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