animals and in animals pretreated with S/R pregabalin (400 mg/kg). N = 6 in each case, there was no statistical difference (unpaired, two tailed Student’s t test) between the treatments. D. Depression of respiration induced by S/R-pregabalin (400 mg/kg ip) in naïve mice and in mice that had been pretreated with morphine for 6 days. N = 7 in each case. Statistical analysis (unpaired, two tailed Student’s t test) of the AUC for both treatments demonstrated that there was no statistical difference between the degree of respiratory depression induced by pregabalin in the naïve and morphine-treated mice.
Figure 4
Figure 4. Reversal of morphine tolerance by S-pregabalin
A. The low dose of S-pregabalin (20 mg/kg ip) in naïve mice and mice that had been pretreated with morphine for 6 days produced little depression of respiration. N = 6. B. In mice that had been pretreated with morphine for 6 days acute injection of morphine (10 mg/kg ip) did not depress respiration i.e. the mice were tolerant. Whereas, with a simultaneous injection of pregabalin (20 mg/kg ip) injection of morphine (10 mg/kg ip) did depress respiration in mice that had been pretreated with morphine for 6 days. C. AUC analysis of the data in A & B [see ref 18] indicated that in morphine pretreated mice pregabalin + morphine induced significantly greater depression of respiration than morphine alone (P<0.05). N = 6 in each case.

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