Adulterants in opioids are the rule: Implications for clinical care

 

The opioid epidemic continues to devastate the United States across demographic and socioeconomic groups; two-thirds of the 63,632 Americans who died of drug overdoses¹ in 2016 died of prescription or illicit opioids.

In 2015, Theodore J. Cicero, PhD, professor of psychiatry at Washington University, St. Louis, reported on a fundamental change in the nature of the ongoing opioid epidemic: What started as prescription opioid overprescribing, leading to diversion, abuse, and opioid addiction, was transitioning to illicit heroin distribution and consumption. Prescription opioids, namely, extended-release oxycodone (Oxycontin), were perceived initially as pure and safe, as they were specifically dosed and physician prescribed. In addition, filling a prescription for opioids was not associated with the shame or stigma of buying illicit drugs off the street. Because those drugs were seen as therapeutic and pharmacologically “legitimate,” many clinicians and the lay public alike were surprised to see the surge of opioid addiction and overdoses.

Dr. Cicero and others noted² that prescription opioids, whether taken originally for analgesic or recreational purposes, became a “gateway” to heroin, which already was making its way into the United States from Mexico,³ as heroin was cheap and becoming cheaper, easier to find, easy to use, and “pure.” Prescription opioids, on the other hand, were becoming more expensive, and physicians were facing increased regulations in prescribing them. Thus, as prescription opioid use became more and more stigmatized, heroin use was seen, paradoxically, as a more practical alternative. The amount of opioids prescribed in the United States has peaked; physicians are prescribing opioids less often; and the averaged dose has dropped as well, according to the Centers for Disease Control and Prevention.⁴ The first wave of deaths was attributable to prescription opioids, and the second was tied to illicitly obtained potent fentanyl analogs (manufactured in China and smuggled primarily through Mexico), which is added to heroin and sold in the United States.⁵

Many addiction experts and health policy leaders were not surprised by the increases in HIV, TB, and hepatitis B and C that followed the increasing use of intravenous opioids. However, few had experience with previous opioid epidemics in the United States, the most recent being the heroin epidemic occurring in the 1960s-1970s in the aftermath of the Vietnam War. At that time, the notion that heroin was contaminated with other psychoactive drugs, medications, fillers, and other adulterants was a foregone conclusion – though in public health and treatment discussions, this issue is hardly ever raised. We believe this to be a significant lapse in policy and planning. Surveillance by the Drug Enforcement Administration shows that acetyl fentanyl–laced heroin costs a little more on the street than regular heroin. Yet it sells, because users believe its extreme potency produces a better high, thus worth the extra cost. This phenomenon underscores an important point: Opioid addicts often are in search of a better high and will go to any lengths – even risking their lives – to get it.

The “cutting” or “adulteration” of street drugs is common practice in the manufacturing, distribution, and selling of illicit drugs, and the motive is to increase profit. The term “adulterant” generally refers to addition of substances with some psychoactive effects, such as caffeine, ephedra, or even paracetamol. These substances are cheaper than the main substance, have similar or complementary effects when added, and thus help conceal the fact that the desired substance has been cut or diluted. Substances without psychoactive properties such as lactose, other sugars, or talc, are added to a drug primarily to increase the bulk or weight of the illicit substance, or for aesthetic purposes to fool the user. Some adulterants simply are the result of the particular manufacturing process used to make the drug. For example, illicitly manufactured methamphetamine frequently is contaminated by nonstimulant impurities such as lead or mercury (extremely toxic heavy metals), or from carcinogenic solvents used in the synthesis. The local anesthetic lidocaine often is added to cocaine, and the reasons are intuitive: Both drugs are fast-acting local anesthetics.

More intriguing is the story of the antiparasitic medication levamisole. The DEA has estimated that 60%-89% of the seized street cocaine contains levamisole. Levamisole appears to be partly metabolized into an amphetamine-like compound, which could increase dopamine concentration in the reward pathway and thus activate endogenous opioids: It can mimic the effects of cocaine at a fraction of the cost. Levamisole is associated with several types of severe blood disorders, including leukopenia, agranulocytosis, multifocal inflammatory leukoencephalopathy, and neutropenia; a common presentation is vasculitis resulting in loss of limbs. Thus, a real danger in adulterants such as levamisole is their toxicity beyond those of the drug to which they are added, causing numerous medical consequences – including death.

 

The consideration of adulterants is important in another, emerging problem: Cocaine, colloquially thought of as a drug of the 1980s, is making a comeback. A record amount of cocaine is coming across the Mexican border with increased seizures of drug. Also, the number of acres producing cocaine is increasing, the price per unit sold is decreasing, and the prevalence of use has increased. Unfortunately but predictably, cocaine-related deaths are up: National Vital Statistic Systems data indicate that cocaine-related deaths involving opioids climbed from 2000-2006 and 2012-2015. Opioids, primarily heroin and fentanyl, have been driving the recently reported increases in cocaine-related overdose deaths.⁶ At the March 12, 2018, Drug Enforcement Administration panel on the reemergence of cocaine and cocaine-related deaths, experts reported that adulterants, including fentanyl, were responsible for many cocaine-related deaths. Strikingly, the most recent data from the state of Florida suggest that fentanyl is found as a factor in nearly all cocaine-related deaths, and cocaine commonly is found in fentanyl and fentanyl analog-related deaths.

If stigmata of opioid overdose (for example, miotic pupils and respiratory depression) are present in a patient considered to have overdosed on cocaine, naloxone should be administered, as the clinical presentation may be tied to the presence of opioid adulterants. Then, the patient should be engaged in treatment in a long-term care model with evidenced-based therapies, including medication-assisted treatment and contingency management. An important point, however, as described by Thomas Kosten, MD, professor of psychiatry at Baylor University, Houston, is that while we have multiple pharmacologic treatments for opioid overdose and addiction, none exist for cocaine overdose, craving, addiction, or withdrawal.⁷ Dr. Kosten has pioneered novel treatments for cocaine addiction, including anti-cocaine vaccines, but none has been proven safe and effective as of 2018.

Indeed, in the context of the opioid epidemic, the demand for opioid use treatment has increased, though the consequences of addiction, and thus areas requiring treatment in the opioid-addicted patient, are high in number and complexity.⁸ As we discussed previously, unfortunately, most management is aimed solely at reversing the overdose, stabilizing the patient medically, and discharge. We suggest that prior to discharge, the physician should determine whether the overdose was accidental, a suicide⁹ attempt, passive suicidality (for example, asking “Would you be better off dead?”),¹⁰ extreme risk-taking behavior (akin to playing Russian roulette,¹¹ or other causes. We have suggested that naloxone is similar to cardiopulmonary resuscitation: It is a critical life-saving intervention but not an end in itself. Rather, the need for naloxone should serve as a gateway to comprehensive evaluation, diagnosis, treatment, and long-term care.

 

 

Dr. Gold is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville, and professor of psychiatry (adjunct) at Washington University in St. Louis. He also serves as chairman of the scientific advisory boards for RiverMend Health. Dr. Srivastava is a fourth-year resident in the department of psychiatry at Washington University.

References

1 NCHS Data Brief. No. 294. December 2017.

2 N Engl J Med. 2015;373:1789-90.

3 DEA Strategic Intelligence Section. 2017 National Drug Threat Assessment: Drug Enforcement Administration, U.S. Department of Justice, 2017.

4 Centers for Disease Control and Prevention, press release. Mar 29, 2018.

5 MMWR. 2018. Mar 30;67(12):349-58.

6 Am J Public Health. 2017 Mar;107(3):430-2.

7 “Q&A: Thomas Kosten, MD: Anti-drug vaccines.” RiverMend Health.

8 “Q&A: Stacy Seikel, MD. Opioid addiction.” RiverMend Health.

9 N Engl J Med. 2018 Apr 26;378:1567-9. doi: 10.1056/NEJMp1801417.

10 Innov Clin Neurosci. 2014 Sep;11(9-10):182-90.

11 Am J Psychiatry. 187 May;144(5):563-7.

 

The opioid epidemic continues to devastate the United States across demographic and socioeconomic groups; two-thirds of the 63,632 Americans who died of drug overdoses¹ in 2016 died of prescription or illicit opioids.

In 2015, Theodore J. Cicero, PhD, professor of psychiatry at Washington University, St. Louis, reported on a fundamental change in the nature of the ongoing opioid epidemic: What started as prescription opioid overprescribing, leading to diversion, abuse, and opioid addiction, was transitioning to illicit heroin distribution and consumption. Prescription opioids, namely, extended-release oxycodone (Oxycontin), were perceived initially as pure and safe, as they were specifically dosed and physician prescribed. In addition, filling a prescription for opioids was not associated with the shame or stigma of buying illicit drugs off the street. Because those drugs were seen as therapeutic and pharmacologically “legitimate,” many clinicians and the lay public alike were surprised to see the surge of opioid addiction and overdoses.

Dr. Cicero and others noted² that prescription opioids, whether taken originally for analgesic or recreational purposes, became a “gateway” to heroin, which already was making its way into the United States from Mexico,³ as heroin was cheap and becoming cheaper, easier to find, easy to use, and “pure.” Prescription opioids, on the other hand, were becoming more expensive, and physicians were facing increased regulations in prescribing them. Thus, as prescription opioid use became more and more stigmatized, heroin use was seen, paradoxically, as a more practical alternative. The amount of opioids prescribed in the United States has peaked; physicians are prescribing opioids less often; and the averaged dose has dropped as well, according to the Centers for Disease Control and Prevention.⁴ The first wave of deaths was attributable to prescription opioids, and the second was tied to illicitly obtained potent fentanyl analogs (manufactured in China and smuggled primarily through Mexico), which is added to heroin and sold in the United States.⁵

Many addiction experts and health policy leaders were not surprised by the increases in HIV, TB, and hepatitis B and C that followed the increasing use of intravenous opioids. However, few had experience with previous opioid epidemics in the United States, the most recent being the heroin epidemic occurring in the 1960s-1970s in the aftermath of the Vietnam War. At that time, the notion that heroin was contaminated with other psychoactive drugs, medications, fillers, and other adulterants was a foregone conclusion – though in public health and treatment discussions, this issue is hardly ever raised. We believe this to be a significant lapse in policy and planning. Surveillance by the Drug Enforcement Administration shows that acetyl fentanyl–laced heroin costs a little more on the street than regular heroin. Yet it sells, because users believe its extreme potency produces a better high, thus worth the extra cost. This phenomenon underscores an important point: Opioid addicts often are in search of a better high and will go to any lengths – even risking their lives – to get it.

The “cutting” or “adulteration” of street drugs is common practice in the manufacturing, distribution, and selling of illicit drugs, and the motive is to increase profit. The term “adulterant” generally refers to addition of substances with some psychoactive effects, such as caffeine, ephedra, or even paracetamol. These substances are cheaper than the main substance, have similar or complementary effects when added, and thus help conceal the fact that the desired substance has been cut or diluted. Substances without psychoactive properties such as lactose, other sugars, or talc, are added to a drug primarily to increase the bulk or weight of the illicit substance, or for aesthetic purposes to fool the user. Some adulterants simply are the result of the particular manufacturing process used to make the drug. For example, illicitly manufactured methamphetamine frequently is contaminated by nonstimulant impurities such as lead or mercury (extremely toxic heavy metals), or from carcinogenic solvents used in the synthesis. The local anesthetic lidocaine often is added to cocaine, and the reasons are intuitive: Both drugs are fast-acting local anesthetics.

More intriguing is the story of the antiparasitic medication levamisole. The DEA has estimated that 60%-89% of the seized street cocaine contains levamisole. Levamisole appears to be partly metabolized into an amphetamine-like compound, which could increase dopamine concentration in the reward pathway and thus activate endogenous opioids: It can mimic the effects of cocaine at a fraction of the cost. Levamisole is associated with several types of severe blood disorders, including leukopenia, agranulocytosis, multifocal inflammatory leukoencephalopathy, and neutropenia; a common presentation is vasculitis resulting in loss of limbs. Thus, a real danger in adulterants such as levamisole is their toxicity beyond those of the drug to which they are added, causing numerous medical consequences – including death.

 

The consideration of adulterants is important in another, emerging problem: Cocaine, colloquially thought of as a drug of the 1980s, is making a comeback. A record amount of cocaine is coming across the Mexican border with increased seizures of drug. Also, the number of acres producing cocaine is increasing, the price per unit sold is decreasing, and the prevalence of use has increased. Unfortunately but predictably, cocaine-related deaths are up: National Vital Statistic Systems data indicate that cocaine-related deaths involving opioids climbed from 2000-2006 and 2012-2015. Opioids, primarily heroin and fentanyl, have been driving the recently reported increases in cocaine-related overdose deaths.⁶ At the March 12, 2018, Drug Enforcement Administration panel on the reemergence of cocaine and cocaine-related deaths, experts reported that adulterants, including fentanyl, were responsible for many cocaine-related deaths. Strikingly, the most recent data from the state of Florida suggest that fentanyl is found as a factor in nearly all cocaine-related deaths, and cocaine commonly is found in fentanyl and fentanyl analog-related deaths.

If stigmata of opioid overdose (for example, miotic pupils and respiratory depression) are present in a patient considered to have overdosed on cocaine, naloxone should be administered, as the clinical presentation may be tied to the presence of opioid adulterants. Then, the patient should be engaged in treatment in a long-term care model with evidenced-based therapies, including medication-assisted treatment and contingency management. An important point, however, as described by Thomas Kosten, MD, professor of psychiatry at Baylor University, Houston, is that while we have multiple pharmacologic treatments for opioid overdose and addiction, none exist for cocaine overdose, craving, addiction, or withdrawal.⁷ Dr. Kosten has pioneered novel treatments for cocaine addiction, including anti-cocaine vaccines, but none has been proven safe and effective as of 2018.

Indeed, in the context of the opioid epidemic, the demand for opioid use treatment has increased, though the consequences of addiction, and thus areas requiring treatment in the opioid-addicted patient, are high in number and complexity.⁸ As we discussed previously, unfortunately, most management is aimed solely at reversing the overdose, stabilizing the patient medically, and discharge. We suggest that prior to discharge, the physician should determine whether the overdose was accidental, a suicide⁹ attempt, passive suicidality (for example, asking “Would you be better off dead?”),¹⁰ extreme risk-taking behavior (akin to playing Russian roulette,¹¹ or other causes. We have suggested that naloxone is similar to cardiopulmonary resuscitation: It is a critical life-saving intervention but not an end in itself. Rather, the need for naloxone should serve as a gateway to comprehensive evaluation, diagnosis, treatment, and long-term care.

 

 

Dr. Gold is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville, and professor of psychiatry (adjunct) at Washington University in St. Louis. He also serves as chairman of the scientific advisory boards for RiverMend Health. Dr. Srivastava is a fourth-year resident in the department of psychiatry at Washington University.

References

1 NCHS Data Brief. No. 294. December 2017.

2 N Engl J Med. 2015;373:1789-90.

3 DEA Strategic Intelligence Section. 2017 National Drug Threat Assessment: Drug Enforcement Administration, U.S. Department of Justice, 2017.

4 Centers for Disease Control and Prevention, press release. Mar 29, 2018.

5 MMWR. 2018. Mar 30;67(12):349-58.

6 Am J Public Health. 2017 Mar;107(3):430-2.

7 “Q&A: Thomas Kosten, MD: Anti-drug vaccines.” RiverMend Health.

8 “Q&A: Stacy Seikel, MD. Opioid addiction.” RiverMend Health.

9 N Engl J Med. 2018 Apr 26;378:1567-9. doi: 10.1056/NEJMp1801417.

10 Innov Clin Neurosci. 2014 Sep;11(9-10):182-90.

11 Am J Psychiatry. 187 May;144(5):563-7.

 

The opioid epidemic continues to devastate the United States across demographic and socioeconomic groups; two-thirds of the 63,632 Americans who died of drug overdoses¹ in 2016 died of prescription or illicit opioids.

In 2015, Theodore J. Cicero, PhD, professor of psychiatry at Washington University, St. Louis, reported on a fundamental change in the nature of the ongoing opioid epidemic: What started as prescription opioid overprescribing, leading to diversion, abuse, and opioid addiction, was transitioning to illicit heroin distribution and consumption. Prescription opioids, namely, extended-release oxycodone (Oxycontin), were perceived initially as pure and safe, as they were specifically dosed and physician prescribed. In addition, filling a prescription for opioids was not associated with the shame or stigma of buying illicit drugs off the street. Because those drugs were seen as therapeutic and pharmacologically “legitimate,” many clinicians and the lay public alike were surprised to see the surge of opioid addiction and overdoses.

Dr. Cicero and others noted² that prescription opioids, whether taken originally for analgesic or recreational purposes, became a “gateway” to heroin, which already was making its way into the United States from Mexico,³ as heroin was cheap and becoming cheaper, easier to find, easy to use, and “pure.” Prescription opioids, on the other hand, were becoming more expensive, and physicians were facing increased regulations in prescribing them. Thus, as prescription opioid use became more and more stigmatized, heroin use was seen, paradoxically, as a more practical alternative. The amount of opioids prescribed in the United States has peaked; physicians are prescribing opioids less often; and the averaged dose has dropped as well, according to the Centers for Disease Control and Prevention.⁴ The first wave of deaths was attributable to prescription opioids, and the second was tied to illicitly obtained potent fentanyl analogs (manufactured in China and smuggled primarily through Mexico), which is added to heroin and sold in the United States.⁵

Many addiction experts and health policy leaders were not surprised by the increases in HIV, TB, and hepatitis B and C that followed the increasing use of intravenous opioids. However, few had experience with previous opioid epidemics in the United States, the most recent being the heroin epidemic occurring in the 1960s-1970s in the aftermath of the Vietnam War. At that time, the notion that heroin was contaminated with other psychoactive drugs, medications, fillers, and other adulterants was a foregone conclusion – though in public health and treatment discussions, this issue is hardly ever raised. We believe this to be a significant lapse in policy and planning. Surveillance by the Drug Enforcement Administration shows that acetyl fentanyl–laced heroin costs a little more on the street than regular heroin. Yet it sells, because users believe its extreme potency produces a better high, thus worth the extra cost. This phenomenon underscores an important point: Opioid addicts often are in search of a better high and will go to any lengths – even risking their lives – to get it.

The “cutting” or “adulteration” of street drugs is common practice in the manufacturing, distribution, and selling of illicit drugs, and the motive is to increase profit. The term “adulterant” generally refers to addition of substances with some psychoactive effects, such as caffeine, ephedra, or even paracetamol. These substances are cheaper than the main substance, have similar or complementary effects when added, and thus help conceal the fact that the desired substance has been cut or diluted. Substances without psychoactive properties such as lactose, other sugars, or talc, are added to a drug primarily to increase the bulk or weight of the illicit substance, or for aesthetic purposes to fool the user. Some adulterants simply are the result of the particular manufacturing process used to make the drug. For example, illicitly manufactured methamphetamine frequently is contaminated by nonstimulant impurities such as lead or mercury (extremely toxic heavy metals), or from carcinogenic solvents used in the synthesis. The local anesthetic lidocaine often is added to cocaine, and the reasons are intuitive: Both drugs are fast-acting local anesthetics.

More intriguing is the story of the antiparasitic medication levamisole. The DEA has estimated that 60%-89% of the seized street cocaine contains levamisole. Levamisole appears to be partly metabolized into an amphetamine-like compound, which could increase dopamine concentration in the reward pathway and thus activate endogenous opioids: It can mimic the effects of cocaine at a fraction of the cost. Levamisole is associated with several types of severe blood disorders, including leukopenia, agranulocytosis, multifocal inflammatory leukoencephalopathy, and neutropenia; a common presentation is vasculitis resulting in loss of limbs. Thus, a real danger in adulterants such as levamisole is their toxicity beyond those of the drug to which they are added, causing numerous medical consequences – including death.

 

The consideration of adulterants is important in another, emerging problem: Cocaine, colloquially thought of as a drug of the 1980s, is making a comeback. A record amount of cocaine is coming across the Mexican border with increased seizures of drug. Also, the number of acres producing cocaine is increasing, the price per unit sold is decreasing, and the prevalence of use has increased. Unfortunately but predictably, cocaine-related deaths are up: National Vital Statistic Systems data indicate that cocaine-related deaths involving opioids climbed from 2000-2006 and 2012-2015. Opioids, primarily heroin and fentanyl, have been driving the recently reported increases in cocaine-related overdose deaths.⁶ At the March 12, 2018, Drug Enforcement Administration panel on the reemergence of cocaine and cocaine-related deaths, experts reported that adulterants, including fentanyl, were responsible for many cocaine-related deaths. Strikingly, the most recent data from the state of Florida suggest that fentanyl is found as a factor in nearly all cocaine-related deaths, and cocaine commonly is found in fentanyl and fentanyl analog-related deaths.

If stigmata of opioid overdose (for example, miotic pupils and respiratory depression) are present in a patient considered to have overdosed on cocaine, naloxone should be administered, as the clinical presentation may be tied to the presence of opioid adulterants. Then, the patient should be engaged in treatment in a long-term care model with evidenced-based therapies, including medication-assisted treatment and contingency management. An important point, however, as described by Thomas Kosten, MD, professor of psychiatry at Baylor University, Houston, is that while we have multiple pharmacologic treatments for opioid overdose and addiction, none exist for cocaine overdose, craving, addiction, or withdrawal.⁷ Dr. Kosten has pioneered novel treatments for cocaine addiction, including anti-cocaine vaccines, but none has been proven safe and effective as of 2018.

Indeed, in the context of the opioid epidemic, the demand for opioid use treatment has increased, though the consequences of addiction, and thus areas requiring treatment in the opioid-addicted patient, are high in number and complexity.⁸ As we discussed previously, unfortunately, most management is aimed solely at reversing the overdose, stabilizing the patient medically, and discharge. We suggest that prior to discharge, the physician should determine whether the overdose was accidental, a suicide⁹ attempt, passive suicidality (for example, asking “Would you be better off dead?”),¹⁰ extreme risk-taking behavior (akin to playing Russian roulette,¹¹ or other causes. We have suggested that naloxone is similar to cardiopulmonary resuscitation: It is a critical life-saving intervention but not an end in itself. Rather, the need for naloxone should serve as a gateway to comprehensive evaluation, diagnosis, treatment, and long-term care.

 

 

Dr. Gold is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville, and professor of psychiatry (adjunct) at Washington University in St. Louis. He also serves as chairman of the scientific advisory boards for RiverMend Health. Dr. Srivastava is a fourth-year resident in the department of psychiatry at Washington University.

References

1 NCHS Data Brief. No. 294. December 2017.

2 N Engl J Med. 2015;373:1789-90.

3 DEA Strategic Intelligence Section. 2017 National Drug Threat Assessment: Drug Enforcement Administration, U.S. Department of Justice, 2017.

4 Centers for Disease Control and Prevention, press release. Mar 29, 2018.

5 MMWR. 2018. Mar 30;67(12):349-58.

6 Am J Public Health. 2017 Mar;107(3):430-2.

7 “Q&A: Thomas Kosten, MD: Anti-drug vaccines.” RiverMend Health.

8 “Q&A: Stacy Seikel, MD. Opioid addiction.” RiverMend Health.

9 N Engl J Med. 2018 Apr 26;378:1567-9. doi: 10.1056/NEJMp1801417.

10 Innov Clin Neurosci. 2014 Sep;11(9-10):182-90.

11 Am J Psychiatry. 187 May;144(5):563-7.