Introduction to illicit drug Addiction

Although prescription opioids undoubtedly contributed to opioid misuse through expansion of prescription practices and aggressive marketing strategies by pharmaceutical manufacturers starting in the late 1990s and through 2010, illicit opioids are currently the primary contributor to morbidity and mortality in the opioid epidemic.(8,4,5) Before prescription opioids increased in recreational use, it was the semisynthetic morphine derivative heroin that was the sole illicit opioid abused by injection.

Opioids were the most common drug class resulting in overdose deaths in the United States in 2019. (37)

Opioid Use Disorder

Diagnostic Criteria

According to DSM-V a problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:

1. Opioids are often taken in larger amounts or over a longer period than was intended.
2. There is a persistent desire or unsuccessful efforts to cut down or control opioid use.
3. A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects.
4. Craving, or a strong desire or urge to use opioids.
5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home.
6. Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids.
7. Important social, occupational, or recreational activities are given up or reduced because of opioid use.
8. Recurrent opioid use in situations in which it is physically hazardous.
9. Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.
10. Tolerance, as defined by either of the following: a. A need for markedly increased amounts of opioids to achieve intoxication or desired effect. b. A markedly diminished effect with continued use of the same amount of an opioid. Note: This criterion is not considered to be met for those taking opioids solely under appropriate medical supervision.
11. Withdrawal, as manifested by either of the following:
12. The characteristic opioid withdrawal syndrome (refer to Criteria A and B of the criteria set for opioid withdrawal, pp. 547–548)
13. Opioids (or a closely related substance) are taken to relieve or avoid withdrawal symptoms

Associated Features Supporting Diagnosis

 Opioid use disorder can be associated with a history of drug-related crimes (e.g., possession or distribution of drugs, forgery, burglary, robbery, larceny, receiving stolen goods). Among health care professionals and individuals who have ready access to controlled substances, there is often a different pattern of illegal activities involving problems with state licensing boards, professional staffs of hospitals, or other administrative agencies. Marital difficulties (including divorce), unemployment, and irregular employment are often associated with opioid use disorder at all socioeconomic levels(1 p.543)

1. Heroin

Heroin, which was the first tradename given to the semisynthetic diacetylmorphine synthesized by Bayer in 1895, was marketed as an over-the-counter medication for cough suppression that supposedly lacked morphine’s addictive side effect.(6)It took but 12 years to require a prescription for heroin, and in 1924 the US Congress banned its sale, importation, and manufacture. Today, heroin is a DEA controlled substances act schedule I drug with no medical indication. Its illicit status remains as a major drug of abuse with one of the highest risks of dependence and harm among all drugs of abuse.(7)In addition to heroin’s abuse and harm potential, its injection poses risks of transmission of blood-borne pathogens such as human immunodeficiency virus (HIV), hepatitis B, and hepatitis C.(9)Injection of heroin results in onset of analgesic, euphoric, and sedative effects within 1-3 minutes, lasting up to 5 hours.

Heroin itself is a prodrug that crosses the blood-brain barrier more readily because of its increased lipophilicity compared with morphine. It is rapidly hydrolyzed to 6-monoacetylmorphine and further to morphine in both the central nervous system and the periphery.(10) Although injection of heroin remains a primary route of abuse in the United States, insufflating or inhaling the vapors of higher-purity heroin alone or in combination with fentanyl and its analogues has been on the rise in recent years.(11) A major contributor to the opioid overdose epidemic is the unpredictable composition and strength of the product that the user is buying. Prior to the emergence of fentanyl and other synthetic opioids, heroin was the sole illicit opioid available in powder form(12).

The purity of heroin varies widely and common adulterants or cutting agents may impact the acute and chronic pharmacological and toxic effects of the preparation.(38) Some inert agents simply serve the purpose of diluting heroin to increase profit margins, whereas others do possess pharmacological activity and adulterate the product. Until the late 1980s, caffeine, procaine, acetaminophen, and phenobarbital were considered the main adulterants for heroin; however, since the 1990s caffeine and acetaminophen are most commonly reported in Europe.(38, 39) The purity of heroin overall remains low, with an average of 15% pure heroin in samples from Europe in 2014 and ranging from 6% to 60% in samples from the United States.(38,40) In the United States most heroin is diluted with mannitol, starch, or lactose as inert ingredients, but even the addition of strychnine has been reported to vaporize heroin for inhalation at a lower temperature similar to the purpose of caffeine and procaine.(40)With the introduction of fentanyl and other synthetic opioids to the illicit supply, heroin is now increasingly adulterated with more potent opioids, presenting an increased overdose risk to users.

2. Fentanyl Derivatives

The structurally most diverse and currently most impactful class of illicit opioids is fentanyl analogues and illicitly produced fentanyl itself. Most fentanyl analogues entering the United States for illicit use are manufactured in China.(41) Fentanyl has high affinity for the μ-opioid receptor (Ki, 1.01 nmol/L) and a half-life (t1/2) of 3.65 hours. Initially, novel synthetic opioids were derivatives synthesized shortly after fentanyl in the 1970s and later approved by the US Food and Drug Administration (FDA) for anesthesia and analgesia.(42) Illicit fentanyl derivatives include lofentanil, ocfentanil, furanylfentanyl (“Fu-F”), α-methylfentanyl (“China white,” “Persian white,” “China girl,” “crocodile,” “synthetic heroin”), 4-fluorofentanyl, valerylfentanyl, and others. Even slight structural modifications to the fentanyl structure can convey substantial changes in potency, leading to overdoses with potentially fatal outcomes.(43)

3. Benzamide and Piperazine Derivatives

In contrast to the fentanyl analogues, new illicit opioid receptor agents to enter the illicit drug market are AH-7921 and U-47700, both benzamide derivatives, and MT-45, a piperazine derivative. AH-7921 (doxylam) structurally resembles a crossover between an opioid, a histamine receptor antagonist, and the NMDA-receptor antagonist phencyclidine (PCP).(45) It was initially synthesized in the 1970s but never developed into a drug because of its effects on multiple receptors and resulting off-target and adverse effects. Several fatalities with AH-7921 have been reported, primarily as a result of polydrug exposure despite its low potency equivalent to morphine at μ-opioid receptors. (44) A structural isomer of AH-7921, U-47700 (“U4,” “pink heroin,” “pinky,” “pink”) was synthesized by Upjohn in the 1970s but never pursued as an opioid for pain management. It possesses about 7.5 times the potency of morphine in the mouse tail-flick test, binds preferentially to the μ-opioid receptor (Ki, 0.91 nM), and has a short duration of action similar to heroin after all routes of administration (oral, intravenous, insufflated, rectal, or inhaled/smoked).(46,47)

The primary overdose symptoms are respiratory depression, unconsciousness, bradycardia, hypothermia, and abdominal pain, which are reversable with naloxone administration. Overdoses are more likely to occur with co-use of U-47700 with fentanyl, heroin, benzodiazepines, or gabapentin. MT-45 was placed into controlled substances act schedule I as recently as 2018 after initial reports of its abuse appeared in 2013 in conjunction with the appearance of synthetic cannabinoids and cathinones sold as herbal incense and supplements (eg, “Wow”).(41 ,48)  MT-45 may also exert pharmacological effects through non-opioid-receptor pathways, as adverse effects include alopecia, hearing loss, dermatitis, Mees lines, and cataracts.(49.50)

4. Desomorphine

A derivative of codeine that attracted media attention in 2014 is desomorphine, better known by its street name, “krokodil.” The heroin substitute is primarily used in Russia, the Ukraine, and other Eastern European countries, with rare reports of use in Western Europe, the United States, and other parts of the world.(51) Its name stems from the scaly green skin discoloration that often turns necrotic in users who inject the self-made drug subcutaneously (“skin-popping”). Self-made desomorphine is derived from codeine using a reduction process similar to synthesizing methamphetamine from pseudoephedrine.)(52,53)

 Codeine is either extracted from diverted prescription formulations using an acid-base procedure or obtained illegally and then reacted with hydroiodic acid and red phosphorous under heat to produce desomorphine. This reaction may lead to a number of toxic side products such as phosphoric acid and generation of toxic fumes, all of which impact the health of the cook and the user as the side products are injected with the desomorphine, leading to tissue damage and eventual necrosis.(53, 54) Neurological effects are also notable with desomorphine use, as it is a strong inhibitor of cholinesterase, leading to memory, speech, and motor impairment with frequent abuse. In addition, the injection of contaminants and synthesis by-products contribute to pathological changes at both the injection sites and systemically, often leading to limb amputations within months and death within 2-3 years of continued abuse(52,54)

Acute Toxicity

The most serious adverse effect of an opioid overdose is respiratory depression progressing to apnea and cardiac arrest. The depression of respiratory drive and gastrointestinal motility are primarily mediated by μ-opioid receptors, and recent work indicates that activation of the β-arrestin-2 pathway is a major contributor.(55-56) Respiratory depression can develop within minutes of an opioid injection, inhalation, or insufflation, whereas it can take longer with an oral overdose to reach systemic circulation and cross the blood-brain barrier.(57) Certain opioids are associated with an increased risk of seizures, including tramadol, morphine, and meperidine.(58-59)Accidental opioid overdoses have been associated with a number of risk factors, among them being white, having higher educational attainment, having lower income, having an unstable housing situation, having witnessed others overdose, having a positive HIV or hepatitis C status, and having had buprenorphine treatment episodes. Furthermore, specific populations are at higher risk of an overdose, such as individuals who were recently incarcerated or went through substance use treatment and individuals with chronic pain, a mental health condition, or who were under psychological distress.(60)

An uncommon adverse effect associated with the use of fentanyl during anesthesia is muscle rigidity of the diaphragm and chest wall, commonly referred to as “wooden chest syndrome.”(61)

Chronic Toxicity and Long-Term Effects

Chronic use of opioids in either therapeutic or recreational settings can impact cardiac conduction, which has been shown for methadone, loperamide, and tramadol but is also known for other opioids.(62-63) Most opioids have little direct cardiac effects but may cause bradycardia, hypotension, and vasodilation as a result of their sympatholytic effects. In the absence of comorbidities, long-term opioid therapy has been associated with endocrinopathy with symptoms including decreased libido, erectile dysfunction, infertility, amenorrhea, hot flashes and night sweats, decreased muscle mass and

strength, depression and anxiety, tiredness and fatigue, and osteoporosis and fractures.(64, 65) Although changes in law and prescription practices on the national, regional, and local levels have reduced misuse of prescription opioids and resulting opioid use disorders, the increase in foreign-manufactured illicit fentanyl and derivatives entering the United States and adulterating other illicitly manufactured or sold opioids fuels the ongoing opioid epidemic. This shift in opioid availability is the main contributor to a rise in opioid use disorders, overdoses, and opioid-related deaths.(66)

Conclusions

Amid a continued rise in opioid overdoses and increased prevalence of overdose-associated deaths, the opioid epidemic continues to impact millions of Americans and others around the world. Because of their euphoric effects and high risk of dependence, opioids have a high risk of abuse and addiction, which complicates their therapeutic use in the treatment of acute and chronic pain conditions. Important considerations that have shaped the misuse of an opioid in the past 2 decades are its selectivity for the μ-opioid receptor, its half-life, its potency, and, in some cases, its ability to activate dopaminergic reward pathways for longer periods. Many of the emerging illicit structures with potent opioid activity remain poorly studied and require further investigations in regard to specific pharmacological effects and toxicity.(37)