Opiate Abuse: A Review of the Combined Use of Opioids and

Benzodiazepines

Melwani Amran and Julaeha

Magister Pharmacy, Faculty of Pharmacy, 17 Agustus 1945 University, Jakarta, Indonesia

Keyword: Opioids, Heroin, Benzodiazepines, Opiat Abuse.

Abstract: This article reviews studies investigating the pharmacological interactions and epidemiology of combined

opioid and benzodiazepine (BZD) use. A search of English language publications from 2015 to 2023 was

conducted using PubMed and PsycINFO®. Our search identified approximately 10 articles suitable for

inclusion in this paper with the search characteristic of combined opiate and BZD use. Despite numerous

reports indicating that opioid and BZD abuse is ubiquitous worldwide, the reasons for abuse of these drugs

are not entirely clear. While opioid users may use BZDs therapeutically to treat anxiety, mania or insomnia,

the data reviewed in this paper suggest that BZD use is primarily recreational. For example, co-users reported

seeking BZD prescriptions to increase opioid intoxication or 'sobriety', and using doses that exceeded the

therapeutic range. As few clinical studies have investigated the pharmacological interactions and abuse

potential of their combined use, this hypothesis has not been extensively evaluated in a clinical setting.

Therefore, our analysis encourages further systematic investigation of BZD abuse among opioid users. Co-

abuse of BZDs and opioids is substantial and has negative consequences for general health, overdose mortality

and treatment outcomes. Clinicians should address this important and under-recognised issue with more

cautious prescribing practices and increased vigilance for patterns of misuse.

INTRODUCTION

It is estimated that around 61 million people

worldwide will use opioids in 2020. Nonmedical use

of opioids is reported in all regions and almost all

countries. Prevalence rates are highest in North

America, South-West Asia, Oceania and South Asia

(UNODC, 2022). The United States and many other

Western countries are experiencing an increase in the

use and abuse not only of opioids but also of other

drugs that affect the activity of the central nervous

system. In particular, the use of benzodiazepines, the

most commonly prescribed tranquillisers, has risen

sharply over the past decade, with an estimated 3% of

the general population receiving long-term

prescriptions for these drugs. Benzodiazepines are

approved for a wide range of conditions, particularly

anxiety and sleep disorders. In addition,

benzodiazepines are generally considered to be of

good overall safety, but like opioids, benzodiazepines

have the potential for dependence and toxicity when

used for long periods and at high doses.

Unbeknownst to many patients and prescribers,

benzodiazepines are far more dangerous when

prescribed in combination with opioids than when

taken separately. Benzodiazepines and opioids

suppress breathing, increasing the risk of potentially

fatal apnoea. Accumulating data show that drugs such

as benzodiazepines contribute significantly to opioid-

related deaths. The US Centers for Disease Control

and Prevention (CDC) has recognised this threat and

is urging doctors to avoid prescribing opioids and

benzodiazepines together whenever possible. In

addition, the US Food and Drug Administration

(FDA) has placed a black box label on the

combination drug, highlighting the dangers of

concurrent prescribing. Nevertheless, concomitant

prescribing is still a common practice among doctors.

However, it is known that the risk of harm (or benefit)

from using strong opioids or benzodiazepines

depends on the context. For example, a combination

of drugs may be prescribed to treat anxiety and

chronic pain. This review summarises the currently

available evidence on the risk of serious harm to

patients when opioids and benzodiazepines are used

together and categorises the results according to

different clinical and outpatient conditions.

Benzodiazepines and opioids are among the most

194

Amran, M. and Julaeha, .

Opiate Abuse: A Review of the Combined Use of Opioids and Benzodiazepines.

DOI: 10.5220/0012641900003821

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 4th International Seminar and Call for Paper (ISCP UTA ’45 JAKARTA 2023), pages 194-204

ISBN: 978-989-758-691-0; ISSN: 2828-853X

commonly abused classes of psychoactive drugs in

the world (Grytten, 1998; Joranson et al., 2000;

Substance Abuse and Mental Health Services

Administration, 2008). Not surprisingly, the

concurrent use of these two classes of drugs has

attracted the attention of researchers and clinicians

since the 1970s (Kleber and Gold, 1978). The aim of

this review is to gain a better understanding of the

motivations for and consequences of their

concomitant use. Using PubMed and PsycINFO, we

searched for English-language articles on this topic

published between 1970 and 2012.

Different combinations of the following search

terms were used: opioid, benzodiazepine, heroin,

methadone, polydrug abuse, concomitant use, co-

administration, prescription opioid, midazolam,

valium, diazepam, alprazolam, flunitrazepam,

pharmacological interactions and epidemiology.

Using this method, we identified more than 5,000

publications. After removal of duplicates, titles and

abstracts were checked for relevance by the authors.

Data from approximately 10 articles were included in

this manuscript. This review and synthesis of this

literature focuses on clinical studies investigating the

pharmacological interactions between opioids and

BZDs and the epidemiology of their co-abuse.

Clinical research is the focus of this paper. At times,

however, preclinical data are used to complement

these findings and to support the authors' conjectures

about the motivations and risks underlying the co-use

of opioids and BZDs.

This review begins with a brief overview of the abuse

of each drug alone, followed by a review of the

clinical literature investigating the pharmacological

interactions between opioids and BZDs. Finally, we

review reports on the prevalence and consequences of

BZD and opioid co-abuse. It is hoped that this review

will lead to a better understanding of: how these drugs

interact pharmacologically; which populations abuse

these two drugs and why; the prevalence of their co-

abuse; and the clinical implications of this behaviour.

METHODS

This research was conducted based on a literature

review approach, which was obtained from 20

international and national papers that included

discussions on data visualisation and digital field data

retrieval, which were then made into review papers

through the 20 journals, in order to provide additional

knowledge that hopefully can add new insights, made

in such a way as to produce new scientific work in the

form of narrative reviews. Our search identified

approximately 20 articles suitable for inclusion in this

paper, with the search characteristic of combined

opiate and BZD use. Despite numerous reports

indicating that opioid and BZD abuse is ubiquitous

worldwide, the reasons for abuse of these drugs are

not entirely clear. While opioid users may use BZDs

therapeutically to treat anxiety, mania or insomnia,

the data reviewed in this paper suggest that BZD use

is primarily recreational.

RESULTS AND DISCUSSION

20 Literature on the misuse or deliberate abuse of

opioids and tranquillisers, mostly with

benzodiazepines. In addition to opiate

contraindications with benzodiazepines, there are

also opiate contraindications with gabapentin,

cocaine and alcohol. Data were obtained from

retrospective cohort analyses and post-mortem

analyses of deceased patients. All data showed death

or serious adverse effects with the use of

benzodiazepines and opiates. In general, most data

showed that the use of opiates with benzodiazepines

or other centrally acting drugs increased over the

years and that the combination of these drugs

increased the risk of death.

Abrahamson's study found that concomitant use

of opioids and benzodiazepines may increase non-

overdose mortality. In addition, the concurrent use of

opioids and pregabalin also increases the risk of

death. Meanwhile, Visconti's research shows that

using opiates with alcohol may cause very few deaths.

Patients on opioid replacement therapy with

buprenorphine or methadone. The data from this

study showed that benzodiazepines were involved in

most deaths. Interestingly, patients on methadone

replacement therapy may have a higher risk of death

and adverse effects of severe respiratory illness when

using a benzodiazepine concomitantly than patients

on buprenorphine replacement therapy. Although the

use of benzodiazepine with opioids (methadone or

buprenorphine) may cause a risk of death or acute

respiratory side effects, benzodiazepine is

particularly needed in PTRM patients.

benzodiazepine to treat anxiety in PTRM patients.

Use is controlled with an individual dose.

4 A BRIEF OVERVIEW OF

OPIOID ABUSE

The opioid class of drugs includes natural opiates

Opiate Abuse: A Review of the Combined Use of Opioids and Benzodiazepines

195

(e.g., morphine, codeine, salvia divinorum), semi-

synthetic opioids (e.g., heroin, oxycodone,

hydromorphone, hydrocodone, salvanorin A), and

synthetic opioids (e.g., methadone, buprenorphine,

and fentanyl; National Institutes on Drug Abuse/U.S.

Dept. of Health and Human Services, 2009). Opioids

have multiple effects: they alter body temperature,

cause sedation, depress respiration, induce eating,

decrease gastrointestinal transit, affect urine output,

and produce either euphoria or dysphoria

(Broekkamp et al., 1984; Teasdale et al., 1981; Wise,

1989). These effects are primarily produced by

actions at the three opioid receptor subtypes: μ, κ and

δ. Of the subtypes, the μ opioid receptor is the best

known and most studied. Activation of the G protein-

coupled μ receptor leads to acute changes in neuronal

excitability. It is the agonist action of opioids on μ

receptors that is thought to underlie their ability to

relieve pain, suppress cough and relieve diarrhoea.

Important indicators of abuse potential are the extent

to which a drug produces reinforcing effects and

positive subjective effects. These are typically

assessed in humans using subjective questionnaires

and drug self-administration paradigms (Comer et al.,

2008a; Haney and Spealman, 2008). Preclinically,

self-administration and conditioned place preference

(CPP) paradigms are commonly used to study the

reinforcing and rewarding effects of drugs (Epstein et

al., 2006; Haney and Spealman, 2008; Willner, 1997).

The abuse potential of μ-opioid receptor agonists has

been extensively demonstrated in rodents, non-

human primates and humans (for reviews see Kieffer

and Gavériaux-Ruff, 2002; Preston and Jasinki, 1991

and Trigo et al., 2010). This research indicates that

heroin has considerable potential for abuse, and

epidemiologically its abuse is a significant public

health problem (Comer et al., 2008b; European

Monitoring Centre for Drug and Alcohol

Dependence, 2010; Jasinksi and Preston, 1986).

Worldwide, an estimated 9.2 million people are

regular heroin users, with an estimated 1.2 million

active heroin users in the USA (0.6 % of the

population aged 15-64; Bammer, 1999; Epstein,

1997; United Nations Drug Control Programme

(UNDCP), 2001; United Nations Office for Drug

Control, Crime Prevention (UNODC), 2002; 2010).

In 2009, about 180 000 persons aged 12 years or older

used heroin for the first time. In the same year, 507

000 people sought treatment for heroin use, and

nearly 20 % (> 200 000) of all emergency department

visits for illicit drugs included reports of adverse

reactions to heroin or other heroin-related

consequences (Substance Abuse and Mental Health

Services Administration (SAMSHA), 2010).

Like heroin, μ-receptor-selective prescription

opioids, including morphine, hydrocodone,

hydromorphone, fentanyl, buprenorphine and

oxycodone, have demonstrated significant abuse

liability in humans (Comer et al., 2008b; Middleton

et al., 2011; Walsh et al., 2008; Zacny and Lichtor,

2008). Abuse of buprenorphine is particularly

prevalent in Europe, where buprenorphine treatment

was widely available several years before its use in

the US (Auriacombe et al., 2001; Carrieri et al.,

2006). Recreational use of prescription opioid

analgesics has risen sharply in the United States over

the past two decades. Data from epidemiological

surveys, treatment admissions and emergency

department records also indicate an increasing

prevalence of prescription opioid misuse (Cicero,

2005; Gilson et al., 2004; Substance Abuse and

Mental Health Services Administration, 2010). In

some parts of the US, unintentional drug poisoning

deaths from opioid analgesics have increased by 20%

in recent years (2005-2009: New York City

Department of Health and Mental Hygiene, 2011).

The 2009 National Survey on Drug Use and Health

(NSDUH) found that the number of new initiates for

non-medical use of opioid analgesics (2.2 million)

was second only to marijuana (2.4 million) and

surpassed well-known drugs of abuse such as cocaine

(0.6 million), methamphetamine (0.15 million) and

ecstasy (1.1 million) (Substance Abuse and Mental

Health Services Administration, 2010). Recent

estimates put the prevalence of non-medical use of

prescription opioids in the past year at about 5.3

million, with up to 13% of these individuals meeting

DSM-IV criteria for abuse or dependence (Becker et

al., 2008; Substance Abuse and Mental Health

Services Administration, 2009). Prescription opioids

are often abused in combination with

benzodiazepine-type drugs. Together, opioids and

BZDs accounted for the majority of ED visits for non-

medical use of psychotherapeutics (Substance Abuse

and Mental Health Services Administration, 2011a).

5 BRIEF OVERVIEW ON

BENZODIAZEPINE ABUSE

Benzodiazepines are among the most widely

prescribed psychotropic drugs in the world (Coach,

1990). These drugs, whose core chemical structure is

the fusion of a benzene and a diazepine ring, act as

positive allosteric modulators of the GABA receptor

complex.

Benzodiazepines act to enhance the effects of

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GABA by increasing chloride (Cl-) flux and the rate

of channel opening. These drugs are a commonly

used and effective treatment for anxiety disorders and

an adjunctive treatment in several psychiatric and

neurological conditions (Bateson, 2004; Campo-

Soria et al, 2006; Doherty, 1991; Low et al, 2000;

McKernan et al, 2000; Saunder and Ho, 1990).

Activation of the GABA/barbiturate/steroid receptor

sites is thought to produce the muscle relaxant effects

of benzodiazepines (Bateson, 2004; Campo-Soria et

al., 2006; Saunder and Ho, 1990), and activation of

the various α GABA subunits has been implicated in

their sedative and anxiolytic effects (Low et al., 2000;

McKernan et al., 2000). Unlike some of their other

effects, the reinforcing effects of BZDs are not easily

attributed to a single receptor subtype (Licata and

Rowlett, 2008). A number of BZDs have been shown

to act as reinforcers in rodents and non-human

primates, including: diazepam, chlordiazepoxide,

flurazepam, lorazepam, medazepam and midazolam

(Bergman and Johanson, 1985; Findley et al, 1972;

Gotestam, 1973; Griffiths et al, 1981, 1990; Licata

and Rowlett, 2008; Nader et al, 1991; Szostak et al,

1987; Yanagita, 1970; Yanagita and Takahashi,

1973).

Human laboratory studies have shown that these

drugs maintain self-administration behaviour (for

reviews see Cole and Chiarello, 1990; Griffiths and

Weerts, 1997; Griffiths and Wolf, 1990; see also

Griffiths and Ator, 1981 and Woods et al, 1987,

1992), although BZDs are generally considered weak

reinforcers compared to the self-administration

responses elicited by other drugs (opioids, cocaine,

amphetamine) (Ator, 2005; Weert et al., 1998; Weerts

and Griffiths, 1998). Nevertheless, their easy

availability, combined with their positive subjective

effects, has made BZDs a widely abused class of

drugs.

Abuse of BZDs is typically defined as

recreational, non-medical use for the purpose of

getting intoxicated or 'high' (Griffiths and Johnson,

2005). However, there remains a provocative debate

as to whether BZD abuse is recreational or medical

adjunctive (aberrant drug use associated with the

therapeutic utility of the drug) in nature (Rosenbaum

et al, 2005). In any case, reports of abusive patterns

of use began to emerge soon after the widespread

clinical use of GABAA agonists and allosteric

modulators (Ator and Griffiths, 1987; Bergman and

Griffiths, 1986; Strang et al., 1994). There is

considerable evidence to suggest that benzodiazepine

misuse remains widespread. The 2010 National

Survey on Drug Use and Health found that there were

an estimated 186,000 new users of benzodiazepines

(Substance Abuse and Mental Health Services

Administration, 2010). According to the Treatment

Episode Data Set (TEDS), the number of people

seeking treatment for BZD abuse nearly tripled

between 1998 and 2008 (Substance Abuse and

Mental Health Services Administration, 2011b). Data

also indicate that benzodiazepines are often abused in

combination with other drugs, most commonly

opioids (Crane and Nemanski, 2004; Substance

Abuse and Mental Health Services Administration,

2011b).

6 PHARMACOLOGICAL

INTERACTIONS BETWEEN

OPIOIDS AND

BENZODIAZEPINES

Several studies have attempted to elucidate the

mechanisms underlying the co-abuse of opioids and

BZDs by examining how these two types of drugs

interact.

Preclinical research has shown that opioids and

BZDs have significant modulatory effects on each

other (Duka et al, 1980; LaBuda and Fuchs, 2001;

Lopez et al, 1990; Moroni et al, 1978; Rocha et al,

1993; Sasaki et al, 2002; Soria et al, 1991; Tien,

2007). One possible mechanism to explain this

modulatory interaction is that BZDs may alter the

pharmacokinetics of opioids. For example, Spaulding

et al. (1974) studied hepatic methadone

concentrations following different doses of diazepam

in methadone-dependent rats. They found that

diazepam was a non-competitive inhibitor of

methadone metabolism. Shah et al (1979) and Liu et

al (1978) also reported that when diazepam was

administered one hour before methadone, there was

an increase in methadone concentrations in liver and

brain tissue and a decrease in urinary and hepatic

methadone metabolites. Research using human liver

microsomes also showed that N- N-demethylation of

methadone by the liver enzyme CYP3A4 was

competitively inhibited by diazepam (Iribarne et al.

1997).

Chang and Moody (2005) also used human liver

microsomes and examined the effects of several

BZDs on the metabolism of buprenorphine (a partial

μ-receptor agonist and κ-receptor antagonist, partly

metabolised by CYP3A4). They found that a BZD

(midazolam) inhibited the rate of metabolism of

buprenorphine. However, other studies suggest that

there is not always a pharmacokinetic interaction

between BZDs and buprenorphine. Megarbane et al

Opiate Abuse: A Review of the Combined Use of Opioids and Benzodiazepines

197

(2005) found that pretreatment with flunitrazepam

did not alter the plasma or striatal kinetics of

buprenorphine in rats. Kilicarslan and Sellers (2000)

examined the effect of the same drugs in human liver

microsomes and again found that co-administration

did not alter the plasma concentration or kinetics of

either drug.

Although studies suggest that BZDs may inhibit

the metabolism of some opioid drugs, BZDs are weak

competitive inhibitors of CYP3A4, only one of

several hepatic enzymes that metabolise these drugs

(Moody et al, 2004). Therefore, this inhibition may

not always be sufficient to cause clinically relevant

interactions. The few clinical studies in this area seem

to support this conclusion (Table 1). Pond et al (1982)

studied the effects of 9 days of oral diazepam

treatment in methadone-treated patients. No

differences in plasma levels of methadone or its

metabolites were reported. Another clinical trial

investigated the effects of two doses of diazepam in

combination with different doses of methadone

(Preston et al., 1986). Analysis of plasma drug levels

did not indicate any pharmacokinetic interaction.

Although some studies suggest that BZDs and

opioids alter each other's pharmacokinetic effects,

this interaction may have limited clinical

significance. Therefore, many believe that it is the

pharmacodynamic interactions of these drugs that

underlie their co-abuse. There is considerable

preclinical evidence to suggest that the analgesic

(Pick, 1997), hyperphagic/hyperdipsic (Cooper,

1983), anxiolytic (Agmo et al, 1995; Primeaux et al,

2006) and rewarding (Lorens and Sainati, 1978;

Spyraki et al, 1985) effects of BZDs are mediated in

part via opioidergic mechanisms. However, some

studies have failed to find this interaction (LaBuda

and Fuchs, 2001; Soubrie et al., 1980; Tripp and

McNaughton, 1987). Contrasting data have also been

reported on the role of BZDs and GABA in opioid

analgesia (Fennesy and Sawynok, 1973; Ho et al.,

1976; Ito et al., 2008; Mantegazza et al., 1979;

Palauglu and Ayhan, 1986; Sivman and Ho, 1985;

Yoneda et al., 1976; Zonta et al., 1981).

Preclinical evidence that BZDs enhance the

rewarding and reinforcing effects of opioids may

provide the best indication of why these drugs are co-

used (Panlilio et al, 2005; Walker and Ettenberg,

2001, 2003, 2005). In particular, individuals may use

opioids and BZDs together to enhance the μ-agonist

effects of opioids (e.g. opioid intoxication). For

example, Stitzer and colleagues (1981) reported that

72% of methadone patients who were regular

benzodiazepine users reported using diazepam to

enhance the effects of their daily methadone dose.

Similarly, heroin users reported that the intensity and

duration of the heroin effect was prolonged by the

addition of intravenous flurazepam (Strang, 1984).

Chen and colleagues (2011) also found that among

methadone clients who reported a history of BZD use,

45.5 % reported that they used to: "get high", "have a

good time" or "have an intense, exciting experience".

Few clinical studies have examined the effects of

BZDs in combination with opioids under controlled

laboratory conditions (Table 1). One such study,

conducted by Preston and colleagues (1984) in

methadone-maintained patients, found that two doses

of oral diazepam (20 and 40 mg) given in

combination with various doses of methadone

(between 50-120 mg) produced greater pupil

constriction (an indicator of μ-agonist effects) than

either drug alone (diazepam alone has no effect on

pupil diameter: Hou et al., 2006; Sigg et al., 1971).

Their study also assessed subjective effects using a

visual analogue scale. They found that methadone in

combination with the highest dose of diazepam

produced greater opioid-like effects than methadone

alone.

These findings were later confirmed by several

studies reporting similar interactions (Farre et al.,

1998; Lintzeris et al., 2006; 2007; see review by

Lintzeris and Nielsen, 2010). For example, Lintzeris

and colleagues (2007) found that co-administration of

diazepam (40 mg) with methadone or buprenorphine

was associated with increases in peak subjective

ratings of 'strength of drug effect' and 'sedation'

compared with each opioid alone. These researchers

also reported similar results with lower "therapeutic"

doses of diazepam (10, 20 mg; Lintzeris et al., 2006).

Positive subjective effects (e.g. 'liking' the drug) are

generally correlated with the reinforcing effects of a

drug and are therefore an indicator of its abuse

potential (Griffiths and Johnson, 2005; Lynch and

Carroll, 2001). In support of this idea, Spiga and

colleagues (2001) found that pretreatment with

diazepam produced dose-related increases in

subjective ratings of drug 'liking', 'high', 'strength of

drug effect' and 'good effects', as well as dose-related

increases in methadone self-administration in

methadone-maintained participants.

7 THE CO-ABUSE OF

BENZODIAZEPINES AND

OPIOIDS IN HUMANS

Research suggests that the abuse liability of BZDs

may be notable only in certain clinical populations,

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notably recreational users of other drugs of abuse and

detoxified alcoholics (Cole and Chiarello, 1990). In

addition, abuse of BZDs has been consistently

reported in the literature in patients maintained on

opioid agonists such as methadone and, more

recently, buprenorphine (Barnas et al., 1992, Brands

et al., 2008; Kleber and Gold, 1978).

The prevalence of BZD use among methadone-

maintained clients (identified by positive urine tests)

ranges from 51 % to 70 % (Gelkopf et al., 1999;

Hartog and Tusel, 1987; San et al., 1993; Stitzer et al.,

1981). Rates in this range have also been reported for

buprenorphine maintenance clients (Lavie et al.,

2009; Neilsen et al., 2007; Thirion et al., 2002) and

active heroin users (Darke et al., 1992, 1995).

The US Treatment Outcome Prospective Study

(TOPS) found that 73 % of heroin users entering

treatment reported BZD use in the previous year (Du

pont, 1988). Almost 25% of these individuals

reported daily use of BZDs. Similarly, 65-70% of

methadone-maintained patients in Baltimore (n=12)

and Philadelphia (n=17) were found to have positive

urine screens for BZDs within a single month. This

study also reported the 6-month prevalence of more

than 50% of urine tests positive for BZDs: Baltimore

= 80%, Philadelphia = 47.9% (Stitzer et al., 1981). A

later study using a much larger sample (n= 547) found

a similar 6-month prevalence of sedative use among

methadone clients in three US cities (Baltimore =

66%, Philadelphia = 53% and New York City = 44%;

Iguchi et al., 1993; see also Iguchi et al., 1989). This

study also reported a high lifetime prevalence of

sedative use among clients of methadone clinics:

Baltimore = 94%, Philadelphia = 78%, New York

City = 86%. Although this study assessed the use of

BZDs and barbiturates, rates of barbiturate use were

much lower.

Since these studies, there has been little research

in the US on BZD use among patients on opioid

replacement therapy (but see Chen et al, 2011).

However, recent studies in Europe continue to show

a high prevalence of opioid and BZD co-use. A

survey conducted in France among buprenorphine-

maintained patients reported a lifetime prevalence of

benzodiazepine use of 67 % and a 30-day prevalence

of 54 % (Lavie et al., 2009; see also Laqueille et al.,

2009). In Spain, a study of patients in methadone

treatment programmes found that 46.5 % were

regular users of BZDs (Fernández-Sobrino et al.,

2009). These figures were closely matched by a Swiss

study, which reported that 51.5% of patients in a

methadone maintenance programme were 'regular'

BZD users (Meiler et al., 2005). In Germany, weekly

urine screening for BZD use was carried out among

patients in heroin-assisted treatment and methadone

maintenance. This study found that the weekly

average of BZD-positive tests was 52.3 % for heroin-

assisted treatment and 60.3 % for methadone

maintenance (Eiroa-Orosa et al., 2010). A more

recent German study found even higher rates of BZD-

positive tests among methadone clients (70%; Specka

et al., 2011).

Most European studies have reported rates of

acute benzodiazepine use among methadone and

buprenorphine clients similar to those reported in the

USA, with comparatively lower rates of BZD use

reported in similar UK populations. In samples of

patients in methadone treatment, estimates of daily

BZD use have been reported to be around 35%, with

over 50% of the sample reporting multiple uses per

month (Metzger et al., 1991).

A number of studies have found not only

significant BZD misuse among these populations, but

also significant levels of physical dependence on

BZDs. Other studies have found that between 18%

and 54% of those newly admitted to methadone

treatment also required detoxification from BZDs

(Gelkopf et al., 1999; Rooney et al., 1999; Specka et

al., 2011). Researchers concluded that these findings

indicate a high prevalence of physical dependence on

BZDs among heroin users seeking treatment. A

similar prevalence of BZD dependence was found in

an Australian study, where 22 % of heroin users had

a current diagnosis of benzodiazepine dependence

(Darke et al., 1993).

In several of their studies, Darke and colleagues

have consistently found recurrent patterns of BZD use

among heroin/methadone users (Darke et al., 2010;

Darke and Hall, 1995; Darke and Ross, 1997). In

1993, they reported that 26.6% of methadone clients

admitted daily benzodiazepine use (Darke et al.,

1993). In another study, 41 % of heroin users reported

using BZDs weekly (or more) in the last few months

(Ross et al., 1996). Subsequent research found that 1

in 3 heroin users had been prescribed a BZD in the

previous month (Darke et al., 2003), 2 in 3 heroin

users reported non-medical use of BZDs in the

previous year and 91 % reported lifetime use (Ross

and Darke, 2000).

In addition to demonstrating the prevalence and

frequency of BZD use in this population, this type of

research has also shown that opioid-dependent

populations have a preference for certain BZDs.

Preference for diazepam (Du pont, 1988; Iguchi et al.,

1993), midazolam (Bruce et al., 2008) and alprazolam

(Fernández-Sobrino et al., 2009) has been reported.

Another group of researchers used the Norwegian

Prescription Database to investigate the prevalence of

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199

BZD use among patients in opioid maintenance

treatment. Analysis of this database, which has

recorded all prescriptions for the whole population

since 2004, showed that 40% had received at least one

BZD prescription in the previous year, which is 8

times higher than the general age-matched population

in the country. The most commonly

sought/prescribed BZD was oxazepam, closely

followed by diazepam (Bramness and Kroner, 2007).

A report from Malaysia found that almost 75% of a

large sample of opioid users (97.6% were heroin

users) reported concurrent use of BZDs within the

past year (Navaratnamand and Foong, 1990).

Diazepam use was relatively uncommon in this

sample (1.6%). Flunitrazepam was the most

commonly used BZD (51.4%), followed by:

alprazolam 10.8%, triazolam 4.4%, lorazepam 4.0%,

nimetazepam 2.8% and nitrazepam 0.4%. Similarly,

a study in Israel found that of the 66.6% of

methadone-maintained patients who regularly

misused BZDs, 92.9% regularly used flunitrazepam,

54.3% diazepam, 38.6% oxazepam, 20% brotizolam,

20% lorazepam, 15.7% alprazolam and 4.3%

nitrazepam (Gelkopf et al., 1999). This survey also

found that the doses of BZDs used exceeded the

normal therapeutic range, with the mean maximum

amount of BZDs abused per day equivalent to 93.2

mg of diazepam (the maximum daily dose

recommended by the FDA is 40 mg of diazepam).

However, lower mean daily doses of diazepam (30-

45 mg) have been reported in other studies (Dupont,

1988; Iguchi et al., 1993).

8 COMPLICATIONS OF

BENZODIAZEPINE AND

OPIOID CO-ABUSE

As polydrug use of BZDs and opioids appears to be

common, it is important to investigate the potential

adverse events that may result. Polydrug use has been

shown to be a significant predictor of overdose (Kerr

et al, 2005). Data suggest that 62-72% of patients

treated for overdose have used more than one drug

class (Backmund et al, 1999; Darke et al, 1996). This

percentage is even higher (71-98%) when only fatal

overdoses are considered (Cook et al., 1998; Grass et

al., 2001; New York City Dept. of Health and Mental

Hygiene, 2011; Perret et al., 2000; Schmidt-Kittler et

al., 2000). Respiratory depression is the primary

mechanism of death from opioid overdose (White and

Irvine, 1999).

Respiration is mainly controlled by medullary

respiratory centres together with input from

chemoreceptors and other sources. Opioids inhibit

these respiratory centres via μ- and δ-opioid receptors

(White and Irvine, 1999). Inhibitory GABA receptors

are also highly concentrated in these areas (Skatrud et

al, 1988). Therefore, both opioids and BZDs, used

separately or concurrently, are capable of altering

respiratory rate.

Laboratory studies have investigated the

combined effects of these two drugs on breathing.

Preclinical research by Gueye and colleagues (2002)

found that the combination of high doses of

midazolam (160 mg/kg, intraperitoneal) and

buprenorphine (30 mg/kg, intravenous) produced

rapid and prolonged respiratory depression, greater

than either drug alone. Rodents receiving the

combination showed significant increases in PaCO2

(partial pressure of arterial carbon dioxide), decreases

in arterial pH and PaO2 (partial pressure of arterial

oxygen), and delayed hypoxia (deprivation of

adequate oxygen supply). Similarly, another study in

rodents found that rapid and sustained respiratory

depression was only observed when buprenorphine

(30 mg/kg, i.v.) and flunitrazepam (40 mg/kg, i.v.)

were co-administered (i.e. this dose of buprenorphine

alone had no significant effect; Megarbane et al.,

2005).

Nielsen and Taylor (2005) performed a similar

experiment in rats using multiple doses of two

opioids. They found that intraperitoneal (i.p.)

pretreatment with diazepam (20 mg/kg) abolished the

protective plateau or ceiling effect often observed

with increasing doses of buprenorphine (0.03, 0.1, 0.3

mg/kg, i.v.) on respiration (see Walsh et al., 1994 for

more on the ceiling effects of buprenorphine). In the

same study, pretreatment with diazepam potentiated

the dose-dependent inhibition of respiration observed

with increasing doses of methadone (0.1, 0.3, 1.0

mg/kg, i.v.; see also similar findings by McCormick

et al., 1984 and Borron et al., 2002). As

benzodiazepines can have respiratory depressant

effects, depending on the dose and route of

administration, it remains to be determined whether

BZDs act to potentiate this effect of opioids or simply

act in an additive manner to depress ventilation

(Carraro et al., 2009; Mak et al., 1993; Zacharias et

al., 1996). Further studies are warranted to explain the

pharmacological interaction that may occur with

BZDs and buprenorphine, as well as other opioids.

In one of the few clinical studies to investigate

this interaction, patients undergoing anaesthesia were

given lorazepam with either fentanyl or

buprenorphine. Of the 88 patients enrolled, 11

developed respiratory depression requiring manual

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ventilation. All of these 11 participants had received

buprenorphine (Faroqui et al, 1983). More recent

clinical research has only used lower doses within the

therapeutic range (diazepam 0, 10, 20 mg) and has

therefore not been able to confirm these findings

(Lintzeris et al. 2006). Nevertheless, prolonged

respiratory depression after medical use of opioids in

combination with BZDs has been observed by

anaesthesiologists since the 1980s (Forest, 1983;

Papworth, 1983; Sekar and Mimpriss, 1987).

Other clinical data provide more direct evidence

of the risks of this drug combination. Clinical studies

have shown that the concomitant use of BZDs and

opioids is associated with the occurrence of fatal and

non-fatal opioid overdoses (Darke et al, 1996; Perret

et al, 2000; Schmidt-Kittler et al, 2001). Almost half

of all heroin users report at least one non-fatal

overdose (Pollini et al., 2006), and BZDs have been

identified in 50-80 % of heroin-related deaths (Grass

et al., 2003; Oliver and Keen, 2003; Stenhouse and

Grieve, 2003; Ward and Barry, 2001).

Opioid agonist treatments also carry a risk of

overdose, particularly full agonists such as

methadone. A recent retrospective analysis of drug

interactions and adverse events in methadone patients

found significant evidence of additive CNS and

respiratory depression when methadone was

combined with benzodiazepines (Lee et al., 2012).

Accordingly, BZDs have been implicated in 40-80%

of methadone-related deaths (Brugal et al., 2005;

Chan et al., 2006; Ernst et al., 2002; Mikolaenko et

al., 2002; Pirnay et al., 2004; Wolf et al., 2004; Zador

and Sunjic, 2000) and up to 80% of buprenorphine-

related deaths (Kintz, 2001; Pirnay et al., 2004;

Reynaud et al., 1998).

Although the risk of overdose is low with

buprenorphine, this risk increases when

buprenorphine is injected and used in combination

with other tranquillisers (Corkey et al, 2004; Paulozzi

et al, 2009; Pirnay et al, 2004; Vormfeld and Poser,

2001; Walsh et al, 1994; Wolff, 2002). Up to 60% of

some samples of heroin users report a history of

injecting buprenorphine and BZDs (Vicknasingam et

al., 2010). Buprenorphine maintenance is becoming a

common treatment for opioid dependence, and human

laboratory studies of combined opioid and BZD use

are limited. A study by Reynaud et al (1998)

examined the post-mortem analysis of opioid-

dependent individuals. Urine, blood and tissue

samples were analysed and no medications other than

buprenorphine and a BZD drug were found to have

contributed to the deaths.

Another complication of the combined use of

opioids and BZDs is the antidotal treatment of acute

overdose or intoxication. Naloxone is well known for

the treatment of opioid overdose. In an effort to

reduce the number of deaths from opioid overdose,

programmes have been implemented in parts of

Australia, the United States and the United Kingdom

to prescribe naloxone to non-medical practitioners for

administration in suspected cases of opioid overdose.

The concomitant use of BZDs by the opioid users

targeted by these programmes may make it more

difficult for typically prescribed doses of naloxone to

reverse respiratory depression.

We know that naloxone is effective in the

treatment of opioid overdose, but we do not know

how concomitant use of BZDs might alter this.

However, there are preclinical data suggesting that

naloxone may also be of direct benefit in the

treatment of BZD overdose (Dingledine et al, 1978;

Soubree' et al, 1980). A retrospective analysis found

that the addition of between 0.2 and 1.0 mg of

flumazenil (a GABAA receptor antagonist) to low

doses of naloxone (0.4-0.8 mg) improved mental

function in patients following buprenorphine

overdose in whom BZDs were co-ingested

(Me'garbane et al., 2010). Although caution should be

exercised in the use of flumazenil due to the risk of

seizures and the need for close monitoring during

administration, these data suggest that flumazenil and

naloxone may serve as an antidotal treatment in cases

of benzodiazepine and opioid overdose.

There are no prospective human studies

evaluating how the co-administration of BZDs may

alter the effectiveness of naloxone in reversing opioid

overdose. More clinical data are also needed to

evaluate novel treatment approaches using naloxone

for BZD overdose. In any case, naloxone is an

interesting and important consideration in the

treatment of opioid and BZD co-abuse.

In addition to the potential to exacerbate drug-

related harm, the co-abuse of opioids and BZDs is

further complicated by the possibility of physical

dependence on and withdrawal from opioids and

BZDs (Puntillo et al, 1997). Clinical indicators of

opioid withdrawal include: abdominal cramps,

diarrhoea, bone and muscle pain, insomnia and

anxiety (Herridge and Gold, 1988). Symptoms of

benzodiazepine withdrawal include autonomic

instability, increased anxiety, fear, dread,

restlessness, confusion and panic attacks. Abrupt

BZD withdrawal can lead to fatal refractory seizures

(Durbin, 1994). Traditional therapeutic approaches to

BZD dependence that have been used in opioid users

include tapered detoxification with barbiturates, long-

acting BZDs and/or antiepileptics (Bleich et al, 2002;

Kristensen et al, 2006; McDuff et al, 1993; McGregor

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201

et al, 2003; Ravi et al, 1990).

Some researchers have also suggested BZD

maintenance strategies for people on agonist

maintenance treatment (Weizman et al, 2003).

Although this may prove to be a useful treatment

modality, clinicians and treatment providers may be

reluctant to maintain BZD dependence because of the

risks described above and the lack of evidence-based

justification. In any case, studies focusing on

polydrug detoxification are scarce and the

effectiveness of these strategies has not been

extensively investigated.

Further complicating the treatment prognosis for

this population, studies have found that, compared

with individuals who abuse only opioids, BZD and

opioid polydrug abusers: have a significantly longer

duration of opioid use, use higher doses of opioids,

and are more likely to abuse additional drugs

(excluding BZDs) (Meiler et al., 2005; Rooney et al.,

1999; Ross et al., 1996, 2000). Meiler et al (2005)

reported that among methadone-maintained patients,

those who were regular BZD users received higher

daily methadone doses and were more likely to abuse

alcohol. Similarly, a study by Ross and Darke (2000)

found that heroin users with a lifetime diagnosis of

dependence on BZDs were more likely to have a

lifetime diagnosis of alcohol dependence (83 % vs. 60

%) and cocaine dependence (23 % vs. 4 %) than those

with no lifetime diagnosis of dependence on BZDs.

Given these findings, it is not surprising that research

has shown poorer treatment outcomes for these

polydrug users. Although it has not been shown to

alter retention in methadone maintenance, BZD use

during methadone maintenance is associated with

poorer treatment outcomes in terms of general health,

legal problems and alcohol use (Brands et al., 2008;

Eiroa-Orosa et al., 2010).

The increased negative factors associated with

BZD and opioid polydrug use also extend to

psychological variables. Compared with a control

group of heroin users, heroin users who were

physically dependent on BZDs were much more

likely to use antidepressants daily and more likely to

report a history of depression, including thoughts of

self-harm (Rooney et al, 1999). Other studies have

also found an increased frequency of psychiatric

comorbidity in this population. Studies have shown

that opioid users who regularly use BZDs are almost

three times more likely to have had a psychiatric

hospital admission in the previous year. They are also

almost twice as likely to have been prescribed

medication for emotional problems and have a much

poorer psychiatric status (Eiroa-Orosa et al., 2010).

Other research has found higher rates of anxiety and

depressive disorders in similar comparisons (Rooney

et al., 1999; Ross and Darke, 2000).

Opioid users who abuse BZDs have also been

shown to report behaviours associated with increased

risk of HIV and hepatitis C (HCV) infection, such as

injecting more frequently and sharing injecting

equipment more frequently and with more people

(Breen et al, 2004; Darke et al, 1992, 1995; Forsyth

et al, 1993; Kintz et al, 2001; Klee et al, 1990).

However, studies directly comparing the prevalence

of blood-borne diseases between opioid users who co-

abuse BZDs and those who do not are few and have

reported conflicting results. Meiler et al. (2005) found

no significant differences in HCV and HIV infection

between methadone clients who regularly use BZDs

and those who do not. In contrast, Bleich et al, (1999)

found significantly increased rates of HCV in a cohort

of methadone clients who also abused BZDs.

Although research has shown that polysubstance

abuse typically increases rates of HCV and HIV

infection, more data are needed to specifically assess

the impact of combined BZD use on rates of

infectious disease transmission among opioid users

(Backmund et al., 2005, Nurutdinova et al., 2011).

9 CONCLUSIONS

There is ample evidence of significant co-use of

BZDs and opioids. Opioids have considerable

therapeutic utility, but their euphoric effects make

them among the most commonly abused drugs in the

world. Compared with opioids, BZDs are thought to

have very limited euphoric effects and, when used

alone, are less likely to be abused. Drug users appear

to have discovered that BZDs can enhance the

positive subjective effects of opioids. Thus,

individuals may combine opioids and BZDs to

achieve greater levels of euphoria. Further clinical

studies are needed to investigate these hypotheses in

controlled laboratory settings.

People in opioid substitution treatment worldwide

appear to be particularly vulnerable to co-abuse of

opioids and BZDs. It appears that the addition of the

BZD drug to methadone or buprenorphine may allow

them to achieve a more potent opioid effect, often

described as 'heroin-like'. Further research is needed

to clarify the increased abuse potential of this drug

combination. Do BZDs enhance the reinforcing

effects of opioids? Or is the increased abuse potential

simply an additive effect of combining two

reinforcing drugs? Individuals with chronic pain who

use prescription opioids may use BZDs to enhance

the euphoric effects of their opioids. Anecdotal

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reports from users and clinical data showing that

these individuals do not use therapeutic doses suggest

that BZD use among these individuals is primarily

recreational. However, the possibility remains that

prescription opioid users may be self-medicating for

inadequate pain management or co-occurring mood

or anxiety disorders. These types of conditions, for

which BZDs are effective, are common among heroin

users. Studies examining the prevalence of affective

and anxiety disorders among co-users of prescription

opioids and BZDs may help to determine whether

their co-use is recreational or therapeutic.

Future studies should also look at how these

people obtain BZDs. There is a wealth of research

showing the many ways in which people obtain

prescription opioids. Opioid abusers often: forge

prescriptions, obtain opioids from friends and family,

attend emergency departments with complaints of

pain, or buy opioids on the street (Ballantyne and

LaForge, 2007; Fishbain et al., 1992). This

knowledge of the liability of opioid misuse has raised

awareness among health care professionals, and

greater caution is required when considering patients

for opioid therapy. Research has shown that BZDs are

the most commonly sold controlled prescription drug

on the Internet, with 89% of these sites selling these

drugs without a prescription (National Center on

Addiction and Substance Abuse at Columbia

University, 2006). This study also found that 70% of

the sites requiring a prescription allowed the

prescription to be faxed, creating the potential for

individuals to forge or alter prescriptions or send the

same prescription to multiple sites. There is also a

trend towards online consultation rather than a

prescription. In this case, the consumer fills in an

online questionnaire, which is reportedly evaluated

by a doctor associated with the online pharmacy. Less

is known about the prevalence of illegal street sales

of BZDs. A high incidence of questionable internet

'prescriptions' and street sales may suggest the need

for stricter national policies to regulate the

availability of these drugs. On the other hand, if BZDs

are mainly obtained through doctors, this may suggest

the need for increased vigilance on the part of doctors.

Much is still unknown about the interactions between

opioids and BZDs. Although BZDs are widely used

in the treatment of anxiety disorders, efforts must be

made to prevent the potentially lethal interaction that

can occur when opioids and BZDs are administered

concomitantly. Benzodiazepines have been shown to

abolish the protective ceiling effect of buprenorphine

on respiratory depression, an important benefit of this

treatment. In opioid-using populations, clinicians

may wish to consider non-CNS depressants such as

low-toxicity antidepressants (i.e. SSRIs), atypical

antipsychotics or buspirone instead of BZDs. Non-

pharmacological treatments such as imagery,

distraction, meditation and desensitisation could also

be considered as initial or adjunctive treatment for

anxiety disorders.

This review also raises important questions about

how to treat people who co-abuse these two drugs.

This issue is complicated by the possibility of dual

physical dependence on opioids and BZDs in these

individuals. More research is needed into the safety

and benefits of BZD maintenance strategies, although

they may not prove to be a viable treatment approach.

Future studies investigating the administration of the

opioid antagonist naloxone may prove useful in the

treatment of combined BZD and opioid overdose.

When used together, the combination of opioids and

BZDs has serious adverse effects on physical and

mental health and sobriety. In addition to increasing

the risk of overdose, polydrug use of BZDs and

opioids can exacerbate the criminal, psychological

and medical problems commonly seen in drug users.

Therefore, we recommend that prescribers be vigilant

for patterns of misuse in patients receiving one or

both types of medication. Drug treatment centres

should also warn users of the risks of this drug

combination and encourage treatment for abuse of

both drugs.

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