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Opioid substitution therapy

Risk factors for mortality, hospitalisation and imprisonment in substance misuse patients

Opioid substitution therapy (OST) is currently the gold standard treatment for patients with illicit opioid addiction (most commonly to heroin). Its use is evidence based, with proven reductions in negative outcomes and increased positive outcomes for patients taking OST compared with those who do not. However, mortality rates and adverse outcomes, including hospitalisation and imprisonment, are still higher in illicit drug users and patients on OST compared with the general population.
Polydrug use, male gender, increased age and injection of drugs are associated with higher mortality. Time points associated with the greatest risk of mortality include the first 2 weeks of commencing or discontinuing OST; during hospitalisation; within the first 28 days of discharge from hospital; and within the first 2 weeks of discharge from prison.
Risk factors for hospitalisation include hepatitis C-positive status, HIV-positive status and co-morbid mental health disorders. The greatest risk factor for imprisonment and criminal recidivism is polydrug use. Continuity and consistency of OST are associated with lower risk of mortality, hospitalisation and re-incarceration.
This article summarises the risk factors of these adverse outcomes in order to raise awareness among pharmacists and other healthcare professionals working with OST patients, as it is their role to optimise patient safety and reduce adverse outcomes.
Keywords: addiction; hospitalisation; mortality; opioid; opioid substitution therapy; OST; prison.
Original submitted: 10 January 2018; Revised submitted: 28 March 2018; Accepted for publication: 01 June 2018; Published online: 6 July 2018

Drug user injecting heroin in foot

Source: Julien Behal / PA Archive / PA Images

Overdose and drug-related death contribute to the increased mortality rate in patients using illicit drugs and opioid substitution therapy (OST); however, other multi-faceted and complex risk factors include age, gender, timing, injecting practices, polydrug use, discharge from hospital and release from prison

Key points

  • Risk factors for mortality include polydrug use (particularly with benzodiazepines), male gender, increasing age, injecting practices, and certain time points.
  • On initiation of opioid substitution therapy (OST), mortality risk is highest within the first two weeks of treatment commencement and treatment cessation.
  • Mortality is highest during hospitalisation and in the first 28 days following discharge.
  • Following imprisonment, mortality risk is highest within the first one to two weeks after release.
  • Continuity of OST care is associated with lower rates of mortality and re-incarceration following release from prison (healthcare professionals should try and prevent “stopping and starting” OST therapy).


For patients with illicit opioid addiction (most commonly to heroin), opioid substitution therapy (OST) has been shown to be protective and to reduce harm across a wide spectrum of outcomes, including reductions in all-cause mortality, illicit drug use, criminal activity and the risk of HIV infection, and lead to improvements in physical and mental health. OST utilises prescribed drugs, such as methadone and buprenorphine, to replace the use of illicit drugs. The evidence base for OST is substantial, and it forms the basis for clinical substance misuse practice in the UK[1] (see previous learning article, Clinical management of drug misuse and dependence: an update), and is embedded in past and present public policy on the treatment of opiate-dependent patients[2].

However, mortality and adverse outcomes persist in this patient cohort, more so than for the general population[1],[3],[4].

The risk factors associated with illicit drug use (i.e. adverse life circumstances such as dysfunctional family environment and economic and social deprivation)[5] also contribute to these poor outcomes, creating a “dynamic state” of interrelated problems[4]. To maximise success, OST must occur within an optimal context in which risk factors associated with negative outcomes (e.g. mortality, hospitalisation and imprisonment) are identified.

Awareness of risk factors by healthcare professionals is crucial in optimising patient safety and reducing adverse outcomes. Therefore, it is imperative that those working with OST patients, including GPs, community pharmacists providing OST supervision, addiction keyworkers and mental health service professionals, are aware of the issues and time-points that pose greatest risk to OST patients.

This article aims to review the evidence in published literature, to outline the risk factors for mortality (all-cause and drug-related deaths [DRDs]), hospitalisation and imprisonment in patients taking illicit opiates and/or OST, in order to raise awareness of these among healthcare professionals working with OST patients.

Sources and selection criteria

A structured literature search was undertaken to identify published studies investigating the risk factors for mortality and institutionalisation (i.e. being placed or kept in a residential institution such as a hospital or a prison) associated with illicit drug use and OST. The literature search was based on the PICO search strategy (P: patient/population; I: intervention/indicator; C: control/context; and O: outcome). The PICO strategy is used to frame a research question and to answer it using evidence-based medicine[6],[7]. The first literature search in April 2016 included the search term “primary care” as the context in which the patient group of interest existed. As OST can also be initiated in prison, a second literature search, which did not include the search term “primary care”, was undertaken to identify any further studies that did not specify primary care as the context (see Table 1).

Both searches were executed in four databases on Ovid:

  1. Embase;
  2. Health Management Information Consortium (HMIC);
  3. Medline;
  4. Medline In-Process.

The results were limited to English language articles. The review was not systematic, as it did not restrict references to controlled studies, but did include observational studies, and did not undertake meta-analyses of the existing literature.

PICO StrategySearch 1Search 2
Table 1: Structured literature search to identify risk factors associated with mortality, hospitalisation and imprisonment during illicit drug use and opioid substitution therapy (OST)
Population & InterventionOpiate substitution treatmentOpiate substitution treatment
 Opiate substitution treatment*.mp.Opiate substitution treatment*.mp.
 Opiate substitution therap*.mp.Opiate substitution therap*.mp.
 Buprenorphine, naloxone drug combination/ or buprenorphine/Buprenorphine, naloxone drug combination/ or buprenorphine/ 
ContextCommunity health services/ or community pharmacy services/ 
 Primary health care/ 
OutcomeHospitalisation/ or “length of stay”/ or patient admission/ or patient discharge/ or patient handoff/ or patient readmission/ or patient transfer/Hospitalisation/ or “length of stay”/ or patient admission/ or patient discharge/ or patient handoff/ or patient readmission/ or patient transfer/
mp: map to title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier.


The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) defines a DRD as a death “happening shortly after consumption of one or more illicit psychoactive drugs, and directly related to this consumption”[8]. The EMCDDA reports that the UK has the highest incidence of DRDs in Europe with 55.9 deaths per million in 2013, three times the European average of 19.2 deaths per million.

The ‘baseline’ definition of a DRD has been agreed for the UK Drugs Strategy as the following[9]

a. A death where the underlying cause is attributable to “mental and behavioural disorders owing to psychoactive substances”, such as

  • Opioids;
  • Cannabinoids;
  • Sedatives or hypnotics;
  • Cocaine;
  • Other stimulants, including caffeine;
  • Hallucinogens;
  • Multiple drug use;
  • Use of other psychoactive substances.

b. Or where a drug listed under the Misuse of Drugs Act (1971) known to be present in the body at the time of death and death occurred by:

  • Accidental poisoning;
  • Intentional self-poisoning by drugs;
  • Medicaments and biological substances;
  • Assault by drugs, medicaments and biological substances;
  • Event of undetermined intent;
  • Poisoning.


Risk factors for mortality

Although overdose and DRD contribute to the increased mortality rate in patients using illicit drugs and OST, there are other multi-faceted and complex risk factors, which include age, gender, timing, injecting practices, polydrug use, discharge from hospital and release from prison.

Polydrug use

Data from the National Treatment Outcome Research Study (NTORS) in England suggest that the strongest predictor of overdose deaths in OST patients is polydrug use, particularly with benzodiazepines and amphetamines[10]. There has been further implication of benzodiazepines, if co-prescribed, in increased risk of DRD[11].

Gender and age

NTORS data for England indicate a gender difference for overall mortality among OST patients with a male:female ratio of 7:1[10]. In addition, it was illustrated that the lowest mortality rate was for 15–24-year-olds and the highest was for older patients of 45–54 years of age[7].

Recorded DRD rates in Scotland in 2015 showed that 73% of deaths were among people aged over 35 years[12]. Bird et al. established that male gender and older age (>34 years) were risk factors for DRD among injecting drug users (IDUs)[13]. Further work also indicated that, while DRD in younger IDUs (<34 years) were still prevalent in Scotland, IDUs of >35 years were at the greatest risk because of the epidemiology of injecting drug use[14].

However, more recent work suggests that the gender difference is only evident in OST patients until the age of 34 years, after which males and females are at equivalent risk compared with each other, although both genders continue to increase their overall risk as they age[15].

There is an increasingly ageing patient demographic in OST[16]. Older people with drug problems (OPDP) experience greater morbidity and mortality than those of comparable age in the general population, and are at greater risk of DRD than younger people who use drugs[17].

Drug users who inject

Patients who inject suffer a significantly reduced life expectancy. Copeland et al. used life-course data to examine the causes of death within a subset of Scottish patients in the Edinburgh Addiction Cohort study[18]. Several causes of premature death were identified that included accidental overdose, hepatitis C, HIV/AIDS, suicide, cardiovascular disease (CVD), respiratory disease, alcohol-related morbidity and renal failure. Subsequent studies corroborate that overdose and infectious diseases are also major causes of mortality among OST patients[15],[19], and that hepatitis C and alcohol abuse increase the risk of mortality from all causes[19].

The findings that overdose, hepatitis C and HIV/AIDS are major causes of death in IDUs and OST patients correspond with earlier work on a larger sample of patients included in the Edinburgh Addiction Cohort study[20], which identified overdose (in IDUs aged ≤34 years) and infectious diseases from non-sterile injecting equipment (in IDUs aged≥25 years) as the most preventable causes of death, underpinning the drive for utilisation of clean needle exchange and the continued need to support this service[20].


Evidence shows that the highest risk period for mortality is within the first two weeks of OST treatment and initiation, and within the first two weeks of OST discontinuation[21],[22]. The period of highest relative risk is the first week following treatment commencement[23].

These findings have been recently re-verified. The risk of both all-cause mortality and DRDs have been shown to be higher during the first four weeks of treatment, with diminishing risk as treatment continues, but then an elevated risk for the first four weeks following treatment cessation[24].


Data linkage studies using Scottish data have shown that DRD risk and non-DRD suicide risk are highest during hospitalisation compared with any time after discharge[25]. This risk appears to be higher for IDUs compared with non-injecting drug users[26]. With DRD risk highest during hospitalisation, this may indicate that some deaths will be owing to overdose and will, therefore, occur on admission to hospital[25]. However, within the post-discharge era, discrete time points pose an individual and varying degree of risk, with the first 28 days post-discharge being the period of greatest risk. The post-discharge risk declines from days 29 to 90 following discharge and then continues to decline until after one year post-discharge[25],[26]. History of psychiatric hospital admission is also associated with elevated DRD risk[11],[22]. It is not clear whether the elevation in risk in the period post-discharge is attributable to loss of tolerance[26], but it is possible that the underlying cause of risk post-discharge differs from that causing maximal risk during hospitalisation.

Liberation from prison

It has been shown both in the USA[27] and in Scotland[28] that offenders released from prison have a higher mortality rate than the general population, primarily attributable to underlying substance abuse. Female offenders in particular are at increased risk of suicide and DRD. There is some evidence of a causal relationship between substance abuse and mortality in the period following release from prison; substance abuse (of alcohol and/or drugs) is associated with increased mortality post-imprisonment, independent of sociodemographic, criminological and familial factors, and of other psychiatric disorders[29].

For offenders of both genders, the greatest risk is posed within the first 1–2 weeks after release[27],[28],[30],[31]. For IDUs newly released from prison, the risk of DRD is 3–8 times higher during the first 2 weeks post-release compared with weeks 3–12 post-release[30],[32],[33],[34].

Introducing OST in prisons does not appear to have had a protective effect on the high risk associated with the initial two-week post-liberation period. While the introduction of an OST policy in prisons has been positively associated with an overall decrease in DRD over the 12-week period post-discharge, it has not had an impact on the proportion of DRDs that occur within the first 2 weeks post-discharge[35]. However, continuing OST initiated during incarceration, while in the initial four-week post-release period, is associated at an individual level with lower mortality rates and reduction of the risk of death by 75–83%[31].

Moreover, the duration of prescribed OST post-release is related to mortality; OST prescribed for the four weeks post-release period is associated with the lowest mortality, with partial and no OST associated with incremental increases in mortality[31]. This protective effect of OST post-prison extends to both overdose mortality and all-cause mortality[36]. Such findings indicate that ‘continuity of care’ in the post-release period is essential in mitigating the elevated risk of mortality[37].

Prisoners receiving OST have a reduced hazard and rate of all-cause deaths and unnatural deaths while still in prison, particularly during the first four weeks of imprisonment, which is a time of elevated risk because of suicide and non-intentional overdose[38].

Increased time in prison has been associated with a lower in-prison[28] and post-liberation[27] mortality rate. However, work by Kimber et al. suggests that the probability of cessation of injecting decreases with imprisonment, with more than one incarceration increasing the risk of mortality[39]. In addition, multiple short episodes of incarceration (of <six months’ duration) are associated with increased mortality[28].

Risk factors for hospitalisation

Perhaps unsurprisingly, heroin-using adults access emergency medical care more often than the general population[40]. Similarly, people receiving OST utilise hospital emergency facilities and are admitted to hospital more frequently than the general population[41]. In addition, the rate of general acute and/or psychiatric admissions with a clinical diagnosis of drug misuse in Scottish hospitals is increasing over time[42].

In a cohort of drug treatment patients in Scotland, the hospital episode rate (HER) was double that of the general population[43]. Among drug treatment patients, the HER increased with age, female gender and hepatitis C-positive status[43]. The most frequent diagnoses accounting for the elevated frequency of hospital episodes were mental disorders (40 times higher than for the general population), diseases of the skin/subcutaneous tissue, external causes (e.g. injuries), infectious diseases and circulatory system diseases[43].

Internationally, HIV-positive status has been shown to be a determinant of contact with hospital care in treatment clients[44], as it is for illicit drug users[40]. Lack of social support and chronic pain are associated with increased hospitalisation in OST patients with a history of alcohol abuse[45].

Various facets of OST and its provision may influence hospitalisation rates. Although the prescribed quantity of methadone is not associated with hospitalisation, receipt of unobserved dosing (i.e. ‘take home’ doses) is associated with decreased hospital admission[46]. The provision of primary medical care to OST patients reduces emergency care utilisation and overnight hospital admissions[44]. Treatment with buprenorphine and increasing time on buprenorphine maintenance treatment are associated with decreased access and utilisation of emergency care but have no significant effect on hospitalisation incidence or duration[47].

Risk factors for imprisonment

The risk factors associated with problem drug use, namely adverse life circumstances, such as a dysfunctional family environment, and economic and social deprivation[5], are also interconnected with the relationship between problem drug use and criminal behaviour, making inferences of causality difficult[48]. However, previous reports of an association between drug misuse and crime have been confirmed by a meta-analysis of 30 international studies[49]. In addition, the overall strength of the relationship has been quantified; the risk of drug users offending is around three times greater than the risk of non-drug users offending[49]. The drug–crime association in drug users is strongest for acquisitive crime[50].

Drug–crime interdependence is most prevalent with increasing age, female gender and the use of crack, cocaine and heroin[49]. The gender/opiate/cocaine relationship has been further delineated; there is a higher incidence of involvement in crime for users of both opiates and cocaine than for users of one or other, and this phenomenon is stronger in females than males[50]. among repeat offenders with substance abuse problems, criminal recidivism is associated with amphetamine, heroin and polydrug use, and with injecting of drugs[51]. In addition, drug users who did not seek treatment reported higher levels of substance misuse, more money spent on drugs, more time incarcerated and earned more illegal income compared with those who did seek treatment[52]. Similar observations also apply to those seeking treatment; comparison of acquisitive offenders and non-offenders within the Drug Treatment Outcomes Research Study (DTORS) indicated that offenders had a higher incidence of using heroin, crack and cocaine, with polydrug use most strongly associated with acquisitive crime (e.g. burglary, theft and robbery)[53].

Initiation of OST during incarceration is not in itself protective against re-incarceration, rather, it is continuity of OST post-release that is associated with a 20% lower risk of re-incarceration[54]. Methadone maintenance treatment for eight months or more is associated with a 70% reduction in re-incarceration rates[55]. This protective effect of continuity of treatment by the individual on their re-incarceration rate is similar to its protective effect on the individual’s risk of post-liberation mortality, as discussed above.

The most consistent overall predictors of criminal behaviour in people receiving OST appear to be heroin use[53],[56],[57], cocaine use[54],[57], injecting of drugs[53],[56],[57] and criminal activity prior to treatment initiation[56],[58]. Continuity of treatment, however, appears to be the most significant predictor of reduced criminal activity[56],[58],[59],[60].


Healthcare professionals working with OST patients are able to play a key role in minimising the risk of mortality and adverse outcomes for this group of patients. The beneficial input of healthcare providers is, however, not limited to the provision of OST. As this article indicates, there are underlying factors within the OST patient group that influence the rate of mortality, hospitalisation and imprisonment, which include older age, male gender, polydrug use, injecting practices and HIV status. These factors will be apparent to healthcare professionals who, if they are aware of their associated risk, will be able to proactively offer support to minimise the risk.

There are key time points at which the risk and rate of mortality and negative outcomes are greater. For mortality, times of maximal risk are within the first 2 weeks of OST initiation and discontinuation[21],[22],[23], during hospitalisation[25], within the first 28 days following hospital discharge[25],[26] and within the first 2 weeks following discharge from prison[27],[28],[30],[31]. These time points are key intervals during which OST providers, within community or institutional pharmacies, will have contact with such patients, thereby providing times when targeted, individualised health interventions will be of optimal importance.

With regard to adverse outcomes, the use of crack, cocaine and heroin are associated with crime[49]. Provision of primary medical care reduces hospitalisation rates[44] and continuity of OST reduces both mortality[31],[36],[37] and re-incarceration rates[53] following discharge from prison. Therefore, provision of consistent OST and care within the primary care setting represents a crucial opportunity for healthcare workers to minimise risk.

A common area where continuity of care can be broken is hospital admission and discharge for OST patients, especially if these patients are admitted or discharged within the out-of-hours (OOH) period. Protocols for these time points will be varied and changeable between different trusts, hospitals and OST community prescribing teams (CPTs). Community pharmacists should contact their local addiction prescribing teams for the most reliable and up-to-date information pertinent to their local hospital and OOH services for patients receiving OST, as the description of such protocols lies beyond the scope of this review.

Some hospitals have substance misuse liaison teams who can help bridge OST care between primary and secondary teams. For hospitals without these teams, hospital pharmacists can communicate with OST CPTs on admission and prior to discharge, in order to maintain the appropriate dose and continuity of treatment. This can allow community OST teams to anticipate review consultations for OST where possible.

Communication at the primary/secondary care interface on hospital admission can be challenging if the patient is admitted at weekends or within the OOH period. A further complicating factor is that OST-prescribing information is not always available on emergency care summaries (available via the Scottish hospital-based record system [Clinical Portal]), as is it recorded by specialist addictions teams who cannot access patient medical records (e.g. GP or hospital records). Secondary care teams in the OOH period could contact the patient’s dispensing community pharmacy team for dose confirmation if the CPTs are not available. While methadone has a long half-life, patients may not come to harm if one daily dose is missed, until the required checks are made. However, many patients do not feel able to tolerate delayed/missed doses and, in turn, OST patients can take irregular discharge from hospital when suffering withdrawal effects, in search of street-opiates, leading to increased risk of overdose or relapse, as well as potentially exacerbating underlying medical conditions.

OST provision in the OOH period is still poorly described and is in need of further research. Owing to the risk of overdose, many non-specialist clinicians are reluctant to prescribe in lieu of missing information, and this leads to missed doses, discharges, relapses and heightened overall risk for the OST patient.

A further risk factor on discharge from hospital at weekends or within the OOH period is that community pharmacies do not have access to medical records and are often staffed by locums and non-regular staff, which leads to possible communication breakdowns or lack of information at handover between pharmacists. If three or more days of OST have been missed, tolerance is lowered and OST dosages need to be reduced. If the pharmacist is in any doubt of OST dose, the CPT/hospital discharge team should be contacted. On discharge from hospital within normal hours, community pharmacists should check post-hospital discharge doses, where possible.

Overall, there is no ‘one-size-fits-all’ model of care to improve the continuity of care as it is variable between locations, hospitals, trusts and different OST CPTs. A common sense approach with good communication would appear prudent, given the level of risk of the patients involved. Community pharmacists dispensing OST should prioritise fostering good working relationships with their local OST CPTs and should contact their local CPT for more information on care pathways and contact numbers relevant to their local hospital and CPT team.

All healthcare professionals working with OST patients should be aware of and, if possible, trained in naloxone administration, as the drug can save the life of opiate misusers who overdose. Naloxone is a short-acting opiate antagonist that temporarily reverses the effects of an opioid overdose, allowing time for the patient to be hospitalised for treatment. It is only a temporary treatment and an emergency ambulance must also be called when it is given (via an intramuscular injection in the outer thigh). Naloxone is now available under patient group directions (PGD) in some areas of England to supply and administer with the intent of saving a life, as well as without prescription. Environments in which it is most likely to be needed include prisons, drug treatment centres and hostels.

Naloxone has been widely available in Scotland for a number of years without PGD or prescription, and the rest of the UK may adopt a similar position in the future. While anyone can legally administer naloxone without the patient’s consent with the intent to save a life, there are ethical issues surrounding this situation, and guidance should be sought, in advance, from local addictions teams. Ensuring adequate stock and competency in the administration of naloxone are strongly recommended for those working with this patient group. Healthcare professionals should contact their local drug treatment teams (details of this team should be on the bottom of OST prescriptions) for more information on where to source training and supplies, relative to their location and healthcare trust. More legal information on naloxone use and storage is available[61]. However, the rules and guidance are developing rapidly and local drug treatment services remain the best source for information on current practice.


For the OST patient group, there are various interrelated risk factors associated with increased risk of mortality, hospitalisation and imprisonment. Healthcare professionals should be aware of the times and circumstances when patient safety will be of greatest concern, and judicious, evidence-based intervention is needed.

In particular, pharmacists encountering patients receiving OST in their professional practice should be aware of local contacts and protocols to maximise treatment retention, and minimise risk and dropout from treatment.

Financial and conflicts of interests disclosure

The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this manuscript. No writing assistance was used in the production of this manuscript.

Citation: Clinical Pharmacist DOI: 10.1211/CP.2018.20205007

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