Explaining the high mortality among opioid-cocaine co-users compared to opioid-only users. A systematic review

Abstract

Rationale

The opioid crisis in North America has recently seen a fourth wave, which is dominated by drug-related deaths due to the combined use of illicitly manufactured fentanyl [IMF] and stimulants such as cocaine and methamphetamine.

Objectives

A systematic review addressing the question why drug users combine opioids and stimulants and why the combination results in such a high overdose mortality: from specific and dangerous pharmacokinetic or pharmacodynamic interactions or from accidental poisoning?

Results

Motives for the combined use include a more intensive high or rush when used at the same time, and some users have the unfounded and dangerous belief that co-use of stimulants will counteract opioid-induced respiratory depression. Overdose deaths due to combined (intravenous) use of opioids and stimulants are not likely to be caused by specific pharmacokinetic or pharmacodynamic interactions between the two drugs and it is unlikely that the main cause of overdose deaths is due to accidental poisoning.

Conclusion

The unexpectedly high overdose rates in this population could not be attributed to accidental overdosing or pharmacokinetic/pharmacodynamic interactions. The most likely explanation for the high rate of drug-related deaths in opioid-cocaine co-users is careless overdosing with either cocaine, opioid(s) or both, probably facilitated by the high level of preexisting impulsivity in these co-users and a further acute increase in impulsivity following cocaine use. The primary corollary is that cocaine users should avoid IMF use in the same time window. In addition, IMF users should refrain from cocaine use to avoid impulsive IMF overdosing.

Keywords:

• IMF
• heroin
• fentanyl
• stimulants
• opioids
• cocaine
• overdose deaths

Introduction

Epidemiology

In the US, the triple wave of the opioid crisis (1^st wave: prescription opioids, 2^nd wave: heroin, 3^rd wave: illicitly manufactured fentanyls [IMFs]) has recently seen a 4^th wave, which is dominated by drug-related deaths due to the combination of IMFs and stimulants such as cocaine and methamphetamine.^1,2 Between 2002–2017 in the U.S., co-use of cocaine and heroin increased linearly (past-30-day use; AOR = 1.06; 95% CI: 1.03–1.10)³ which is also reflected in a rising number of cocaine-related (fatal) overdoses.^2,4

The term “opioid” is generally meant to be the broader term, and includes natural opiates (e.g.,opium, morphine, codeine), semi-synthetic derivatives of opiates (e.g., heroin, hydromorphone, oxycodone), and synthetic compounds (i.e., fentanyl, fentanyl analogues, methadone, tramadol). In this review, opioid refers to any opioid (natural, semi-synthetic or synthetic) if not further specified.

Opioids, notably IMFs, have a much smaller safety margin (between desired and lethal dose) than cocaine, and opioids are thus far more life-threatening than cocaine. So, it is understandable that the increased number of overdose-deaths involving opioids, specifically fentanyl, accounted for most of the increase in cocaine-involved overdose deaths in recent years^2,5–7 and continue to contribute to the public health burden in the U.S. The rate of drug-related overdose deaths involving both cocaine and opioids increased nearly 5.5 times from 0.7 per 100,000 in 2009 to 3.8 per 100,000 in 2019, while the rate of overdose deaths involving cocaine without opioid involvement increased just over 1.5 times from 0.7 to 1.1.⁶ Between 2016–2017, death rates involving both cocaine and opioids, particularly synthetic opioids increased dramatically from 1.3 to 2.3 per 100,000.⁷ In 2019, any opioid and synthetic opioids were involved in 76% and 64% of cocaine-involved overdoses, respectively^{6, 8} suggesting that increases in cocaine-involved overdose deaths in 2019 were mainly driven by the co-use of (synthetic) opioids. With regard to cocaine-involved non-fatal overdoses with and without an opioid, the rate increased between 2006–2016 annually by 14.7% and 11.3%, respectively; in 2016, 27% of non-fatal cocaine-involved overdoses including an opioid.⁷ According to National Poison Control data (N = 15,391; reported between 2015–2021), the proportion of fatal and non-fatal fentanyl-related poisonings in the U.S. increased for co-use of methamphetamine by 669% and for cocaine by 374%.⁹ Similarly, in British Columbia, Canada, health insurance data from a random general population sample (N = 1,089,682) showed a two-fold higher risk for fatal overdose in people who used both opioids and stimulants compared to people who used opioids only: HR= 2.02 (95% CI: 1.47–2.78, p < 0.001).¹⁰ Finally, more than half of treatment-seeking opioid users in the U.S. reported regular stimulant use^11,12 and between 2012–2019, the number of heroin-cocaine treatment admissions increased 2.3-fold¹³ with a RRR of 2.4 (95% CI: 2.34–2.46) for non-Hispanic Black, compared to non-Hispanic White patients.¹³

Public health concern

The growing co-use of opioids and cocaine (and other stimulants) presents significant challenges for public health. In fact, the dramatic increase in fatal opioid overdosing together with stimulants points to stimulant use as a potential risk factor in these drug-related deaths, especially if these drugs are injected. Of those who died from co-used opioids and stimulants in January–June 2019, nearly 34.8% had injected the drugs.¹⁴ Used in combination, opioids and cocaine may mask typical clinical presentations of one another, impeding a rapid diagnosis of the overdose when arriving at the critical care unit and its treatment.¹⁵ Furthermore, the combined use of opioids and cocaine impedes and confounds the assessment of the cause-of-death and the specific overdose risks associated with each of the two drugs. Scientific understanding on the factors contributing to opioid overdose deaths involving cocaine is lacking.¹⁶ Considering that opioids, and especially fentanyl, are far more toxic than cocaine, the increase in cocaine-involved overdose deaths between 2012–2017 in the U.S. is presumably driven by fentanyl and other opioids.^7,8 However, the available overdose studies about the co-use of cocaine and opioids do not provide information about the cause of death. In the current systematic review, we try to establish why the combined use of cocaine with opioids results in such a high overdose mortality. The main questions that we address here are why people co-use cocaine and opioids and whether overdose death from cocaine-opioid use result from specific and dangerous pharmacokinetic or pharmacodynamic interactions or from accidental poisoning or overdosing?

Motives to co-use cocaine and opioids

There has traditionally been a subset of opioid users who prefer to simultaneously inject a stimulant, typically cocaine, together with an opioid in what has been colloquially referred to as speedballing (i.e., simultaneous use of heroin and cocaine) and a common practice for decades.¹⁷ Users report that the simultaneous use of stimulants and opioids is more reinforcing than either drug alone i.e., a synergistic high giving a more intense euphoria, or rush.^18,19 However, Leri et al. (2003) claimed that simultaneous co-use of cocaine and heroin does not induce a novel set of subjective effects and that it is not more reinforcing than either drug alone, especially when the doses of heroin and cocaine are high. Although the results are not ubiquitous (for review see ref.²⁰), pre-clinical data endorse that cocaine plus heroin was in self-administration paradigms more rewarding than cocaine or heroin alone²¹ and self-administration of cocaine in Rhesus monkeys was enhanced by otherwise inactive doses of heroin.²² Accordingly, self-administration of both cocaine and heroin produces a synergistic increase in extracellular dopamine concentration in the nucleus accumbens, the reward pathway^23,24 and similar supra-additive effects have been noted in comparable studies in both rodents^{21, 25,26} and non-human primates,^{22, 27–29} though one study in Rhesus monkeys showed a sub-additive effect³⁰ and another study reported apparently discrepant results regarding synergy.³¹ Similarly, the combination of methamphetamine and morphine produced behavioral stimulation that was dramatically stronger than either drug alone.^32,33

Mixing cocaine with opioids is sometimes used to ‘mellow down’ the ‘upper’ effects of cocaine or - conversely - cocaine is used to counteract the depressant after-effects of the opioid. Opioids, and especially fentanyl, induce heavy sedation and a tranquilizing effect that make daily functioning arduous, inciting the (subsequent) use of cocaine or methamphetamine to counteract the fentanyl effect³⁴ As such, this drug combination may derive from the reduction of the unwanted side effects of one drug by the other due to compensatory mechanisms of action and/or from enhanced effects of the combination.¹⁷ Furthermore, cocaine may alleviate the severity of symptoms of withdrawal from heroin.¹⁷ Finally, some users have the unfounded and dangerous belief that co-use of stimulants will counteract opioid-induced respiratory depression, because - as outlined below - cocaine does not impact brain hypoxia induced by high doses of heroin.³⁵

Risks of combined use

Mixing heroin and cocaine increases the risk of overdose or permanent damage to the body. It is especially risky because taking an opioid (a depressant) and cocaine (a stimulant) together causes a dangerous “push-pull” reaction in the body which can result in an irregular heart rate, heart failure, and death. In addition, regular cocaine but opioid-naïve users may suddenly die from a heroin overdose because they are not (yet) tolerant for the opioid. Moreover, qualitative interviews documented that cocaine users who have no history of opioid use are largely unprepared to recognize and respond to an overdose.³⁶ Indeed, mortality risk and excess mortality were significantly greater among subjects with cocaine-opiate use disorder than those with only cocaine use disorder.³⁷

Methods

A systematic literature review was performed on October 10^th, 2023 to retrieve studies, including studies published or ahead of print about risk factors that severely increase the mortality of combined use of opioids and cocaine. Our search for relevant data was focussed on the most prominent factors and mechanisms involved in fatalities reported following use of either opioids or cocaine, like respiratory depression and cardiac effects, respectively. In a first step, handbooks on basic pharmacology and drug abuse^38,39 were consulted to select the pathophysiological mechanisms, where opioids and cocaine could adversely interact, resulting in and explaining the excess mortality observed following the use of this combination. The mechanisms included effects on their common metabolic routes which could lead to an acute firm increase in internal dose of either opioids or cocaine when used in combination.

Using the PRISMA-protocol and focussing on these suspected interactions, appropriate key words were selected to conduct a systematic literature search using Medline (PubMed) and EMBASE to detect studies performed in humans and published since 1995. Key words selected were: “overdose”, “cardiovascular”, “arrhythmia*” “respiratory”, “carboxylesterase”, “decision-making” and “impulsivity”. This search string was combined with the string “(fentanyl or opioid or heroin or methadone or speedball) and with cocaine”. Exclusion criteria: case reports, letters or commentaries.

The selection of appropriate studies was performed by JvA and WvdB in two rounds. A total of 1,202 studies were identified from the initial search and 1,078 articles remained after duplicates were removed. These 1,078 studies were further processed, i.e., the title and abstract were screened to determine eligibility applying the above inclusion and exclusion criteria. In a second round, the full texts of the selected 27 studies were checked for eligibility. In addition, 12 additional relevant studies, primarily referring to effects of either opioids or cocaine alone, were retrieved via the reference lists of the previously selected 27 studies (e.g. reviews), resulting in 39 studies in total; 35 have been described in the Results section (see also Table 1) and four in the Discussion. Figure 1 shows the PRISMA flow chart for the identification, screening, and inclusion of the studies. See ‘Supplementary material’ for PRISMA checklist.

Figure 1. PRISMA flow diagram.

Table 1. Studies retrieved with details about number of subjects and gender.

Pharmacokinetic interactions
Number	Number (% male)	Reference
In-vitro	n.a.	^40
Computational systems pharmacology	n.a.	^41
In-vitro	n.a.	^42
Pre-clinical	Male rats	^43
In-vitro	n.a.	^44
In-vitro	n.a.	^45
Pharmacodynamic interactions
Clinical study	N = 89 (84.3%)	^46
Experimental study	N = 9 (100%)	^47
Experimental study	N = 29 (79.3%)	^48
Review	n.a.	^49
Handbook	n.a.	^38
Handbook	n.a.	^39
Clinical study	N = 17 (41.1%)	^50^,^51
Case study	One male	^52
Handbook	n.a.	^53
Retrospective case series	N = 1,125 (760 with documented QTc interval)	^54
Review	n.a.	^55
Review	n.a.	^56
Review	n.a.	^57
Pre-clinical	Male rats	^35
Review	n.a.	^58
Accidental overdosing
Experimental study	N = 27 (66.7%)	^59
Meta-analysis / review	52 studies	^60
Handbook		^61
Experimental study	N = 145 (72.0%)	^62
Experimental study	N = 145 (27.5%)	^63
Experimental study	N = 70 (74.2%)	^64
Experimental study	N = 74 (79.7%)	^65
Experimental study	N = 526 (77.2%)	^66
Experimental study	N = 94 (% not reported)	^67
Adulteration of cocaine
Case series of patients	N = 9 (% not reported)	^68
Survey data	N = 465 (61.3%)	^36
Survey data	N = 2,107	^69
Lab-confirmed drug samples	N = 718	^70

n.a.: Not applicable.

Pharmacokinetic interactions

Pharmacokinetic interactions i.e., drug-drug interactions (DDIs), occur when two substances are metabolized by the same enzymes or the same metabolic route. As a result, the two substances compete for the same metabolic enzymes so that one of the two substances can prolong and potentiate the biological effects of the other. As explained below this may be the case with cocaine and heroin when co-used.

Cocaine is a pharmacologically active compound, which is primarily further metabolized by plasma choline-esterase and two liver carboxylesterases (human carboxylesterase hCE-1 and hCE-2) to ecgonine methyl ester and benzoylecgonine which are both pharmacologically inactive.^{40, 45} Heroin (diacetylmorphine) is an inactive prodrug which is rapidly converted in two steps to pharmacologically active 6-monoacetylmorphine (6-MAM) and morphine⁴³ by liver hCE-2 and hCE-1 and plasma cholinesterase.^{40, 44,45} Cocaine and heroin have therefore a common metabolic pathway, i.e., they compete for the same metabolizing enzymes. The metabolic steps differ, however, in kinetics: the K_m-value of hCE1 and hCE2 for cocaine is 0.12 and 0.39 mM, respectively and for heroin 6.3 and 6.8 mM, respectively. This implicates that both carboxylesterases inactivate cocaine 17 to 52-times more efficient (rapid) than heroin.⁴⁴ Furthermore, cocaine competitively inhibits hCE-1- and hCE-2-hydrolysis of heroin to 6-MAM (K_i = 530 and 460 µM, respectively) and of 6-MAM hydrolysis to morphine (K_i = 710 and 220 µM, respectively) with very modest potency.⁴² In conclusion: cocaine and heroin show a pharmacokinetic interaction, but considering the large differences in affinities (K_m and K_i) between cocaine and heroin for their metabolizing enzymes, this interaction is very modest and does not lead to prominent elevations in heroin plasma levels when used in combination with cocaine. Another pharmacokinetic may occur between cocaine and fentanyl, as cocaine, like fentanyl, can also be metabolized via CYP3A4 into norcocaine. Drug-drug interaction studies where plasma cocaine concentrations were simulated with and without the presence of fentanyl showed, however, that the predicted AUC-profiles of cocaine were very similar and therefore unaffected by fentanyl probably, because cocaine is mainly metabolized by cholinesterase enzymes.⁴¹ Therefore, the pharmacokinetic interaction between cocaine and either heroin or fentanyl is not likely to seriously contribute to the high rate of cocaine-heroin overdose deaths.

Pharmacodynamic interactions

Respiratory depression

Bronchial hyperreactivity has been reported following inhalation of heroin mixed with cocaine,⁴⁶ but this is unlikely to lead to fatalities.

Respiration is controlled primarily by respiratory centers in the brainstem along with input from peripheral chemoreceptors and other sources.⁷¹ via direct depression of the respiratory center in the medulla of the central nervous system, opioids may induce respiratory depression that can progress to hypoventilation, apnea, brain hypoxia (low cerebral oxygen level) and ultimately death.

Small doses of cocaine cause acute respiratory stimulation while very high doses of cocaine, like opioids, may cause respiratory arrest.⁷² At the same time, cocaine causes peripheral vasoconstriction and a dose dependent cerebral vasodilation increasing cerebral blood flow facilitating oxygen entry into the brain. For example, it has been shown that cocaine delivered to rats at doses below 0.25 mg/kg and at optimal self-administration doses (0.5 and 1.0 mg/kg) modestly increased oxygen levels in the nucleus accumbens. Heroin at a low reinforcing dose (0.05 mg/kg) also increased oxygen levels in the nucleus accumbens, but it caused a strong monophasic oxygen decrease in the nucleus accumbens during overdose (0.6 mg/kg). When combined at moderate doses, cocaine (0.25 and 0.5 mg/kg) slightly increased the oxygen increases induced by heroin alone (0.5 and 0.1 mg/kg), but when moderate doses of cocaine were combined at high doses of heroin (1 mg/kg cocaine plus 0.2–0.6 mg/kg heroin) oxygen decreases in the nucleus accumbens due to heroin were no longer compensated by oxygen increases due to cocaine, resulting in oxygen decreases similar to high doses of heroin alone.³⁵

Still, mixing heroin with a stimulant, like cocaine, is hazardous, because cocaine increases the oxygen demand while the depressant heroin reduces the breathing rate. As the opioid receptor-like receptor (ORL1) appears to be implicated in the rewarding and addictive properties of cocaine and other drugs of abuse,^73–76 it cannot be excluded that cocaine and opioids (also) interact at the level of respiratory control via mu and delta opioid receptors.

In summary, concurrent cocaine use cannot prevent overdose (deaths) due to respiratory depression and hypoxia in cases of opioid overdosing. However, high doses of cocaine may result in reduced cerebral oxygenation and respiratory failure giving an additive effect on respiratory arrest when cocaine and opioids are simultaneously used. This may partly explain the high mortality in opioid-cocaine co-users.

Cardiovascular complications

The use of cocaine is associated with numerous adverse cardiovascular effects, including cardiac arrythmias, myocardial infarction, and neurological effects like headache, seizure, and stroke^57,58 while fatal cocaine overdosing is typically caused by cardiac arrhythmias, seizures or respiratory failure³⁸ with cardiovascular complications accounting for the majority of cocaine-related deaths.^{55,56, 58} Physiologically, acute administration of cocaine causes - in addition to tachycardia and hypertension - an increase in myocardial oxygen consumption i.e., a higher oxygen demand.³⁸

In contrast to cocaine, heroin overdose is clearly and specifically identified by reduced consciousness, miosis, and respiratory depression.^38,39 In general, no prominent cardiovascular effects are observed following heroin use, but the following acute opioid-induced cardiovascular effects may occur: orthostasis, syncope, and bradycardia with hypotension primarily through the µ-opioid receptor-mediated vasodilatation. Experienced opiate users treated i.v. with morphine (0, 5 and 10 mg/70 kg) administered in combination with and without cocaine (0, 8, 16 and 32 mg/70 kg) showed significantly increased peak heart rate, diastolic pressure and systolic pressure, but the effects were mainly driven by cocaine.⁴⁷ In addition, cocaine use is a known risk factor for QTc interval prolongation, which can lead to life-threatening dysrhythmias including Torsades de Pointes.⁵⁴ Therefore, a possible dangerous pharmacodynamic interaction may occur in methadone maintenance patients who also use cocaine,⁵² because through the same mechanism both methadone^50,51 and cocaine^{48,49, 54} may prolong the QTc-interval and the risk of (fatal) ventricle fibrillation.⁵² In conclusion, with exception of patients treated with methadone and those with opioid withdrawal, which may go along with adverse cardiovascular events, no major cardiovascular complications are expected to occur when cocaine is co-used with heroin or fentanyl. Thus, hazardous cardiovascular interactions cannot explain the high incidence in opioid-cocaine fatal cases, because there was no major increase in methadone use or use of higher methadone doses during the 4^th wave of the opioid epidemic.

Overall

Based on the above, it is obvious that health dangers of speedballing may result from de-compensation of vital functions due to diminished intra-brain oxygen inflow induced by high-dose heroin coupled with an enhanced (cardiac) oxygen demand induced by cocaine.^{35, 53}

Accidental overdosing

Impulsivity and risk-taking

Heroin and cocaine abusers, as well as heroin cocaine i.v. co-use, have higher impulsivity (discount rates for delayed rewards) than non-drug-using controls.^62,63 A recent meta-analysis with 59 studies showed that individuals with a history of cocaine or opioid use had increased risky decision-making when compared to controls.⁶⁰ In particular, chronic cocaine users showed higher levels of impulsivity, sensation seeking and risk-taking propensity than heroin users^{59, 67} and cocaine-dependent subjects were more impulsive than non-drug using subjects.^64,65 Similarly, a cross-sectional observational study showed that patients with lifetime cocaine dependence, and those with comorbid cocaine and opiate dependence were more impulsive than subjects with opiate dependence alone.⁶⁶ Together, these observations draw attention to the role of impulsivity in (fatal) overdosing in mixed cocaine-opioid users. In addition to these apparent personality traits of individuals with a history of cocaine use, acute cocaine use has been shown to cause an increase in extracellular dopamine with an overstimulation of the dopaminergic postsynaptic receptors, inducing excitation and the euphoric ‘rush’.⁶¹ Under such circumstances, the already predisposed (impulsive) user may become reckless and careless which may facilitate overdosing with either cocaine, any opioid(s) or both. Moreover, cocaine’s relatively short half-life of 40 to 90 min may contribute to multiple dosing and thus erroneous handlings.

Adulteration of cocaine with potent opioids

Because of an emerging trend to lace cocaine with opioids,^{68, 70} many cocaine users are unaware of highly potent opioids in their cocaine supply. For instance, findings from a survey among 172 participants with past-month cocaine and/or opioid use showed that only 5.4% of cocaine users without an opioid use history suspected that fentanyl was in their drugs, compared to 41.2% of their peers with an opioid use history.³⁶ The unpredictable fluctuation in quality generates uncertainty for consumers about their cocaine supply and increases the risk for unintentional exposure to highly potent opioids. Obviously, the latter population is at higher risk of opioid overdosing since they are more likely to be opioid-naïve (read: no opioid tolerance). Fortunately, there is a growing awareness among people who attend nightclubs and dance festivals that cocaine can contain fentanyl.⁶⁹

Summary and conclusions

Because of the much smaller safety margin (between desired and lethal dose) of opioids, notably IMFs, compared to cocaine, opioids are far more life-threatening than cocaine. Their combined use was shown to lead to a higher mortality compared to the use of either drug alone. Their combined use was shown to lead to a higher mortality compared to the use of either drug alone. For instance, their simultaneous intravenous use as injected speedballs, is a known predictor of overdose and overdose deaths.⁷⁷ The high mortality of combined use of cocaine and heroin/opioids does, however, not result from pharmacokinetic and probably also not from pharmacodynamic interactions between the two types of drugs.

Deception of cocaine users by offering them opioid adulterated cocaine may easily lead to fatal overdosing. However, qualitative findings, suggest that the increase in overdose deaths involving both highly potent opioids (IMFs) and stimulants is largely due to intentional co-use and not driven by systemic adulteration of illicit stimulants with IMFs.^78–80 Therefore, the unexpectedly high overdose rates in this population could not be attributed to accidental overdosing, pharmacokinetic or pharmacodynamic interactions, whereas trait/state impulsivity is a possible risk factor for (fatal) overdosing in this population.

It is tentatively concluded that the high overdose mortality rate in mixed cocaine-opioid users may at least partly result from careless overdosing with either cocaine, any opioid(s) or both, facilitated by a combination of already existing high (trait) impulsivity in combination with an acute increase in (state) impulsivity due to cocaine use resulting in extreme risk-taking behaviors. The issue currently addressed is not unique to cocaine and opioid use, but probably also extends to combined methamphetamine and opioid use which presumably also has an increased mortality risk compared to the use of either drug alone. However, the scientific literature of combined cocaine-opioid use is more developed and the incorporation of methamphetamine-opioid co-use would be too much for one review and affect readability. Whatever the mechanism/reason, cocaine-opioid co-users are at increased risk for mortality compared to opioid-only users. The two primary implications of this conclusion are that in the same time window (a) cocaine users should avoid IMF use, and (b) IMF users should refrain from cocaine use to avoid impulsive IMF overdosing.

Disclosure statement

The authors declare no conflict of interest.

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Funding

The author(s) reported there is no funding associated with the work featured in this article.