MRC Biostatistics Unit
Sheila M. Bird, MRC Biostatistics Unit, CAMBRIDGE CB2 0SR
“Success has a thousand fathers, failure is an orphan”.
On December 8th 2014, we marked success. In 15 prisons in England, we ceased to randomize eligible prisoners (those with a history of heroin injection) in the N-ALIVE pilot Trial and, as of 9th December, offer naloxone-on-release (NOR) to already-randomized participants who have not yet been released and who were assigned to our control group.
Why? For two reasons which, on behalf of our Trial Steering and Data Monitoring Committee, the N-ALIVE team set out for the Research Ethics Committee and then explained also to our highly committed prison-based N-ALIVE workers and local Principal Investigators, to the Mental Health Research Network which adopted the N-ALIVE pilot Trial, and to our prisoners and governors (available here)
First, internal evidence from the N-ALIVE pilot Trial itself together with the 3-year results from Scotland’s National Naloxone Programme demonstrate that, notwithstanding ex-prisoners’ very high risk of overdose death soon after release, their altruism and concern for others is such that, when naloxone is administered, the recipient is twice as likely (36: 17) to be some-one other than the ex-prisoner. This makes the individually-randomized N-ALIVE main Trial impossibly large, and the effect-size to be observed smaller due to potential contamination between randomized groups.
Secondly, the 5-years before versus 3-years after evaluation of Scotland’s National Naloxone Programme has demonstrated a very highly significant 36%-effectiveness for its National Naloxone Programme (which combines THN and NOR) at reducing opioid-related deaths which occurred in the 4-weeks after prison-release: down from 193/1960 (9.8%) in 2006-2010 to 76/1212 (6.3%) in 2011-2013. The lower 95% confidence limit on effectiveness exceeds 20%, and cost-effectiveness is assured: only around 300 naloxone-kits were issued per opiate-related fatality prevented. For this reason, the N-ALIVE team has recommended that already-randomized participants who are released on or after 9th December 2014 be offered naloxone-on-release. The N-ALIVE pilot Trial will follow-up all participants per-protocol.
Many – including three of my former PhD students at MRC Biostatistics Unit (Seaman, Hutchinson & Merrall) – have contributed biostatistically over a 20-year stretch to this week’s success. We first quantified the very high risk of overdose death in the first fortnight after prison-release (Seaman et al, BMJ 1998), then validated it (Bird & Hutchinson, Addiction 2003), and meta-analysed it on an international scale (Merrall et al, Addiction 2010).
For male HIV-infected injectors released from Edinburgh Prison during 1983-94, we initially quantified the first fortnight risk as 8 times higher than at comparable other times at liberty. In 2003, Bird and Hutchinson – having shown that 34 out of 57 male DRDs in the 12-weeks post-release in 1996-1999 had occurred in the first fortnight – proposed a randomized controlled trial of naloxone-on-release to reduce prisoners’ opioid-related deaths soon after release.
The proposed trial was impossible before 2005 when naloxone was added to UK’s Exempt List of Prescription Only Medicines that can be administered by anyone in an emergency to save life. But its feasibility was enhanced because Strang and colleagues had documented that some-one else is present at most opiate overdoses, present others are willing to help, but had lacked suitable training and means. The pilot phase of the proposed trial, known as the N-ALIVE pilot Trial (Strang et al, Journal of Urban Health, 2013), was funded by the Medical Research Council in 2008.
On 1st January 2011, the N-ALIVE Trial led by its three musketeers of Parmar (Director of MRC Trials Unit @ UCL), Bird (MRC Biostatistics Unit, Cambridge) and Strang (Director of National Addiction Centre, University of London) were overtaken by Scotland’s ministerial decision to implement take-home naloxone (THN) and naloxone-on-release (NOR) as a funded public health policy.
Crucially as described elsewhere (Bird et al, Drugs: Education, Prevention and Policy 2014, online on 18 November 2014), Scotland was also the first nation to implement a science-led before/after evaluation of its National Naloxone Programme (NNP). Wales introduced its NNP later in 2011.
Therefore, only in England and between May 2012 & 8 December 2014, has the N-ALIVE pilot Trial randomized eligible prisoners (those with a history of heroin injection) to receive on release an N-ALIVE pack which either contains naloxone (to be administered intramuscularly in the event that the ex-prisoner overdoses) or does not. There was no placebo – by opening their pack, prisoners know immediately upon release whether they have been assigned NOR or to the control group.
What now? Scotland’s NNP evaluation will continue for 5-years. Meanwhile, Jane Ellison, England’s parliamentary under-secretary of state for public health and England’s Chief Medical Officer, Dame Sally Davies, have asked Public Health England to develop briefing to support local areas in their commissioning of naloxone and in their preparation for amendments to medicines regulations on naloxone which come into force in October 2015 and allow the wider distribution and administration of naloxone in England.
This is of course excellent and, we suggest, should be complemented by monitoring: to ensure that England indeed issues a minimum of 9,000 naloxone-kits (THN and NOR) annually and ideally 20,000 (see Bird et al, Drugs: Education, Prevention and Policy, 2014 online), these targets being respectively nine and 20 times England’s near-1,000 opioid-DRDs per annum.
Unlike in Scotland, monitoring of England’s NNP and its opioid-DRDs with a 4-week antecedent of prison-release will be tardy due to the late registration of inquest-deaths in England. Legislation is needed to sort this out, which Royal Statistical Society, Sense about Science and associated charities are calling for. In England, not even fact-of-death is registered until the inquest-verdict has been reached on cause-of-death. The second reason was revealed by Dr Julian Huppert MP who recently asked parliamentary questions on the number of registered opioid-DRDs in England in 2011 and in 2012 who had been released from prison in the 4-weeks prior to death (Scotland’s primary outcome) and was told that the data were not readily available.
We must hope and ensure that, by October 2015, a different answer is forthcoming to Dr Huppert’s spot-on, on-the-spot question.